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
B~",,~~\~~ 0'
...............
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- - -- - - - \
'f<:h1l--
Peripheral arteria l arcade
'l-;:-hlj-- MU li er muscle
(non -Asian)
!!I f/:f<>h:';/)-- C;;a,nd of Wolfring Levator aponeurosis -
- ---H!9"
Orbicularis ocu li m . ----~6 (pretarsal portion)
CfI+---Tarsus
1-\\\--- ~Aeil)onliar gland Eyelid crE'as'e - - -- - ----'t::? (Asian) ~-- MaJqina
arterial arcade
Gland of Ze"s - - -- -----\'io'f'll Gland of Mo ll
Figure 1-1
Cross section of the upper eyel id.
(Illustration b y Chris tin e Gralapp.)
adherent to Tenon capsule. These tissues blend at the limbus, where a series of radiating ridges called the palisades of Vogt appear. This area contains corneal stem cells. The cell morphology of the conjunctival epithelium varies from stratified cuboidal over the tarsus to columnar in the fornices to squamous on the globe. Multiple surface folds are present. Goblet cells account for up to 10% of basal cells of the conjunctival epithelium; they are most numerous in the tarsal conjunctiva and the inferonasal bulbar conjunctiva. The substantia propria of the conjunctiva consists of loose connective tissue. CALT, which consists of lymphocytes and other leukocytes, is present, especially in the fornices.
6 • External Disease and Cornea
Lymphocytes interact with mucosal epitheli al cells through reciprocal regulatory signa ls mediated by growth factors, cytokines, an d neuropeptides. The palpebral conj un ctiva shares its blood supply with the eyelids. The bulbar conjunctiva is supplied by the an terior ciliar y arteries branching off the ophthalmic artery. These capillaries are fenestrated and leak fluorescein just like the choriocapillaris. Sensory innervation is controlled by the lacrimal. supraorbital, sup rat rochlear, and infraorbital branches of the ophthalmic division of crania l nerve V Nelson JD, Cameron JD. The conjunctiva: anatomy and physiology. In: Krachmer JH, Mannis MJ, Holland EJ, eds. Cornea. 2nd ed. Vol 1. Philadelphia: Elsevier/Mosby; 2005:37- 43.
Cornea The cornea is a transparent, avascular tissue that measures 11-12 mm horizontally and 10-11 mm vertically. Its refractive index is 1. 376, although, in calibrating a keratometer, a refractive index of 1.3375 is used to account for the combined optical power of the anterior and posterior curvatures of the cornea. The cornea is aspheric, although its rad ius of curvature is often recorded as a spherocylindr ical convex mirror representing the central anterior corneal surface, also called the corneal cap. The average radius of curvature of th e central cornea is 7.8 mm. The cornea thus contributes 74%, or 43.25 diopte rs (D), of the total 58.60 dioptri c power of a normal human eye. The cornea is also the major source of astigmatism in the optical system . See Measurement of Corneal Topography in Chapter 2 fo r more information on corneal opticS. For its nutrition, the cornea depends o n glu cose diffusing from th e aq ueous humor and oxygen diffusing through the tea r film. In addition, the peripheral cornea is supplied with oxygen from the limbal circulation. The cornea has one of the body's highest densities of nerve endings, and the sensitivity of the cornea is 100 times that of the conju nctiva. Sensory nerve fibers extend from the long ciliary nerves and form a subep ith elial plexus. Neurotransmitters in the cornea include acetylcholine, catecholamines, substance P, calcitonin gene - related peptide, neuropeptide Y, intestinal peptide, galanin, and methionine-en kephalin.
Epithelium The corneal epithelium is composed of stratified squamous epi thelial cells an d makes up about 5% (0.05 mm) of the total corneal thickness (Fig 1-2; see also Chapter 2, Fig 2-1) . The epithelium and tear film form an optica ll y smooth surface. Tight junctions between superficial epithelial cells prevent penetration of tear fluid into the stroma. Continuous proliferation of perilimbal basal epithelial cells (limbal stem cells; see Chapter 3) gives rise to the other layers that subsequently differentiate into superficial cells. With maturation , these cells become coated with microvilli on their outermost surface (which causes them to appear dark by scanning electro n mic roscopy and bright by specular microscopy) and then desquamate into the tears. This process of differentiation takes about 7- 14 days. Basal epith elial cells secrete a continuous, 50-n m-thick basement membrane, composed of type IV collagen, laminin, and other proteins.
CHAPTER 1: Structure and Functi o n of the Externa l Eye an d Cornea. 7
Epithelium - - - - -- - -
Stroma
. . ,...:J
oescemet's,:~::==~~t""·""'-_""""~_"~_,:..:. Figure 1·2
Normal cornea, The epithelium, normally 5 cell layers, will thicken to maintain a
smooth surface (H&E x32).
Stroma Optimal corneal optics requires a smooth sur face with a healthy tea r film and epithelium. Clari ty of the cornea depends on the tight packing of epithelial cells to produce a laye r \vith a nearly uniform refract ive index and mi n ima l light scattering. The regular arrangement of stromal cells and macromolecules is also necessary for a clear cornea. Keratocytes vary in density and size th roughout the stroma and form a spirali ng 3·dimensional net· work th roughout the cornea. They are fo und as flattened fib roblasts between the collagen lamellae (Fig 1·3) . These corn eal fi broblasts conti nually d igest and manufacture stromal molecules. The denSity of keratocytes declines in the normal population but to a lesser degree than does that of endothelial cells. The denSity also declines with corneal surgery and may not recover completely. Beneath the acellu lar Bowman layer, the corneal stroma is composed of an extracellular matrix formed of collagens and proteoglycans. Type I and type V fibrillar collage ns are intertwi ned with fila ments of type VI collage n. The major corneal proteoglycans are decori n (associated with dermataI) sulfate) and lumican (associated with keratan sulfate). The concent rations and ratio of proteoglycans vary from anterior to posterior. Similarly, the posterior stroma is "wetter" than the anterior (3.85 mg H ,O /mg dry weig ht vs 3.04). Other wateHoluble proteins, analogous to le ns crystallins, may be secreted by ke ratocytes or contained in the epithelial cells to control th e optical properties of the cornea. The lamellae of the anterior stroma are short, narrow sheets with extensive interweaving behveen layers, whereas the posterior stroma has long, \vide, thick lamellae extending from
8 • Extern al Di sease and Cornea
A ...... _ • .. Figure ' -3
~_
.._
Keratocytes IAI are flattened fibroblasts IBI situated between the corneal lamellae.
(Reproduced with permission from Oyster CW The Human Eye: Structure and Function. Sunderland, MA. Smauer Associates; 1999:331.)
limbus to limbus with minimal interlameLlar connections. The human cornea has little elasticity and stretches only 0.25% at normal lOP. The lattice arrangement of collage n fi brils embedded in the extracellular matrix is partly res ponsible fo r corneal transparency. Th is pattern acts as a diffraction grating to reduce light scattering by means of destruct ive interference. Scattering is greater anteriorly. resulting in a higher refractive index that decreases fro m 1.40 1 at the epithelium to 1.380 in the stroma and 1.373 posteriorly. The cornea is transparent because the size of the lattice elements is smaller tha n the wavelength of visible light. Transparency also depends on keeping the wate r content of the corneal stroma at 78%. Corneal hydration is largely controlled by intact epithelial and endothelial barriers and the function ing of the endothelial pump, which is linked to an ion -transport system controlled by temperature-dependent enzymes such as Na+,K+-AT Pase. In addition, negatively charged stromal glycosam inoglycans tend to repel each other, producing a swelling pressure (SP). Because the lOP tends to compress the corn ea, the overall imbibitio n pressure of the corn eal stroma is give n as lOP - SP. The total tra nsendothelial osmotic force is calculated by adding the im bibition pressure and the various electrolyte gradients produced by the endothelial transport channels. Corneal hydrat ion varies fro m anterior to posterior) with in creasin g wetness closer to th e endothelium and resistance of th e movement of water laterally within the stroma. See also BCSC Section 2, Fundamentals and Prin ciples of Ophthalmology. Hollingsworth l, Perez- Gom ez J, Mutalib HA, Efron N. A popu lation study of th e normal cornea usi ng an in vivo, slit-sca nning confocal microscope. Optom Vis Sci. 200 I;78( 10):706- 711. Jester lV, Moller- Pedersen T, Huang J, et al. The cellular basis of cornea l transparency: evidence for "corneal crystallins:' J Cell Sci. 1999;112(P1 5) ;61 3-622. Piatigorsky J. Review: a case for corneal crystalli ns. J OCliI Pharmacol Tiler. 2000; 16(2):
173- 180.
Endothelium The endothelium is made up of closely interdigitated cells arranged in a mosaic pattern of mostly hexagonal shapes. Hu man endothelial cells do not proliferate in vivo, but they can divide in cell culture. Although some recent evidence cites the possibility of peripheral
CHAPTE R 1:
Structure and Fun ctio n of the External Eye and Cornea . 9
corneal endothelial stem cells, cell density declines throughout life. Cell loss results in enlargeme nt and spread of neighborin g ceLis to cover any defec ti ve area, especially as a result of trauma o r surgery. CeLl density va ries over the endothelial surface; normall y, the concentration is highest in the periphery. Descemet's membra1le is the basement membrane of the corneal endothelium. It increases in thickness fro m 3 ~m at birth to 10- 12 ~m in adults, as the endothelium gradually lays down a posterior amorphous nonbanded zone. Bourne WM, Nelson LR, Hodge DO. Cen tral corneal endothelial cell changes over a ten-year period. If/vest Ophthalmol Vis Sci. 1997;38(3) :779-782. Foste r CS, Azar OT, Dahlman CH, eds. Smolin al1d Thoft's The Comea: Scient ific FOlllldations and Clinical Practice. 4th ed. Philadelph ia: Lippincotl Williams & Wilkins; 2004. Nishido T. Cornea. In: Krachmer 1H, Ma nnis MJ. Holland £1. eds. Comea. 2nd cd. Vol I. Philadelphia: Elsevier/Mosby; 2005:3- 26. vVhikehart DR, Parikh CH, Vaughn AV. Mishler K, Edelhauser HE Evidence suggesting the existe nce of stem cells for the human co rneal endothelium. Mol Vis. 2005; I 1:816-824.
Biomechanics of the cornea The cornea is a composite material consisting of collagen fibrils that stretch from limbus
to limbus packaged in lamellae that are arranged in parallel fash ion and embedded in an extracellular matrix of glycosaminoglycans. The layers slide easily over each other, indicating a very low shear resistan ce, but the stroma itself is an inelastic. an isotropic structure that distributes tensile stress unequally throughout its thickness, depending on corneal hydration. When the cornea is in a dehydrated state, stress is distributed either principally to the posterior layers or uniformly over the ent ire structure. When the corn ea is healthy or edematous, the anter ior lam ellae take up the strain .
Corneal rigidity affects the results of lOP measu rements and procedu res. In vivo measurements using a fo rced air jet generate force or pressure on the cornea that can measure its rigidity (corneal hysteresis). Such measurements infer that cornea l biomechan ics con sists of more than central pachometry alone but also includes viscosity. bioelasticity. hy-
dration, regional pachometry, and probably other factors that have yet to be elucidated.
Sclera The sclera is composed primarily of type I collagen and proteoglycans (decorin, biglycan, and aggrecan ). Other com ponents include elastin and glycoproteins sti ch as fibronect in.
Fibroblasts lie along collagen bundles. The long posterior ciliary nerves supply the anterior sclera. An intrascleral loop (Axen/eld loop) from a branch of o ne of these nerves sometimes form s a visible nodule over the ciliar y body. No rmally a densely white tissue. sclera becomes more tran slucent when thinning oc-
curs or the water content changes, falling below 40% or rising above 80%. For example, senile scleral plaques are areas of calc ium phosphate deposits just anterior to th e in ser-
tions of the medial and lateral rectus muscles th at become dehydrated and reveal the blue color of the underl ying uvea. Rada JA, Joh nson JM. Sclera. In: Krachmer TH. Mannis Ml. Holland EJ, eds. Cornea. 2nd ed. Vol I. Ph iladelphia, Elsevier/ Mosby; 2005,27-35.
CHAPTER
2
Examination Techniques for the External Eye and Cornea
Exam ination of the pat ient begins the moment th e exam iner ente rs the room. Because
readers should alread y be familiar with the basic techniques of the complete ocular exam ination, this chapte r describes how to recogn ize abnormalities produced by disorders of the external eye and corn ea. Practical Ophthalmology: A Manu al for Beginn ing Residents (5th ed, American Academy of Ophthalmology; 2005) offers a concise review of exam ination techniques.
Vision Visua l acuity testing is an essential part of an examination, and the refracti on of a patie nt with an abnormal cornea requires special attention. If visual acui ty is reduced because of
corneal irregular ity, it may be necessary to use a rig id gas-permeable (RGP) contact lens with overrefracti on. One method for obtaining a patient's best visual acuity is to take ker-
atometry readin gs and select a la rge-diameter RGP contact lens with a base curve halfway between the 2 powers and with a power near th e patient's spherical eq ui valent. Topical anesthes ia helps reduce tearing as the spherica l overrefractio n is perform ed.
BCSC Section 3, Clin ical Optics, di scusses various met hods of evaluating visual fun ction.
External Examination Physical examination of the eye begins with inspection and palpation. The examiner observes th e pat ient's appearance and notes the condit ion of the skin . the position and ac-
tion of the eyelids, the presence of preauricu lar lymph nodes, and the placement of the globes. Eversion of th e eyelids permits exam ination of the p alp ebral conjunctiva. Infants
and frightened patients ma y need to have their eyelids ge ntl y pried open with the thumbs or a retractor.
Common measurements include palpebral fiss ure height and levator function. The examiner should also measu re any visible or palpable mass by its height and longest dimension. Tear production may be measured with sterile filter-paper strips.
11
12 • External Di sease and Cornea
External examination of the outer eye and adnexa begins with the examiner looking at the patient, preferably in daylight or bright room light, and then proceeding to magnification with focal illumi nation. The simplest magnifying instruments are loupes and condensing lenses like those used for indirect ophthalmoscopy. Many handheld penlights and transilluminators are also available; these tools are helpful at the bedside and for external surgical procedures.
Slit-Lamp Biomicroscopy The slit-lamp biomicroscope has 2 rotating arms-l for the slit illuminato r and the other for the biom icroscope-mounted on a common axis. The illumination unit is essentially a projector with a light beam that is adjustable in width, height, direction, intensity, and color. The biom icroscope is a binocular Galilean telesco pe with multiple magnifications. A headrest immobilizes the patient, and a joystick lever and adjustable eyepieces allow the examiner to focu s the stereoscopic image. The illumination and microscope arms are parfocal. arranged so that both focus on the same spot, with the slit beam centered in the field of view. This setup provides direct illuminatio n, and purposeful shifting of alignment allows for indirect illumination. Variations of these illumination tech niques, using both dark-field and bright-field contrast, are used to examine the anterior segment of the eye. Leibowitz HM, Waring GO Ill , eds. Corneal Disorders: Clinical Diagnosis and Management. 2nd ed. Philadelphia: Sau nders; 1998:34-8 1.
Direct Illumination Methods Diffuse illumination With diffuse illumination, the light beam is broadened, reduced in intensity, and directed at the eye fro m an oblique angle. Diffuse illumination is usually used at low magnification to give an overview of the eyelids. conjunctiva. sclera, and cornea. Swinging the illuminator arm to produ ce highlights and shadows can enhance the visibility of surface changes. Slit illumination With slit illum ination, the light and the microscope are fo cused on the same spot, and the slit aperture is adjusted from wide to narrow. Broad-beam illumination, using a slit width of around 3 m m, can help the exami ner visualize opaque lesions. Slit-beam illumination, using a beam width of about 1 mm or less, gives an optical section of the cornea (Fig 2-1). A very narrow slit beam helps identify refractive index differences in transpare nt structures as light rays pass through the cornea, anterior chamber, and lens. The examiner can reduce the height of a narrow beam to determine the presence and amou nt of cell and flare in the anterior chamber.
Specular reflection Specular reflections are normal light reflexes bounCing off a surface. An example is the bright round or oval spot seen reflected from the oettlar surface in a typical fl ash
CHAPTER 2:
Examination Tech niqu es for the External Eye and Cornea.
13
Figure 2-1 Slit section of norma l corn ea . 1, Tear fi lm. 2, Epithe li um . 3, Anterior stroma w ith high de nsity of keratocyte s. 4, Posterior stroma w ith lower density of keratocytes. 5, Descemef s membra ne and endothelium . (Reprodu ced with permission from Krachmer JH, Mannis MJ, Holland EJ, eds. Cornea. 2nd ed. Vall. Philadelphia: Elsevier/Mosby; 2005:20 1. © CL Martonyi, WK Kellogg Eye Center, Un ive rsity of Michigan.)
photograph of an eye. These mirror images of the light source can be annoying, and it is tempting to ignore them during slit-lamp examination. However, the clarity and sharpness of these reflections from the tear film give clues to the condition of the underlying tissue. A faint reflection also comes from the posterior corneal surface. The examiner can enhance this specular reflection by using a light beam at an appropriate angle, revealing the corneal endothelium (Fig 2-2). Following are the steps for examining the corneal endothelium with specular reflection: I. Begin by setting the slit-beam arm at an angle of 60" from the viewing arm and
using a short slit or O.2 -mm spot. 2. Identify the very bright mirror image of the lightbulb's filament and the paired epithelial and endothelial Purkinje light reflexes. 3. Superimpose the corneal endothelial light reflex onto the filament's mirror image, giving a bright glare. 4. Use the joystick to move the biomicroscope slightly forward in order to focus the endothelial reflex.
14 • External Disease and Cornea
B Figure 2-2 A, Corn eal endothelium seen with specular reflect ion using the sli t-lamp biomicroscope at x40 magnification . B, Fuchs endothelial dystrophy seen in specular microscopy showing guttae . (Pan A reproduced with permission from Krachmer JH, Manms MJ, HoI/and EJ. eds Cornea. 2nd ed Vol 1. Philadelphia. ElseVier/Mosby; 2005:208. © CL Manonyi. WK Kellogg Eye Cemer. Un/v8rs/ry of Michigan; parr 8 photograph courresy of John E. $ulphm, MD.)
Specular microscopy is monocular, and I eyepiece may require focusing. A setting ofx25 to x40 is usually needed to obtain a clear view of the endothelial mosaic. Cell density and morphology are noted; guttae and keratic precipitates appear as nonreflective dark areas.
Indirect Illumination Methods
Proximal illumination Turning a knob on the illumination ann slightly decenters the light beam fro m its isocentric position, causing the light beam and the microscope to be focused at different but adjacent spots. This technique, proximal illumi nation, highlights an opacity against deeper tissue layers and allows the examiner to see smaU irregularities that have a refractive in dex similar to that of their surroundings. Moving the light beam back and forth in small oscillations can help the examiner detect small 3-dimensionallesions.
Sclerotic scatter Total internal reflection in the cornea makes possible another form of indirect illum inati on. sclerotic scatter. Decentering th e isocentric light beam so that an intense beam shines on the limbus and scatters off the sclera causes a very faint glow of the cornea. Reflective opacities stand out against the dark field, wh ereas areas of reduced light transmission in the cornea are seen as shades of gray. This technique is effective in demonstrating epithelial edema and nebulae (Fig 2-3).
Retroillumination Ret roillumination can be llsed to examine more than one area. Retroillumination frol11 the iris is performed by displacing the beam tangentiall y wh ile examining the cornea. The
CHAPTER 2:
Examination Techniques for the Externa l Eye and Cornea.
15
Figure 2-3 Corneal vert icu latta in Fabry disease demonstrated by sclerotic scatter agai nst the dark background of a we ll-dilated pupil. (Reproduced with permission from Krachmer JH, Mannis MJ, Holland EJ, eds. Cornea . 2nd ed. Vol 1 Philadelphia: Elsevier/Mosby; 2005212. © CL Martonyi, WK Kellogg Eye Center, University of Michigan.)
examiner observing the zone between the light and dark backgrounds can detect subtle corneal abnormalities. Retroillumination from the fundus is performed by aligning the light beam nearly parallel with the examiner's visual axis and rotating the light so it shines through the edge of the pupil. Opacities in the cornea or lens are highlighted against the red reflex, and iris defects are transilluminated (Fig 2-4). Farrell TA, Alward WLM, Verdick RE. Fundamentals of slit-lamp biomicroscopy. In: The Eye Exam and Basic Ophthalmic Instrument s [DVD ]. San Francisco: American Academy of Ophthalmology; 1993. (Reviewed for currency 2007.) Martonyi CL. Slit lamp examination and photography. In: Krachmer JH, Mannis MJ, Holland EJ, eds. Co rnea. 2nd ed. Voll. Ph iladelphia: Elsevier/Mosby; 2005:191 - 223.
Clinical Use Slit-lamp examination is performed in a logical sequence: l. eyelids 2. eyelid margins
3. tear film 4. conjunctiva 5. cornea
6. aqueo us humor 7. iris 8. lens 9. vitreous
16 • External DiseClse and Cornea
Figure 2-4
dus.
Epithel ial fi ngerpri nt dystrophy is best visualized in ret roi llum ination f rom the f un-
(Reproduced with permission from Krachmer JH, Mannis MJ, Holland EJ, eds. Cornea. 2nd ed. Vol 1 Philadelphia'
Elsevier/Mosby; 2005:217. © CL Martonyi, WK Kellogg Eye Center, University of Michigan.)
After adjusting the focus of the eyepieces, the clinician usually begins the examination with direct illumination of the eyelids, conjunctiva, and sclera. A broad beam illuminates the cornea and overlying tea r film in the optical section. Details are examined with a narrow beam. The clinician estimates the height of the tear meniscus and looks for mucin cells and other debris in the tear film. Discrete lesions are measured with a slit-beam micrometer or an eyepiece reticule. Retroillun1ination and indirect illumination accentua te fine changes. The examiner then uses specular reflection to inspect the endothelium and has the patient shift gaze in different directions so that each corneal quadrant can be surveyed. A slit beam is used to judge the corneal th ickness and the depth of the anterior chamber. A short beam or spot will show flare or cells in the aqueous humor. Direct, slit, and retroillumination tech niques are used to identify abnorn1alities of the iris and lens. The experienced examiner actively controls the light beam with multiple illumination methods to sweep across the eye, using shadows and reflections to bring out details. Having the patient blink can also help the examiner distinguish changes of the ocular surface from tiny opacities floating in the tear film. After initial low-power screening, much of the slit -lamp examination is performed using higher magnifications. Except for the anterior vitreous humor, deeper and peripheral intraocular structures require special lenses. A contact lens allows examination of the intermediate and posterior portions of the eye and is often combined with angled mirrors and prisms for gonioscopy and peripheral fundus exami nation.
CHAPTER 2: Examination Techniques fo r the Externa l Eye and Cornea. 17
Stains Hydroxyxanthene dyes such as fluorescein have been in clinical use for more than a cen· tury. They are commonly used to detect corneal epithelial lesions, to aid in applanation tonometry, and to evaluate lacrimal drainage and deficient tear flmv. In clinical practice, fluorescein is used to detect disruption of intercellular junctions, and rose bengal and lissamine green are used to evaluate abnormal epithelial cells and ocular surface changes associated with insufficient tear-film protection.
Fluorescein Topical fluorescein is a nontoxic, water-soluble dye that is available in several forms: as a 0.25% solution with an anesthetic (benoxinate or prop.racaine), an antiseptic (povidoneiodine), and a preservative; as a 2% nonpreserved unit·dose eyedrop; and in impregnated paper strips. Fluorexon is a related macromolecular compound available as a 0.35% nonpreserved solution that will not stain most contact lenses. Staining is easily detected with a cobalt blue filter. Fluorescein is 1110St commonly used for applanat ion tonom etry and evaluation of the tear film. Tear breakup time (TBUT) is measured by instilling fluorescein, asking the patient to hold the eyelids open after I or 2 blinks, and counting the seconds until a dr y spot appears. The appearance of dry spots in less than 10 seconds is considered abnormal. TBUT is fur ther discussed in Chapter 3. Fluorescein will stain punctate and macroulcerative epithelial defects (pos itive staining), and it can highlight nonstaining lesions that project through the tear film (negative staining). Different disease states can produce various punctate staining patterns (Fig 2-5). Fluorescein that collects in an epithelial defect will diffuse into the corneal stroma and cause a green flare in the anterior chamber. In the dye disappearance test, the tear meniscus is observed fo r the disappearance of flu orescein. Prolonged presence of the dye suggests a blockage of the drainage system . The Seidel test is used to detect seepage of aqueous humor th rough a corneal perforation. The exam iner applies fluorescein using a moistened strip or concentrated drop to the site of suspected leakage and looks for a flo w of clear fl uid streaming through the orange dye under cobalt blue light (Fig 2-6).
Rose Bengal and lissamine Green Rose bengal and lissamine green (both available as a I % solution or on impregnated strips) are other water-soluble dyes; they stain the cornea and conjunctiva when a disruption occurs in the protective mucin coating. These dyes are routinely used for evaluating tear defiCiency states and detecting various epithel ial lesions. Lissamine green is better tolerated and has fewer tox.ic effects on cultured hu man corneal epithelial cel ls. See also Chapters 3 and 4. Sron AJ, Evans VE, Smith
IA.
Grading of corneal and co njunctival staining in the context of
other dry eye tests. Cornea. 2003;22(7):640-650. Faulkner WJ, Varley GA. Corneal diagnostic techniques. In: Krachmer JH , Mannis MJ, Hoiland EJ, eds. Comea. 2nd ed. Vol I. Philadelphia: Elsevier/Mosby; 2005:229-235.
18 • Externa l Di sease and Cornea
BUlbar~
conjU nctiva~
Fornix Figure 2-5
~ ....
;
....... . .
Pattern
Exa mple
Diffuse
Viral co njun ctivit is Trauma Toxicity
Inferior
Blepharoconjunctivitis Lagophthalmos Trichiasis
Interpalpebral
Dry-eye syndrome Exposure Neurotrophic keratopathy
Superior
Superior limbic ke ratocon j u nctiviti s Foreign body under lid Trichiasis
Superior conjunctivitis
Superior limbic keratoconjunctivitis
3 and 9 o'clock
Contact lens
Lower conjunctiviti s
Mechanical Meibomian gland dysfunction
~
Punctate staining patterns of the ocul ar surface. (Illustration by Joyce Zavarro.)
-
CHAPTER 2: Examination Techniques for the External Eye and Cornea. 19
Figure 2-6 Lea kage of aq ueous from the anterior cha mber (arrow) followin g a corneal laceration. Concentrated fluorescein on the edge of the aqueou s rivulet (Seidel test) indicates an act ive flow of fluid from a leaki ng anterior chamber.
Clinical Evaluation of Ocular Inflammation In clinical practice, it is helpful to use key distinctive features to categorize a patient's problem. The major disease mechanisms of the outer eye that the clinician should recognize by the history and examination are the following: infection im mune alteration neoplasia maldevelopment degeneration trauma
These pathogenic categories are discussed in greater detail in individual chapters later in this volume. Because redness is often a feature of infection, alJergy, neoplasia, injury, and other conditions, the following sections introduce the most common signs of ocular in flammation. (Table 2-1 is a summary of changes seen in the external eye and cornea.) Leibowitz HM, Waring GO III, eds . Corneal Disorders: Clinical Diagllosis and Management. 2nd ed. Philadelphia: Saunders; 1998:502 - 5 ~
Eyelid Signs of Inflammation Individual skin changes should be described by their size, shape, and borders. Multiple lesions or a generalized skin eruption should be characterized by arrangement and distribution, using such te rms as disseminated, grouped, or confluent. Several commonly encountered cutaneous lesions and their accompan yin g characteristics are described in Table 2-1.
20 • External Disease and Co rne a
Table 2·1 Common Cli nical Changes of t he External Eye and Cornea TIss ue
Finding
Ey elid
Macule Papule Vesicle Bulla Pustule Keratosis Eczema Eros ion Ulcer Hyperem ia
Conjunctiva
De sc ription
•
Chalasis Chemosis
Tearing Mucus excess Discharge Papilla
Foll ic le Pseudomembrane Membrane Gra nuloma Ph lyctenule
Cornea
Punctate ep ithe li al erosion Epithe lial defect Pun ctate epit he lial erosion Punctate ep ithelial keratitis Epithelial ede ma
Spot of skin color change Solid, raised spot Blister filled with serous fluid Large blister Pus-filled bliste r Sca ling from accumulated keratinizi ng cells Scaly crust on a red base Exco riated epidermal defect Epidermal erosion with deeper tissue loss Focal or diffuse dilati on of the subepithelial plexus of conjunctival blood vessels, usually w ith increased blood flow; ot her changes include fu siform vascular dilations, saccular aneurysms, petechiae, and intra conjunctival hemo rrhage Laxity of con junctiva, sometimes wit h prolapse ove r the eyelid Conjunctival edema caused by a transudate leaking through fenest rated conju nctival capillaries as a resu lt of altered vascular in teg rity (e g, inflammat ion and vasomotor changes) or hemodynamic changes (eg , impaired ve nous drainage or intra vascular hyposmol arity) Excess tears from increased lacrimation or impai red lacrimal outflow Increased amount of mucin relative to aqueous compone nt of tears Exudate on the conjunctival surfa ce, vary ing fro m proteinaceous (serous) to cellular (purulent) Dilated, te langiectatic conjunctiva l blood vessels, varying from dotlike changes to enlarged tufts surrounded by ed ema and inflamma tory ce ll s Focal lymphoid nodu le with access ory vasculari zation Inflammatory coagulum on the conjunctival surface that does not bleed during removal Inflammatory coagu lum suffusing the conjunctival epithelium that bleeds when stripped Nodule of chronic inflammatory cells with fibrovascular proliferation Nodule of chro nic i nflammatory cells, often at or near the limbus Loss of individ ual ep ithelial cells in a stipple d pattern Focal area of ~pitbeli alloss Fine, slightly depressed stippling caused by altered or desquamated supe rficial epithelium Swollen, slightly rai sed epith elia l cells that can be finely scatte red , coarsely grouped, or arran ged in an arborescent pattern Swollen epithelial cells (intraep ithelia l edem a) or intercellular vacu oles (microcystic edema ) (Continued)
CHAPTER 2: Examination Techniq ues for the External Eye and Cornea . 21
Tab le 2·' (continued) Ti ssue
Finding
Desc ription
Bulla Epith elial defect
Fluid pocket within or under the epith elium Focal area of epith elial loss, caused by trauma (a brasion ) or other condi tion Branching linear epithelial ridge with swo llen ce ll s, terminal end bulbs, and possible central ul ceration Ep ithelial defect. stromal loss, stromal inflammation, or any combination of these changes Stra nd (filament ) or clum p (mucous plaque ) of mucus and deg enerating epithelial cells attached to an altered ocular suriace Coin-shaped inflammatory opacity in the anterior portion of Bowman layer Focal yellow-whi te infiltrate composed of neut rophi ls
Den drite Ulcer Filament
Subepitheli al in filt rate Suppurative stromal keratiti s Nonsuppu rative stromal ke ratitis
Sclera
Epi scleri tis Nonn ec rotizing scleritis Necrotizing scleritis
Focal gray-white infiltrate of lymphocytes and other mon onuclear cel ls; also called interstitial keratitis, especially w hen accompanied by st romal neovascu larizatio n Focal or diffu se dilation of radial sup erficial episcleral vessels Dilated deep epi scle ral vessels with scleral edema Area of ava scula r scle ra
Cellular infiltratio n and edema of the upper eyelid can cause eyelid droop ing, called mechanical blepharoptosis. Protective ptosis is a resu lt of ocu lar surface discomfo rt and photophobia.
Conjunctival Signs of Inflammation Most forms of conjunctivitis heal \vithout compli cation s, but permane nt changes may occur with more seve re or chronic inflam mation. Keratini zation of th e ocular surface epithelium may occur over a chronically inflamed, indurated lesion. Chemosis may occur acutely or develop into conjunctivochalasis over time, with redlll/ dant folds that may even protrude over the lower eyelid. Conjunctiva l scarri ng can range ~om subepith elial reticu lar or lacy fibrosis to extensive symblepharon formation, with eyelid distortion and secondary dry-eye changes. Identifying the principal clin ical feature of ocular inflammation can hel p in the diffe rential diagnosis of common causes of conju nctivitis (Table 2-2) . Two common changes are papillae and folli cles.
Papillae Papillae are vascular changes seen most easily in the palpebral conjunctiva where fibrou s septae anchor the conjunctiva to the tarsus. With progression, these dilated vessels sprout spokeli ke capillaries that become surrounded by edema and a mixed inflam matory cell infiltrate, producing raised elevations under the conjunctival epithelium (Fig 2-7) .
22 • External Disease and Cornea
--------"------
Table 2-2 Common Causes of Conjunctival Inflammation Finding
Examp les
Papillary con j unctivitis
Al lergic conjunctivitis Bacterial conjunctivitis Adenovirus con junctivitis Herpes simplex virus conjunct ivitis Mol luscum contagiosum blepha roconjunctivitis Chlamydial con ju nctivitis Dru g-indu ced (eg, dipivefrin) co njunctivitis Severe viral or bacterial con junctivitis Stevens-Johnson syndrome Chemical burn Cat-scratch disease Sarcoidosis Foreign -body reactio n Stevens-Johnson syndrome Ocula r cicatricial pemphig oid Graft-vs-host disease Factitious conjunctivitis Mechanical or chemica l trauma
Fo llicular conjunctivitis
Conjunctival pseudomembrane or membran e
Conj unctiva l granuloma
Conjunctival eros ion or ulceration
--
@
c~/l( Anchoring septa
~
- --=- . @
Iil
~~\
Blood vessel
--
Conjunctival epithelium
hir
Neutrophil s, lymphocytes, and other le ukocytes
Figure 2-7 Cross-sectional d iagram of conjunctival papilla with a central vasc ular tu ft surrounded by acute and chronic le ukocytes .
A m ild papi llary reactio n produces a smooth , velvety appearance (Fig 2-)!A),-Chronic or progressive changes result in enlarged vascular tufts that obscure the underlying blood vessels (Fig 2-SB). Connective tissue septae restrict inflammatory changes to the fibro vascular core, producing the appearance of elevated, polygonal, hyperemic mounds. Each papilla has a central red dot that represents a dilated capi llary viewed end-on. The palpebral and forniceal conjunctiva beyond the tarsus is less helpful in revealing th e nature of an inflamm ato ry reaction because the anchoring septae become sparser toward the fornix and permit und ulat ion of less adherent tissue. With prolonged. recurrent, or severe con junctival in flammation , the anchoring fibers of the tarsal conjunctiva stretch and weaken, leading to confluent papillary hype rtrophy (F ig 2-SC). The furrows between these enlarged fi brovascular stru ctures collect mucus and pus.
CHAPTER 2:
Examination Techniques for the Externa l Eye and Cornea.
23
A
Figure 2-8 papillae .
Papillary conjunctiviti s. A, Mild papillae. B, M oderate papillae. C, Marked (giant)
24 • External Disease and Co rnea
Follicles Co njunctival lympho id tissue is normally present within th e substantia propria except in neonates, who do not have visible fo llicles. Conjunctival fo ll icles are rou nd or oval clusters of lymphocytes (Fig 2-9). Small follicles are often visible in the norm al lower fo rnix. Clusters of enlarged, no ninflamed fo ll icles are occasionally seen in t he inferotemporal palpebral and forn icea l conjunctiva of ch ildren and adolescents, a condition knmvn as benign lymphoid jolliculosis (Fig 2-(0). Follicular conjunctivitis involves red ness and new o r enlarged follicl es (Fig 2- 11 ). Vessels surro und and encroach on the raised surface of follicles but are not prominently visible within th e follicle. Follicles can be seen in the inferior and superior tarsal conjunctiva and, less often, on the bulbar or limbal conjun ctiva. T he y must be differentiated fro m cysts produced by tubular epithelial in fo ld ings duri ng chron ic inflammation.
Corneal Signs of Inflammation Inflammation can affect any layer of the cornea. The pattern of corneal inflammation, or keratitis, can be described accordin g to the following:
distribution: diffuse, foca l, or multifocal depth: epithelial, subepithelial, st romal, o r endothelial
t
Conjunctival blood vessels
Figure 2-9 Cross-secti onal diag ram of conjunctival follicle with mononuclear cells obscuring conjunctival blood vessels.
A
Figure 2-10
Benign folliculosis. (Courtesy of Kirk R
Wi/he/mus, MD.J
B ............u
Figure 2-11 Follicular conjunctivitis . A, Inflammation of the right eye from glaucoma medication. B, Right eye showi ng follicular conjunctivitis in the inferior forn ix. (Courtesy of John E. Sutphin, MD.}
~
CHAPTER 2:
Examination Techniques for the External Eye and Cornea.
25
location: central or peripheral shape: dendritic, disciform, and so on
The clinician should also note any structural or phYSiologic changes associated with keratitis, such as ulceration or endothelial dysfunction. Punctate epithelial keratopathy is a nonspecific term that includes a spectrum of biomicroscopic changes from punctate epithelial granularity to erosive and inflammatory changes (Fig 2-12). Stromal inflammation may be manifested by the presence of new blood vessels. Active corneal blood vessels most commonly come from the linlbal vascular arcades and migrate into the peripheral cornea. Cells can also enter the stroma from the tear film through an epithelial defect or, less often, from direct interlamellar infiltration of leukocytes at the limbus. Inflammatory cells enter from aqueous humor in the presence of endothelial injury. In a vascularized cornea, inflammatory cells can emanate directly from infiltrating blood and lymphatic vessels. Stromal inflammation is characterized as suppurative or nonsuppurative (Fig 2-13 ). It is further described by distribution (focal or multifocal infiltrates) and by location (cen tral, paracentral, or peripheral). Necrotizing stromal keratitis is a severe form of infiltrate without the liquefaction associated with suppuration. The various morphologic changes of corneal infl ammation, categorized by the principal clinical features, aid in differential diagnosis (Table 2-3). Endothelial dysfunction often accompanies corneal stromal inflammation and contributes to epithelial and stromal edema. Swollen endothelial cells called inflammatory pseudoguttae are visible by specular reflection as dark areas of the normal mosaic pattern. Keratic precipitates (KP) are clumps of inflammatory cells on the back of the cornea that come from the anterior uvea during the course of keratitis or uveitis. The clinical appearance ofKP depends on the composition: Fibrin and other proteins coagulate into small dots and strands. Neutrophils and lymphocytes aggregate into punctate opacities. Macrophages form larger "mutton-fat" clumps.
Inflammation can lead to corneal opacification. Altered stromal keratocytes fail to produce some water-soluble factors and, consequently, make new collagen fibers that are disorgani zed, scatter light, and form a nontransparent scar. Scarring can also incorporate calcium complexes, lipids, and proteinaceous material. Dark pigmentation of a residual corneal opacity is often a result of incorporated melanin or iron salts. Corneal inflammation can also lead to neovascularization. Superficial stromal blood vessels originate as capillary buds oflimbal vascular arcades in the palisades ofVogt. New lymphatiC vessels may also form but cannot be seen clinically. Subepithelial fibrous ingrowth into the peripheral cornea is called a pannus or vascularized pannus (Fig 2-14) . Neovascularization may invade the cornea at deeper levels depending on the nature and location of the inflammatory stimulus. Any vessel tends to remain at a Single lamellar plane as it grows unless stromal disorganization has occurred. Leibowitz HM, Waring GO III, eds. Cornea l Disorders: Clinical Diagnosis and Management. 2nd ed. Philadelphia: Saunders; 1998:432-479.
26 • External Diseas e and Cornea rcorneal epjtheti um~
A
c
B
!
D Figure 2·12
Punctate lesions of the corneal epit helium. A, Punctate epithelia l erosions. B, Pu nctate epithel ial kerat itis. C, Punctate epithe lial erosions in dry eye with lissamine green staining most apparent in the nasal and temporal conjunctiva. 0 , Punctate epithelial keratitis. (Part C courtesy of Minas Coroneo, MD.)
CHAPTER 2:
Exami nat io n Techn iques for t he Externa l Eye and Cornea. 27
Figure 2-13
Inflammation of the corn eal stroma. A, Suppurative keratitis. B, Nonsuppurative, non necrotizing (disciform ) stromal keratitis.
Table 2-3 Common Causes of Corneal Inflammation Findin g
Examples
Pun ctate epithe li al erosio ns
Dry-eye syndrom e Toxic ity Atopic keratoconjunctivitis Ad enovi rus keratoconjunctiv itis Herpes sim pl ex vi rus epi t helial ke ratitis Thygeso n su perficial punctate kerat itis Bacteria l keratiti s Fungal ke ratiti s Herpes simp lex virus st romal keratitis Varicella -zoster virus stromal keratitis Syphilit ic in terstitia l keratitis Blepharitis-associated marginal i nfiltrates Periphe ral ulcerative keratitis caused by co nn ective tissue diseases Moo ren ulcer
Punctate epith eli al kerat itis
Stromal kerati ti s, suppurative Stroma l keratit is, nonsuppurative
Perip hera l keratitis
28 • Externa l Disease and Cornea
Figure2-14
Corneal pannus.
fCourresy of Kirk R. WI/he/mus, MD.)
Scleral Signs of Inflammation
I
Episcleritis and scleritis may be nodularor diffuse, and anterior scleritis may be necrotizing or nonneerotizing. The red-free light filter can help identify which layer of blood vessels is dilated. Areas of increased translucency (scleromalacia) are detected by direct observation and by transillumination.
Corneal Pachometr A corneal pachometer measures corneal thickness, a sensitive indicator of endothelial physiology that correlates well with fu nctional measurements such as aqueous fluorophotometry. The normal cornea has an average central thickness of about 540 fim. ote that in the Ocular Hypertension Treatment Stud y, the average corneal thickness was higher, at 573 ± 39 fim , but it was acknowledged that these numbers were probably higher than those of the general population. The cornea becomes thicker in the paracent ral zone and peripheral zone. The thi nnest zone is abo ut 1.5 mm temporal to the geographic center. Brandt JD, Beiser JA, Kass MA, Gordon MO. Central corneal thi ckness in the Ocular Hypertension Treat ment Study (O HTS). Ophthalmology. 2001; 108:1779- 1788.
O ptical pachometry can be performed using a device that attaches to the slit-lamp biomicroscope, but the device is somewhat imprecise. Ultrasonic pachometry is both easier and more accurate. Instrumentation is based on the speed of sound in the normal cornea (1640 m/sec). The applanating tip must be perpendicular to the surface because errors are induced by tilting. Improved Signal processing and other methods, such as lase r interferometry, allow the examiner to map the corneal thickness very precisely. Scann ing slit and Scheimpflug anterior segment imaging ca n produce maps of the entire corneal thickness (Fig 2- 15).
CHAPTER 2:
Examination Techniques for the External Eye and Cornea. 29
Scheim pflug image map depicting multip le points of corneal thi ckn ess measurement (in micrometers). (Courtesy of George J.
Figure 2-15
Florakis, MD.}
Corneal pachometry can help in diagnosing corneal thinning disorders and can also be used to assess the function of the corneal endothelium. Folds in Descemet's membrane are first seen ·when corneal thickness increases by 10% or more; epithelial edema occurs when corneal thickness exceeds 700 ).lm. A central corneal thickness greater than 650 ).lm suggests a higher risk for symptomatic corneal edema after intraocular surgery. Optical coherence tomography (OCT) and high-resolution ultrasonography are newer techniques that can be used to image the cornea, including curvature and thickness, as well as the anterior segment.
Corneal Edema The corneal endothelium maintains corneal clarity through 2 functions: by acting as a barrier to the aqueous humor and by provid ing a metabolic pump. Alteration of either function by damage or maldevelopment leads to corneal edema, a condition of abnormal homeostasis resulting in excess fluid within the corneal stroma and/or epithelium. Increased permeability and insufficient pump sites occur with decreased endothelial cell density lower than 500 cells/mm', although the critical number for clinically evident edema is not an absolute. Acute corneal edema is often the result of an altered barrier effect of the endothelium or epithelium. Chronic corneal edema is usually caused by an inadequate endothelial pump. When functioning normally, the endothelial pump balances the leak rate to maintain the corneal stromal water content at 78% and the central corneal thickness at about 540 ~m. Stromal edema alters corneal transpa rency, but visual loss is most severe when epithelial microcysts or bullae occur. A posterior collagenous layer, or retrocorneal membrane, can arise after endothelial cell damage. The physiology of the endothelium is discussed in BCSC Section 2, Fundamentals and Principles of Ophthalmology. Various traumatic, inflammatory, and dystrophic mechanisms can produce corneal edema (Table 2-4). The examiner should consider duration, laterality, and the presence
30 • Externa l Disease and Cornea
Table 2-4
Causes of Corneal Edem a
Type
Cause
Acute
Trauma (eg, epithelial defect. int raocular surgery) Inflammation (eg, infectiou s or immune- mediated keratitis, cornea l graft rejection) Hypoxia (eg, contact lens overwear) Hydrops from ruptured Descemet's memb rane (eg, keratoconus) Increased intraocu lar pressure Trauma or toxins (eg, intraocular surgery) Fuchs dystrophy Posterior polymo rph ous dystrophy Iridocorneal endotheli al syndrome Reta in ed lens fragment
Chron ic
of associated ocular disease in identifying the unde rlying etiology. Clinical examination should use the various illumination techniques of slit-lamp biomicroscopy. Early signs include patchy or diffuse haze of the epithelium, mild stromal thickening, faint deep stromal wri nkles (Wa ite-Beetham lin es), Descemet's membrane folds, and a patchy or diffuse posteri or collagenous layer. Endothelial alterations include reversible changes such as pseudoguttata and permanent alterations such as corneal guttae (cornea guttata).
Corneal thickness and intraocular pressure Corneal thickness affects the measurement of lO P. Thicker corneas cause falsely higher lOP readings and thinner corneas cause falsely lower pressure readings. Thicker corneas resist the indentation inherent to nearly all methods of lOP measu rement, including applanation, air-puff, Tonopen) and pneumotonometry. Therefore, patients with normal
(nonedematous) but thick corneas may have artifactually elevated lOP because of in creased corneal rigidity and resistance to deformation . Conversely, edematous corneas with a correspond in g decrease in rigidity and resistance to deformation may have an
artifactually lower lOP. Th in corn eas (which may have an artifactually lower lOP reading) may be an independent risk factor for glaucomatous damage to the optic nerve by a mechan ism not yet determined. Correction ofIOP for pachometry does not fully explain the lowe r risk for thicker corneas. See SCSC Section 10, Glaucoma . Brandt JD. Corneal thickness in glaucoma screening, diagnosis, and management. Curr Opin Ophthalmol.2004;15(2}:85-89 . Doughty M], Zaman ML. Hu man corneal thickness and its impact on in traocular pressure measures: a review and meta -analysis approach. Surv Ophthalmol. 2000;44(5):367-408.
Esthesiometr Esthesiometry is the measurement of corneal sensation, which is a function of the ophth almic branch of cranial nerve V. Its primary use is in the evaluation of neurotrophic keratopathy. In most clinical circumstances) reduced corneal sensitivity can be diagnosed
qualitatively without special instruments, but quanti tative esthesiometry is useful in unusual cases and for research. The examiner does not apply topical anesthesia (or any other
I
CHAPTER 2:
Exam ination Techniques for the Externa l Eye and Cornea.
31
topical agent, preferably) to the eye if corneal sensation is to be evaluated. The patient, too, should be advised not to apply topical medications before the examination . Corneal sensation is most easily tested in comparison to a normal fellow eye. A rolled wisp of cotton fro m a cotton-tipped applicator is touched lightly to corresponding quadrants of each cornea. The patient is asked to report the degree of sensation in the first eye ) relative to that of the fellow eye, and sensation is recorded as normal, reduced, or absenV for each quadrant. This method can be used to detect most clinically relevant cases of reduced corneal sensation . The handheld esthesiometer (Coche-Bonnet) is a contact device that gives quantitative information about corneal sensation. This device contains a thin, flexible, retractable nylon filament. The patient's cornea is touched with the filament, which is extended to the full length of 6 cm. The filament is then retracted incrementally in O.S-cm steps until it becomes rigid enough to allow the patient to feel its contact. This length is then recorded. EstheSiometry readings may vary with user technique, but in general a lower number, or shorter filament, indicates reduced corneal sensation. After the central cornea's sensitivity is measured, a map is produced of the cornea (and sometimes of the bulbar conjunctiva) by testing the superior, temporal, inferior, and nasal quadrants sequentially. Tvw noncontact esthesiometry methods have also been described, one using air, the other using air mixed with carbon dioxide. Noncontact corneal esthesiometry stimulates the corneal nerves by releaSing a controlled pulse of air at a predetermined pressure (in millibars). The subject indicates verbally whether the stimulus is felt, and a stimulus threshold can be determined. Faulkner Wl, Varley GA. Corneal diagnostic techniques. In: Krachmer ]H, Mannis Ml, Holland EJ, eds . Cornea. 2nd ed. Vol 1. Philadelphia: Elsevier/Mosby; 2005:229-2 35. Goins KM. New insights into the diagnosis and treatmen t of neurotrophic keratopathy. Owl
Surf 2005;3(496 - 110.
Anterior Segment Photography External and Slit-Lamp Photography External eye photography is usually performed with a single-lens reflex camera. Magnification up to \:\ (life-size) can be obtained with a bellows, extension ring, or close-focUSing lens. Digital or 3S-mm cameras may also be attached with an adapter to a slit lamp and will produce excellent-quality images, particularly if used with external illumination. Slit-lamp photography and videophotog raphy allow a permanent record of most anterior segment conditions. Martonyi CL. Slit lamp examination and photography. In: Krachmer JH, Mannis Ml, Holland El, eds. Cornea . 2nd ed. Vol I. Philadelphia: Elsevier/Mosby; 2005:191-221.
Specular Photomicroscopy Because slit~lamp illumination techniques are only semiquantitative and slit-lamp photography is difficult, clinicians may want to use specular photomicroscopes to photograph
32 • Exte rna l Disease and Cornea
the endothelium fo r closer evaluation. Specular reflection allows vis uali za tion of th e corneal endothelial mosaic. Wide-field specul ar microscopy can be performed throughout the ent ire cornea, thus allowing the stud y of regional variability. Specular microscopy can be an important d iagnostic tool, especially for differenti ati ng between difficult or overlapping diagnostic entities, such as between the iridocorneal endothelial (lCE) syndrome and posterior polymorphous corneal dystrophy. Contact specular microscopy techniques involve the use of a photomicroscope attached to an applanating cone and a coupling fluid . They are best performed foll owing the appl ication of a topical anesthetic (although noncontact techniques also exist). A relatively clear cornea is generally required to obtain a good specular image. As fine focus is obtained, the endothelial mosaic comes into view (Fig 2- 16). The stroma and epitheliulll can also be examined and photographed. Mos t instruments have a pachometer attached to the fo cusing apparatus so that corn eal thickness can be measured. Both contact and non contact specular microscopes may include a computer for analyzin g th e images. The following parameters can be calculated from a specular or confocal image. (Note th at these parameters have implications for th e cornea's response to surgica l manipulation.)
Density. The normal endothelial cell density dec reases with age. Endothelial cell density normally exceeds 3500 cells/m m' in childre n and graduall y declines with age to about 2000 cells/mm' in older people. An average value for adults is 2400 cells/mm' (1500-3500) , with a mean cell size of 150- 350 fUll '- Corneas with low cell densit y (eg, fewer than 1000 celis/nUll') might not tolerate intraocular surgery. Coefficient of va riation. The standa rd deviation of the mean cell area divided by the mean cell area gives the coefficient of variation, a un itless number normall y less tha n 0.30. Polymegathism is increased va riation in individual cell areas; it typically in creases with contact lens wear. Corneas with Signi fi cant polymegathism (>0.40) 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
"
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
---,-- ---=-..._. .. ... - ..... ....... --_ --...-.... _ _ ......... _.........
-.- -
=- ~,;,.
121'1_'''''_ " ''''' .. _ _ .'". ... uU _ _ ... _Uo
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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,
Limbal zone Peripheral zone Paracentral zone
Central zone
Figure 2-22 Topogra phic zones of the corn ea. (Illustration by Christine Gralapp.)
38 • Externa l Disease and Cornea
Optical axis
, 1 '-
Corneal apex
Temporal
Figure 2-23
Line of sight (visual axis) Corneal vertex
,,, ,
,,
Corneal vertex and apex . (Illustration by Christine Gralapp.)
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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Figure 2·26 Topogra phy of a patie nt with keratoconus . The top image shows axial cu rvature, the bottom, tange ntial curvature. Note that the steeper curve on the bottom is more closely aligned to the cone. (Courtesy of John E. Sutphin, MD.)
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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The top image shows mean curvature in keratoconus for the same patient as in
Figure 2-26. The local curvature outlines the cone, as shown by the thinnest point in the pachometry map in the bottom figure . (Counesy of John E. Sutphin, MD.)
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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Figure 2·28 Keratography of a norm al co rnea wi th regular asti gmatism. The white circl e indicates the pupil . Simulated keratom etry is 41.3, 46.2@102. (Courtesy of John E. Sutphin. MD.J
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
Deficient or unstable TF lipid layer ~
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nitial lacrimal stimulation
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/ Refractive surgery Cl wear Topical anesthesia
Goblet cell, glycocalyx mucin loss epithelial damage - apoptosis
Figu re 3-2 The mechan isms of dry eye. (Reproduced with permission from The definition and classification of dry eye disease: report of th e Definition and Classificalion Subcommittee of the International Dry Eye WorkShop (2007). Ocul Surf. 2007:5(2):75-92.)
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.
Dry eye
I
I
I
I
I
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Effect of the environment Internal Low blink rate behavior, VTU, microscopy Wide lid aperture gaze position Ag ing Low and rogen pool Systemic drugs: antihistamines, ~- blockers, antispasmodics, diuretics, and some psychotropic drugs External Low relative humidity High wind velocity Occupational environment
Figure 3·3
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
<5 <5
Visua l symptoms
Schirmer score (mm/ 5 min)
*M ust have sig ns AND symptoms . TSUT = fluorescein tear break-up time, MGD
=
4'
3 Severe frequ ent or constant w ithout stress
Severe an d/ or disabl ing and constant
Annoy ing . chroni c and/ or co nstant, limiting activity
Constant and! or possibly disabling
+/-
+/ ++
Moderate to marked Marked central
Marked
Filamentary keratitis, mucus clumping. i tear debris. ulceration Trich iasis, keratinizat ion, symblepharon Immediate
Severe punctate erosions
<2
meibomian gland disease.
Reprinted with permission from The definition and classification of dry eye disease: report of the Definition and Classification Subcommittee of the International Dry Eye Workshop (2007). Ocul Surf.
2007;5(2);75-92.
includes all of the previously noted measures as well as punctal occlusion and occasionall y lateral tarsorrhaphy_ The mainstay of treatment for dry-eye syndrome is the use of topical tear substitutes (eyedrops, gels, and ointme nts). Preservative-free tear substitutes are recomme nded to avoid toxicity in patients who use these agents frequently. Demulcents are polymers added to artificial tear solutions to improve their lu bricant properties. Demulcent solutions are muco mi metic agents that can briefly substitute fo r glycoproteins lost late in the disease process. Demulcents alo ne, however, cannot restore lost glycoproteins or conjunctival goblet cells, reduce corn eal cell des quamation, or dec rease osmolarity. Until relatively recently, all demulcent solutions contained preservatives, Preservative-free demulcent solutions were in troduced after it \vas recognized that preservatives increased corneal desquamat ion. The elim inat ion of preservatives from traditional demulcent solu tions has
CHAPTER 3: Oc ular Surface Disease: Dia gnostic Ap proa ch. 59
Figure 3-9
Labia l gland biopsy. (Courtesv of
Minas T. Coroneo, MD.)
Table 3-3 Systemic Diseases Associated With Dry Eye Autoimmune disorders Primary Sjogren syndrome Second ary Sjogren syndrome associ ated with Rheumatoid arthritis Systemic lupus erythe matosus Progressive systemic sclerosis (scl eroderma) Polymyositis and dermatomyositis Primary biliary cirrho sis Graft-vs-host disease Immune react ions after radiation to hea d and neck Infiltrati ve processes Lymphoma Amyloidosis Hemochromatosis Sarco idosis Infectious processes HIV-diffuse infiltrative lymphadenopath y syndro me Trachoma Neuropathic dysfunction Multiple scle rosis Cranial neuropathies (Bell palsy, vasculitis) Park inson disease Alzheimer disea se Endoc rine dysfunction Androge n deficiency
60 • Externa l Dis ease and Cornea Table 3-4 Recommended Treatment for Dry Eye Seve rity
Therapeutic Options
Mild
Artificial tears w ith preservatives up to 4x daily Lubricating ointment at bedtime Hot compresses and eye lid massage
Moderate
Artificial tears without preservatives 4x daily to hourly Lubricating oi ntment at bedtime Topical anti-infla mm atory treatment (cyclos porine A 0.05% 2x daily) Reversible occlu sion, lower puncta (plugs)
Severe
All of the above Punctal occlusio n (lower and upper) Topical serum drops (20%) 4-6x daily Topical co rticosteroids (nonpreserved if available ) Moist environment (humidifier, moisture sh ields) Tarsorrhaphy (late ral and medial) Bandage lenses (rarely)
led to improved corneal barrier fu nction. and subsequent atte mpts have been made to improve fu nction even further by adding various ions to the solutions. Topical cyclosporine A 0.05% has been approved by the FDA as a treatment for the inflammatory component of dry eye and is considered to be a majo r advance. Modulation of the ocular surface inflammatory response might reduce destruction of lacrimal acini and increase neural responsiveness. thereby improving lacrimal secretion. Topical cyclosporine is thus being used earlier in the course of this diseasej a small percentage of patients may even gain long- term benefit after an initial course of cyclosporine is stopped. Approximately 70% of patients with moderate to severe dry eye seem to benefit from the use of topical cyclosporine. which to date has shown minimal side effects. Also. short courses of topical corticosteroids have been used off- label to interrupt the inflammatory cycle in dry-eye patients. Other treatments that have been successfully used in the treatment of severe dry eye are dilute solutions of hyaluronic acid and autologous serum drops (requi ring special formulation). The composition of diluted autologous serum is somewhat sim ilar to that of normal tears. particularly in relation to growth factors, and therefore some of the benefit may relate to the trophic function of these substances. Pharmacologic stimulation of tear secretion has been attempted with many compounds. with varying degrees of success. The cholinergiCagonists pilocarpine and cevimeline stimulate muscarinic receptors present in salivary and lacrimal glands. thereby increasing secretion . Although stud ies have shown both to be effective in treating both xerostomia and dry eye in patients with Sjogren syndrome. they are approved only for the treatment of xerostomia. It is uncertain as to whether th ese agents show long-term benefits. Treatment of filamentary keratopathy. which sometimes accompanies severe dry-eye conditions. is best directed at controlling the underlying condition. particularly if ATD is responsible. Acetylcysteine 10%. dispensed in an eyedrop container. can be used as a mucolytic agent and is helpful in alleviating these symptoms. Topical anti-inflammato ry agents may also be helpful. Wearing goggles. shields. or moisture bubbles can decrease the tear evaporation. although these strategies are generally unacceptable to patients. The
CHAPTER 3: Ocular Surface Disease: Diagnostic Approach. 61
surface area available for evaporation can also be decreased simply by fitting the patient with spectacles. which can be furthe r augmented with plastic side shields. Soft contact lenses are used with a high degree of risk in dry-eye patients. although gas-permeable lenses are frequently well tolerated. Scleral contac t lenses may also be helpful in patients with severe dry-eye symptoms. Dry-eye symptoms may be exacerbated by topical glaucoma medications. Chronic use of both topical P-blockers and miotic agents can decrease conjunctival goblet cell density. Topical P-blockers have been associated with an increased incidence of dry eye. possibly due to reduced corneal sensitivity. Oral administration of drugs such as the carbonic anhydrase inhibitors (eg. acetazolamide and metha zolamide) can decrease tear production . See also BCSC Section 10. Glaucom a. Many differe nt systemic medications (diuretics, antihistam ines. anticholinergics, and psychotropics) decrease aqueous tear production and increase dry-eye symptoms. These drugs should be avoided as much as possible in patients with symptoms of ATD (see Table 3-6). The psychological problems associated with a highly symptomatic. incurable. chronic disease can require considerable support. Quality-of-Iife studies have shown that the impact of moderate to severe dry eye is similar to that of having moderate to severe angina. O rganizations such as the Sjogren Syndrome Foundation (www.sjogrens.org) can provide valuable resources to these patients. In certain settings. consultation with physicians who specialize in pain management can be very useful. Surgical treatment is generall y reserved for patients with severe disease for whom medical treatment is either inadequate or impractical. Patients with moderate to severe dry eye may be helped by punctal occlusion. Tear drainage may be decreased with either reversible or irreversible punctal occlusion. Reversible punctal occlusion can be performed in a number of ways, with varying degrees of effectiveness, using light cautery of the puncta (Fig 3-10). collagen implants. or silicone punctal plugs
SURGICAL MANAGEMENT
Figure 3·10
Use of cautery for punctal occlusion .
(Courresyof Charles $ . Bouchard. M D.}
62 • External Disease and Corn ea
Figure 3- 11
Silicone punctal plug. (Counesy of llincenr P. deLuise, MD.)
(Fig 3-1 1). Collagen plugs usually dissolve withi n days and do not cause complete canalicular occlusion. Reversible occlusion may be used as a trial measure before irreversible punctal occlusion is performed. Punctal plugs are available in a variety of sizes and sha pes for easy insertion and removal. Instruments that ass ist in proper sizi ng of the punctal open ing are commercially available. Excessive dilation of the puncta shou ld be avoided. Silicone plugs will generally re main in place for mon ths to yea rs unless they fit loosely or are man ually displaced. Once a plug has been disp laced, subsequent plugs are more likely to be displaced. Most silicone plugs are continuously visible at the slit lamp, making it obvious if they become displaced. One disadvantage of punctal plugs is that they can be inadver tent ly inserted into the nasolacrimal system and require surgica l removal. One type of plug is designed for intracanalicular placement. If the plug protrudes from the punctum, conjunctival abrasions may occur. Gra nuloma formation at the punctal open ing has been observed and requires removal of the plug. In addition, punctual occlusion may lead to redu ced tear flow. It appears that the effect of topical cyclosporine is additive to the effect of pun ctum plugs. When patients have successfull y tolerated reversible punctal occlusion, ir reversible punctal occlusion can be performed in the most cost-effective manner \vith a disposable cautery, a hyfrecator, or a rad iofreq uency probe. Although the procedure is usually permanent, the canaliculi and puncta may recanalize following thermal occlusion. The value of punctal occlusion for ocular surface disease other than dry eye is unprove n. The procedure is recom mended primarily for patients in whom basal tear secretion is minimal. with punctate keratopathy, and without significant ocu lar surface inflammation or infection; this includes especially older patients, in whom the risk of iatrogenically induced epiphora is minimaL Correction of eyelid maJpositions such as entropion and ectropion may also be useful in managing patients with dr y eye. Reduction of the palpebral ape rture by means oflateral and/or medial tarsorrhaphy can be performed in severe KCS when more conservative measures have failed. Lateral tarsorrhaphy may limit the temporal visual field and produce a cosmetic defect.
CHAPTER 3: Oc ular Surface Disease: Diagnostic App roach . 63
The definiti on and classification of dry eye disease: report of the Defi nition and Classification Subcommittee of the International Dry Eye WorkShop. Ocul Surf 2007;5 (2}:75- 92. Lemp MA. Advances in understanding and managing dry eye disease. A m J Ophthalmol. 2008; 146(3):350-356. Pflugfelder SC, Beuerman RW, Stern ME, eds. Dry Eye and Ocular Surface Disorders. New York: Informa Healthcare; 2004. Preferred Practice Patterns Comm ittee, Corn ea/External Disease Panel. Dry Eye Syndrome. San Francisco: American Academy of Ophthalmology; 2008. Stern ME, Pflugfelde r Sc. Inflammation in dry eye. Ocul Surf 2004;2(2) :124- t 30.
Sjogren Syndrome Patients with ATD are considered to have Sjogren syndrome (55) if they have associated hypergammaglobulinemia, rheumatoid arthritis, or antinuclear antibody. Involvement of the salivary glands is common, resulting in dry mouth and predisposing to peri odontal disease. Mucous membranes thro ughout the body may be affected (ie, vaginal, gastric, and respiratory mucosae) and greatl y impact patients' quality of life. Sjogren syndrome can be divided into 2 clinical subsets. Primary 55 includes patients who either have iIldefined systemic im mune dysfu nction or lack any evidence of immune dysfu nction or connective tissue disease. Secondary SS occurs in patients with a well-defined, generalized connective tissue disease. Secondary SS is most commonly associated with rheumatoid arthritis, although numerous other autoimmune diseases are also frequently encountered. The revised international classification criteria for Sjogren syndrome are in Table 3-5 . Associated symptoms can include fever, fatigue, Raynaud phenomenon, arthralgias, and myalgias. Although the precise cause(s) of ATD in SS is unknown, it is generally considered to be a T-cell- mediated inflammatory disease leading to destruction of the lacrimal glands. PrO-inflam mato ry cytokines (IL- I a and IL-10, IL-6, IL-8, TGF- 0J' TN F-a), immu ne activation molecules (ICAM- l , HLA-DR, CD40, CD40 ligand), and proteolytic enzymes (MMP- 2, MMP-3, MMP-9, MMP-13) have been reported to be expressed at elevated levels in both lac rimal and ocular surface tissue in patients with SS. These inflammatory mediators playa role in lacrimal tissue destruction, in part, by increasing the rate of programmed cell death (apoptosis). Lacrimal gla nd histology provides many insights into the pathogenesis of SS. The histologic changes are usually identical to those noted in the salivary glands, with focal and/or diffuse lymphocytic infiltration associated with areas of glandular dest ru ction. Experimental models ofSS show progressive infiltration of auto reactive CD4' T cel ls, B cells, and smaller numbers of CD8' T cells consistent with a cell -mediated pathogenesis. As the disease advances, fibrous replacement of the glandular tissue may occur. Sensory nerves in the cornea and conjunctiva make up the afferent branch of the lacrimal reflex arc. Sympathetic and parasympathetic nerves form the efferent limb of the reflex arc; these terminate in the lacrimal gland and, when stimulated, induce lacrimal production of water, electrolytes, and protein . Peripheral nervous system dysfunc tion may be present in as many as 20% of patients with SS and might contribute to ATD. Androge nic hormones have an important influence on the functional activity of the lacrimal gland, as well as on its imm un ologic microenviro nment. Androgenic receptors
64 • External Disease and Cornea
Table 3-5 Criteria f or the Classification of Sjogren Syndrome
~----------------
1. Ocul ar symptoms Definition: A positive respon se to at least 1 of the foll owin g 3 questions: a. Have you had dai ly, pers istent, troub leso me dry eyes for more than 3 months? b. Do you have a recurrent sensation of sand or grave l in the eyes? c. Do you use tear su bstitutes more tha n 3 times a day? 2. Oral sy mptoms Defin ition : A positive response to at least 1 of th e following 3 questions: a. Have you had a daily feeling of dry mouth for more than 3 months? b. Have you had recurrent or persistently swo ll en salivary g lands as an adult? c. Do you frequently drink liquids to aid in swallowing dry foods? 3. Ocula r signs Definiti on : Objective evidence of oc ular invo lvement, determin ed on the basis of a positive result on at least 1 of the following 2 tests: a. Schi rmer I test (<: 5 mm in 5 minutes) b. Rose bengal sco re (>4 van Bijsterve ld sco re) 4. Histopathologic features Defi nition: Focus score> 1 on minor salivary gl and b iopsy (focus defined as a conglomeration of at least 50 mononuclear cells; focus score defin ed as the number of foci in 4 mm 2 of glandular tissue) 5. Sali va ry gland in vo lve m ent Defin ition: Objective evidence of salivary gla nd involvement, determined on the basis of a positive result on at le ast 1 of the foll owing 3 tests: a. Salivary scintography: delayed uptake and/or sec retion b. Parotid sial ogra phy: diffuse sialecta sis w ithout obstruction c. Unstimulated salivary flow «1. 5 mL in 15 minutes) 6. Autoantibodies Definition: Presence of at least 1 of the fo ll owin g serum autoantibodies: a. Antibodies to Ro/SS-A b. Antibodies to La/SS-B antigens Excl usion criteria : Preexisting lymphoma, acq uired immunodeficiency syndrome, sarcoidos is, or chronic graft-vs-host disease, prior hea d and neck irradiation , hepatitis C, use of anticholinergic medications Prim ary Sjogren syndrome: Presence of 4 ou t of 6 item s or presence of 3 of 4 objective criteria (item s 3-6) Second ary Sjogren syn drom e: A co mbination of a posi tive response to item 1 or 2 plus a positive response to at least 2 items from among 3, 4, and 5
are found within the epithelial cell n uclei of th e conjunctiva, cornea, and meibomian and lacrimal glands. Deficiency of androgeni c hormones may playa contributing role in the progression of 55. The precise nature of th is relatio nship requi res furth er study. Viral infections such as Epstein-Barr virus (EBV), type I human T-cell Iymphot ropic virus (HTLV-l), hepatitis C, and human immunodeficiency virus (HIV) have been associated with the development of Sjogren-like syndromes in both animal models and humans. Viral infection may contribute to ch roni c autoimmune destruction of lac rimal and salivar y glands. Tuisku IS , Konttinen YT, Konttinen LM, Tervo 1M. Alterations in corneal sensitivity and nerve morphology in patients with primary Sjogren's syndrome. Exp Eye Res. 2008;86{6): 879-885.
CHAPTER 3:
Ocula r Surface Disease: Diagnostic Approach. 65
Vitali C, Bombardieri S, Jonsson R, et a1. Classification criteria for Sjogren's syndrome: a revised version of the European criteria proposed by the American -European Consensu s Group. Ann Rheum D is. 2002;61(6):554-558 .
Non- Sjogren Syndrome In non - Sjogren syndrome, ATD can be due to disease of the lacrimal gland, lacrimal gland obstruction, or reflex hyposecretion. Lacrimal disease may be primary, due to congenital conditions such as Riley-Day synd rome (familial dysau tonomia); congenital alacrima, or absence of the lacrimal gland; anhidrotic ectodermal dysplasia; Adie syndrome; and idiopathic autonom ic dysfunction (Shy-Drager syndrome). Secondary causes of lacrimal disease include sarcoidosis, chronic graft-vs-host disease, HIV, xerophthalmia, and surgical ablation of the lacrimal gland. Obstruction oflacrimal outflow may be caused by severe cicatricial conjunctivitis (trachoma , erythema multiform e, chemical burns, and cicatricial pemphigoid), in which the lacrimal excretory ducts present in the superior conjunctival fornix are destroyed. Decreased lacrimal secretion can occur as a result of interruption of either the afferent or efferent limb of the reflex arc. Interruption of the afferent limb of the reflex arc can be caused by viral disease (eg, herpes simplex [HSV], varicella-zoster [VZV]), contact lens wear, peripheral neuropathies (eg, diabetes, Bell palsy), surgical disruptio n (eg, laser in situ keratomileusis [LASIK], photorefractive keratectomy [PRK], penetrating keratoplasty [PK], extracapsular cataract extraction [ECCE]), and aging. Decreased corneal sensation following either PRK or LASIK often results in dr y-eye symptoms lasting several months. These symptoms typically resolve following the restoration of normal corneal sensitivity. The efferent limb of the reflex arc can be affected by numerous different systemic anticholinergic medications (Table 3-6) .
Evaporative Tear Dysfunction Increased tear-film evaporation is most commonly caused by MGD but may also be caused by disease of the meibo mian glands, poor app osition of the eyelids to the ocular surface, increase of the palpebral aperture, and contact lens wear. Symptoms consist of burning, foreign-body sensation, redness ofthe eyelids and conjunctiva, filmy vision, and recurrent chalazia. Signs of ETD include decreased TBUT, MGD, abnormal aqueous tear production, and a characteristic linear pattern of rose bengal/lissamine green staining of the inferior conjunctiva and cornea and eyelid margin.
Meibomian Gland Dysfunction Meibomian gland dysfunction occurs as a result of progressive obstruction of the meibomian gland orifices due to keratin ization. There is a subsequent reduction of lipid delivery to the ocular surface and increased inflammation of the eyelid characterized by hyperemia of the eyelid margin and tarsal conjunctival surface. Meibomian secretions may be clear, cloudy, or thickened. Meibomian orifices may be inspissated (plugged) and may become
66 • Ext ernal Disea se and Cornea Table 3·6 Medications With Anticholinergic Side Effects That Decrease Tear
Production Antihypertensives Clonid ine (at-blocker) Prazosin (ai- blocker) Prop ra nolol (~-blocker) Reserpine M ethyldopa, guanethidine Antidepressants and psychotropics Am it riptyline , nortriptyline Imip ramine, desip ram ine, clom ipramine Doxepin Phenelzin e, tranylcypromine Amoxapin e, trimipramine Ph enothiazines N itrazepam, diazepam Diuretics, sometimes in co mbination with other antihypertens ive drugs Cardiac antiarrhythmia drugs Di sopyramide Mexiletine A miodarone Parkinson disease medications Trihexyphenidyl Benztropine Biperiden Procyclidine Antiulcer agents Atropin e-like agents Metoclopramide, other drugs that decrease gastric motility Muscle spasm medications Cyclobenzaprine Meth ocarbamol Decongestants (nonprescription cold remedies) Ephedrin e Pseudoeph edrine Antihistamines Anesthetics Enflurane Halothane Nitrous oxide Bisphosph onates Hormonal: estrogen replacement. androgen antagonists
posteriorly displaced as a result of scarring of the marginal and tarsal mucosa. A variable amount of meibomian gland dropout may also be present. MGD is now recogn ized as a common yet frequentl y overlooked cause of ocular irritation. It can be broadly classified into obstructive, or hyposecretory, resulting from cond itions such as anterior blepharit is, acne rosacea, and pemph igoid; and nonobst ructive, or hypersecretory, resulting from meibomian seborrhea. Patients with MGD develop lipid tear deficiency, which results in tear-film instability, increased rate of tearfilm evaporat ion, and elevated tear osmolarity.
PATHOGENESIS
CHAPTER 3:
Ocul ar Surface Disease: D iag nostic Approach. 67
Symptoms consist of burning, foreig n ~ body sensati on, redness of the eyelids and conjunctiva , filmy vision, an d recurrent chalazia. Inflam mation is usua lly confi ned to the posterior eyel id margins, conjunctiva, and cornea, although patients may occasionally have associated se borrheic changes on the ante ri or eyelid margin (Fig 3- 12). T he posterior eyelid margins are often irregular and have prominent, telangiectatic blood vessels (brush marks) coursing from the posteri o r to anterior eyelid margins. The meibomian gland orifices may pout or show metaplasia, with a white plug of kerat in protein ex ~ tending thro ugh the gland ular orifice. They also may become posterio rl y di splaced on the eyelid margin. Meibomian secretions in active disease may be turbid and have increased viscos ity. Followi ng yea rs of meibomian gland infla mmatio n, extensive atro phy of the meibomian gland acini may develop and eyelid compression no longer express the meibo ~ m ian secretions. Atrophy of meibomian gland acini and derangement of glandular architecture can be shown by transillumination of the eyelid as well as in frared photography. Foam may appear in th e tear meniscus along the lower eyeLid. Patients frequentl y have an unstable tear film with rapid TBUTs, particularly in long-standi ng d isease with meibomia n gland atrop hy an d reduced lipid production. Mi ld to severe ocular surface inflammat ion may accompany MG D, which may include th e foll owing manifestations:
CLINICAL PRESENTATION
• bulbar and tarsal conj unctival inj ection pap illary reaction on the inferior tarsus episcleritis punctate epithelia l erosions in the infer ior cornea marginal epith elial and sub epithelial infiltrates corneal neovascul ari zation and scarring (pannus) corneal thi nn in g Patients with MGD are frequently noted as havi ng one or more manifestations of rosacea) including facial telangiec tasia in an axial distri bution (forehead, cheeks> nose, and
Figure 3-12
Meibom ian gland dysfunction.
68 • External Di sease and Cornea
chin), persistent erythema, papules, pustules, hypertrophic sebaceous glands, and rhin ophyma (see Rosacea later in the chapter). Alterations of the chemical composition of the meibomian secretions have been observed in patients '\lith MGD; however, the precise relationship between these changes and the disease process requires further elucidation. Eyelid hygiene is the initial treatment for patients with blepharitis. These measures incl ude the application of warm compresses to the eyelids for several minutes in order to liquefy thickened meibomian secretions and soften adhere nt incrustations on the eyelid margins. The application of heat should be followed by gentle massage of the eyelids to express retained meibomian secretions. Eyelid massage can be followed by cleansing the closed eyelid margin with a clean washcloth, a cotton ball, or a commercially available pad. A diluted solution of a nonirritating shampoo, a commercially available solution designed for this pur pose, or a di lute sodium bicarbonate solution (1 teaspoon of salt to 1 pint of boiled water), may facilitate cleansing. Routine performance of eyelid hygiene measures once or twice daily may improve the chronic symptoms of blepharitis. Short-term use of topical antibiotics to reduce the bacterial load on the eyelid margin may be helpful. If the signs and symptoms of MGD are not adequately controlled with eyelid hygiene, systemic tetracycli nes can be very effective. Treatment may be initiated with tetracycline 250 mg orall y every 6 hours for the first 3- 4 weeks, followed by a tapering dose guided by clinical response (usuall y 250-500 mg daily). Because tetracycl ine must be taken on an empty stomach and requires more frequent dOSin g, doxycycline and mi nocycline are now used with increasing frequency. The doses of doxycycline and minocycline are 100 mg and 50 mg, respecti vely, every 12 hours fo r 3-4 weeks, tapering to 50- 100 mg per day, based on clinical response. Lower doses may be equally effective. It often takes 3-4 weeks to achieve a cl inical response. Therapy must often be continued on a chronic basis. Erythromycin can be used as alternative therapy in patients with known hypersensitivity to tetracycline or in children. Patients with MG D should be informed that therapy may control but not eliminate their condition. Side effects of the systemic tetracycl ines include photosensitization, gastrointestinal upset. and, in rare instan ces, azotemia. Chronic use may lead to oral or vaginal candidiasis in susceptible patients. The use of tetracycli nes is contraindicated during pregnancy, fo r women who are nursing, and in patients with a known hypersensitivity to these agents. These agents should be used with caution in women in the child-bearing age range, women with a family history of breast cancer, patients with a history of liver disease, and patients taking certain anticoagulants (eg, warfari n). Tetracyclines may also reduce the efficacy of oral contraceptives. These antibiotics should also be avoided in children younger than 8 years of age because they cause permanent discoloration in teeth and bones. Topical corticosteroids may be required for short periods in cases with moderate to severe inflammation, particularly those wi th corneal infiltrates and vascularization. Patients treated with topical corticosteroids should be warned about the complications of chronic use, because this stubborn condition may prompt patients to become dependent. Preliminary evidence has shown some benefit from the use of systemic omega-3 fatty acid supplements in some patients with MGD. The ultimate benefits and precise dosage requ ired for a beneficial effect remain to be determined. MANAGEMENT
CHAPTER 3:
Ocular Surface Di sease: Diagnostic Approach .
69
Bron AJ. Tiffany JM. The contribution of meibomian disease to dry eye. Owl Surf 2004;2(2): 149- 165.
Driver P), Lemp MA. Meibomian gland dysfu nction. Surv Ophthalmol. 1996;40(5):343 - 367. Preferred Practice Patterns Committee, Cornea/External Disease Panel. Blepharitis. San Francisco: American Academy of Ophthalmol ogy; 2008.
Rosacea Rosacea (sometimes called acne rosacea) is a chronic acneiform disorder that can affect both the skin and eyes. This d isease has no proven cause. It is associated with cutaneous sebaceous gland dysfun ction of the face, neck, and shoulders. Although rosacea has generally been thought to be more common in fair-skinned individuals, it may simply be more difficult to d iagnose in persons with dark skin. It is infrequently diagnosed by ophthalmologists, in spite of its relatively frequent association with blepharitis and/or ATD. Diagnosis can be made difficult by dim lighting in ophthalmologic offices and may be made easier by asking about related symptoms. Although alcohol can contribute to a worsening of this disorder because of its effect on vasomotor stability, most patients \vith rosacea do not have a history of excessive alcohol intake. Experimental studies based on immunohistochemical stai ning of inflamm atory cell infiltrates have shown th is d isease to represent a delayed hypersensitivity reaction . Dysfunction of the meibomian and other lipid-producing glands of the eyelids and skin of the face are believed to be responsible for these infiltrates. PATH OG ENESIS
CLI NICAL PRESENTATION A skin cond it ion that frequently involves the eyes, rosacea is characterized by excessive sebum secretion with a frequently recalcitrant chronic blepharitis. Eyelid margin telangiectasia is very com mon, as are meibomian gland distortion, disruption, and dysfunction, which can lead to recurrent chalazia. Ocular involvement can also progress, leading to chronic conjunctivitis, marginal corneal infiltrates, sterile ulceration, episcleritis, or iridocyclitis (Fig 3-13) . If properly treated, these lesions can resolve with few sequelae. Repeated bouts of ocular surface inflammation can bring about corneal neovascularization and scarring, often in a characteristic triangular configuration (Fig 3-14). This disorder is generally fou nd in patients aged 30-60, with a slight female preponderance. However, ocular rosacea can be encountered in younger patients and is often underdiagnosed. Facial lesions cons ist of telang iectasias, recurrent papules and pustules, and midfacial erythema (Fig 3-15) . Rosacea is characterized by a malar rash with unpredictable flushing episodes, sometimes associated with the consumption of alcohol, coffee, or other foods. Rhinophyma, thickening of th e skin and connective tissue of the nose, is a characteristic and obvious sign associated with this disorder, but such hypertrophic cutaneous changes occur relatively late in the disease process.
The ocular and systemic diseases are managed simultaneously, with system ic tetracyclines as the mainstay of therapy. Tetracyclines have anti-inflammatory properties that include suppression of leuko cyte migration, reduced production of nitric oxide and reactive oxygen species, inhi bition of matrix metalloproteinases, and inhibition of phospholipase A2. In addition, tetracyclines m ay reduce irritative free fatty acids and diglycerides by suppressing bacterial lipases.
MANAG EM ENT
70 • External Disease and Cornea
Figure 3-13
Figure 3-14
Marginal ke rat it is associated with rosacea.
Rosacea with chronic superficia l keratopathy and corneal neovascularization.
With time, oral therapy with doxycycl ine or millocycline can be tapered. [n addition to oral therapy, application of topical metro nidazole 0.75% gel (Metrogel ) or 1% cream (No ritate) to the affected facial areas can significantly reduce facial erythema. Ulcerative keratiti s can be associated with infectious agents in rosacea, or it may have a sterile inflammatory etiology. Once it is ascertained that ulceration is noninfectious, topical corticosteroids, used judiCiously, can play a significant role in reducing sterile inflammation and en hancing epithelialization of the cornea. In advanced cases with scarring and neovascularization. conservative th erapy is generally recomm ended. Penetratin g keratoplasty in rosacea patients is a high-risk procedure that may have a poor prognosis if the ocular surface is severely compromised.
CHAPTER 3: Ocular Surface Disease: Diagnostic Approach. 71
Figure 3-15
Facial characteristics of moderate acne rosacea . (Counes yofJamesJ. Reidy. M D.)
Bron AJ, Benjamin L, Snibson GR. Meibomian gland disease. Classification and grading of lid changes. Eye. 199 1;5(Pt 4);395-411. Stone DU, Chodosh J. Ocular rosacea: an update on pathogenes is and th erapy. Cllrr Opin Ophthalmol. 2004; 15(6);499-502.
Seborrheic Blepharitis Seborrheic blepharitis may occur alone or in combination with staphylococcal blepharitis or MGD. Inflam mation occurs primarily at the anterior eyelid margin; a variable amount of crusting, typicall y of an oily or greasy nature, may be found on the eyelids, eyelashes, eyebrows, and scalp. Patients with seborrheic blepharitis often have increased meibomian gland secretions that appear turbid when expressed. Signs and symptoms include chronic eyelid redness, bu rn ing, and occaSionally foreign-body sensation. A small percentage of patients (app roxi mately 15%) develop an associated keratitis or conjunctivitis. The keratitis is characteri zed by punctate epithelial erosions distributed over the inferior third of the cornea. Approximately one third of patients with seborrheic blepharitis have AT D.
CLINICAL PRESENTATION
72 • Externa l Disease and Cornea
Eyelid hygiene is the primary treatment in patients with blephar itis. Th is regimen was detailed earlier, in the discussion of MGD. Concurrent treatm ent of scalp disease (eg, with coal tar-based shampoos) can also improve blepharitis. If inflammation is a prominent component of the blepharitis, a brief course of topical corticosteroid applied to the eyelid margins may be helpful. If blepharitis invol ves primarily the posterior eyelid margin (eg, MGD), systemic antibiotics such as doxycycline are the mainstay of treatment. Blepharitis caused by bacteria (eg, staphylococcus) often responds to the use of a top ical antibiotic ointment such as bacitracin or bacitracin-polymyxin B. (Staphylococcal blepharitis is discussed further in Chapter 5.) MANAG EMENT
Chalazion CLINICAL PRESENTATION A chalazion is a localized lipogranulomato lls inflammation involving eithe r the meibomian or Zeis glands. It usually develops spontaneously as a result of obstruction of one or more of the glands. The nodules develop slowly and are typically painless. The overl ying skin is erythematous (Fig 3- 16). The lesion disappears in weeks to months when the contents drain either externally through the eyelid skin or internally through the tarsus, or when the extruded lipid is phagocytosed an d the granuloma dissipates. A small amount of scar tissue may remain. Occasionally, patients \\lith a chalazion may experience blurred vision secondary to astigmatism induced by its pressure on the globe.
Sebaceous material trapped in a plugged Zeis or meibomian gland extrudes into adjacent tissues, ""here it elicits chronic granulomatous inflammation. A zonal granulomatous inflam matory response centered around lipid is seen histologically. As is typical of all granulomas, epithelioid cells are prominent. Also present are admixtures of other cells, including lymphocytes, mac rophages, neutrophils, plasma cells, and giant cells. It must be emphasized that basal cell, squamous cell, and PATHOGENESIS AND LABORATOR Y EVA LUATION
Figure 3-16
Chalazion. (Courtesy of Vincent P. deLuise, MD.)
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Ocular Surface Disease: Diagnostic Approach.
73
sebaceous cell carcinoma can masquerade as chalazia or chronic blepharitis. The histo~ pathologic examination of persistent, recurrent, or atypical chalazia is therefore quite in1portant. Because most chalazia are sterile, topical antibiotic therapy is of little or no value. Chalazia may be treated with hot compresses and attempted expression of the inflamed meibomian gland. Lesions that fail to respond to conservative therapy may be treated with intralesional injection of a corticosteroid (0.1-0.2 mL triamcinolone 10 mg/m L), incision and drainage, or a combi nation of both. In general, an intralesional corticosteroid injection works best with small chalazia, with chalazia on the eyelid margin, and with multiple chalazia. An intralesio nal corticosteroid injection in patients with dark skin may lead to depigmentation of the overlying eyelid skin and thus should be used \vith caution. Larger chalazia are best treated with surgical drainage and curettage. Internal chalazia require vertical incisions through the tarsal conjunctiva along the meibomian gland to facilitate drainage and avoid horizontal scarring of the tarsal plates. Surgical drainage usuall y requires perilesional anesthesia. Recurrent chalazia should be biopsied to rule out meibomian gland carcinoma. Systemic tetracycl ines can be of benefit in patients with associated rosacea. MANAGEME NT
Epstein GA , Putterman AM. Combined excision and drainage with intralesional corticosteroid injection in the treatment of chronic chalazia . Arch Ophthalmol. 1988;106(4):514- 516.
Hordeolum Hordeola are discussed in Chapter 5.
Sarcoidosis
Sarcoidosis is a multisystem disorder characterized by the development of non caseating granulomatous inflammation in affected tissues. Evidence suggests that the etiology of systemic sarcoidosis is linked to a genetically predetermined enhancement of cellular immune responses (T hl /CD4+) to a lim ited number of microbial pathogens. Ocular involvement is seen in up to 50% of affected patients. Nontender small (millet seed) or large nodules may be seen in the eyelid skin and in the canthal region. Lacrimal gland involvement occurs in up to 25% of patients with ocular involvement, resulting in KCS. Concomitant enlargement of the lac rim al and saliva ry glands combined with the presence of dry eye is known as Mikulicz syndrome. Patients with Lofgren syndrome present with erythema nodosum, hilar adenopathy, and iridocyclitis. Patients presenting with uveitis, fever, and facial nerve palsy (uveoparotid fever) have Heerfordt syndrome. Conjunctival granulomas have been observed in approximately 7% of patients with ocular involvement. Such granulomas are often small and easily overlooked, and they may be difficult to distinguish from normal conjunctival follicles. The most common corneal finding is calcific band keratopathy, often associated with chronic uveitis or elevated serum calcium levels. Num mular keratitis, thickening of Descemet's membrane, and deep stromal vascularization as a result of chronic intraocular inflammation can be
74 • Externa l Disease and Cornea
seen. Granulomatous uveitis wi th mutton -fat keratic precipitates and iris nodules occurs in as many as two thirds of patients with ocular involvement. Periphlebitis is the most common fundus finding. Chronic cysto id macu lar edema and exudative retinal detachment are related to intense and long-standing inflammation. Granulomatous involvement of the optic nerve is also seen. Moller DR, Chen £S . ·What causes sarcoidosis? Curr Opin Pu/m Med. 2002;8(5):429 - 434.
See also BCSC Section 9, Intraocular Inflammation and Uveitis, for illustrations and further discussion of sarcoidosis.
Desquamating Skin Conditions: Ichthyosis Ichthyosis represents a diverse group of hereditary skin disorders characterized by excesSively dry skin and accumulation of scale. The disease is usually diagnosed during the fi rst year of life. Ichthyosis vulgaris, an autosomal dominant trait, is the most common hereditary scaling disorder, affecting 1 in 250-300 people. Ocular involvement varies with the form of ichthyosis. Eyelid scaling, cicatricial ectropion, and conjunctival thickening are common. Primary corneal opacities are seen in 50% of patients with X-linked ichthyosis but are rarely seen in ichthyos is vulga ris. Dots or filament -shaped opacities appear diffusely in pre-Descemefs membrane or in deep stroma and become more apparent with age without affecting vision. Nodular corneal degeneration and band keratopath y have been described. Secondary corneal changes such as vascularization and scarring fro m severe ectropion -related exposure can develop. Ichthyosis is a prominent feature in several ge netic disorders, induding SjogrenLarsson, Rud, and Conradi syndromes, congenital keratitis-ichthyosis-deafness (KID) syndrome, Refsum disease, and congenital he midysplasia with ichthyosiform eryth roderma and limb defects (CHILD). Vasculari zi ng ke ratitis is a prominent feature of KID syndrome; it may wo rsen with isotretinoin therapy. Treatment for the ichthyosis spectrum is aimed at hydrating the skin and eyelids, removing scale, and slowing the turnover of epidermis when appropriate. These disorders are not responsive to corticosteroids.
Ectodermal Dysplasia Ectodermal dysplasia is a heterogeneous group of conditions characterized by the following: presence of abnormalities at birth nonprogressive course diffuse involveme nt of the epidermis plus at least one of its appendages (hair, nails, teeth, sweat glands) various inheritance patterns
Ectodermal dysplasia is a rare hereditary condition that displays variable defects in the morphogenesis of ectodermal structures, induding hair, skin, nails, and teeth. It has been observed to be a component in at least 150 distinct hereditary syndromes.
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Many ocular abnormalities have been described in the ectodermal dysplasias, including sparse lashes and brows, blepharitis, ankyloblepharon, hypoplastic lacrimal ducts, diminished tear production, abnormal meibomian glands, dry conjunctivae, pterygia, corneal scarring and neovascularization, cataract, and glaucoma. These changes may be due to limbal stem cell deficiency. Anhidrotic ectodermal dysplasia is characteri zed by hypotrichosis, anodontia, and anhidrosis. Sweating is almost completely lacki ng, and hyperpyrexia is a common problem in childhood. Atopic disease is often an associated fi nding. The ectodactyly-ectodermal dysplasial-clefting (EEe) synd rome is an association of ectodermal dysplasia, cleft lip andl or palate, and a clefting deformity of the hands andlor feet ("lobster claw deformity").
Xeroderma Pigmentosum Xeroderma pigmentosum (XP) is a recessively transmitted disease characterized by impai red ability to repair sunlight-induced damage to DNA. During the first or second decade of life, the patient's exposed skin develops areas offocal hyperpigmentation, atrophy, actin ic keratosis, and telangiectasia-as thou gh the patient had received a heavy dose of radiat ion. Many cutaneous neoplasms appear later, including squamous cell carcinoma, basal cell carcinoma, and melanoma. Ophthalmic manifestations include photophobia, tearing, blepharospasm, and signs and symptoms of KCS. The conjunctiva is dry and inflamed with telangiectasia and hyperpigmentation. Pingueculae and pterygia often occur. Corneal complications include exposure keratitis, ulceration, neovascularization, scarring, and even perforation. Keratoconus, band-shaped nodular corneal dystrophy, and gelatinous dystrophy have also been reported. Ocular neoplasms occur in 11 % of patients, most frequently at the limbus. Squamous cell carcinoma is the most frequent histologic type seen, followed by basal cell carcinoma and melanoma, similar to the cutaneous tumors. The eyelids can be involved with progressive atrophy, madarosis, trichiasis, scarrin g, symblepharon, entropion, ectropion , and sometimes even loss of the entire lower eyelid. Mannis MJ, Macsai MS, Huntley AC, eds. Eye and Skin Disease. Philadelphia: LippincottRaven; 19%3- 12, 39-44,131-145.
Noninflammatory Vascular Anomalies of the Conjunctiva Causes of conjunctival hyperemia include the follOWing: inflammation: infection, allergy, toxicity, neoplasia direct irritation: foreign body, aberrant eyelashes reflex response: eyestrain, emotional wee ping systemic or topical vasodilators: alcohol, oxygen, carcinoid tumor autonomic dysfunction: sympathetic paresis, sphenopalatine ganglion syndrome vascular engorgement: venous obstruction, hyperviscosity Conjunctival vascular tortuosity may result from trauma or from disorders such as rosacea and Fabr y disease that cause chronic conjunctival vascular dilation. Systemic
76 • External Di sease and Cornea
conditions that cause slu dg ing and segmentation of blood flow in conjunctiva l vessels, as well as conjunctival varicosit ies and aneurysms, include hypertension diabetes mellitus sickle cell disease mul tiple myeloma polycythemia vera
Causes of subco njunctival hemorrh age and. less commonly. of bloody tears are listed in Table 3-7 . Hereditary causes of conjunctival telangiectasia and hemorrhage are hereditary hemorrhagic telangiec tasia and ataxia -telang iectasia.
Hereditary Hemorrhagic Telangiectasia Spontaneous hemorrhage from telangiectatic vessels of the palpebral and bulbar conjunctiva may occur in individuals with hered itary hemorrhagic telangiectasia (Rendu-OslerWeber disease), a vascular disorder that also invol ves the skin, nasa l and oral mucous membranes, gastrointestinal tract, lu ngs, and brain. This dominantly in herited (b ut occasionally sporadic) disease is usually not appare nt in early ch ildhood. and its onset durin g early adult life may be subtle. Initial manifestations may be intermittent. painless gastroin testinal bleeding leading to iron deficiency anemia or recurrent ep istax is following min or trauma or occurring spontaneously. Conjunctival hemorrhage may be associated with fo reign-body sensation. and it usually occurs spontaneously or after minor trau ma. such as ru bbing of the eyelids. The hemorrhage may extend into the subepithelial connective tissues or may be external (bloody tears). Conjunctival bleeding can be copious. but in most instances it can be controlled with local pressure. The conjunctival telangiectasias appea r sharpl y circumscribed. are slightly elevated. and are composed of arbori zing di lated channels. Typically. they involve the palpebral region. although lesions of the bulbar conjunctiva have also been reported. Histologic study has shown superficial. dilated. thin-walled vascular channels. Similar findings have been noted in telangiec tat ic lesions of the skin and nasal and oral mucous membranes. It is likely that hemorrhage results fro m minor trauma to these superficial vessels; however. intravascular factors affecting bleedi ng time may also play a role.
lymphangiectasia Lymphangiectasia may be a developmental anomaly or may occur in association wit h trauma or inflammation. Unlike lymphangiomas. which are cellular proliferations of lymphatic
Tabte 3-7 Causes of Subconjunctival Hemorrhage Ocular
Systemic
Conjunctiva l. orbital , or crani al traum a Acute vi ral or bacterial conjunctivitis
Sudden veno us congestion (Va lsalva maneuver) Vascular fragi lity Thrombocytopenia and impaire d clotting Systemi c febri le illness Ocul ar surface neovascularization
Pterygium, pinguecula
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Ocu lar Su rf ace Disease: Diagnostic Approach.
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channel elements, Iymphangiectasias are irregularly dilated, periodically hemorrhage-filled lymphatic channels of the bulbar conjunctiva. Surrounding conjunctival edema or subconjunctival hemorrhage may also be present, especially upon crying or exertion. Treatment is local excision or diathermy. Lymphangiectasia must be distinguished from ataxia-telangiectasia (Louis -Bar syndrome), in which the epibulbar and interpalpebral telangiectasia of the arteries lacks an associated lymphatic component. The conjunctival lesions of Louis-Bar syndrome are a marker for associated cerebellar and immunologic abnormalities (eg, hypogammaglobulinemia), which are conducive to sinopulmonary in fection and lymphoreticular proliferations, particularly T-cell leukemias. The epibulbar vascular lesions do not acquire a tumefactive characteristic (hamartia) because they are simple telangiectasias that grow with the patient and the eyeball. No episodic events of hemorrhage or swelling are encountered. Ataxia-telangiectasia is discussed and illustrated in greater detail in BeSe Section 6, Pediatric Oph thalmology and Strabismus.
Nutrition al and Physiologic Disorders Vi tam in A Deficiency PATHOGEN ESIS Vitamin A is an essential fat -soluble vitamin. Human disease can be caused by too little or too much vitamin A intake. Table 3-8 presents an overview of vitamin A m etabolism. Vitamin A deficiency xerosis (dryness of th e conjunctiva and cornea), associated with loss of mucus production by the goblet cel ls, can occur in epithelial cells of the gastrointestinal, genitourinary, and respiratory tracts. T he ocular consequence is the Bit6t spot, a superficial foamy, gray triangular area on the bulbar conjunctiva that appears in the palpebral aperture (Fig 3-17). This spot consists of keratinized epithelium, inflammatory cells, debris, and Corynebacterium xerosis. These bacilli metabolize the debris and produce the foamy appearance. Vitamin A deficiency leads to xerophthalmia, wh ich is responsible for at least 20,000100,000 new cases of blindness worldwide each yea r. At greatest risk of xerophthalmia are malnourished infants and babies born to vitamin A-deficient mothers, especially infants who have another biological stressor, such as measles or diarrhea. Superficial concurrent infections with herpes simplex, measles, or bacterial agents probably further predispose the child to keratomalacia and blindness. Although xerophthalmia usually results from
-- - - - - --------------
Ta b le 3-8 Meta bolism of Vitamin A Leve l
Meta bo lite
Diet Intestine Portal circulation Liver Target tissues
Plant (carotenoids) and animal (retinyl-palmitate and retinol) foods Retinol -micelle Retinyl-palmitate Retinol-retinol-binding protein Retinoic acid (epithelium, epidermis , and lymphocytes) Retinal (rod photoreceptors)
78 • External Dis.e ase and Co rnea
Figure 3-17 Conjunctival xerosi s with focal kerat inizat ion (Bit6t spot) as a res ult of vitamin A deficiency. (Counesy of Vincem P deluise, MD.)
low dietary intake of vitam in A, decreased absorption of vitamin A may also be responsible. When vitamin A deficiency and xerophthalmia occur in countries with a low rate of malnutrition, the condition is usually caused by un usual self-imposed dietary practices, chronic alcoholism, or lipid malabsorption (particularl y cystic fibrosis, biliary cirrhosis, and bowel resection ).
Nyctalopia (night blindness) is often the earl iest symptom of hypovitami nosis A, but retinal function does not alvvays correlate with anterior segment findings. Xerophthalmic f undus, a rare associated abnormality, features yellow-white spots in the peripheral retina. Prolonged vitamin A deficiency leads to involvement of the external eye, including xerosis, metaplastic keratinization of areas of the conjunctiva (Bitot spots), corneal ulcers and scars, and eventually diffuse corn eal necrosis (keratomalacia). The World Health Organization classifies the ocular surface changes into 3 stages:
CLINICAL PRESENTATION
1. conjunctival xerosis, without (X I A) or with (X I B) Bitot spots 2. corn eal xerosis (X2) 3. corneal ulceration , with keratomalacia involving less than one th ird (X3A) or more than one third (X3B) of the corneal surface
Patien ts with chronic alcoholism mal' present with persistent epithelial defect and corneal ulceration unresponsive to anti microbial therapy. Night blind ness with an abnormal electroretinogram , visual field constriction, and conjunctival xerosis or Bitot spots may be the presenting manifestation of the chron ic malabsorption syndromes just mentioned. Laboratory diagnosis of low serum level of vitamin A or retinol-binding proteins is usually used to confirm the clinical suspicion.
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Systemic vitamin A deficiency, best characterized by keratomalacia, is a medical emergency with an untreated mortality rate of 50%. Although the administration of oral or parenteral vitamin A will address the acute manifestations of keratomalacia, these patients are usually affected by a much larger protein-energy malnutrition and should be treated with both vitamin and protein-calorie supplements. Problems with malabsorption may prevent oral administration from being effective in patients with acute vitamin A deficiency. Maintenance of adequate corneal lubrication and prevention of secondary infection and corneal melting are essential steps in treating keratomalacia, but identification and proper treatment of the underlying causes are vital to successful clinical management of the ocular complications. As a result of the beneficial effects of systemic retinoids in xerophthalmia, studies were undertaken to determine if topical retinoids would be useful in reversing the squamous metaplasia and s),mptoms associated with dry-eye syndromes. Although double-blind, placebo-controlled studies failed to demonstrate the efAcac)' of topical therapy for patients with dry eye alone, subsequent stud ies revealed that topical retinoids were primarily useful in conditions with conjunctival kerati ni zation, such as Stevens-Johnson syndrome, cicatricial pemphigoid, radiation-induced d ry eye, drug-induced pseudopemphigoid. and toxic epidermal necrolysis. Currently, an ophthalmic preparation of topical retinoic acid is not commercially available in the United States. MANAGEMENT
Harris EW, Loewenstein ]1, AZar D. Vitamin A deficiency and its effects on the eye. bzt Oph-
tha/mo/ Ci;II. 1998;38(1): 155-161Sommer A. West KP Jr. Vitam ill A Deficiency: Health, Survival, and \'ision. New York: Oxford University Press; 1996.
Vitamin C Defici ency Ascorbic acid, or vitamin C, is an essential vitamin for humans because we lack its synthetic enzyme, L-gulonolactone oxidase. A major act ion mechanism of ascorbic acid is its effect as a cofactor on the hydroxylation of lysine and proline in ribosomal collagen synthesis. Impairment of hydroxylation secondary to ascorbic acid deficiency results in unstable collagen fiber formation. Following transport through the ciliary epithelium. ascorbic acid is about 15-20 times more concentrated in aqueous humor than in plasma. In scurvy, subconjunctival and orbital hemorrh age may occur. In a vitam in C-deprivation trial extending over approx_imately 3 months. some subjects developed xerosis. In animal studies, scorbutic guinea pig corneas subjected to injury showed impaired wound healing. Animal studies also suggest that the alkali-burned cornea represents a localized scorbu tic state in which adequate collagen cannot be synthesized for stromal wound repair. In rabbit eyes, topical and paren teral ascorbate can restore the ascorbate level in aqueous humor after an alkali burn and Significantly reduce the incidence of corneal ulce r and perforation. A well-controlled, prospective. case-controlled study proving the clin ical efAcacy of topical or systemic ascorbate in humans has yet to be done. Pfister RR, Paterson CA. Ascorbic acid in the treatment of alkali burns of the eye. Ophtlwlmol-
agy. 1980;87( 10): 1050-1 057.
80 • Externa l Disease and Cornea
Structural and Exogenous Disorders Exposure Keratopathy Exposure keratopathy can result from any disease process that limits eyelid closure. Lagophthalmos can be caused by the following:
PATHOGENESIS
neurogenic diseases such as seventh nerve palsy • degenerative neurologic conditions such as Parkinson disease • cicatricial or restrictive eyelid diseases such as ectropion drug abuse blepharoplasty skin disorders such as Stevens- Johnson syndrome or xeroderma pigmentosum
Proptosis caused by thyroid eye disease or other inflammatory or infiltrative orbital diseases can also result in exposure keratopathy. CLIN ICAL PRESENTATION Exposure keratopathy is characterized by a punctate epithelial keratopathy that usually involves the inferior third of the cornea, although the entire corneal surface can be involved in more severe cases. Large, coalescent epithelial defects may result, which may lead to ulceration, melting, and perforation. Symptoms are similar to those associated with dry eye, including foreign -body sensation, photophobia, and tearing, unless there is an associated neurotroph ic component resulting in corneal anesthesia.
Therapy is similar to that desc ribed for severe dry eye. In the earliest stages, nonpreserved artificial tears during the day and ointment at bedtime may suffice. Taping the eyelid shut at bedtime ca n be helpful if the problem is primarily one of noc turnal exposure. The use of bandage contact lenses can be hazardous in these patients because of a high in cidence of des iccat ion and in fection. In cases where th e problem is likely to be temporary or self- limited, a temporary tarsorrhaphy using tissue adhesive or sutures should be performed. However, if the problem is likely to be long-standing, definitive surgical therapy to correct the eyelid position is mandatory. Correction of an y associated eyelid abnormalities, such as ectropion and /o r trichiasis ) is also indicated. Most commonly) surgical management consists of permanent lateral and/or medial tarsorrhaphy. Insertion of gold or platinum weights into the upper eyelid is also an effective technique to promote eyelid closure. Implantation of an eyelid weight does not alter the dimension of the horizontal eyelid fissure and thus creates a less obvious cosmetic change than does a lateral tarsorrhaphy. Reported complications of gold weight implants include in fection, shifting, extrusion, induced ast igmatism, unacceptable ptosis, and noninfectious inflammatory response to the gold. The weights remain stable when exposed to MRI. In cases of paralytic ectropion of the lower eyelid, a horizontal tightening procedure may also be beneficial in correcting the flaccid lower eyelid. See BeSe Section 7, Orbit, Eyelids, and Lacrimal System, for further discussion of lagophthalmos and proptosis.
MANAGEMENT
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Ocular Surface Disease: Diagnostic Approach.
81
Floppy Eyelid Syndrome Floppy eyelid syndrome usually occurs in obese individuals who are often suffering from obstructive sleep apnea and consists of chronic ocular irritation and inflammation. Patients have a flimsy, lax upper tarsus that everts with minimal upward force applied to the upper eyelid. Clinical findings include small to large papillae on the upper palpebral conjunctiva, mucus discharge, and corneal involvement ranging from mild punctate epitheliopathy to superficial vascularization CFig 3-18). Keratoconus has also been reported in patients wit h floppy eyelid syndrome. The problem may result from spontaneous eversion of the upper eyelid when it comes into contact with the pillow or other bedclothes during sleep. Direct contact of the upper eyelid with bed linens may traumatize the upper tarsal conjunctiva, indUCing inflammation and chronic irritation. The condition may be unilateral if the patient always sleeps in the same position. Treatment consists of covering the affected eyeCs) with a metal shield or taping eyelids closed at night or performing surgical eyelid-tightening procedures. Differential diagnosis includes vernal conjunctivitis, giant papillary conjunctivitis, atopic ke ratoconjunctivitis, bacterial conjunctivitis, and toxic keratopathy. See also BCSC Section 7, Orbit, Eyelids, and Lacrimal System. Pham TT, Perry jD. Floppy eyelid syndrome. CUff Opin Ophthalmol. 2007;18(5):430- 433.
Superior limbic Keratoconjunctivitis The pathogeneSiS of superior limbic keratoconjunctivitis (SLK) has not been established, although it is thought to result from mechanical trauma transmitted from the upper eyelid to the superior bulbar and tarsal conjunctiva. An association with autoimmune thyroid disease has been observed .
PATHOGENESIS
• Figure 3-18
Floppy eyelid syndrome with papillary response on superior ta rsus. (Courtesy of
Vincent P deLuise. MO.)
82 • External Disease and Cornea
SLK is a chronic, recurrent condition of ocular irritation and redness. The condition typically develops in adult women 20- 70 years of age. and may recur over a period of 1-10 years. The condition usuall y resolves spontaneously. It is often bilateral, although I eye may be more severely affected than the other. SLK can be associated with ATD or blepharospasm. Ocular findi ngs may include the following: CLI NICAL PR ESENTATION
a fine papillary reaction on th e superior tarsal conjunctiva injection and thickening of the superior bulbar conjunctiva (Fig 3-19A) hypertrophy of the superior limbus fi ne punctate fluorescei n and rose bengal staining of the superior bulbar conjunctiva above the limbus and superior cornea just below the limbus (Fig 3-19B) superior corneal filamentary keratopathy
Hyperprol iferation . acan thosis. loss of goblet cells. and keratini zat ion are seen in histologic sectio ns of the superior bulbar conjunctiva. The condition can often be diagnosed by clinical signs; however. scrapings or imp ression cytology of the superior bulbar co njunctiva showing characteristic features of nuclear pyknosis with "snake nuclei;' increased epithelial cytoplasm-to-nucleus ratio. loss of goblet cells. and keratinization may be helpful in diagnosing mild or confusing cases. Patients with SLK should have thyroid fu nction tests. including T 4 • TSH. and anti thyro id antibody levels. LABORATORY EVA LUATION
A variety of therapies have been rep orted to provide temporary or permanent relief of symptoms. Treatments include topical anti-inflammatory age nts. largediameter bandage contact le nses, superior punctal occlusion, thermocauteri zation of the superior bulbar conjunct iva, resection of the bulbar conjunctiva superior to the limbus, topi cal cyclosporine, autologous seru m eyedrops, and conjunctival fixation sutures.
MANAGEMENT
Sa hin A, Bozkurt B, Irkec M . Topica l cyclosporine A in the treatment of superior limbic keratoconjunctivitis: a long-term follow-up. Cornea. 2008;27(2): 193-195. Theodore FH , Ferry AP. Superior limbic keratoconj unctivitis. Clinical and pathological correlations. Arch Ophthalmol. 1970;84{ 4):481 - 484. Yamada M, Hatou S, Mochizuki H. Conju ncti val fixation sutures for refractory superior limbic keratoconjunctivitis. BrJ OphthalnJOI. 2009;93( 12 ): 1570- 1571. Yang HY, Fujishima H, Toda I , Shima"laki J, Tsubota K. Lacrimal pun cta I occlusion for the treatment of superior limbic keratoconju nctivitis. Am I Ophthalmol. 1997;124(1) :80-87.
A ......_ _
B
Figure 3-19 A, Superior li m bic keratoconjunct iv itis . B, Ro se be ngal dye sta inin g patte rn in superior limbic ke ratoconjunct ivitis. (Courtesy of Vincent P deL uise, MD.)
CHAPTER 3:
Ocular Surface Disease: Diagnostic Approach. 83
Recurrent Corneal Erosion Recurrent erosions typically occur either in eyes that have suffered a sudden, sharp, abrading injury (fingernail, paper cut, tree branch) or in patients with preexisting epithelial basement membrane dystrophy. This condition may also occur more commonly after PRK. The superfiCial injury produces an epithelial abrasion that heals rapidly, frequently leaving no clinical evidence of damage. After an interval varying from days to years, symptoms suddenly recur without any obvious precipitating event. Symptoms subside spontaneously in most cases, only to recur periodically. In contrast to shearing injuries, small superficial lacerating injuries involving the cornea rarely result in recurrent erosions. Poor adhesion of the epithelium is thought to be caused by underlying abnormalities in the epithelial basement membrane and its associated filament network. The precise nature of these abnormalities has yet to be full y determined. Gelatinase activity (MMP-2 and -9) is up-regulated in the epithelium of patients with recurrent corneal erosions. Gelatinases alter the epithelial basement membrane during wound healing by cleaving collagen types IV, V, VII, and X. They also act on the adhesive macromolecules fibronectin and laminin, which are thought to mediate attachment of the basal epithelial cells to the basement membrane. Activation of MMPs on a chronic basis may be either a result of, or the cause of, poor epithelial adherence that leads to the symptoms of recurrent corneal erosion. Some patients with recurrent corneal erosions have been noted to have MGD, and increased levels of MMPs have been observed in the tear film of patients with MGD.
PATHOGENESIS
Recurrent corneal erosions are characterized by the sudden onset of eye pain, usually at night or upon first awakening, accompanied by redness, photophobia, and tearing. Individual episodes may vary in severity and duration. Minor episodes usually last from 30 minutes to several hours; typically the cornea has an intact epithelial surface at the time of examination. More severe episodes may last for several days and are often associated with greater pain, eyelid edema, decreased visual acuity, and extreme photophobia. Minor episodes resolve rapidly; often, when the patient is examined within hours of an acute recurrence, no abnormality is discernible on slit-lamp exam ination. Many patients seem to suffer from ocular discomfort that is out of proportion to the amount of observable pathology. However, slit-lamp examination using retroillumination can frequently reveal subtle corneal abnormalities (eg, epithelial cysts). The corneal epithelium is loosely attached to the underlying basement membrane and Bowman layer, both at the time of a recurrent attack and between attacks when the cornea appears to be entirely healed. During the acute attack, the epithelium in the involved area frequently appears heaped up and edematous. Although no frank epithelial defect may be present, Significant pooling of fluorescein over the affected area is often visible. CLINICAL PRESENTATION
The key to making the distinction between posttraumatic ero sion and dystrophic erosion in a patient who has no clear-cut history of superficial trauma lies in careful examination of the contralateral eye follOWing maximal pupillary dilation. Occasionally, subtle areas of loosely adherent epithelium can be identified by gentle pressure with a surgical sponge follOWing the instillation of topical anesthetics. The presence of basement membrane changes in the unaffected eye implicates a primary basement
LABORATORY EVA LU ATION
84 • Externa l Disease and Cornea
membrane defect in the pathogenesis, whereas the absence of such findings suggests a posttrau matic etiology. Other clinical conditions with associated abnormalities of the epithelial basement membrane include diabetes mellitus and dystroph ies of the stroma and Bowman layer (see also Chapter 10 on corneal dystrophies). MANAGEMENT Traditional the rapy for this condition in the acute phase consists of frequent lubrication with antibiotic ointments and cycloplegia, followed by use of nonpreserved lubricants or hypertonic saline solu tion (5% NaCl) during the day and ointment at bedtime for 6- 12 months to promote proper epithelial attach ment. Hypertonic agents provide lubrication and may transiently produce an osmotic gradient, drawing fluid from the epithelium and theoretically promoting the adherence of epithelial cells to the underlying tissue. Some patients find hyperton ic medications unacceptably irritating, although many others do qu ite well with this therapy indefinitely. Systemic tetracyclines (doxycyline 50 mg bid) and topical corticosteroids (f1uoromethalone 0. 1% tid for 1 month) have been shown to be ve ry efficacious. The mode of action is thought to be via localized inhibition of MMPs. Although use of a therapeutic bandage contact lens may be helpful, proper patient education and judicious monitoring are crucial. The ideal therapeut ic lens should have a flat base curve and high oxygen transmissibility (Dk). New-generation soft contact lenses with surface treatments that decrease bacterial adherence may offer a better safety profile. Concomitant use of a topical broad -spectrum antibiotic 3-4 times daily may reduce the possibility of secondary infection. Ap plication of preservative-free topical ketorolac 4 times daily may improve patient com fort in the first 24 hours. Occasionall y, judicious use of topical corticosteroids is necessary to treat associated secondary keratitis or uveitis. Patients with recalcitrant disease should be trea ted by a stepwise sequence of interventions. When consistent conservat ive management fails to control the symptoms, more invasive surgical therapy may be indica ted. In patients with posttraumatic recurrent erosions, anterior stromal micropuncture can be very effective (Fig 3-20) . Using a specially designed 25-gauge needle with a bent top, the clinician makes numerous superficial puncture wounds in th e involved area, produci ng a firm adhesion between the epithelium and the unde rlying stroma. This procedu re should be used with caution in the visual axis. Rarely is a Significant scar visible for mo re than a few months afte r this procedure. The treatment may need to be repeated in patients who were at first adequately controlled but later become symptomatic, usually because the area of treatment was inadequate. Histologic studies have revealed that the lesio ns produced by this procedure create subepithelial scars. Use of diathermy to create similar lesions in experimental animals has shown that the efficacy of these procedures is related to their ability to stimulate the formation of new basement membrane complexes. In patients with dystrophic, degenerative, or other severe secondary basement membrane disorder-related recurrent erosions, the procedure of choice is epithelial debridement, which can easily be performed at the slit lamp. Following adequate application of topical anesthetic, loosely adherent epithelium is debrided using a surgical sponge, a spatula, or a surgical blade. Care must be taken not to damage the underlying Bowman layer. Light application of an ophthal miC diamo nd burr to Bowman layer in the affected area (outside the vis ual axis) may be effective in reducing recurrences in resistant cases.
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85
Figure 3-20 Anterior stromal puncture. The needle is used to encourage microcicatrization among epithelium, Bowman layer, and stroma . (Reproduced with permission from Kenyon KR, Wagoner MD. Therapy of recurrent erosIOn and persistent defects of the corneal epithelium. Focal POints: Clinical Modules for Ophthalmologists. San Francisco: American Academy of Ophthalmology; 1991. module 9. Illustration by Laurel Cook.)
Because a Significant amount of discom fort can be ex pected for 3- 4 days followi ng this procedure, the patient will likely be more tolerant if debridement is performed at the ti me of a pain ful recur rent episode. Topical anti biotic ointment, cycloplegia, an d, in some cases, bandage contact lenses are used until ree pithelialization is complete. Oral an algesics are often necessary in the fi rst 24 hours. Excimer laser phototherapeutic keratectomy is an alternative moda lity fo r treati ng patients with recalcitrant rec urre nt erosions, partic ula rl y the dystrophic variant. By creating a large, shaJ low zo ne of ab lation, this procedure can minimize the refractive effects; it can be used to correct an associated myopic refractive erro r as well. The mechanism of action of this proced ure for this condition has yet to be established. (See BeSe Section 13, Refractive Surgery, for further discussion.) D ursu n D, Kim Me. Solomon A, Pflugfelder Sc. Treatment of recalcitrant recurrent corneal erosions with in hibitors of mat rix metalloprotei nase-9, doxycycline and cort icosteroids. Am ] Ophthalmol. 2001;132(1 ):8- 13. Reidy lJ, Paulus MP, Gona S. Recurrent erosions of the cornea: epidem iology and treatment. Comea. 2000; 19(6):767-771. Wang L, Tsang H, Caroneo M. Treatment of recurrent corneal erosion syndrome using the combination of oral doxycycl ine and topical corticosteroid. Clin Experiment Ophthalmol. 2008;36(1 ):8 - 12.
Persistent Corneal Epithelial Defect Persistent corn eal epithelial defects are generally related to some underlying disease process. Common causes of these defects incl ude
PATHOGENESI S
• herpeti c corn eal disease
86 • External Di sease and Cornea
delayed postsurgical epithelial healing chemical burns toxicity from topically applied medications recurrent corneal erosions dry-eye syndromes infections neuroparalytic keratopathy neurotrophic keratopathy anterior segment necrosis Persistent corneal epithelial defects are characterized by central or paracentral areas of chronic nonheali ng epithelium that resist maximal therapeutic endeavors. They frequently have elevated, rounded edges and may be associated with significant underlying stromal inflammatio n. Corneal anesthesia is frequently an accompanying sign, and it should always be evaluated. Left untreated, this condition ca n progress to vascularization and corneal opacification or scarring. Alternatively, progressive inflammation can lead to necrosis and thinning of the stroma, occasionally resulting in perforation.
CLINICAL PRESENTATION
The d iagnosis is based on careful history taking, with particular attention to the preservatives present in any ophthalmic medications being administered. The lesions are frequently round or oval epithelial defects with grayish edges that are rolled under without heaped margins. The defects tend to be inferior or inferonasa l and can be associated "'-lith an intense, coarse superficial keratitis. The inferonasal predilection of these lesions may be a result of the area's easy access and the protective effect of Bell phenomenon on the superior cornea. KCS is a frequently accompanying disease. Other associated cond itions include corneal hypoesthesia as a result of previous cataract extraction or keratoplasty and prior herpes zoster or herpes si mplex infections.
LABORATORY EVALUATION
MANAGEMENT Some medications used to treat ocular surface disease and glaucoma may impair epithelial wound healing and result in th e formation of persistent corneal epitheli al defects. The drugs most frequentl y implicated include topical anesthetics; topical nonsteroidal anti-inflammatory agents (1 SA IDs); trifluridine; ~ -blockers; carbonic anhydrase inhibitors; and, in sensitive ind ividua ls, all drops containing the preservative benzalkonium chloride (BAK) . Some auth ors refer to the condition as toxic ulcerative keratopathy. This clinical problem is frequently unrecogni zed and usually presents as a diffuse punctate keratopathy. In some instances, pericentral pseudodentritiform lesions and pseudogeographic defects may occur. These cli nical fi ndings are often miSinterpreted as a worsening of the underlying disease and thus may lead to even larger doses of the offending medication . Frank ulceration and even corneal perforation can result. In addition to removin g the offending stimu lus or aggravating drugs or treating the underlying condition, a number of strategies have been llsed to manage persistent epithelial defects. Pharmacologic therapies have included systemic tetracycline, chosen for its anticollagenolytic effect, unrelated to the drug's antimicrobial properties. Generally, conventional therapies can be effective in promoting closure of the epithelial defect. These include frequent lubrication with nonpreserved ointments and, if
CHAPTER 3:
Ocu lar Surface Disease: Di agnostic Approach •
87
necessary, temporary tarsorrhaphy or permanent lateral canthoplasty to encourage epithelial migration and minimize mechanical trauma from exposure and desiccation. Persistent epithelial defects often occur in patients with diabetic retinopathy following epithelial debridement during vitreoretinal procedu res. Diabetic neuropathy is thought to be a potential cause of neurotrophic keratopath y and nonhealing epithelial defects. For more extensive insults, such as alka li inj uries or other causes of devastating ocular surface trauma , damage to limbal stem cells cannot be overcome by conventional conservative therapies. Various strategies using healthy conjunctiva or limbal stem cells have been used with success in ocular surface reconstruction. (Limbal stem cell dysfunction is discussed at the end of this chap ter; surgery of the ocular surface is covered in Chapter 14.)
Neurotrophic keratopathy Neurotrophic keratopathy results fro m damage to CN V, which causes corneal hypoesthesia or anesthesia . The dam age may be caused by surgical trauma (ablation of the trigeminal ganglion, PK, large limbal incisio ns, LASIK), cerebrovascular accidents, aneurysms, multiple sclerosis, tumors (eg, acoustic neuroma, neurofibroma, or angioma), herpes zoster ophthalmicus, herpes simplex keratitis, Hansen disease (leprosy), or the toxjcity of certain topical medications (a nesthetics, NSAIDs, P-blockers, and carbonic anhydrase inhibitors). Reduction of corneal sensat io n has been encountered with both type 1 and type 2 diabetes mellitus, presu mab ly as a result of prolonged hypoglycemia. Hereditary causes include va rious types of hereditary sensory neuropathy and familial dysautonomia (Riley-Day syndrome) . Animal models have shown that tear-film osmola rity increases following corneal denervation. In addition to the ocular surface fin dings associated with a depressed tearing reflex, an additional mechanism for corneal disease was at work in these animal models, related to the trophic influence of CN V.
PATHOGEN ESIS
As a result of corneal denervation or damage to eN Y, neurotrophic keratopathy generally involves the central or inferior paracentral cornea. Herpes zoster ophthalmicus can lead to a severe neu rotrophic keratopathy. A patient showing other signs of herpes zoster ophthalm iclls should undergo an assessment of corneal sensation to detennine the relative level of risk. Corneal sensation may return to some extent during healing but usually remains permanently de pressed. NeurotrophiC keratopathy resulting from herpes simplex keratitis can result in persistent epithelial defects in the absence of replicating virus or active corneal inflam mation. These epithelial defects stain intensely with fluorescein and are surrounded by raised, rolled-up gray edges (Fig 3-21). Progressive sterile ulceration or superinfection can result in perforation and loss of the eye. Hereditary sensory and autonomic neu ropathy, type 3 (familial dysautonomia, RileyDay syndrome), is an autosomal recessive disorder that occurs almost exclusively in people of Ashkena zi Jewish descent. Clinical features include alacrima, vasomoto r instabiLity, decreased or absent deep tendon reflexes, absence of lingual fungiform papillae with impaired taste, and relative indifference to pain and temperature. Patients exhibit an in creased sensitivity to adrenergiC and cholinergic agents, suggesting functional autonomic denervation. This condition can lead to dramatic, persistent, nonhealing epithelial defects
CLINICAL PRESENTATION
88 • Externa l Disease and Cornea
Figure 3·21
Neurotrophic ulcer. (Courtesy of Kenneth M Goins, MD.)
in infants. Autonomic dysfunction dim.inishes aqueous tear productio n by the lacrimal gland and leads to secondary conjunctival xerosis. Affected individuals frequently develop keratitis ranging in severity from mild punctate stippling of the lowe r portion of the corneal epithelium to frank neurotrophic ulcerations.
Management of persisten t epithelial defects due to neurotrophic keratopathy includes treatmen t of the underlying d isease and use of the full spectrum of approaches outlined earlier in the chapter for dry eye and exposure keratopat hy. It is particularly important to choose ointments or eyedrops without potentially toxic preservatives. such as BAK, for patients with neurotrophic keratopathy. Management of toxic ulcerative ke ratopathy includes discontinuation of the offending agent, patching, and the use of nonpreserved medications. Medications with specific activity against MMPs, such as system ic tetracyclines and topicalmedroxyprogesterone, may help prevent or halt stromal melting in more severe cases. Corneal collagen cross-li nking. early in the course of a melt, has been used in a small number of pat ients and has been very effective. Autologou s serum drops can be very useful in treating neurotrophic keratitis. Recent clinical studies of to pically applied neuropeptides and neurotrophins to treat neurotrophic keratitis have shown promising results. However, these therapies remain experimental at this tim e. Lateral and/or medial tarsorrhaphy is freq uently requ ired to prevent surface desiccat ion. Tarsorrhaphy decreases tear-film evaporation and tear-film osmolarity. presumably by redUCi ng th e surface area of corneal exposure. In rare cases, low-water-content, highly oxygen-permeable therapeutic contac t lenses may be used. PK, although gene rally hazardous in cases of neurotrophic keratopathy, has been used with increasing success in patients with residual scarring from clinicall y inactive herpes zoste r keratopathy. Concomitant lateral tarsorrhaphy and permanent puncta I occlusion appear to improve the long-term survival of the corn eal graft. Surgical fixation of preserved am niotic membrane has been reported to encourage healing of persistent epithelial ulcerations. Partial or total MANAGEMENT
CHAPTER 3:
Ocular Su rface Disease: Diagnostic A pproach . 89
conjunctival flaps will prevent corneal melting, but they should be used as a last resort in order to preserve the eye. Goins KM. New inSights into the diagnosis and treat ment of neurotrophic keratopathy. Ow l Surf 2005;3(2):96- 110. Koj im a T, Higuch i A, Goto E, Matsumoto Y, Dogru M, Tsubota K. Autologous seru m eye drops fo r the treatment of dry eye diseases. Cornea. 2008;27(Suppi I ):S2S- S30. Muller Lj, Marfurt CF, Kruse F, Tervo TM. Corneal nerves: stru cture, contents and function. Exp Eye Res. 2003;76(5):521-542. Schnitzler E, Sport £, Seiler T. Irradiation of cornea with ultraviolet light and riboflavin administration as a new treatment for erosive corneal processes, preliminary results in four patients. Klill Monatsbl Augenheilkd. 2000;217(3): 190- 193.
Trichiasis and Distichiasis
Trichiasis refers to an acquired condition in which eyelashes emerging fro m their normal anterior origin are curved inward toward the corn ea. Most cases are probably the result of subtle cicatricial entropion of the eyelid margin . Trichiasis can be idiopath ic or secondary to chronic inflam matory conditions. Distichiasis is a co ngenital (often autosomal dominant) or acquired condit ion in which an extra row of eyelashes emerges from the ducts of meibomian glands. These eyelashes can be fine and well tolerated or coarser an d a threat to corneal integrity. Aberrant eyelashes emerge from the tarsus as a result of chronic inflam matory conditions of the eyelids and conjunctiva such as trachoma, ocular cicatricial pemphigoid, Stevens-Johnson syndrome, chronic blepharitis, or chemical burns. Aberrant eyelashes and poor eyelid positio n and movement should be corrected. Aberrant eyelashes may be removed by epilat ion, electrolysis, or cryotherapy. Mechanical epilation is temporary because the eyelashes will normally grow back within 2-3 weeks. Electrolysis works well only for removing a few eyelashes, although it may be preferable in younger patients fo r cosmetic reasons. Cryotherapy is still a common treatment for aberrant eyelashes, but freeZi ng can result in eyelid margin thinning, loss of adjacent normal eyelashes, and pe rsistent lanugo hairs that may continue to abrade the cornea. Treatment at - 20 o e should be lim ited to less than 30 seconds to minimize complications. The preferred surgical technique for aberrant eyelashes is a tarsotomy with eyelid margin rotation. For further disc ussion, see BeSe Section 7, Orbit, Eyelids, and Lacrimal System. Factitious Ocular Surface Disorders Factitious disorders include a spectrum of self-induced injuries with sym ptoms or physical findings inte ntiona lly produced by the pat ien t in order to assume th e sick rol e. Factitious conjunctivitis usuall y shows evidence of mecha nica l injury to the inferio r and nasal quadran ts of the cornea and conjunctiva. The areas of involvement show sharply delineated borders. Patients often have medical training or work in a medical setting, an d they generally shO\.I/ an att itude of serene indiffere nce. The detached conjunctival tissues usually show no evidence of inflam mation by pathologic examination. Other types of noncorneal factitious ocular disorders include self-induced solar reti nopathy, eyelid ulceration, and an isocoria.
90 • Externa l Disea se and Corn ea
Mucus-fishing syndrome
Mucus-fishing syndrome is charac terized by a well-circumscribed pattern of rose bengal or lissamine green staining on the nasal and inferior bulbar conjunctiva. All patients have a history of in creased mucus production as a nonspecific response to ocular surface damage. The incitin g event is typicall y KCS. Patients usually demonstrate vigorous eye rubbing and compulsive removal of the m ucus strands from the fornix (m ucus fi shing) . The resultant epithelial injury heightens th e ocular su rfa ce irritation, which, in turn, stimulates additio nal mucus production) resulting in a vic io us cycle. Topical anesthetic abuse Clinical application of topical an esthetics has become an integral part of the modern practice of ophthalmology. However, ind iscriminate use of topical anesthetics can cause serious ocul ar surface toxicity and com plications. Local anesth etics are known to inhibit epithelial migration and division. Loss of microvilli, reduction of desmosomes and other intercellular contacts, and swelling of mitochondria an d lysosomes have been reported in ultrastructural stud ies. The cl inical features of anesthetic abuse are charac teri zed by the failure of the presenting conditi o n, such as corneal abras ions or infectio us keratitis, to respond to appropriate therapy. In itiall y, a punctate keratopath y is seen. As the ab use continues, the eye becomes more injected and epithelial defects ap pear or take on a ne urotrophic appearance. As the process goes on, keratic precipitates and hypopyon develop, th us mi micking an in fectious course. Diffuse stromal edema, dense stromal infiltrates, and large ring opaci ty are common presenting signs (Fig 3-22). Stromal vascularization may take place in ch ro nic abuse, and secondary infection may ensue. Because of the presence of corneal infiltrates and anter ior segment inflammation, infectious keratitis must be ruled out through corneal scraping, culture, or biopsy. Differential di agnosis includ es bacterial, fu ngal, herpetic, and amebic keratitis. Suspicion should be maintained in the face of negative cultures in any patien t who is not responding to appropriate therapy. Often the diagnos is is made only when the patient is discove red concealing the anestheti c drops. Once the diagnOSiS is made and infectious keratitis is ruled o ut, corneal healing usually occurs if all exposure to anesthetics is removed. In advanced cases, permanent corneal scarr ing or perforation may occur. OccaSionally, anesthetic abuse may continue after surgery. Psych iatric counseling is sometimes helpful.
Dellen Desiccation of the epithelium and subepithelial tiss ues occurs at or near the limbus adjacent to su rface elevations such as those produced by pterygia, large mtration blebs, or dermoids. Because the tear fil m is interrupted by these surface elevations, normal bli nking does not wet the involved area properly. Clinically, del/en are saucerlike depressions in the corneal surface. The epithelium exhibits punctate irregularities overlying a thinned area of dehydrated corneal stroma. Treatment \\l ith frequent ocular lubricat.ion o r pressure patch ing accelerates the healing process and restores stromal hydration.
CHAPTER 3:
Ocular Su rface Disease: Diagnostic A pproach . 91
Figure 3-22 Topical anesthetic overuse with persistent corneal epithel ial defect and necrotic ring opacity. (Courtesy of Kirk A. Wilhelmu$, M O,)
The orbital and conjunctival tissues surrounding the sclera also playa role in maintaining scleral hydration. This func tion becomes especially evident during surgical procedures, when the conjunctiva and extraocular muscles are removed from th e scleral surface. The exposed sclera becomes thinner and partiall y translucent unless it is continually remoistened. Removal of the perilimbal conjunctiva and interference with the \vetting effect of the tear film (as after excision of a pterygium by the bare sclera technique) can cause the underlying sclera to become markedly thinned and translucent, forming a scleral delle.
Ocular Surface Problems Secondary to Contact Lens Wear
Metabolic epithelial damage Contact lens overwear syndromes can be manifested in several forms. Ce ntral epithelial edema (Sattle r veil) is found after many hours of wear, more commonly wi th hard contact lenses. This epitheli al edema causes blu rred vision that may persist for many hours or even progress to acute epithelial necrosis. Although acute epithelial necrosis is rarely seen, central epithelial edema can create epithelial erosions or frank ulceration. Physiologic stress as a resu lt of hypoxia with lactate accu mulation and impaired carbon dioxide efflux is responsible for these complications. Microcystic epitheliopathy, another condition caused by impaired metabolic activities in epithelium, shows fi ne epithelial cysts best seen with retroilluminat ion. This condition has been observed most commonly in patients using extended-wear soft contact lenses. The cysts may either be asymptomatic or cause recurrent brief episodes of pain and epiphora. It takes up to 6 weeks following discontinuation of contact lens wear for the cysts to resolve.
92 • Externa l Disease and Cornea
Toxic conjunctivitis Conjunctival injection, epithelial staining, punctate epithelial keratopathy, erosions, and microcysts are all potential signs of conjunctival or corneal toxicity from contact lens solutions. Any of the proteolytic enzymes or chemicals used for cleaning contact lenses, or the preservative-containing soakin g solution, can be the culprit. Cleaning agents such as BAK, chlorhexidine, hydrogen peroxide, and other substances used for chemical sterilization , if not properly removed from contact lenses, can cause an immediate, severe epitheliopathy with accompanying pain. See Chapter l 3.
Allergic reactions The preservative th imerosal can produce a delayed hypersensitivity response, resulting in conjunctivitis, keratitis with epithelial involvement, and even coarse epithelial and subepithelial opacities. Thimerosal may also be implicated in contact lens-induced SLK. T he ocular signs of this disorder include injection of the superior bulbar conjunctiva, epitheliopathy of the cornea and conjunctiva, papillary conjunctivitis, and some superficial pannus. This condition has declined in prevalence, probably as a result of the replacement of thimerosal by other preservatives in contact lens solutio ns.
Neovascularization Neovascular ingrovvth into the peripheral cornea (micropannus) is common in soft contact lens wearers. Less than 2 mm of such growth is believed to be acceptable; contact lens wear should be discontinued if the neovascularization extends farther than 2 mm into the cornea. SuperfiCial pannus is rarely associated with hard or rigid gas-permeable (RGP) contact lens wear but is encoun tered more frequently in patients using soft lenses. This type of neovascularization is probably caused by hypoxia and chronic trauma to the li mbus, which leads to the release of angiogenic mediators. Other causes of pannus such as staphylococcal or chlamydial keratoconjunctivitis should be considered in the presence of appropriate accompanying signs. Deep stromal neovascula rizat ion has been associated with extended-wear contact lenses, espeCially in aphakia. This condition is not usually symptomatic unless there is secondary lipid deposition . Deep neovascu larization of the cornea is often irreversible and is best managed by discontinuing contact lens wear and resorting to other alternatives, such as spectacle correction. Stein RM, Stein HA. Corneal complicat ions of contact lenses. Focal Points; Clinical Modules Jor
Ophthalmologists. San Francisco: American Academy of Ophthalmology; 1993, module 2.
Limbal Stem Cell Deficiency The ocular surface is composed of permanently renewing populations of epithelial cells. These epithelial cells are replaced th rough proliferation of a distinct subpopulation of cells known as stem cells. The corneal stem cells are located in the basal cell layer of the limbus, whereas the conjunctival stem cells may be uniformly distributed throughout the bulbar surface or located in the fornices. Stem cells have an unlimited capacity for self-
PATHOGENESIS
CHAPTER 3: Ocu lar Surface Disease: Diagno st ic A pproach. 93
renewal and are slow cycling (low mitotic activity) . Once stem cell differentiation begins, it is irreversible. The process of differentiatio n occurs by means of transit amplification. Transit-amplifying cells, which have a limited capacity for self-renewal, can be fou nd at the limbus as well as at the basal layer of the corneal epithelium. Each of these cells is able to undergo a finite nu mber of cell divisions. Corneal and conjunctival stem cells can be identified only by indirect means, such as clonal expansion and identification of slow cycling. Approximately 25%-33% of the limbus must be intact to ensure norm al ocular resurfaCing. The norrnallimbus acts as a barrier against corneal vascularization from the conjunctiva and invasion of conjunctival cells from the bulbar surface. When the limbal stem cells are congenitally absent, injured, or destroyed, conjunctival cells migrate onto the ocular surface, often accompanied by superficial neovascularization. The absence of limbal stem cells reduces the effect iveness of epithelial wound healing, as evidenced by compromised ocular surface integrity with irregular ocular surface and recurrent epithelial breakdown. See Table 3-9 for an etiologiC classification oflim bal stem cell deficiencies.
Table 3-9 Etiologic Classification of limbal Stem Cell Deficiency 1. Idiopathic 2. Trauma Chemical/thermal burns 3. Iatrogenic A. Local i. Surgery Multiple ocular surface operations Cryothe ra py ii. Radiation and radiotherapy iii. Contact lens use iv. Local chemotherapy (eg , anti metabolites such as 5-fluorouracil, mitocycin C) B. Systemic i. Medications: hydroxyurea ii. Graft-vs-host disease 4. Autoimmune Stevens-Johnson syndrome Ocular cicatrical pemphigoid 5. Eye disease Neoplasia and degeneration (eg, pterygium) Neurotrophic ke ratitis Infections (eg, herpetic, trachoma ) Atopy Peripheral corne al ulcers (eg, Fuchs margina l keratitis) Anterior segment ischemic syndrome 6. Congenital and hereditary Aniridia Multiple endocr ine neoplasia Ectodactyly-ectodermal dysplasia -clefting syndrome KID (keratitis-ict hyosis-deafness) syndrome (due to mutations in the GJB2 gene coding for connexin -26 Xeroderma pi gm entosa LADD (/acrimo-auriculo-dento -digital) syndrome/Levy-Hollister syndrome)
94 • Extern al Disease and Co rn ea CLIN ICAL PRESENTATION Clinically, stem cell defiCiency of the cornea can be observed in several ocu lar surface disorders. Patients usually suffer from recurrent ulceration and decreased vision as a result of the irregular corneal surface. Corneal neovascularization is invariably present in the involved cornea. A wavelike irregularity of the ocular surface emanating from the limbus can be more easily observed following the installation of topi ~ cal fluo rescein (Fig 3~23 ) . In some cases, increased epith elial permeability can be observed clinically by diffuse permeation of topical fluorescein in to the anterior stroma. Stem cell defiCiency states res ul t from both prim ary and secondary causes. Primary causes include congenital ani ri di a, ectodermal dysplasia, sclerocornea, KID syndrome, and congenital erythrokeratoderm ia. Secondary causes include chemical burns, thermal burns, contact lens wear, ocular surgery, and chronic cicatricial conjunctiv itis (cicatricial pemphigoid, trachoma, Steve n s~J oh nson synd rome), pterygia, and dysp last ic or neoplas~ tic lesions of the limbus.
Impress ion cytology of the involved corneal surface usually shows the presence of goblet cells and conjunctival epithelium. There are no practical diagnostic tests for Iimbal stem cell defiCiency at this time; however, it is li kely that such tests will be developed in the fu ture.
LABORATORY EVALUATION
Replacement of stem cells by limbal transplantation seems to be the logi~ cal choice for ocular surface reconstruction in diseases associated with limbal stem cell defiCiency. When the limbus is focall y affected in 1 eye, as with a pterygiu m, a limbal or conjunctival autograft can be harvested from the ipsilate ral eye. For un ilateral moderate or severe chemical injuries, a li mbal autograft can be obtained from the healthy fellow eye. For bilateral limbal defiCiency, as with Stevens~ Jo hnson syndrome or bilateral chemical burns, a li mbal allograft fro m an H LA~matched living related donor (o r, if unavailable, an eye bank donor eye) can be considered. SystemiC immune suppression is re quired follow~ ing limbal allograft transplantation. Dramatic restoration of the ocular surface with limbal reconstruct ion has been reported in selected cases with desperate clinical situations. (See the discussion of ocular surface surger y in Chapter 14.)
MANAGEMENT
Fi gure 3·23 Stem cell deficiency. A wavelike irregularity of the ocular surface is seen fo llowing Installation of topical fluorescein . (CounesyofJamesJ. Reidy. MD.}
CHAPTER
4
Infectious Diseases of the External Eye: Basic Concepts and Viral Infections
Defense Mechanisms of the External Eye The external eye contains diverse tissues intricately linked to protect aga inst infection. The ocular adnexa-periorbita, eyelids and lashes, lacrimal and meibomian glands- produce, spread, and drain the preocular tear film, physica ll y protect the sensitive ocular mucosa, and cushion the globe. Lymphoid tissues withi n the conjunctiva, lacri mal glands, and lacrimal drainage tract furn ish acqui red immune defense. The bony orbit and eyelids protect the eye fro m external injury. Normal eyelid position and function prevent desiccation of the ocular su rface and promote tear turnover by periodic closure. Eyelid blinking pumps tears from the lacrimal gland onto the ocular surface and into the lacrimal sac. Tear turnover dilutes and removes microbes from the tear fil m. In addition, solubl e macromolecules secreted by the lacrimal gland exert an timicrobial properties:
• Tear lysozyme degrades bacterial ceJl wa Jls, while terial plasma membranes.
~-lys in
in the tears d isrupts bac-
Tear lactoferrin inhibits bacterial metabolism by scavenging free iron, augments tear antibody fun ction , and may influence complement activation.
Immunoglobulins in the tear film , particularly secretor y IgA, mediate antigen specifi c immunity at the ocular surface. Components of both the classic and alternative complement pathways are also fo und in the tear film . • Meibomian gland- deri ved lipids reduce evaporation of the tear film and indirectly protect the corneal epithelium from desiccation and injur y. Mucin expression by ocular surface cells as well as goblet cell- derived mucin inhibits attachment of microbes to ocular surface epithelium.
Cytokines, including epidermal gro,,1h fac tor (EGF), transform ing growth factor betas (TGF-~ s), and hepatocyte growth factor (HGF) are present in the tears. The contribution of these cytokines to ocular su rface defense is a promising area of basic investigat ion.
BCSC Section 2, Funda mentals and Pri nciples of Ophthalmology, discusses the biochemistr y and metabolism of the tear film and cornea in detail.
95
96 • External Disease and Cornea Lamberts OW. Physiology of the tear film. In: Foster CS, Azar OT, Dahlman CH, eds. Smolin and Thoft's The Cort/ea: SCientific FOllndatio1lS and Clinical Practice. 4th ed. Philadelphia: Lippincott Williams & Wilkins; 2005:577 - 599.
Pflugfelder SC, So lomon A, Stern ME. The diagnosis and management of dry eye: a twentyfive-year review. COrl/ea. 2000;19(5):644-649.
The epithelium of the ocular su rface forms a mechanical barrier against microbial invasion. Phagocytosis and subsequent digestion of bacteria, combined with rapid cycling of epithelial cells, aid in the removal of microbes. Antigen-presenting cells such as Langerhans cells in the conjunctiva carry antigen to regional lymphatic tissue and facilitate an acquired immune respo nse. In response to microbial invasion, ocul ar su rface epithelial cells secrete interleukin- I (IL-I) and other cytokines that boost the local immune response th rough the enhancement of immune-cell migration, adhesion, and activation. Human conju nctiva contains a complete spectrum of immunologically competent cell types. Un infected conjunctival epithelium possesses CDS+ cytotoxic/suppressor T lymphocytes and Langerhans cells. Conjunctival substantia propria contains CD4+ helper T cells and CDS+ T cells in roughl y equal numbers, along with natural killer T cells, mast cells, B lymphocytes, plasma cells, macrophages, and occasional polymorphonuclear leukocytes. Hyperplasia of conjunctival lymphoid follicl es and painful swelling of draining preauricular lymph nodes accompany conjunctival infection by viruses, Chlamydia, and Neisseria species. The vascu lar and lymphatic channels of the conjunctiva transport humoral and cellu lar immune components to and from the eye. Duri ng an infection, infla mmatory mediators promote vascular dilation, permeability, and diapedesis from conjunctival blood vessels. The healthy cornea has classically been considered devoid of leukocytes, but activated Langerhans cells and other dendritic cells normally present in the peripheral corneal epitheli um can migrate rapidly to the central cornea. Upon infection, the constitutive cells of the cornea, the keratocytes in particular, augment the inflammatory cascade by the secretion of proinflammatory cytokines. Lymphocytes and Ileutrophil s are recruited into the cornea from th e tear film , the limbal vascular arcades, and the anterior cham ber. For a more extensive, illustrated discussion of ocular immunology, see BeSe Section 9, Intraocular Inflammation and Uveitis.
Normal Ocular Flora Bacterial colonization of the eyelid marg in and conjunctiva is normal and beneficial for the eye. Interactions between ocular surface mucosa and resident nonpathogen ic bacteria redu ce opportunities for pathogenic st rains to gain a foothold. The spectrum of normal ocular Oora varies with the age and even the geographic locale of th e host. Following vaginal birth, the infant's eye commonly harbors multiple bacterial species, including Staphylococcus aureus, 5 epidermidis, streptococci, and Escherichia coli. During the first 2 decades of li fe, streptococci and pneumococci predomi nate. With increasing age, gram-negative bacteria are more commonly isolated, but the most commonly isolated bacteria remain S epidennidis and other coagulase-negative staphylococci, S aureus, and diphtheroids
CHAPTER 4:
Infectious Diseases/Externa l Eye : Basic Concepts and Viral Infections •
97
Table 4·' Relative Prevalence of the Norm al Flora of the Oute r Eye Microorgani sms Staphylococcus epiderm idis Staphylococcus aureus Micrococcus spp Corynebacterium spp (diphtheroids ) Propionibacterium acnes Streptococcus spp'" Haemophilus influenzae* Moraxella spp Enteric gram -negative bacill i Bacillus spp Anaerobic bacteria Yeasts (Malassezia furfur, Candida spp, etc) Filamentous fung i Demodex spp
Normal Conjunctiva
Norm al Eyelid Margin
+++ ++ + ++ ++
+++ ++ ++ ++ ++
+
±
±
± ± ±
+
± +
± ++
"'More common in ch il dre n.
(Table 4· 1). Under the appropriate culture conditions, Propioniba cterium acnes, Malasse· zia furfu r, and Ca ndida species may also be cultured from the eye. The parasites Demodex folliculorum and Demodex brevis are detected on the eyelid margins of normal healthy individuals and, with advancing age, become almost ubiquitous. Clinically, the use of antibiotics or topical corticosteroids, or a condition such as dry eye that prevents normal tear turnover, may alter the spectrum of eyelid and conjunctival flora. Osato MS. Normal ocular flora. In: Pepose JS, Holland GN , Wilhe1mu s KR, eds. Ocular Infection and Immunity. St Louis: Mosby; 1996: 191- 199.
Pathogenesis of Ocu lar Infections Infection of the ocular surface can follow transp lacental passage of the pathogen to the fetus; direct contact in the birth canal during delivery; exposure to fomites, fingers, airborne particles, or sexual contact; hematogenous seeding (rare); extension from contiguous adnexal disease; and spread from the upper respiratory tract through the nasolacrimal duct. The acquisition of infection is enhanced by circumstances that facilitate contact with the pathogen . Epidemic adenoviral conjunctivitis develops after mucosal contact with secretions from an infected person. Sexually transmitted ocular infections such as gonococcal and chlamydial conjunctivitis are spread thro ugh ocular contact with infected genital secretions during sexual activity. Zoonotic infections such as cat -scratch disease and Lyme disease are transmitted by contact with an infected animal host or vector. The risk of opportunistic infection by environmental pathogens may be enhanced by use of chemically disinfected but not fully sterilized surgical instruments (Mycobacterium chelonei), use of homemade saline or tap water for contact lens hygiene (Acanthamoeba), or trauma with sailor vegetable matter (Bacillus cereus, various fungi). The initiation, severity, and characteristics of subsequent infection are influenced by the interplay between the virulence
98 • External Disease and Co rn ea
of the pathogen, the size of the inoculum, and the competence and nature of host defense mechanisms. Virulence Successful infection of ocular tissues requires microorganisms to adhere, evade, invade, replicate, and, in some instances, persist. Microbial virulence factors represent evolution~ ary adaptations by each microorganism that increase the odds of infection and organism survival. Adherence
For ocular surface infections acquired externally, ad herence of organisms to ocular surface epithelium is the first step. Many bacteria express adhesins, which are microbial proteins that bind with high affinity to host cell surface molecules. Candida albicans expresses surface proteins that mimic mammalian integrins (transmembrane proteins that mediate cell-cell and cell-extracellular matrix interactions). Vir uses typically express surface proteins or glycoproteins that attach to constitu~ tive cell surface molecules such as heparan sulfate (herpes simplex virus) or sialic acid (adenovirus). Evasion
Adhere nt bacteria evade interaction with unfavorable elements of their phYSical environment, such as immunologic cells or antibacterial molecules in the tears, by the expression of exopolysaccharides organized into a biofUm, a 3-dimensional structure that allows 1nterbacterial communication and Signaling and interferes with phagocytosis. For viruses, evasion of the immune response involves multiple strategies. For example, a he rpes sim plex virus (HSV)-encoded protein (eg, ICP47) successfully competes with antigenic viral peptides for transport into the endoplasmic reticulum, where peptides are loaded onto the majo r histocompatibility (MHC) complex. Thus, HSV-infected cells can be resistant to lysis by cytotoxic T cells. vVatn ick P, Kolter R. Biofilm, city of microbes. J Bacterial. 2000;182{10):2675- 2679 .
In vasion
Few bacteria can overcome intact epithelium. Those that can include Neisseria gonorrhoeae Neisseria meningifidis Corynebacterium diphtheriae Shigella spp
Most bacteria must rely on a break in the epithelial barrier function. Microbial invasion may be facilitated by microbial prot eases that induce cell lysis and degrade the extracellular matrix. Bacterial exotoxins, such as those produced by streptococci, staphylococci, and Pseudomonas aeruginosa, can induce corneal cell nec rosis. Acanthamoeba species and certain fungi secrete collagenases, whereas Pseudomonas elastase and alkaline
CHAPTER 4:
Infecti ou s Diseases/Externa l Eye: Basic Concepts and Viral Infections . 99
protease destroy collagen and proteoglycan components of the cornea an d degrade immunoglobuli ns, com plement, interleukins, and ot her inflammatory cytokin es. Microbial proteases also activate corneal mat rix- derived metalloproteinases (MM Ps) that in turn participate in autodigestion . For viruses, ad herence interactions facilitate invasion by the appropriation of host cell mechanisms. For exa mple, the interaction between adenovirus capsid proteins an d host cell integrins med iates internalization of th e adenovirus by means of an intracell ular signaling cascade that culrn inates in actin polymerization and endocytosis of th e virus.
Replication and persistence Most organism s are cleared from the site of infect ion following acute in fec tion. Some microorganisms persist in the host indefin itely. For example, foLlowi ng p rimary infection, HSV and varicella-zoster virus (VZV) establish latency in trigem inal ganglio n cells. Chlamydia survives and causes local chronic d isease by persistence with in int racellular phagosomes. Biofilm fo rm ation by streptococci within the corneal stroma in hibits recognition of the bacteria by the im mune system and accounts for the relative paucity of inflammation and t he ch ro nic natu re charac teristic of crystalline ke rato pathy, \vhich is caused by this orga nis m. Inoculum Different species and strains of microorgan isms vary intrinsically in th eir capacity to induce infection in th e host. For example, expe ri mental bacterial keratit is in an animal model can be established with an inoc ulum of P aeruginosa smaller tha n t hat required of S aureus. The status of host defense m echanisms further deter m ines t he threshol d of inoculum at which infection occurs.
Host Defense
Intrinsic anatomical mechanisms Intrinsic anatomical mechanisms may pred ispose the eye to infectio n, including the following: Desiccation of the ocular surface epitheliu m mal' result from lagophthalmos, ect ropio n, exophthalmos, a reduced bli nk reflex due to parkinsonism, and keratoconjunctivitis sicca. Microtrau ma to th e epithelium occurs with t richiasis. contact lens wear, use of an ocwar prosth esis, prolonged or intense ad ministration of preservative-containing topical med icati ons, and exposure to a free su rgical suture. Acute traumatic abrasion, bullous ke ratopathy, recurrent corneal erosio n, recurrent epithelial d isruption second ary to co rn eal epithelial and ante ri or stromal dystrophies, retai ned foreign body, or corn eal surgery similarly ca n predispose to infection . Persistent epithelial defects due to neu rotroph ic mechanisms such as postherpetic hypoesthesia, d iabetic neuropathy, or traum atic injury to eN v also mal' precede microbial keratitis.
100 • External Disease and Cornea
Any surgery in which the conj unctival epithelium is disrupted, including strabismus and cataract surgery, can lead to infection of the conjunctiva and the underlying scleral wound.
Immunologic competence Local or systemic immune compromise predisposes to ocular in fection . The use of topical cort icosteroids is a freq uent contributing facto r in the pathogenesis of postoperative infections. Preexisting corneal or conjunctival pathology may cause structural and func tional alterations that affect normal tissue responses to injury, inflammation, or infection. The propensity for development of ocular infection also increases "'lith systemic immune compromise in hosts with acquired immunodeficiencies such as those with AIDS and other chronic debilitating diseases or those on systemic chemotherapy; in such patients, normall y nonpathogenic organisms may cause disease. O'Brien TP, Hazlett LD. Pathogenesi s of ocular infect ion . in: Pepose JS, Holland GN, Wil-
helmu, KR, eds. Ocular Infectioll alld Immunity. St Louis: Mosby: 1996:200-214.
Ocular Microbiolo y Of th e many potentiall y pathogenic microorganisms capable of causing infectious ex ternal eye disease, those encountered most often are listed in Table 4- 2.
Diagnostic Laboratory Techniques The decision to procure clinical specimens fo r culture. antigen detection, or special chemical stains is based on the likelihood of benefit to the patient's condition. Interpretation of diagnostic specimens requires an understanding of the normal flora and cytology of the ocular surface. Appropriate materials should be available for optimal specimen collection (Table 4-3). The reader is encouraged to also review the discussion of specimen collection and handling in BCSC Section 4, Ophthalmic Path ology and Intraocular Tumors.
Specimen Collection and Culturing
Eyelid specimens Eyelid vesicles or pustules may be opened with a sharp-pointed surgical blade or smallgauge needle. Material for cytology is smeared onto a glass slide and fixed in methanol or acetone for immunofluorescent stain ing. Collected vesicular fluid can be inoculated into a chilled viral transport medium for culture isolation in the laboratory. Microbial cultures are obtained by swabbing the abnormal area with a thioglycollate-moistened swab fol lowed by direct inoculation of culture media.
Conjunctival specimens Specimen collection must debride enough surface conjunctival epithelial cells so that intracellular microbes can be seen on chemical stains. Sterile Dacron swabs slightly
CHAPTER 4:
Infectious Diseases/Exte rn al Eye: Basic Concepts and Viral Infections •
Table 4-2 Principal Causes of External Ocular Infections Condition
Viruses
Bacteria
Dermatob lepha riti s
Herpes simplex
Staphylococcus aureus Streptococcus spp
Varicella-zoster Blepharitis
Herpes simplex Molluscum contagiosum
Staphylococcus spp Moraxella spp
Conjunctivitis
Adenovirus
Chlamydia trachomatis Staphylococcus aure us Streptococcus spp Neisseria gonorrhoeae Haemophilus influenzae Moraxella spp
Herpes simplex
Keratitis
Herpes simplex
Dacryoadenitis
Epstein-Barr virus Mumps
Canaliculitis Dacryocystitis
Pseudomonas aeruginosa Staphylococcus aureus Staphylococcus epidermidis Streptococcus pneumoniae Moraxella spp
Fungi
10 1
- --
---
Parasites
Phthirus pubis
Fusarium spp
Acanthamoeba spp
Aspergillus spp Candida albicans
Staphylococcus aureus Streptococcus pneumoniae Actinomycetes Staphylococcus spp Streptococcus spp
Table 4-3 Materials for Collecting Eyelid, Conj unctival, and Corneal Specimens for Ocu lar Microbiology
--
Viral Infections
Chlamydial lnfections
Microbial Infections
Topical anesthetic Dacron swabs
Topical anesthet ic Dacron swabs
Spatula Glass slides Acetone fixative Viral transport medium Ice
Spatula Glass slides Methanol or acetone fixat ive Chlamydial transport m edium Ice
Topical anesthetic Calcium alginate or Dacron swabs Spatula Glass slides Methanol fixative Blood agar plate Chocolate agar plate Sabouraud's dextrose agar plate
102 • Externa l Djsease and Co rn ea
mo istened with thi oglycollate broth may be used to optimize recovery of microbial specim ens. The swabbed material sho uld init ially be plated di rectly onto warmed solid media (blood, chocolate, and Sabouraud's) . Then the "non hand led" d istal end of th e swab may be broken off and placed d irectly into the remaini ng thiogl ycollate broth tube. If these media are not available, specimens should be harvested with any standard culterette tub e sys tem th at contains appropriate transport media. The specimen should be sent immediately to any qu ali fied microbiology laborator y for pro cessing. Co njun ctival biopsy can also be perfor med to help in the di agnosis of conditio ns such as Par inaud oculoglandular syndro me or cicatri cial pemphi goid.
Corneal specimens A cornea l cultu re is indicated in sight· threateniJ1g ulcers (> 1- 2 mm), in ulcers in which an atypical organ ism is suspected, and in any u lcer that is not respo ndi ng to therapy. A microbi al specimen can be collected fro m a corneal ulce r by scrapi ng the lesion with a plat inum Kim ura spatula, sterile needl e, surgical blade, or th ioglycollate-moistened calcium al ginate or Dacron swab. A blade or spatula is preferable for preparing smears for chemkal staining, but either a spaLula or swab is acceptable for inoc ulatio n of culture media; a combination of techniques may provide add ed benefit when few microorganism s are present. Furth ermore, because growth pattern s on culture media vary amo ng different bacteria l species, the material obtained fro m the corn eal ulcer sho uld be used to ino culate m icroscope slides for stajned smears and several d ifferent culture med ia. Specilnens are best inocul ated im med iately on to m icrobiologic media that have been warmed to room te mpera ture in an ticipation of the cul ture procedu re. To avoid contaminat ion and false positives, care must be take n to avoid touch ing the blade or swab to the eyelids, an d a sterile instru ment or swab should be used for each row of C-shaped streaks on each agar plate (Fig 4-1) and for each type of broth cul ture. For a viral culture, a Dacron swab used to obtain viral·i nfected co rn eal or conjun cti val cells is ag itated in a
Figure 4-1
"c" streaks on a chocolate blood agar plate. (CourresyofJamesChodosh, MD.)
CHAPTER 4: In fectio us Di seases/ External Eye: Basic Concepts and Vira l Infections • 103
chilled viral transport medium and discarded. Calcium alginate and cotton swabs should be avoided as the calcium alginate and the wooden shaft of cotton swabs both may inhibit viral recovery. Corneal biopsy may be necessary in cases of apparent and sign ificant microbial in fection when repeated corneal scrapings are negative. A small 2- to 3- mm trephine (disposable dermatologic skin punch) can be used to create a partial-thickness incision, and forceps and scissors are used to excise a lamellar fl ap of cornea. The specimen is generally split into 2 pieces, or separate biopsies are taken so that tissue can be evaluated by both histopathology and microbiology.
Isolation techniques For viral and chlamydial infections, an appropriate tissue-culture cell line is selected for inoculation and exam ined for the development of cytopathic effects (CPE) and cellular inclusions. For bacterial and fungal infections, directly inoculated blood, chocolate, and Sabouraud's aga r and thioglycollate broth are exam ined daily to detect visible growth. Microorganisms are stu died by chemical stain in g, chemical reactions, and antimicrobial sensitivity testing. Acanthamoebae may be identified by troph ozoite trails on blood agar, but nonnut rient agar with an overlay of killed E coli or Enterococcus spp is the optimal isolation med ium. Alexandrakis G, Haimovici R, Miller D, Alfonso EC. Corneal biopsy in the management of progressive microbial keratitis. Am J Ophtlwlmol. 2000; 129(5):571-576.
Staining Methods
See Table 4-4 fo r recommended stains and media in the setting of suspected microbial kerati tis.
Table 4-4 Recommended Stains and Culture Media for Microbial Keratitis Suspected Organism
Stai n
Media
Aerobic bacteria
Gram Acridine orange
Blood agar Chocolate agar Th ioglycoliate broth
Anaerobic bacte ria
Gram Acridine orange
A naerobic blood agar Phenyl ethyl alcohol agar in anaerobic chamber Th ioglycollate broth
Mycobacteria
Gram Acid-fa st Lectin
Bl ood agar Lowenstein-Jensen agar
Fungi
Gram Acrid ine orange Calcofluor white
Bl ood agar (25°C) Sabouraud's agar (25°C) Brain-heart infusion (25°C)
Acanthamoeba
Acridine orange Calcofluor white
Nonnutrient agar with E coli ove rlay Blood agar Buffered charcoal-yeast extract agar
104 • External Disease and Corn ea
Public Health Ophthalmology Nearly 150 million people worldwide are bli nd or have low vision. Corneal diseases, especially infection . are major causes of visual loss. In the absence of an avai lable vaccine for these conditions, specific programs are designed to reduce the risk of communicable diseases. Examples of such efforts are the following: improved hygiene and mass distrib ution of antibiotics to interrupt hyperendemic trachoma eradication of the insect vector to control onchocerciasis vitamin A supplementation in com mun ities with childhood xerophthalmia education abo ut contact le ns disin fectio n in industrialized countries Schwab L. Eye Care in Developing NatiofJ5. 4th ed. London: Manson Publishing; 2007.
Virology and Viral Infections Viruses are small (10-400 nm in diameter) infectious units consisting of a single- or double-stranded nucleic acid genome and a protein capsid shell, with or without an externallipid envelope. In generating a virus taxonomy. the International Committee on Taxonomy of Viruses (lCTV) considers m ultiple virus traits, including morphology, physical properties, nucleic acid type and strandedness, physical state of the genome, proteins expressed, antigenic properties, and serologic cross-reactivity, as well as the biologic effects of infection. Viruses lack the independen t means for energy metabolism, molecular biosynthesis. or repHcation . Viral nucleic acid consists of either RNA or DNA. RNA viral genome may be either single- or double-stranded and, in the case of Single-stranded viruses, either positivesense (same polarity as mRNA) or negative-sense (opposite polarity to mRNA). The transcription of viral nucleic acid to produce the enzymatic and structural proteins necessary for replication varies with the type of vira l genome. Antivira l medications typically target viral gene transcription. Therefore, th e cli ni cal significance of the nucleic acid type lies principally in differences in suscepti bilit y to antiviral medications. The viral capsid is a protein shell that su rro unds the nucleic acid. The capsid interacts internally with the genome to stabilize it, protects the genome from the external environment, and, in the case of nonenveloped vir uses, expresses on its surface the ligand for virus-host cell binding. Viral capsid proteins also help in delivery of the viral genome to the intracellular site of viral replication. T hus, viral capsid structure is integrally related to many viral functions-in particular, transmission. attachment, and entry into host target cells, but also virion assembly and egress. For some virus families, a host cell-deri ved lipid bilayer or envelope surrounds the protein capsid. Viral genome-encoded glycoproteins bound to the membrane act as ligands (antigens) for neutraliZing antibodi es directed against the virus. The viral envelope lipid bilayer is vulnerable to dam age by ult raviolet light, detergents, alcohols, and generaluse antiseptics.
CHAPTER 4:
Infectious Diseases/Externa l Eye: Basi c Concepts and Vi ra l Infections • 1 05
Because of this vulnerability, enveloped viruses such as HSV and human immunode· ficien cy virus (HI V) are intrinsically susceptible to the external enviro nment, and their infectivity is short-lived outside the host. Enveloped viruses are di ffic ult to transmit via fomites or medical instruments, and alcohol treatment of medical instr umentation is gen· erally sufficient to prevent iatrogenic infection. In contrast, nonenveloped viruses such as adenoviruses are relative ly resistant to en· vi ron mental insult and, in some cases, can persist for weeks outside the hu man host. The application of dil ute (I %) bleach to tonometer tips fo r at least 10 minutes is recommended to prevent tra nsmission of adenoviruses, but care must be taken to clean residual bleach from the tonometer tip prior to use. CDC, National Prevention Information Network. [website]. HIV/ AIOS FAQs and Basic Facts. Avai lable at www.cdcnpin.org/scripts/ hiv/ faq.asp. Chodosh ], Stroop WG. Introduction to viruses in ocu lar di sease. In: Tasman W, Jaeger EA , eds. Duanes Foundations of Clinical Ophthalmology. Philadelphia: Lippincott Williams &
Wilkins; 1998,chap 85, pp 1- JO
DNA Viruses: Her esvlruses The structure of all herpesviruses includes a core of linear double-stranded DNA genome, surrounded by an icosahedral protein capsid, an amorphous-appearing protein tegu ment, and finally an envelope studded with viral glycoproteins. Of the 8 known human herpesviruses, those that affect the eye include herpes simplex virus (HSV) types 1 and 2, varicella-zoster virus (VZV), Epstein-Barr vi rus (EBV), cytomegalovirus (CMV), and Kaposi sarcoma-associated herpesvirus (KS HV)/human he rpesvirus 8. The production of viral progeny invariably destroys the infected cell. All herpesvi ruses establish latency in their natural hosts, but the site of latency va ries. For example, whereas HSV types 1 and 2 and VZV establish latent infections in dorsal root ganglia such as the trige minal ganglion, Epstein-Barr virus latency occurs in B lymphocytes. Knipe OM, Howley PM, eds. Fields' Virology. 5th ed. Philadelphia: Lippincott Williams & Wilkins; 2006.
Herpes Simplex Eye Diseases HSV infection is ubiquitous in humans; nearly 100% of those older than 60 years of age harbor HSV in their trigeminal ganglia at autopsy. It has been estimated that one thi rd of the world population suffers fro m recurrent infection. Therefore, HSV infections are a large and worldwide public health problem. HSV type 1 (HSV- I ) and type 2 (HSV-2) are antigenically related and may co infect the same nerve ga nglia. HSV-l more commonl y causes infection above the waist (orofacial and ocular infec tion) and HSV-2 below the waist (gen ital infection), but either virus can cause disease in either location. In industrialized societies, 40%-80% of adults have serum antibodies to HSV- l , wh ich represents a decli ne in infection from previo lls decades, and the age at ,·"hich individuals undergo serologic conversion is increasing; HSV is now more
PATHOGE N ESIS
106 • Externa l Disease and Cornea
commonly acquired in adolescence than in childhood. H SV in fection is spread by direct contact with in fecte d lesions or their sec retions but most com m only occurs as a res ult of exposure to viruses shed asymptomatically. HSV ca n be transmitted to neonates as th ey pass through the birth ca nal of a m other with genital infection and, in the newborn, ca n cause disease confi ned to the skin and m ucous mem branes or syste mi c infection. includ ing encephalitis. BCSC Section 6, Pediatric Ophthalmology arid Strabismus, di sc usses neo natal herpes infectio n in greater detail. Primary HSV- l infection in hum an s occ urs most commonly on skin and muco sal surfaces innervated by CN V (trigem inal nerve) . Primar y infection frequently man ifests as a nonspecific upp er resp irato ry tra ct infec tion and is recognized as HSV less than 5% of the time. HSV spreads from infected skin and mucosal epithelium via se nsory nerve axons to establish latent infection in associated se nsory nerve ga nglia. incl uding th e t rigemi nal ga nglion. Latent in fect ion of the trigeminal ganglion occurs in the absence of recog ni zed primary infect ion , a nd reactivation of the virus may follow in any of the 3 bra nches of CN V, despite prima ry disease in th e area of innervation of I pa rticular branch. Approximately 0.15% of the US population has a hi story of external ocular HSV infection, and, of these, approx.imately one fifth develop stromal kerat itis, the most common blindi ng man ifestation of infec tion. Liesegang TJ. Herpes simplex virus epidemiology and ocula r impo rtance. COrl/ea. 200 I ;20( t ): 1-13.
Primary ocular infection Primary ocular HSV infection typically manifests as a un il ate ral blepha ro conju nctivitis. The conjunctival inflammatory response is fo llicular and accompanied by a palpable prea uricular ly mph node. Ves icles on th e skin (Fig 4-2) or eyelid margin (Fig 4-3) are important for diagnosis. Patients with prima ry ocula r HSV infection can develop epi thelial keratitis (di scussed later in the chapte r), but st romal keratitis and uve itis are u ncommon.
CLINICAL PRESENTATION
Figure 4·2 Skin vesicles of HSV dermatoblepha rit is. (Courtesy of James Chodosh. MD.)
CHAPTER 4: Infectious Diseases/ External Eye: Basic Concepts and Viral Infectio ns. 107
Figure 4-3 Fluorescein staining of an eye with primary HSV infection demonstrates characteristic lid margin ulcers and a coarse dendritic epit helial keratitis. (CourresyofJames Chodos h, MD.)
Signs that can be used to distinguish ac ute HSV ocular infection from that associated with adenovirus include cutaneous or eyelid margin vesicles, or ulcers on the bulbar conjunctiva (HSV) dendritic epi thelial keratitis (HSV) conj unctival membranes or pseudo membranes (adenovirus) Laterality is not a reliable distinguishing feature. Althoug h adenoviral infections are more commonly bilateral, they can be u nilateral, asym metric, or bilateral with delayed involvement of the second eye. HSV ocular infection is typicaLly unilateral, with onl y 3% of patients in th e Herpetic Eye Disease Study (HEDS), a prospective multicenter clinical trial fun ded by th e National Eye Institute in the I 990s, demonstrating bilateral disease (Table 4-5). The presence of bilateral disease should raise th e question of im mun e dysfunction (eg, atopic dermati tis). Demonstration of HSV is possible in productive epithelial in fec tion with viral cu lture or antigen- or DNA-detection methodologies. Serolog ic tests for neutralizing or complement-fixing immunoglobuli ns may show a rising antibody titer during primary in fection but are of no diagnost ic assistance during recurrent episodes. As the majority of adul ts are latently infected with HSV, serologic testing generally is helpful only whe n negative. Laboratory tests are indicated in complicated cases when the clinical di agnosis is uncertain and in all cases of suspected neonatal herpes infection. Vesicles can be opened with a needle, and vesicular flu id cultured . Scrapings from the vesicle base can be tested by cytology or for the presence of HSV antigen. Co njunctival scrapings or im pression cytology specimens can be Similarly anal yzed by culture, antigen detection, or polymerase chain reaction (PCR).
LA BORATORY EVA LUATION
Tabl e 4·5 The HEDS Study Question
Study Design
Findings
Comment
Do top ical cort icostero id s treat strom al keratitis?
106 pat ie n ts w it h st romal keratitis random ized to top ical corti co ste roids or pla cebo for 10 weeks. Treatm ent started with pre dnisolone 1% ax/day and tapered to predn iso lone 1/8% once a d ay. Bo th gro ups rece ived to pical t rifl u ridine.
Yes. Top ical corticostero ids sign ificant ly decreased st romal infl ammati on and shortened du rat ion of kerati ti s.
Th e opti ma l co rticosteroid reg im en was not ev alu ated . Some patients respond to less co rt icosteroid and som e m ay need a sho rte r/long er taper. Delaying corti co stero id s for seve ral wee ks had no d et rim ental effect o n vision .
2
Is oral acyclov ir (in add iti on to treatme nt w ith tr iflur idi ne and co rt icoste roi ds) he lpful in trea ting st rom al ke rat itis?
104 patients w ith strom al ke ratit is ran domi zed to ora l acyc lov ir (400 m g 5x/day ) vs p lace bo for a l D-wee k co u rse. Both g roups also received topica l p rednisolo ne an d t rifluridine.
No . Treatm ent o f non nec rot izing stro ma l kerati t is w ith o ral acyc lovir w as not be neficia l.
Insuffic ient patients with necro ti zing st rom al kerati tis to comment on effectiveness o f acyclovir.
3
Is treatm ent-d o se oral acyc lovir helpfu l in treating HSV iritis?
50 pat ients with i rit is trea ted with
Too few pati ents. A nonstat isti ca ll y si gni ficant trend favori ng th e use o f ora l acyc lov ir.
Many clin ician s favor use of oral acyclovi r for trea tm en t o f HSV iridocy cli tis.
4
Does oral acycl ovi r preve nt patie nt s w ith ep ithel ia l ke ratit is f ro m d eve lop ing st roma l keratitis and irit is?
287 pat ie n ts w ith ep ithelial kerat iti s received 3-week oral acycl ovi r (400 m g 5x/d ay) vs place bo; f o ll owed fo r 12 m o nth s.
No. No dif feren ce in developm ent of stro ma l kerati tis or iriti s.
Best predi ctor fo r stroma l keratitis is h istory o f previous st ro m al kerat itis.
5
Does acyc lovir p roph y laxis m in im ize HSV recu rrences?
703 pat ien ts wi th inactive disease and o ff m edi cations random ized to oral acycl ov ir (400 m g 2x/d ay) vs placebo for 12 m onths; fo ll owed for 18 months.
Rec u rrent oc u lar d isease w as less (approx 50%) in g roup on oral prophy laxis, es pecia ll y t hose with recur rent stro m al ke ratitis.
Long-term prophylaxis recomm end ed fo r pa tients w ith recu rrent HSV strom al keratitis.
6
W hat tri gge rs HSV rec u rrences?
308 pat ients kept we ekly log o f st ress, systemic infecti ons, sun li ght ex pos u re, me nst ruat ion, CL wear, and eye inju ry.
No fac tors confirm ed as trigge rs fo r rec ur re nce.
No.
oral acyclovir (400 m g 5X/day) vs p lace bo fo r lO-wee k co urse .
CHAPTER 4:
In fect io us Diseases/Externa l Eye : Basic Concepts and Viral Infecti ons • 109
Primary ocular HSV infectio n is a self-limited condition. Oral anti vi ral therapy speeds resolution of signs and symptoms. Table 4-6 summarizes the antiviral agents effective against HSV infections.
MAN AGE M ENT
Recurrent ocular infection
Recurrent HSV infection is caused by reactivation of the vi rus in a latently infected sensor y ganglion, transport of the virus down the nerve axo n to sensory nerve endings, and subsequent infection of ocular surface epithelia. HSV latency in the cornea as a cause of recu rrent disease remains a controversial concept. Anecdotal reports that environmental fac tors act as triggers for the rec urrence ofHSV ocular disease we re not confirmed by the HEDS Study Grou p. Psychologic stress, systemic infect ion, sunlight exposure, menstrual cycle, and contact lens wear were not shown to induce recur rent ocul ar HSV infection. An increased rate of recurrence fo r HSV kerat itis was associated with HI V infection in a retrospective study. However, no di ffere nce was found in the severity of HSV keratitis between HI V-infected and uninfected persons, despite the observed discrepancy in recurrence rate.
PATH OGE NES IS
Psychological stress and other potential triggers fo r rec urrences of herpes Simplex virus eye infections. Herpeti c Eye Disease Study Gro up. Arch Ophthalmol. 2000; llS( 12): 16 17- 1625.
Table 4-6 Antiviral Agents in Externa l/ Corneal Infections With Herpes Simplex
Virus Agent
Mechanism of Action
Administration
Dosage for Acute Disease
Vidarabine
Purine analogue Inhibits DNA polym era se
3% ophthalmic ointment*
5x/day for 10 days
Trifluridine
Pyrimidine anal ogue Blocks DNA synthesis
1% ophthalmic solution
ax/day for 10 days
Acyclovir
Act ivated by HSV thymidine kina se to i nhibit viral DNA polym erase
3% ophtha lmic oi ntmentt 200, 400, 800 mg; 200 mg/5 mL suspension 5% dermatologi c ointment:t:
5x/day for 10 days
Famciclovir§
Pro-drug of penciclovir
125, 250, 500 mg
250 mg 3x/day for 10 days
Valacyclovir§
L-va ly l ester of acyclovir
500, 1000 mg
1000 mg 2x/day for 10 days
Pen ciclovir
Inhibits viral DNA polymerase
1% dermatolog ic cream;
ax/day for 4 days
Ganci clovi r
Inhibits DNA polymerase
0.15% topical ophthalmic gel
5x/day until epi thelium hea ls; then 3x/day for 7 days
*No longer manufactured; can be obtained through compoundin g pharmacies. tNot comm ercially ava ilabl e in the United States. lN ot for ophthalmic use. §Optimal dose for ocula r disease not determined.
400 mg 5x/day for 10 days 6x/day for 7 day s
110 • Extern al Disease and Corn ea
Recurrent HSV can affect almost any ocular tissue, including the eyelid, conju nctiva, cornea, iris, trabecu lar meshwork, and ret ina. The most commo n presentatio ns of clinically recogn izable recurrent ocular HSV infect ion incl ude CLINICAL PRESENTATION
• blepharoconjunct iviti s epithelial keratitis stromal ke ratitis iridocyclitis Blepharoconjunctivitis Eyelid an d/or conjunctiva l invo lve ment can occur in patients with recurrent ocular HSV in fec ti on , although it is cli nicall y indistin guishable from pri mary infection. The condition is self- li mited but can be treated with antivirals to shorten the course of ill ness.
Epithelial keratitis Patients with epithelial keratitis complain of fo reign- body sensation, light sensitivity, redness, and blurred vis io n. HSV infection of human corneal epithe liu m man ifests as areas of punctate ep ith elial keratitis that may coalesce into 1 or more arbo ri zing den d rit ic epitheli al ulcers with term inal bulbs at the end of each branch. The cytopath ic swollen corneal epithelium at the edge of a herpet ic ulcer stains with rose bengal and Iissam ine green (Fig 4-4) du e to loss of cell membra ne glycoproteins and subsequent lack of mucin bi nding by the cells. The bed of the ulcer stains with flu orescein (Fig 4-5) d ue to loss of cellular integri ty and absence of intercellular tight jun ctions. Particularly with use of topical corticosteroids, areas of dendritic keratitis may coalesce further and enlarge into a more expansive geographiC epithelial ulce r (Fig 4-6). T he swollen epitheliu m at the ulcer's edge will stain with rose bengal, an d, frequently, dendri tic m orphology can be seen at the periphery of the ulcer. Patients with HSV epithelial kera titis exh ibit a ciliar y flu sh an d m ild conjunctival injection . Mild stro mal edema an d sub epithelial white blood cell infil tration may develop as well beneath the epithelial keratitis. Following resolution of dend rit ic epithelial keratitis, nonsuppurat ive subepithelia l infiltrati on and scarring may be seen just beneath the area of prior epithelia l ulceratio n, resulting in a ghost image, o r ghost dend rite (Fig 4-7), reflec ting the position and shape of the pri o r epithelial involvement. Focal or di ffuse redu ction in corneal sensation develops following HSV epithelial keratitis. The di stributi on of corn eal hypoesthesia is related to the extent, duration, severity, and number of recurrences of herpet ic kerat itis. Sectoral corneal anesth esia may be diffic ult to detect clin icall y and is not a re liable sig n of herpetic disease. Other conditio ns that may produce dendri tiform epitheli al lesions include
CLINICAL PRESENTATION
variceLl a-zoster virus (see th e discussion later in th e chapter) adenov ir us (uncommon) Epstein -Barr virus (rare) epithe lial regeneration line neurotrophic keratopathy (post herpetic, diabetes melli tus) soft contact lens wea r (thimerosal)
CHAPTER 4: Infecti ou s Diseases/ Exte rna l Eye: Basic Concepts and Viral Infecti ons . 111
Fi gure 4-4
Rose bengal staining of herpetic epi thelial keratitis out lin es a typical dendrite. (Cour-
tesy of James Chodosh, MD.)
Figure 4-5
Fluorescein sta ining of herpetic dendritic keratitis. (Courtesy of James Chodosh, MD.)
topical medications (antivirals, ~-blockers ) Acanthamoeba epithelial deposits (iron lines, Fabry disease, tyrosinemia type 11, systemic drugs) LABORATORY EVALUATION
A specific clinical diagnosis ofHSV as the cause of dendritic ke r-
ati tis can usually be made based on the presence of characteristic cl inical features. Tissue
culture and/or antigen detection techniques may be helpful in establishing the diagnosis in atypical cases.
Most cases of HSV epithelial keratitis resolve spontaneously, and there is no evidence to suggest that the form of antiviral therapy influences the subsequent
M ANAGEMENT
11 2 • Extern al Disease and Cornea
Figure 4-6
Herpetic geograph ic epi thelial keratit is.
(Reprinted with permission from Chodosh J. Viral kera-
titis. In: Parrish RK, ed. The University of Miami Bascom Palmer Eye Institute Atlas of Ophthalmology. Boston: Current M edicine; 1999.)
Figure 4-7 Residual stromal inflammation following dendritic epithelial keratitis may leave the impression of a ghost image of th e dendrite. (Reprinted with permission from Chodosh J. Viral keratitis. In: Parrish RK, ed. The University of Miami Bascom Palmer Eye Inst itute Atlas of Opht halmo logy. Boston: Current Medicine; 1999.)
development of stromal keratitis or recurrent epithelial disease. However, treatment shortens th e clinical course and might conce ivably redu ce associated herp etic neuropathy. Mi nimal wiping debridement with a d ry cotton-tipped applicator or cellulose sponge speeds resolution. Antiviral therapy can be used by itself or in combination with epithelial debridement. Topical trifluridine 1% solution 8 times dail y is efficacious for both dendritic and geographiC epithelial keratitis. Treatment of the disease with topical antivi ra ls generally should be discontinued within 10- 14 days to avoid unnecessary toxic ity to the ocular
CHAPTER 4:
Infectious Di seases/Externa l Eye: Basic Concepts and Viral Infections •
113
surface. Acyclovir 3% ophthalmic ointment has been reported to be as effective as and less toxic than trifluridine and vidarabine, but th e ophthalmic form is not ava ilab le in th e United States. Oral acyclovir has been reported to be as effective as topical antivirals for treating epithelial keratitis, an d it has the advantage of no ocular toxi city. For th is reason , oral therapy is preferred by an increasing nu mber of physicians. Valacyclovir, a pro-dru g of acyclovir likely to be just as effective for ocular disease, can cause th rombotic thrombocytopenic purpura/hemolytic urem ia syndrome in severely im munocompromised patients such as those with AIDS; thus, it must be used with caution if th e immune status is unknown. Topical corticosteroids are contraindicated in the presence of active herpetic epithelial keratitis; patients with this disease who are using systemic corticosteroids for other indications should be treated aggressively with systemic antiviral therapy. Stromal keratitis HSV stromal keratitis is th e most common cause of infectious corneal blind ness in the United States, and it is the form of recurrent herpet ic ex ternal disease associated with the greatest visual morbidity. Each episode of stromal keratitis in creases th e risk of future episodes. The pathogenes is of herpetic stromal keratitis in humans remains unknown but probably depends on the type of stromal inflammation (see the following section ). Animal models of herpetic eye disease do not preCisely replicate the human situation; studies of HSV stromal keratitis in mouse models have va riously implicated HSV-specific CD4 and CD8 T lymphocytes and anti-HSV anti bodies in keratitis pathogenesis. Studies also implicate cell -medi ated immunity to corneal an tige ns up-regulated by HSV infec tion and the bystander effects of proi nflammatory cytokine secretion by infected corneal cells.
PATHOGENESIS
Streilein rW, Dana MR, Ksander BR. Im munity causing blindness: five different paths to herpes stromal kerat itis. In/nll/llol Today. 1997;18(9):443- 449 . CLINICAL PRESENTATION Herpetic stromal keratit is can be nonnecroti zing (i nterstitial or disciform ) or necrotizing. and different form s may present Simultaneously. Herpetic interstitial keratitis presents as unifocal or multifoca l interstitial haze or whitening of the stroma in the absence of epithelial ulceration (Fig 4-8) . Mild stromal edema may accompa ny the haze, but epithelial edema is not typical. In the abse nce of Significant extracorneal inflam matory signs such as conjunctival injection or anter ior chamber cells, it may be difficult to ident ify active disease in an area of previous scar and thinning. Long-standing or multiply recurrent HSV interstitial keratitis may be associated with corneal vascu larization. The differential diagnosis of herpetic interstitial kerat itis includes
VZV keratitis Acanthamoeba keratitis syphilis • EBV keratitis mumps keratit is Lyme disease sarcoidosis • Cogan syndrome
114 • External Disease and Cornea
Figure 4·8
Herpetic interstitial keratitis {nonnecrotizingJ.
(Reprinted with permission from Chodosh J.
Viral keraritis _In. Pamsh RK, ed. The University of Miami Bascom Palmer Eye Institute Atlas of Ophthalmology. Boston: Current Medicine, 1999,)
Herpetic disciform keratitis is a primary endotheliitis, which presents as corneal stromal and epithelial edema in a round or oval dist rib ut ion, associated with keratic preci pitates unde rl ying the zone of edema (Fig 4-9). Iridocyclitis can be associated, and th e disciform kerat itis may be confused with uve ilis with secondary corneal endothelial decompensati on. However) in disciform keratitis, disc-shaped stromal edem a and keratic precipitates appea r out of proportion to the deg ree of anterior chamber reaction. Disciform keratitis du e to HSV and that due to VZV are clinically indistinguishable.
Figure 4·9
Herpet ic disciform keratiti s (nonnecrotizing).
(Reprmted with permiSSion from Chodosh J
Viral keraritis_ In. Pamsh RK, ed The University of Miami Bascom Palmer Eye Institute Atlas of Ophthalmology Boston Current Medlcme; 1999.)
CHAPTER 4:
Infectious Diseases/Externa l Eye: Basic Concepts and Viral Infections.
Figure 4·10
115
Necrotizing herpetic stromal keratitis.
Herpetic necrotizing keratitis appears as supp urative corneal inflammation (Fig 4-10). It may be severe. progress rapidly. and appea r clinically indistinguishable from fulminant bacterial or funga l keratitis. Overlying epithelial ulceration is common. but the epithelial defect may occur somewhat eccentric to the infiltrate. and the edges of the epithelial ulcer do not sta in with rose bengal dye. Corneal stromal vascularization is common. The differential diagnosis of herpetic necrotizing keratitis includes microbial keratiti s due to bacteria. fungi. or acanthamoebae. retained foreign body. and topical anesthetic abuse. MANAGEMENT Many past controversies regarding the optimal management of HSV stromal keratitis have been resolved by the HEDS trial (see Table 4-5). Most important. HEDS findings showed that topical corticosteroids given together with a prophylactic an tiviral reduce persistence or progression of stromal inflammation and shorten th e dura tion of HSV stromal keratitis; in addition) long-term suppressive oral acyclovir th erapy reduces the rate of recurrent HSV keratitis and helps to preserve vision, Long-term an tiviral prophylaxis is now recommended for patients with multiple recurrences of HSV stromal keratitis. The HEDS showed no additional benefit of oral acyclovir in treating active HSV stromal keratitis in patients receivin g concomitant topical corticosteroids and trifluridine. When given briefly along with trifluridine during an episode of epithelial keratitis. acyclovir also d id not appear to prevent subsequent HSV stromal keratitis or iritis. The experimental protocol applied by HEDS investigators for patients with herpetic stromal keratitis is a useful starting point for a treatment algorithm. Visually significant herpetic interstitial keratitis is treated initially with 1% prednisolone drops every 2 hours accompanied by a prophylactic antiviral drug. either topical trifluridine qid or an oral agent such as acyclOVir 400 mg bid or valacyclovir 500 mg once a day. T he prednisolone drops are tapered every 1- 2 weeks depend ing on the degree of clinical improvement. The antiviral is used to prevent severe epithelial keratitis should the patient shed HSV while on corticosteroid drops. and it is generally continued until the patient is completely off
116 • Ext erna l Disease an d Co rn ea
corticosteroids or using less than 1 d rop of 1% pred nisolone per day. Pati ents should be tapered to th e lowest possible corticosteroid dosage that controls thei r in fl ammation. Available topical antiviral medications are not absorbed by the corn ea through an intact epithelium, but orally administered acyclovir penetrates an intact cornea and anterior chamb er. In this context, anecdotal evidence suggests that oral acyclovir mi ght benefit the deep corn eal infl ammatio n of d iscifo rm keratit is. T he HEDS showed no add itional benefit when acyclovir was added to trifluridine and pred nisolone fo r th e treatment of he rpetic stromal ke ratitis, but disciform keratitis was not analyzed as a separate group. Some corneal specialists routinely substitute oral acyclovir for topical trifluridine in treating d isciform ke ratitis. Nec rotizing herpetic st ro mal kerat itis is probabl y the least common fo rm of herpetic keratitis. The d iagnosis is frequently one of exclusion foll owi ng negative cultures fo r fungal and bacterial pathogens, but it is suggested by a history of HSV facial, conju nctiva l, and/or corneal infection . The toxicity of topical an tiviral agents may be und esirable in patients \vith necro tizing inflammation and can confuse the clin ical picture. Therefore. an oral antiviral such as acyclovir is preferred. Fortunately, necroti zing herpetic kerati tis appears to be ve ry sensitive to topical corticosteroi ds, and twice a day dosing may be sufficient to control inflalnmation in many patients. Acyclovir for the prevention of reClirrent herpes sim plex virus eye disease. Herpetic Eye Disease Study Group. N Engi / Med. 1998;339(5):300- 306. Ba rron BA, Gee L, Hauck WW, et al. Herpet ic Eye Disease Study. A cont roll ed tria l of oral acyclovir for herpes Simplex stromal keratitis. Oph thalrnology. 1994; 10 I ( 12):187 1- 1882. A controlled trial of oral acyclovir for the preventio n of stro mal kerat itis or iritis in pat ients with herpes Simpl ex virus epithel ia l keratit is. The Epi thelial Keratitis Tr ial. The Herpetic Eye Disease Study G roup. Arch Ophthalmol. 1997;115(6):703- 712. Oral acycl ovi r for herpes Sim pl ex virus eye disease: effect on prevention of epith elial keratitis an d stromal kerat itis. Herpetic Eye Disease Study G roup. Arch Oph thalmol. 2000; 11 8(8) : 1030- 1036. Wi lhelmus KR, Gee L, Hauck WW, et a1. Herpeti c Eye Disease Study. A controlled tri al of topical co rticosteroids fo r herpes Simplex stromal keratit is. Ophthalmology. 1994;101 (1 2): 1883- 1895.
Iridocyclitis Granu lomatous or nongranulomatous iridocyclitis may accompany necrotizing stromal keratitis or occur independently of corn eal disease. Elevated lOP caused by trab eculitis and/or patchy iris t ransillu mi nation defects may be fo und in pat ients with HSV iridocycl itis. Infectious virus has been cultured from the anterior cham ber of such patients an d its presence positively correlated with ocular hypertenSion. Therefore, the d iagnosis of HSV iridocyclitis is suggested by a u nilateral presentation associated with an elevated lOP with or without fo cal iris trans illumi nation defects. A history or clin ical evidence of pri or HSV oc ul ar disease is suggestive. O ne H EDS t rial suggested a statistical trend loward the benefit of oral acyclovir (400 mg, 5 times da ily) in treating HSV iri d ocyclitis in patients also receivi ng topical corticosteroids. but the num ber of patients recruited was too small to achieve statisticall y conclusive results. Complications of herpetic eye disease affect all layers of the cornea. Epitheliopathy is com mo n when topical antiviral treatment is prolonged, and its severity and duration are
CHAPTER 4:
Infectious Diseases/Extern al Eye: Ba si c Concepts and Vira l Infections • 117
directly related to the durat ion of antiviral use. Topical antiviral toxicity presents most commonly as diffuse punctate corneal epithelial erosions with conjunctival injection. Neurotrophic keratopathy may develop in patients with reduced corneal sensation secondary to past herpetic infection. Punctate epi th elial erosions, sometimes with a vortex pattern of punctate fluorescein staining, chronic epithelial regeneration lines, and frank neurotrophic ulcers characterize neurotrophic keratopathy. These ulcers can be dist ingUished from herpetic epithelial keratitis by a relative absence of rose bengal stain ing. Neurotrophic ulcers are typically round or oval an d located in the central o r inferior cornea. Corneal epithelium at the edges of a neu rotrophic ulcer may appear to roll under itself and typically has a gray, elevated appea rance. Li beral use of non preserved lubricating drops, gels, and ointments combined with punctal occlusion are the mainstays of therapy. To prevent progressive stromal thinn ing and perforation, tarsorrhaphy is indicated for neurotrophic ulcers that faU to respond to conservative therapy. On occasion, active or resolVing interstitial stromal keratitis d ue to HSV is associated with a chronic epithelial defect that does not stain with rose bengal. This so-called meta herpetic ulcer probably results from neurotrophic mechanisms or a devitalized corneal stroma. Severe or long-standing disciform kerat itis can result in persistent bullous keratopathy. Stromal inflammation in general, whether interstitial or necrotizing, commonly leads to permanent corneal scarring and irregular ast igmatism. Both scarring and astigmatism may improve with time in some patients. Fitting with a gas-permeable contact lens usually improves visual acuity beyond that achieved with spectacle refraction. In patients with deep corneal stromal vascularization due to prior necrotizing herpetic inflammation, secondary lipid keratopathy may further impair the vision . Topical corticosteroids may suppress new vessel growth and halt additiona l lipid deposition. A controlled trial of oral acyclovir for iridocyclitis caused by herpes Simplex virus. Herpetic
Eye Disease Study Group. Arch Ophthalmol. 1996;1l4(9);I065-1072.
Penetrati ng keratoplasty (P K) is indicated in selected patients with visually Significant stromal scarring and astigmat ism not correctable by spectacle or contact lens. Oral antiviral therapy may improve graft survival by redUCing the risk of HSV recurrence and allow more liberal use of topical corticosteroids. Oral antivirals lack epithelial toxicity and are therefore generally preferable to topical antivirals in patients after PK. The prognosis for successful optical PK approaches 80% in eyes without signs of active inflam mation for at least 6 months prior to surgery. Tectonic PK is indicated in impending or frank corneal perforation due to necrotizing or neurotrophic ulcers. Stromal inflammation, ulceration, and graft failure may develop in inflamed herpetiC eyes undergoing tectonic PK. Therefore, small descemetoceles and perforations in inflamed eyes may best be treated by applying therapeutiC tiss ue ad hesive and a bandage contact lens and delaying PK until inflammation can be controlled. Amniotic membrane transplantation (AMT) may also be used for persistent epithelial defects with and without corneal thinn ing.
SURGICAL TRE ATM ENT
Varicella-Zoster Virus Dermatoblepharitis. Conjunctivitis, and Keratitis As with other herpesviruses, VZV causes a primary infection (varicella, or chickenpox) and subsequent latency, occaSionally followed later by recurrent disease
PATHOGENESI S
11 8 • External Disease and Cornea
(zoster, or shingles). Primary VZV infection occurs upon di rect contact with VZV skin lesions or respi ratory secretions via airborne droplets and is highly contagious for naive in· dividuals. VZV infection is usually a self- li mited infection of childhood rarely assoc iated with long·term sequelae. However, infection of adults or immu nosuppressed indi viduals can be fatal. In child ren, VZV infection man ifests with feve r, malaise, and a vesic ular dermatitis that lasts 7-10 days. Except for eyel id vesicles and follicular conjunctivitis, ocular involvement is uncommon during primary infection. As with HSV, VZV latency occurs in neural ganglia and, in approximately 20% of infected individuals, reactivates later. Of all cases with zoster, 15% involve the ophthalmic division of CN V (trigeminal). VZV infection, whether prin1ary or recurrent, can usually be distinguished from HSV in fection through a careful history and exam inat io n. Distinguishing features of each infection are listed in Table 4-7. CLINICAL PRESENTATION The rash of chickenpox begins as macules and progresses to papules, vesicles, and the n pustules that dry, crust over, and may leave individual scars. Ocular involvement may include follicular conju nct ivitis. occasionall y associated with a ves icu lar lesion on the bulbar conjunctiva or eyelid margins. Punctate o r dendrit ic epitheli al keratj · tis is uncommon. Although subepithelial infiltrates, stromal keratitis, disciform keratitis, uveitis, and elevated lOP are rare, recurrent varicella keratouveitis may cause significant morbidity in some patients. Laboratory confi rmat ion of acute o r recurrent VZV infec tion is possible by immunod iagnostic methods, viral culture, and PC R. Serologic testing is used primarily to identify vari cella-naive adu lts who might benefit from prophylactiC vaccinati on. As with HSV, scrapings from a vesicle base can be tested by cytology, PCR, or cul ture, or for the presence ofVZV antigen. Conjunctival scrapings or corneal impression cytology specimens can be sim ilarly analyzed by culture, antige n detection, or PCR. LABORATORY EVALUATION
MANAGEMENT Because infected individuals shed the virus in respiratory secretio ns be· fore the onset of the characteristic rash , aVO iding infected persons is not always possible.
Table 4-7 Differentiating Features of Eye Disease Caused by Herpes Simplex Virus
and Reactivation of Varicella-Zoster Virus Herpes Simplex Virus
Varicella-Zoster Virus
Dermatomal distribution Pain Dendrite morphology
Incomplete Moderate Central ulceration with terminal bulbs; geographic in presence of corticoste roids
Skin scarring
Post herpetic neuralgia
No No
Iris atrophy Bilateral involvement Recurrent epithelial keratitis Corneal hypoesthesia
Patchy Uncommon Common Sectoral or diffuse
Complete Severe Smaller wit hou t central ulceratio n or te rminal bulbs; dend ritiform mucous plaques occur later Common Common Sectoral
No Rare May be severe
CHAPTER 4: Infecti ous -Diseases/Exte rnal Eye : Ba sic Concepts and
Vi ral In fect io ns • 119
Vaccination against varicella is recommended for anyone older than 12 months of age without a history of chickenpox or with a negative serology. The severity of signs and symptoms may be reduced in clinically Ul patients by the administration of oral acyclovir. Significant keratitis or uveitis can be treated with topical corticosteroids.
Herpes zoster ophthalmicus Following primary infection, VZV establishes latency in sensory neural ganglia. Zoster (shingles) represents endogenous reactivation of latent virus in people
PATHOGENESIS
with a waxing level of immunity to infection. Most patients are in their sixth to ninth decades, and the majority are healthy, wit h no specific predisposing factors. However, zoster is more common in patients on immunosuppressive therapy; in those with a systemic malignancy, a debilitating disease, or HIV infection; and after major surgery, trauma, or radiation.
Zoster manifests as a painful vesicular dermatitis typically local ized to a Single de rmatome on the thorax or face. Patients may complain in itially of fever and mala ise, and warmth, redness, and increased sensation in the affected dermatome. The most commo nly affected dermatomes are on the thorax (T3 through L3) and those supplied by CN V (trigeminal). The ophthalmic division of the trigeminal nerve is affected more often than the maxillary and mandibular branches, and its involvement is referred to as herpes zoster ophthalmicus (H20) (Fig 4- 11 ). A maculopapular rash, followed by vesicles and then pustules, is characteristic. Zoster dermatitis may res ult in large scabs that resolve slowly and leave Significant scarring. Neurotrophic keratopathy and sectoral iris atrophy are characteristic. Inflammat ion of almost any ocular tissue can occur and recur in HZO. Zoster dermat itis is accompanied by pain and dysesthesia. The pain usually decreases as lesions resolve; however, neuralgia in the affected dermatome can continue from months to years. The severity of pain ranges from mild to incapacitating. Ocular involve ment occurs in more than 70% of patients with zoster of the first division of CN V and CLINICA L PRESENTATION
Figure 4 -11
Herpes zoster ophtha lmicus ,
(Courtesy of Vincent P deLuise, MD.)
120 • External Di sease and Co rnea
may appear in association with any branch, including the nasociliary, frontal, or lacrimal branches. Ophthalmic complications also may occur with zoster of the second (maxillary) division of C V. In imm unosuppressed patients. zoster may involve more than one branch of the trigeminal nerve at the same time. can chronically reacti vate. and may be multiply recurrent. Eyelid vesicular eruption can lead to secondary bacterial infection, eyelid scarring, marginal notching, loss of cilia. trichiasis, and cicatricial entropion or ectropion. Scarring and occlusion of the lacrimal puncta or canaliculi may occur. Episcleritis or scleritis associated with zoster may be nodular, zonal, or diffuse. Both punctate and dendritic epithelial kerati tis caused by viral replication in corneal epithelium are common manifestations of ophthalmiC zoster. Dendrites may persist and remain chron ically culture-positive for VZV in AIDS patients. Elevated dendritiform mucous plaques may occur weeks to months after resolution of the skin lesions. Diminished corneal sensation develops in up to 50% of patients. Nummular corneal infiltrates are said to be characteristic of zoster stromal keratitis (Fig 4-12), but the interstitial keratitis, disciform keratitis, and anterior uveitis with increased lOP in HZO are clinically indistinguishable from those caused by HSV infection . Chronic corneal stromal inflammation can lead to corneal vascularization, lipid keratopathy (Fig 4-13), and corneal opacity. Corneal anesthesia may be profound, and neurotrophic keratopathy due to HZO can be extremely difficult to manage. Focal choroiditis. occlusive retinal vasculitis, and retinal detachment have been reported. Ipsilateral acute reti nal necrosis (ARN) temporally associated with HZO is uncommon. Orbital or CNS involvement as a result of an occlusive arteritis may lead to eyelid ptosis, orbital edema, and proptosis. Papillitis or retrobulbar optic neuritis may also develop. Cranial nerve palsies have been rep orted to occur in up to one third of cases ofHZO, with CN III (oc ulomotor) most commonly affected. Cranial nerve involvement may occur
Figure 4-12
Nummular keratitis of herpes zoster ophthalmicus.
(Courresyof Rhea
L. Siatkowski, MD.)
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Infectious Diseases/ Externa l Eye: Basi c Concepts and Viral Infections • 121
Figure 4-13
Li pid keratopathy foll owing herpes zoster ophtha lmicus . (Reprinted with permission from Chodosh J Viral keratitis. In: Parrish RK, ed. The Universi ty of Miami Bascom Palmer Eye Institute Atlas of Ophthalmology_ Boston; Current Medicine; 1999.)
within the orbit or the cavernous sinus. Systemic dissemination is unusual in immuno~ competent patients but can occur in up to 25% of those who are immunocompromised.
Oral antiviral therapy fo r HZO was found in randomi zed clinical trials to reduce viral shedding from vesicular skin lesions, reduce the chance of systemic dissem ination of the virus, and decrease the incidence and severity of the most common ocular complications. Oral antiviral therapy may reduce the duration if not the incidence of postherpetic neuralgia if begun withi n 72 ho urs of the onset of symptoms. There are also reports to suggest that initiating an tiviral therapy after 72 hours, especially in the presence of new vesicles, is beneficial. Amitriptyline has also been repo rted to decrease the duration of postherpet ic neuralgia if given early on and continued until pain symptoms remit. A varicella-zoster vacci ne has recentl y been approved, after testing in 38,000 patients demonstrated a 50% reduction in incidence of zoster and a 66% reduction in postherpetic neuralgia. This vaccine is recommended for immunocompetent individuals over 60 years of age. The current recommendation fo r HZO is oral famciclovir 500 mg 3 times per day, valacyclovir 1 g 3 times per day, or acyclOVir 800 mg 5 times per day for 7-10 days, best if started within 72 hours of the onset of skin lesions. Topical antiviral medications are not effective. Intravenous acyclovir therapy is indicated in patients at risk for disseminated zoster due to immunosuppression. Cutaneous lesions may be treated with moist warm compresses and topical antibiotic ointment. Topical corticosteroids and cycloplegics are indicated for keratouveitis. Oral corticosteroids on a tapering dosage are reconlmended by some for treating patients with HZO over age 60 to reduce early zoster pain and faci litate a rapid return to a normal quality of li fe. However, the use of oral corticosteroids is controversial; their use does not seem to affect the incidence or duration of postherpetic neuralgia.
MANAGEMENT
122 • External Disease and Cornea
Postherpetic neuralgia (PHN) may respond to capsaicin cream applied to the involved skin , but low doses of amitriptyline, desipram ine, clomipramine, or carbamazepine may be necessary to control severe symptoms. Gabapentin (Neuro ntin ) and pregabalin (Lyrica) are also effective in managi ng PHN. Aggressive lubrication with nonpreserved tears, gels, and ointments, comb ined with punctal occlusion and tarsorrhaphy as necessary, may be indicated for neurotrophic keratopathy. In a patient with significant pain, early referral to a pain management speciali st sho uld be considered. Liesegang, TJ . Herpes zoster virus infection. Curr Opitl Op/lthalmol. 2004; 15(6):531 - 536. Oxman MN, Levin M], Johnson GR, et al; Shingles Prevention Study Group. A vaccine to pre· vent herpes zoster and postherpetic neuralgia in older adults. N Engl J Med. 2005;352(22): 227 1-2284.
Epstein-Barr Virus Dacryoadenitis. Conjunctivitis. and Keratitis PATHOGENESIS EBV is a ubiquitous herpesvirus that infects the majority of humans by early adulthood. Spread of EBV occu rs by the shar ing of saliva and results in subcl inical infection in the first decade of life; if acqu ired later in life, it causes infectious mononucleosis. The virus remains latent in B lymphocytes and pharyngeal mucosal epithelial cells throughout life. Ocular disease is uncom mon.
EBV is the most com mon cause of acute dacryoadenitis. characterized by inflammatory enlargement of 1 or both lacri mal glands. Acute follicu lar con junctivitis, Pari nau d oculoglandu lar syndro me, and bulbar conjunctival nodules have been reported in patients with acute infectiolls mono nucleosis and may be the result of EBV in fect ion. T he 3 principal forms of EBV stromal keratitis are associated with EBV on the basis of a history of recent infectious mo non ucleosis and/or persistently high EBV serologiC titers: CLINICAL PRESENTATION
Type J: multi focal su bepithelial infiltrates that resemble adenov iral keratitis Type 2: multifocal, blotchy, pleomorphic infiltrates with active inflammat ion (Fig 4- 14) or granular ring-shaped opacities (inactive form) in anterio r to mid stroma Type 3: multifoca l deep or full-thickness peripheral infiltrates, with or without vascularization, that resem ble interstitial keratitis due to syphilis EBV~assoc i ated keratitis may be unilateral or bilateral and may, in select cases, appear si milar to that induced by HSV, VZV, Lyme disease, adenovirus, or syphilis.
Because of difficulty in isolating the virus, the d iagnosis of EBV infection depends on the detection of ant ibodies to va rious vira l components. During acute infec tio n, first IgM and then IgG ant ibodies to viral capsid antige ns (VCA) appear. Anti- VCA IgG may persist fo r the life of the patient. Antibodies to early antigens also rise during the acute phases of the disease an d subsequently decrease to low or undetectable levels in most individ uals. Antibodies to EBV nuclear antigens appear weeks to months later, providing serologic evidence of past infection. AcyclOVir is not effective treatment for the clinical signs and symptoms of infections mononucleosis, but the impact of antiviral MANAGEMENT
CHAPTER 4:
Infectious Diseases/External Eye: Basic Concepts and Viral Infections.
123
Figure 4·14
Epstein-Barr virus strom al keratitis. (Reprinted With permission from Chodosh J Viral kerati· tis. In: Parrish RK, ed. The University of Miami Bascom Palmer Eye Institute Atlas of Ophthalmology. Boston: Current Medicine; 1999.)
therapy on the corneal manifestations of EBV infection remains unknown. Corticosteroids may be effective in patients with reduced vision due to apparent EBV stromal keratitis, but they should not be administered without a prophylactic antivi ral if HSV infection is a possibility. Chodosh]. Epstein- Barr virus stromal keratitis. Ophtha/m ol Cli11 North Am. 1994;7(4}:549-556.
DNA Viruses: Adenoviruses The Adenoviridae are double-stranded DNA vi ruses associated with significant human disease and morbidity. Forty-nine serotypes subdivide into 6 distinct subgroups (A-F) on the basis of genetic sequencing. Adenovirus subgroups associate broadly with specific clinical syndromes. For instance, subgroup D adenoviruses are strongly associated with epidemiC keratoconjunctivitis. The nonenveloped protein capsid of the adenovirus forms a regular icosahedron. For most adenoviral subgroups, a projecting capsid protein serves as the ligand for the cellula r adenovirus receptor, and the interaction of an adjacent capsid protein \vith cell surface integrins mediates internalization ofthe virus. Knipe DJ"I, Howley PM, eds. Fields' Virology. 5th ed. Philadelphia: Lippincott Williams &
Wilkins; 2006. Originally isolated in 1953 from surgically removed human adenoids, adenoviruses cause a broad spectrum of diseases, including infections of the upper respirato ry tract and ocular surface, meningoencephalitis, acute hemorrhagic cystitis of young boys, diarrhea of children, acute respiratory disease of children and military recruits, and respiratory and hepatic fai lure in an immunocompromised host. Adenoviruses are transmitted by close contact with ocular or respiratory secretions, fomites, or contaminated
PATHOG EN ESIS
124 • External Disease and Cornea
swimming pools. Transmission occurs more readily in populations li ving in close quarters, such as schools, nursi ng homes, military housing, and summer camps. Transmission of adenoviruses by contaminated inst ruments o r eyedrops in ph ys icians' offices may occur. For this reason. lOP measurements should be taken with an instrument with a disposable cover. CLINICAL PRESENTATION Each subgroup (A-F) of adenovir uses and, to a lesser degree. each serotype possesses unique tissue tropisms that revea l th e association of specific adenoviruses wit h distinct clinical syndromes. Most adenoviral eye disease presents cl inically as 1 of 3 classic syndrom es:
1. simple follicu lar conju nctivi tis (multiple serotypes) 2. pha ryngoconjunctival fever (most commonly serotype 3 or 7) 3. epidemic keratoconjunctivitis (EKC; usually serotype 8, 19, or 37, subgroup D)
Different adenoviral syndromes are indistinguishable earl y in infection and may be uni lateral or bilateral. Adenovirai follicular conjunctivitis is self-limited, not associa ted with systemic disease, and often so trans ient that patients do not seek care. Epithelial keratitis, if present, is mi ld and fleeting. Pharyngocol1jul1ctival fever is characterized by fever, headache, pharyngitiS, follic ula r conjunct ivit is, and preauricular adenopathy. The systemic signs and symptoms may mimic influenza. Any associated epithel ial keratitis is mild. Epidelnic kera toconjunctivitis is the only adenoviral syndrome with significant corneal involvement. The infecti on is bilateral in a majorit y of patients and may be preceded by an upper respiratory infection. One week to 10 days after inoculation , severe follicu lar conjunctivitis develops, assoc iated with a punctate ep ithelial keratiti s. The conjunctival morphology is follicular but may be obscured by chemosis. Petechial hemorrhages and, occasio nally, larger subconjunct ival hemorrhages can occur. Preauricular adenopathy is prominent. Pseudomembranes or true membranes (F ig 4-l5) occur predominantly on the tarsal conjunctiva and may be missed on cursory exami nation. Patients complain of tearing, light se nsitivit y, and foreign -body se nsation. Large central geographic corneal erosions can develop and may persist for several days despite patchi ng and lubricat ion. Within 7- 14 days after o nset of eye symptoms, nm ltifocal subepithel ial (stromal) corn eal infiltrates become apparen t on sli t-lamp examination (Fig 4- 16). Photophobia and re duced vis ion from adenoviral subepithelial infiltrates may persist fo r months to years. Epithelial keratitis occurs due to adenovirus replication \,vi thi n the cornea l epitheliu m . Subepithelial infilt rates are likely caused by an imm unopathologic respo nse to viral infection of keratocytes in the superficial corneal stro ma. The evo lu tion of keratitis in EKe is summarized in Figure 4- 17. Chronic compli ca tions of conjunctival membranes in clude subepithelial conjunctival scarring, symblepharon formati on, and dry eye due to alterat ions within the lacrimal glands or lacrimal ducts.
Diagnosis of EKC is suggested in the setting of bilateral fo llicular conju nct ivitis associated with petechial conjunctival hemorrhages, conjunctival pseudomembrane or frank membrane formation, or. later in the clinical course, the presence of bilate ral subepithelial infiltrates. Other adenovi ral ocular syndromes have less LABORATORY EVALUATION
CHAPTER 4:
Infectious Di seases/Extern al Eye: Basic Concepts and Vira l Infection s •
Figure 4-15
Conjunct iva l membranes in a patient w ith EKC . (CourtesyofJamesChodosh, MD.)
Figure 4-16
Subepithelial corneal infiltrates in a patient with EKe.
125
(Courtesy of Vincent P deLuise, MD.)
specific signs, but laboratory diagnos is is only rarel y indicated. Although viral cultures readily diffe rentiate ade novi rus from HSV infection , the clinical disease typically subsides or resolves before resu lts become ava ilable. A rapid im munodetection assay (RPS Adeno Detector [Rapid Pathogen Screening; South Williamsport, PA]) to detect adenovirus antige ns in the conjunctiva is now ava ilable. Paired serologic tite rs 2-3 weeks apart allow confirmation of acute adenovirus infection, but this test is rarely performed. Therapy fo r adenoviral ocular infection is primarily suppo rtive. Cool com presses and art ificial tears may provide symptomatic relief. Topical antibiotics may be indicated only when the clinical signs, such as mucopurulent discharge, suggest an associated bacterial infection or when a viral cause is less certain. For patients wi th conjunctival membranes due to EKe, manual removal by the phys ician with force ps or a cotton swab every 2- 3 days, combined with judicious use of top ical corticosteroids, may speed resolution and prevent scarring. Topical corticosteroids also reduce photophobia and improve vision impaired by adenoviral subepithelial infiltrates. Because corticosteroids may prolong viral shedding fro m adenovir us-infected pat ients
MANAGEMENT
126 • Exte rnal Disease and Cornea
Stage 0
Stage I
Stage II
I
Stage III Figure 4-17
Stage IV
Stage V
Schematic drawing illustrating the natural progression of specific corneal epi-
thelial and stromal pathology in EKe. Stage 0, Poorly stai ni ng , minute punctate opacities within the corneal epithelium. Stage I, Fine punctate epithelial keratitis iPEKI. Stage II, Fine and coarse PEK. Stains brightly with rose bengal. Stage III, Coarse granular infiltrates within deep epithelium, early subepithelial infiltrates, diminished PEK. Stage IV, Classic subepithelial infiltrates without PEK. Stage V, Punctate epithelial granularity adjacent to and distinct from the subepithelial infiltrates. (Adapted from Jones DB, Maroba AY, Wilhelmus KR. Prob!em so!ving in cornea! and external diseases. Course 626. presented at the American Academy of Ophthalmology. Atlanta, GA; 1995.)
and can lead to worsening of HSV infections, their use should be reserved for patie nts with clinical signs of adenovir us infec tion who present with specific indications for treat ment, including conjunctival membranes and reduced vision due to bilateral subepithelial infiltrates. The use of topical corticosteroids does not affect the natural course of the disease, and it may be d ifficult to wean patien ts fro m them. Nonsteroidal anti-inflammatory agents (NSAIDs ) are ineffective th erapy fo r aden oviral subepithelial infiltrates, but they may be helpful in preventing recurrence following tapering of the corticosteroids. Actively in fected people readily tra nsm it ad enoviruses. Vi ral shedd ing may persist for 10-14 days after onset of clinical signs and symptoms. Transmission can be prevented by personal hygiene meas ures, includi ng frequent hand washing; cleaning of towels, pil lowcases, and handkerchiefs; and disposal of contam inated facial tissues. Individuals who work with the public, in schoo ls, or in health care fac ilities in particular should consider a tempo rary leave of absence from wo rk to prevent infec ting others, especially those who are al ready ill. Patients should be considered infectious if th ey are still hype remic an d
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Infectio us, Disea ses/Externa l Eye: Basic Concepts and Viral Infections •
127
tearing. It is more difficult to assess transm issibility in patients treated with topical corti costeroids, as they may appear quiet but still shed the vir us.
DNA Viruses: Poxviruses The Poxviridae encompass a la rge family of enveloped, double-stranded DNA viruses, with a distinctive brick or ovoid shape and a complex capsid structure. The best-known poxviruses are molluscum contagiosum, vaccinia, and smallpox (variola) virus. Molluscum Contagiosum
Moll uscum contagiosum virus is spread by d irect contact with infected individuals. Infection produces 1 or more umbili cated nodules on the skin and eyelid margin and, less commonly, on the conjunctiva. Eyelid nodules release viral particles into the tear film.
PATHOGENESIS
A mollusc um nodule is smooth with an umbil icated central core. It is smaller and associated with less inflammation than a keratoacanthoma. Punctate epithelial erosions and, in rare cases, a corn eal pannus rn ay occur. Any chronic follicular conjunctivitis should instigate a careful search for lid margin molluscum lesions (Fig 4-18). CLINICAL PRESENTATION
The moll usc um contagiosum virus cannot be cultured using standard techn iques. Histopathologic examination of an ex pressed or excised nodule shows eosinophilic, intracytoplasmic inclusions (Henderson -Patterson bodies) within epiderma l cells. Diagnosis is based on detection of the characteristic eyelid lesions in the presence of a follicular conju nctivitis. Spontaneous resolution occurs but can take months to yea rs. Treatment options include complete excision, cryotherapy, or incision of the central portion of the lesion. Extensive facial and eyelid molluscum lesions occur in association with AIDS (Fig 4- 19).
LABORATORY EVALUATION AND MANAGEMENT
Figure 4-18
Single nodu le of molluscum contagiosum at t he upper eyel id marg in.
128 • External Disease and Cornea
Figure 4-19 Mu ltiple molluscum contag iosum lesions on the eyelid of a patient with AI OS. (Courtesy of James Chodosh, MD.)
Vaccinia Discussion of another poxvirus, vaccin ia, was previously removed from the BCSC series because of the eradication of smallpox. More recently, however, concerns of bioterrorism have prompted the reinstitution of a vaccinati on program, especially for military person nel. Ocular complications from self-inoc ulation have resulted, including potentially severe periorbital pustules, conjunctivitis, and kerat itis. Treatment includes topical trifluridi ne. Use of vaccin ia-immune globulin (V lG) is controversial but is indicated for severe disease. Concern about the use of VIG stems from limited rabbit studies that demonstrated a possible increase in corneal scarri ng. Individua ls who are immunosuppressed, atopic, pregnant, breast-feeding, allergic to the vaccine, or living with a high-risk household contact should not receive the vaccine because of the risk of the possibly fatal, progressive vaccinia. Fillmore GL. 'Nard TP, Bower KS, et al. Ocular complications in the Department of Defense Smallpox Vaccination Program. Ophthalmology. 2004; 111 (11):2086-2093. Neff JM, Lane JM, Fulginiti VA, Henderson DA. Contact vaccinia-transmission of vaccinia from smallpox vaccination. lAMA. 2002;288( I 5): 1901 - 1905.
DNA Viruses: Papovaviruses Human papillomaviruses (HPV) are small, nonenveloped, double-stranded DNA viruses with an icosahedral capsid. Persistent vi ral infectio n of susceptible epithelial cells induces cellular proliferatio n and can lead to malignan t transformati on . Papillomavirus proteins can induce transformation of the cell and loss of se nescence. HPV subtypes 6 and II are maintained in a latent state within basal epithelial cells as circular episomes with very limited viral gene transcription and low copy number. Early viral gene products stim ulate cell growth and lead to a skin wart or a conjunctival papilloma. As HPV-contai ning basal epithelial cells mature and differentiate into superficial epithelial cells, they become permissive for complete viral gene ex pression and produce infectious virus. Neoplastic transformation due to HPV 6 or II is ve ry rare. I n contrast, H PV 16 and 18 stereotypically
CHAPTER 4: In fectious Diseases/ Externa l Eye: Basic Concepts and Vira l Infections • 129
integrate their viral genome into host chromosomal DNA, and this in turn is associated with malignant transformation and squamo us cell carcinoma. Recently developed immunization strategies specifically targeted against HPV oncogenes may result in a decreased incidence of these tumors in the future. Verrucae and papillomas are caused by papillomavirus infection of the skin and conjunctival epithelium. Venereally acquired conj un ctival papillomas resemble those on the larynx and urogenital tract. Papillomavi rus-associated conjunctival intraepithelial neoplasia and squamous cell carcinoma share many histologic features with similar lesions in the uterine cervix . Another neoplasm, Kaposi sarcoma of the skin or conjunctiva, is associated with infection by human herpesvirus type 8. These entities are discussed in greater detail in Chapter 8.
RNA Viruses Picornaviruses are negative-sense, single-s tranded RNA viruses with an icosahedral capsid and no envelope. Picornavir idae family members include the enteroviruses (poliovir us, coxsackievirus, echovirus, and enterovirus) and the rhinoviruses, the single most common etiology of the common cold. Toga viruses are positive-se nse, single-stranded RNA with no envelope. Togaviruses with general medical and ophthalmic importance include rub ella, encephalomyelitis, yellow fever, and dengue viruses. Orthomyxoviruses such as influenza virus are negative-sense, single-stranded RNA viruses with an enveloped helical icosahedral capsid. Structurally similar to the orthomyxoviruses, para myxoviruses of ocular importance include mumps virus, measles (rubeola) virus, parainfluenza virus, respiratory syncytial virus, and Newcastle disease virus (a cause of follicular conjunctivitis in poultry handlers). The para myxovirus envelope contai ns hemagglutinin-neuraminidase protei n spikes and a hemolysin, which mediate viral fu sion with the host cell m embrane. Eye infections due to RNA viruses present to the ophthalmologist less often than those due to DNA viruses, and they most commonly manifest as folli cular conjunctivitis associated with an upper respiratory infection. However, certain RNA virus infect ions may cause pathologic changes in Virtually any ocular tissue. For example, influenza virus can induce inflammation in the lacrimal gland, cornea, iris, retina, optic nerve, and other cranial nerves. In measles (rubeola) virus (a paramyxovi rus) infection , the classic triad of postnatall y acquired measles-cough, coryza, and follicular conjunctivitis-can be observed. Mild epithelial keratitis may be present. Less com l11on are optic neuritis, retinal vascular occlusion, and pigmentary retinopathy. Measles keratopath y, a major source of blindness in the developing \vorld, typically presents as corneal ulceration in malnourished, vitamin A-deficient ch ild re n. (For fur ther informat ion on the ocular effects of vitamin A deficiency, see Chapter 3.) A rare and fatal complication of measles virus in fection, subacute scleroSing panencephalitis (SS PE), occurs in about 1 per 100,000 cases, often years after clin ically apparent measles. Mumps virus (a paramyxovirus) infection may result in dacryoadenitis, sometimes concurrent with parotid gland involvement. Follicular conjunctivitis, epithelial and
130 • External Disease and Cornea
stromal keratitis, iritis, trabeculitis, and scleritis have all been reported within the first 2 weeks after onset of parotitis. Rubella virus (a togavirus), when acqu ired in utero, may cause microphthalmos, corneal haze, cataracts, iris hypoplasia, iridocyclitis, glaucom a, and salt-and-pepper pigmentary reti nopathy. Congenital ocular abnormalities due to rubella are much worse when maternal infection ensues earl y in pregnancy. Measles, mumps, and rubella are all uncommon in places where childhood immunization is regularly performed. Corneal biopsy and impression cytology have been useful in helping in the early diagnosis of ra bies virus infection . Rabies virus can be transmitted via corneal tran spl ant. Zaidman G\·\~ Billingsley A. Corneal impression test for the diagnosis of acute rabies encephalitis. Ophthalmology. 1998;105(2P49- 251.
Acute hemorrhagic conjunctivitis (AHC), caused by enterovirus type 70 and coxsackievirus A24 variant, and, less commonly. adenovirus type 11, is one of the most dramatic ocular viral syndromes. Sudden onset of follicula r conjunctivitis associated w ith multiple petechial hemorrhages of bulbar and tarsal conjunctiva characterizes AHC. The hem orrhages may become confluent and appear posttraumatic. Eyelid edema, preauricular adenopathy, chemosis, and punctate epithelial keratitis may be associated with in fection. AHC is highly contagious and occurs in large and rapidly spreading epidem ics. In approximately l out of 10,000 cases due to enterovirus type 70, a polio-like paral ysis follows; neurologic deficits are permanent in up to one th ird of affected individuals. Retroviruses are positive- sense, Single -stranded enveloped RNA viruses th at encode a viral enzyme, reverse transcript ase, that assists in conversion of the single- stranded RNA genome into a circular double-stranded DNA molecule. The viral nucleic acid then integrates into host cell chromosomal DNA. The retrovirus of greatest medical importance is human immunodeficiency virus (HIV), the etiologic agent of AIDS. HIV enters the hu man host via sexual contact at mucosal surfaces, through breast-feeding, or via blood-contaminated needles. Sexually transm itted infection is facil itated by uptake of HIV by dendri tic cells at mucosal surfaces. CD4+ T lymphocytes are a primary target of the virus, as are dendritic cells and monocyte- macrophages. Infection of these cell types induces predictable defects of innate and acqui red (both humoral and cellular) immunity. Primary vi remia results in an infectious mononucleosis-like HIV prodrome, followed by seeding of the peripheral lymphoid organs and development of a measurable immune response. Infected patients may remain otherwise asymptomatic for several years, but CD4+ T lymphocytes are progressively depleted. Clinical immunodeficiency eventually develops. AIDS- related ocular disorders include herpes zoster ophthalmicus, molluscum contagiosum, keratoconjunctivitis sicca, microsporidial keratoconjunctivitis, HIV neuropathy, crypto coccal optic neuritis, re tinal microvasculopathy, choroiditis and re tinitis due to syphilis, mycobacteria, pneumocystosis, toxoplasmosis, cytomegalovirus, HSV, and VZV. For mo re info rmation regarding HIv. see BCSC Section 1, Update on General Medicine, and Section 9, Intraocular Inflamm ation and Uveitis. Cunningham E1 1r, Margolis TP. Ocular manifestations of HIV infection . N Engl JMed. 1998; 339(4)B6- 244 . Goedert JJ. The epidemiology of acquired immunodeficiency syndrome malignancies. Semin Oneal. 2000;27(4); 390- 401.
CHAPTER
5
Infectious Diseases of the External Eye: Microbial and Parasitic Infections
A detailed history and physical exam ination are essential to proper diagnos is of external eye infections. The patient's chief complaint and a complete systemic and ocular history, including the presence of risk facto rs for infections of the external eye, should be noted. A complete eye examination should include special attention to the skin of the face and eyelids, the preauricular lymph nodes, the globe- orbit relationship, ocular discharge, and conjunctiva l and corneal morphology. Diagnostic tests are chosen to differentiate between likely di ag nostic entities and to assist in therapy (eg, antimicrobial sensitivity testing in microbial keratitis).
Bacteriology In bacteria, round or rod-shaped cells with a wide range of sizes, the genetic material is not separated from the cytoplasm by a nuclear membrane; hence, these organisms are refer red to as prokaryotic cells in contrast to eukaryatic cells, which have a membrane-bound nucleus. In prokaryotes, a plasma membrane encloses a single cytoplasmic compartment contain ing DNA, RNA, and protein in an amorphous matrix without membrane-bound cellular orga nelles. Most bacterial genes exist as part of a single circular chromosome. but other ge nes are present on smaller extrachromosomal circles called plasm ids. Plasmid DNA typicall y determines inhe ritance of 1 or a few characteristics such as antibiotic resistance, and it represents an important mechanism by which traits are passed between different bacterial strains and someti mes between bacteria.l species. Bacterial classification is determined by the International Com mittee for System ic Bacteriology (ICSB). Classification is based on microscopic an d colony morphology, enzyme activity, biochemical tests, DNA finge rp rinting, and geno mic sequence (when known). Prokaryote structure determines many aspects of infection pathogenesis. The protective coat or cell wall su rroundin g the plasma membrane of bacteria imparts shape and rigidity to the cell and med iates interactions with the environment, other bacteria, and bacterial viruses. The cell wall also forms the basis of Gram stain reacti on. Bacteria stain violet (gram-positive) or red (gram -negative) based on the structure and biochemical composition of their cell wall. Some bacteria that stain poorly with Gram stain, incl udin g jV1ycobacteria and Nocardia asteroides, can be visualized with acid -fast stain. 131
132 • External Disease and Cornea
Gram-positive bacterial cell walls contain predominantly peptidoglycan and teichoic acid. Gram-negative cell walls are complex and have a thin peptidoglycan layer and an external lipid membrane containing lipopolysaccharide, also referred to as endotoxin. Gram staining of clinical specimens is important not only because it helps to classify a pathogenic organism but also because gram-positive and gram-negative bacteria are typically susceptible to different classes of antibiotic d rugs (Table 5-1). Specialized structures external to the cell wall uniquely facilitate bacterial interactions with a diverse environment.
• flagella : enable some bacteria to negoti ate a liquid environme nt • pili: involved in bacterial conjugation (transfer of bacterial DNA from one bacterial cell to another) • fimbriae: mediate adherence of one bacterium to another and to eukaryotic ceLls adhesins: specific surface-associated molecules or fimbriae that mediate attachment of bacteria to mucosal surfaces Bacteria repli cate by binary fission. A single bacterium can divide approximately every 20 mi nutes. This ability to replicate quickly allows rapid adaptation to envi ronmental changes. The extreme variety of environmental niches also encourages bacterial survival strategies, including engagement of different enzymatic machinery (metabolic pathways) develop ment oflocal bacterial ecosystems (biofilms) capacity to transmit genetic elements (plasm ids) from one bacterial cell to another and, occasionally, from one bacterial species to another
Gram-positive Cocci Staphylococcus species Staphylococci inhabit the skin, skin glands, and mucous membranes of healthy mammals. They grow in grapelike clusters in culture but may be seen Singly, in pairs, or in short chains on smears from ocular specim ens. Staphylococci produce an external biofilm that interferes with phagocytosis and secrete a variety of extracellular proteins-including toxins, enzymes, and enzyme activators-that facilitate both colon ization and disease.
Tab le 5-' Bacterial Classification for Gram Sta ining
Cocci
Rods
Filaments
Gram Positive
Gram Negative
Staphylococcus spp Streptococcus spp Enterococcus spp Corynebacterium spp Propionibacterium spp Bacillus spp
Neisseria spp
Mycobacterium spp Nocardia spp Actinomyces spp
Pseudomonas spp Ente robacte rspp Haemophilus spp Bartonella hense/ae
CHAPTER 5:
Infectious Diseases/Externa l Eye: Microbial and Parasitic Infections.
•
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Staphylococci also produce iantibiotics, small polypeptides that exert antibacterial effects on other bacteria competing for the same natural habitat. Staphylococci adapt quickly and effectively to administered antibacterial agents and may develop resistance to ~ -lactams, macrolides, tetracyclines, and quinolones. Streptococc us species Streptococci inhabit the mucous membranes of the normal upper respirator y tract and female genital tract (Fig 5-1). They grow in pairs and chains. The historical classification of streptococci based on their ability to hemolyze blood-containing agar media is useful for initial recognition of clinical isolates. Another historical means of classification ,vas serologiC grouping based on cell wall carbohydrates (Lancefield groups). These methods are used less today given the availability of genetic sequence data. Disease-causing factors of the highly pathogenic ~-hemolytic S pyogenes and other pyogenic streptococci include the M and M-like proteins, pyrogenic exotoxins, streptolysin, C5a peptidase, and hyaluronidase. M proteins anchor in the cytoplasmic membrane and extend externally through the bacterial cell wall to help the organism resist phagocytosis by neutrophils. Streptolysin lyses erythrocytes, platelets, and neutrophils. CSa peptidase cleaves and destroys the func tion of CSa, an important chemoattractant of neutrophils. Hyaluronidase is believed to act as a tissue invasion factor. 5 pneumoniae appear in smears as lancet-shaped diplococci and express a polysaccharide capsule that resists phagocytosis by macrophages and neutrophils. The toxin pneumolysin is liberated by autolysis and inhibits neutrophil chemotaxis, phagocytosis, lymphocyte proliferation, and antibody synthesis. Enterococcus species Enterococci are gram -positive cocci that may be seen in pairs or in sho rt chains. They are capable of survival in harsh environments but, in humans, are commensal in the gastrointestinal and genitourinary tracts. E faecalis, an important cause of endophthalmitis, uses
134 • Extern al Disease and Cornea
a unique mechanism of plasmid exchange involving the expression of sex pheromones. These chemicals, ""hen expressed on the surface of enterococci, induce a bacterial mating response and exchange of ge netic materi al, a means by which enterococci acq uire antibiotic resistance. Enterococci also produce a cytolysin with potent effects on eukaryotic ceU membranes. Gram-negative Cocci Neisseria species
N gonorrhoeae causes urogen ital, rectal, and pharyngeal infecti ons, as well as hype racute conjunctivitis, and can invade intact corneal epithelium , induce keratolys is of the corneal stroma, and perforate the cornea. N gonorrhoeae is always a pathogen, whereas the closely related species N meningitidis may be commensal in the pharynx without causing disease. /\' gOl1orrhoeae is a bean-shaped, gram-negative diplococcus usually seen within neutrophils on a clin ical smear from ocular or genital sites (Fig 5-2). Gram-positive Rods Corynebacterium species
Corynebacterium species are pleomorphic bacilli that produce palisading or cuneiform patterns o n sm ears. C diphtheriae is an exotoxin-producing cause of ac ute membranous conjunctivitis. Other Corynebacterium species are referred to as diphthe roids and are routinely isolated from the external eye in the absence of clinical infection. C xerosis is commonly seen on histologic sections of vitamin A deficiency- associated conjunctival Bitot spots, but its Sign ificance in conjunctival xerosis is unkn own. Propionibacterium species
P aCnes an d related species are normal inhabitants of human skin. They are aerotolerant but prefer an anaerobic environment. These slende r, slightly curved gram-positive rods
Figure 5·2
Gram-nega tive cocci (Neisseria gonorrhoeae). (Gram x1000).
CHAPTER 5:
Infect ious Diseases/ Extern al Eye: Micro bial and Parasit ic Infecti ons. 135
sometimes have a beaded appearance (Fig 5-3). P acnes is a major cause of chronic postoperative endophthalmitis and a rare cause of microbial keratitis. Bacillus
species
Bacillus species are ubiquitous gram- positive or gram-variable rods commonly found in soil and characterized by the production of spores, a form of the bacteria that allows survival fo r extended periods of time under extremely harsh conditions. Bacillus species are typ icall y motile, and th is featu re m ay play a role in the explosive character of B cereusinduced posttrau m at ic endophthalm itis. B cereus produces a number of toxins that may rapid ly damage ocula r tissues. The closely related genus Clostridium is anaerobic; Bacillus species are aerobes or facu ltative anae robes. Gram-negative Rods
Pseudomonas aeruginosa comprises slender gram -negative rods (Fig 5-4) common ly found as contam ina nts of wate r. P aeruginosa ocular infections are among the most fu lmi nant. Permanent tissue da mage and scarring are the rule followi ng corneal infection. Structural virulence factors of P aeruginosa incl ude polar fl agella, adh esins, and sur face pili. P aeruginosa orga nisms secrete a number of toxins that disrupt protein synthesis and damage cell membranes of ocular cells, as well as proteases that degrade the corn eal stromal extracell ular rnatrix.
Enterobacteriaceae The Entero bacter iaceae fam il y includes multiple ge nera of enteric non-spare-form ing gram -negative rods, including Escherichia coli, Klebsiella, Enterobaet,,; Citrobacter, Serratia, Sa lm onella, Shigella, and Proteus. In particul ar, Klebsiella, Enterobacter, Citrobacter, Serra tia, and Proteus are important causes of kerat itis. Pathogenetic factors include pili, ad hesins. cytolysins, and toxins. Enteropath ogenic E coli express a protein similar to cholera toxin.
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136 • External Di$ease and Cornea
,
Figu re 5-4
Gram-negative rods (Pseudomonas aeruginosa). (Gram x1 000).
Haemophilus species Haemophilus species vary in morphology fro m coccobacilli to short rods. Culture isolation requires enriched media such as chocolate agar. These species are obligate parasites of manlma lian mucous mem branes and commonly inhabit the human upper respiratory tract and mouth. Along with streptococci, they are important agents of bleb infection s follow ing glaucoma filtering surgery. H influenzae can be d ivided into biotypes based on biochemical reactions; encapsulated strains are further divided into serotypes based on their capsular polysaccharides. H influen zae type B (Hib) is the primary human pathogen, and its capsule is a major virulence factor.
Bartonell a henselae The etiologic agent of cat-scratch disease, B henselae appear as gram-negative aerobic rods, best seen by Warth in-Starry stain ing of tissue biopsies. B henselae in fection can be confirmed by cult ure, by polymerase chain reaction (PCR), by imm unocytologic stai ni ng of histologic specimens, and by serology. Cats are the natural reservoir of B henselae, and infection may be transm itted by a cat scratch or by contact with fl eas. (See Parinaud Oculoglandular Syndrome later in the chapter.) Gram-positive Filaments Mycobacterium species Mycobacteria are nonmotile, aerobic , weakly gram-positive, but acid-fast; they appear on smears as straight or slightly curved rods. Lowenstein -Jensen medium is most commonly used fo r cu lture isolation. Mycobacteria are obligate intracell ular pathogens and fall into 2 main grou ps based on growth rate. M tuberculosis and M leprae are slow growers. Ocular infection by M tuberculosis is uncommon, but it can mani fest as a posterior uve itis. The
CHAPTER 5:
Infectious Diseases/Externa l Eye: Microbial and Parasitic Infections.
137
fast-growing, atypical mycobacteria, includin g M fortuitum and M chelonei, more commonly cause ulcerative keratitis and are an important cause of keratitis following refractive surgery.
Nocardia species N asteroides and related filamentous bacilli are gram-variable or gram-positive and weakly acid-fast. They may cause ke ratitis clinically similar to that caused by the atypical mycobacteria.
Actinomyces species Actinomycetes are gram-positive, non-acid-fast anaerobic bacteria that colonize the mouth, intestines, and genital tract. They are an important cause of canaliculitis.
Chlamydia Spec ies Chlamydiae are spherical or ovoid obl igate intracellular parasites of mucosal epithelium with a dimorphic life cycle. The infectious form is the elementary body (EB), which develops within an infected host eukaryotic cell into the intracellular replicating form, the reticulate body (RB). Only the EB survives outside the host, and only the EB is infectious. Reticulate bodies divide by binary fission to produce 1 or more EBs within a cytoplasmic vacuole, seen on light microscopy as a cellular inclusion.
Spi rochete s Spirochetes are characterized by the periplasm ic location of their flagella (en doflagella). They are too narrmv to be seen by light microscopy. Visualization in fresh clinical specimens requires dark-field illumination. Silver staining or immunocytology can aid identification in histopathologic specimens. Treponema pallidum causes venereal syphilis. By dark-field illumination, T pallidum appear fine and corkscrew-shaped, with rigid, uniform spirals. For further discussion of syphilis, see BCSC Section l, Update on General Medicine, and Section 9, Intraocular Inflammation and Uveitis.
Borreli a burgdorfe ri Borrelia species are obligate parasites, best visualized with Giemsa stain. B burgdorferi, the etiologiC agent of Lyme disease and associated Lyme uveitis, is transmitted to humans by tick bites . The preferred hosts for sub adult ticks are rodents, whereas adult ticks feed on deer. B burgdorferi infection of migrating birds may account for the wide distribution of the organism. Pathogenetic factors of B burgdorferi include the expression of proteinases that facilitate tissue invasion, induction of proinflammatory cytokines on binding to phagocytes, and activation of the complement cascade. Although the organism can be cultured from biopsies of erythema migrans skin lesions, it is difficult to recover from blood or synovial fluid . [n general, the diagnosis of Lyme disease is determined by serology and typical clinical findings. See also BCSC Section I, Update on General Medicine, and Section 9, intraocular inflammation and Uveitis.
138 • Externa l Disease and Corn ea
MycolO!lY Fungi are eukaryotes that develop branching filamen ts and reprod uce by means of sexually or asexually produced spores. Fungal cell walls are rigid and contain chitin and polysaccharides. Fungi are classically divided into 2 groups: yeasts are rou nd or oval fungi that reproduce by budd ing and someti mes form pseudohyphae by elongation durin g buddin g, and molds are multicellular fungi composed of tubu lar hyphae, either septate or no nseptate, that grow by branching and apical extension (Table 5-2) . Yeasts may also form hyphae under certain circumstances. The branchi ng hyphae of molds can form a mycelium, an interconnected ne twork of hyphae. Septate fungi are distinguished by walls that divide the filaments into separate cells, each containing one or more nuclei (Fig 5-5) . Dimorphic fungi grow in 2 distinct forms as a result of changes in cell wall synthesis in diffe rent environments. Such fun gi may appear as yeast in the host and as molds in a room-temperature laboratory. Dimorph ic fun gi may be highly virulent pathogens. Fu ngal cell walls stain with Gomori methenam ine silver but, except for Candida, do not take up Gram stain. Classifi cation of filamentou s fungi is based on microscopic features of conidia (fungal elements that form asexuall y) and co nidiophores (the specialized hyphae where conidia are form ed). Most antifungal medications target the stero l ~co n tain i n g cell membrane within the fungal cell wall.
Table
5~2
Fungus
Yeasts
Molds (fil amentous) -
Candida spp Cryptococcus neoforma ns Rhinosporidium
Figure 5~ 5
Septate
Nonseptate
Fusarium spp Aspergillus Curvularia
Mucor Rhizopus Absidia
Septate hyphae of filamentou s fungus (Fusarium sofani). (Gram x10001. (Courresyof
Vincent P deLuise, MD.)
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139
Yeasts
The incidence of mycotic infections in general and yeasts in particular has risen concomitantly with the advent of extensive antibiotic usage in the general population and is closely associated with immunosuppression, whether due to disease or medical therapy. Candida species are ubiquitous in the environment and can be isolated in the absence of clinical disease from the gastrointestinal and genitourinary tracts, the oropharynx, and the skin. C albicans is the yeast most commonly isolated from each of these sites (Fig 5-6). Binding to host tissues is a prerequisite fo r infection; and the C albicans mannan protein, fibrinogen-binding protein, and a primitive, integrin-like protein facilitate adhesion to target tissues. The transformation to a hyphal form and the expression of aspartyl proteases and phospholipases (the latter at the hyphal tip) facilitate penetration of C albicans through tissue barriers. Cryptococcus neoformans is acquired through inhalation and causes subclinical infection of the pulmonary tract. Clinical cryptococcal disease in the brain and optic nerve, eye, lung, skin, and prostate occur in immunosuppressed patients. Rhinosporidium seeberi organisms are present in soil and groundwater and presumably infect humans through contact with these sources. Ocular rhinosporidiosis manifests as sessile or pedunculated papillomatous or polypoid lesions in the conjunctiva, which may be associated with similar lesions in the nose and nasopharynx. Septate Filamentous Fungi
Fusarium species such as F solani and F oxysporum are encountered in warm, humid environments and can cause a fulminant keratitis. Most other filamentous fungal corneal infections are more indolent. Among the genera that have been isolated from the external eye are Aspergillus, Curvularia, Paecilomyces, and Phialophora. Most cases of oculomycosis follow trauma with vegetative matter.
•
Figure 5-6
Yeasts (Candida albicans). (Gram xl 000). (Courresyof James Chodosh, MD)
140 • Externa l Di sease and Corne a
Nonseptate Filamentous Fungi Nonseptate filamentous fu ngi include the Mucor, Rhizopus, and Absidia species in class Zygomycetes, order Mucorales, family Mucoraceae. These ubiquitous fungi cause lifethreaten ing infections of the paranasal sinuses, brain, and orbit in immunocompromised patients, with particular predilection for those with fa ilure of normal phagocytic responses due to ac idosis from diabetes mellitus or renal fa ilure. Fungal invasio n of blood vessels results in ischemic necrosis of affected tissues. Pneumocystis carirJii was formerly classified as Protozoa, but gene sequencing has placed the organism firmly in the Fungi kingdom . P carinii remains one of the primary condit ions associated with HIV infection and is an important cause of choroiditis in affected individuals. Thomas PA . Geraldine P. Oculomycosis. In: Collier L. Balows A, Sussman M. eds. Tapley 6Wilsolls Microbiology and Microbial Infections. 10th ed. Medical Mycology. ed Merz WG, Hay R]. London: Hodder Arnold; 2005;chap 16.
Parasitology Protozoa Acanthamoeba species are aquatic protozoa (unicellul ar eukaryotes) that infect the human cornea and brain with potentially devastating results. The Acanthamoeba life cycle includes the motile trophozoite (I 5-45 ~m in diameter) and the dormant cyst (10-25 ~m in diameter) forms (Fig 5-7). Free-living amebae are foun d in both forms, but only the trophoZOite is infectious. Both forms are fo und in infected human tissues. Cysts are double-walled and very resistant to environmental stressors. Acanthamoeba species are differentiated from one anot her on the basis of their cyst morphology and antigenic composition.
Figure 5-7
Amebic cyst (Acanthamoeba polyphaga). (Calcofluor white xl 0001.
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141
Microsporida are obligate intracellular parasites with a unique means of infection. Microsporida spores enter eukaryotic cells through a polar tube that opens a hole in the eukaryotic cell membrane. Growth and differentiation of the sporoplasm result in the formation of intracellular spores that may be liberated by lysis of the host cell. Of the phylum Microspora, the following genera have been implicated in human infection: Nosema, En~ cephalitozoon, Pleistophora, Vittaforma (formerly Nosema corneum), Trachipleistophora, Enterocytozoon, and unclassified microsporida. Toxoplasma gondii causes one of the most common parasitic infections of humans and is a common cause of chorioretinitis (see BCSC Section 9, Intraocular Inflammation and Uveitis). Cats shed oocysts in their feces after ingestion of T gondii. Oocysts may be ingested by human food animals such as swine and the cyst~ containing meat of these animals eaten by humans. Alternatively, cysts may be ingested directly by human contact with cat feces or feces ~ contaminated water. Transplacental transmission to the fetus of T gondii tachyzoites can result in a devastating fetal infection. See BCSC Section 6, Pediatric Ophthalmology and Strabismus, for discussion of the consequences of maternal transmission of toxoplasmosis.
leishmania species Cutaneous leishmaniasis is transmitted at the bite of its vector, the female sandfly, in endemic areas of tropical Asia, Africa, and Latin America. Leishmania organisms hide within the phagolysosomal system of macrophages. An infected eyelid ulcer may become granulomatous. Scrapings or biopsy material can show intracellular parasites by Giemsa or immunofluorescent stains. The parasites can sometimes be isolated on blood agar or insect tissue culture medium. Helminths
Onchocercal filariae are transmitted by the bite of the blackfly of the genus Simulium. This fly lays its eggs on trailing vegetation in fast-flowing rivers (hence the common name river blindness) and is endemic in parts of sub-Saharan Africa, the Middle East, and Latin America. M icrofilariae penetrate the skin and mature in nodules at the site of the fly bite. Maturation to the point of mating and microfilariae production takes approximately 1 year, and worms can live as long as 15 years in the human host. The adult female worm may grow to 100 cmlong and liberates as many as 1500 microfilariae each day. Skin snips examined microscopically may show microfilariae of approximately 300 ~m in length. Migration of microfiiariae to the skin and eye results in clinical onchocerciasis, and subsequent blackfly bites can carry the organism to others. Microfilariae may enter the peripheral cornea and reach the inner eye. Keratitis (including punctate keratitis and "snowflake" and sclerosing peripheral corneal opacities), anterior uveitis, and chorioretinitis occur upon death of the microfilariae. Onchocerciasis is cumulative; the severity of the disease depends on the degree of exposure to blackfly bites and the density of microfilariae in the tissues. Treatment by nodulectomy, oral ivermectin, and control of local blackfly populations has been successful in selected areas. Loa loa larvae enter the skin at the bite of an infected Chrysops (mango horsefly). Adult worms may grow to 6 cm in length and migrate through the connective tissues, causing transient hypersensitivity reactions. Loa loa may appear beneath the conjunctiva.
142 • External Disease and Cornea
Visceral larval migrans is a multisystem disease in yo ung children caused by the migrating larvae of Toxocara canis and Toxocara caN, natural residents of dogs and cats, respectively. Toxocara larvae develop and mate in the intestines of their natural host; human ingestion of fertilized eggs in pet feces results in infection. Toxocara larvae in the human in testine do not receive the proper environmenta l signals and migrate throughout the
body, invading and destroying tissues as they go. Ocular larval migrans occurs in older children, and the viscera are typically spared. Taenia solium, the pork tapeworm. is transmitted to humans from ingestion of undercooked pork containing the cysticercus stage. ln the stomach, proteolytic enzymes dissolve the cysticercus capsule. Adult worms attach to the intestinal wall by means of suckers at the head (scolex) and release eggs that then disseminate. A hydatid cyst can subsequentl y form in var ious tissues. including the eye and orbit, to cause cysticercosis.
Arthropods Phthirus pubis Phthiriasis is a venereally acqui red crab louse (P pubis) infestation of coarse hair in the pubic, axillary, chest, and facial regions. Ad ult female crab lice (Fig 5-8) and immature nits on the eyelashes cause blepharoconjunct ivitis.
Demodex species D Jolliculorum and D brevis inhabit norma l superficial hair and eyelash follicles and deeper sebaceous and meibomian glands. respectively. Eyelash colonization increases with age. The organi sm may be apparent as cylindrical sleeves around eyelash bases and is associated with blepharitis symptoms. (See Fungal and Parasitic Infections of the Eyelid Margin later in the chapter.)
~ O. t
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'.
Crab louse (Phthirus pubis). IWet mount x200) .
CHAPTER 5:
Infectious Diseases/ External Eye: Microbial and Parasitic Infections.
143
Fly larvae Myiasis occurs when maggots invade and feed on the living or dead tissues of humans or animals. Ophthalmomyiasis (maggot infestation of the eye) can refer to external or internal infestation and involve almost any ocular tissue. Most myiasis occurs when a female fly lands on the host and deposits eggs or larvae. The larvae of some fly species can penetrate through healthy skin and migrate long distances to infest the eye. Extensive larval infestation of a compromised external eye can result in total destruction of orbital contents. Collier L, Balows A, Sussman M, eds . Topley & Wilsons Micro biology and Microbial Infections. 10th ed . Parasitology, ed Cox FEG, Wakelin D, Gillespie SH, Despommier DD. London: Hodder Arnold; 200S.
Prions Prions are altered proteins that cause transmissible lethal encephalopathies, including Creutzfeldt-Jakob disease, scrapie in sheep, bovine spongiform encephalitis, and kuru. Transmission of Creutzfeldt-Jakob disease following corneal transplantation has been reported. Prusiner SB. Shattuck Lecture: neurodegenerative diseases and prions. N Engl 344(20),1516-1 526.
J Med. 2001;
Microbial and Parasitic Infections of the Eyelid Margin and Conjunctiva Staphylococcal Blepharitis Inflammation of the eyelid margins, called blepharitis, is one of the most common causes of external ocular irritation. Blepharitis can have an infectious or in flammatory etiology; the most common causes of blepharitis are staphylococcal infection (usually caused by Staphylococcus aureus but occaSionally other species) and irritation from oily meibomian gland secretions. The sym ptoms, signs, and treatment of infectious staphylococcal blepharoconjunctivitis and meibomian gland dysfunction overlap considerably. In gene ral, the term staphylococcal blepharitis refers to cases in which bacterial infection of the eyelids (and frequently the conjunctiva) is predominant. Meibomian gland dy sfunction and seborrheic blepharitis designate the presence of chronic abnormal oily secretions producing irritative effects in the eyelid margin and conjunctiva (these 2 latter conditions are discussed in Chapter 3). Clinical features that may help in the differential diagnosis of these entities are summarized in Table 5-3.
PATHOGENESIS
Staphylococcal blepharitis is seen more commonly in younger individuals. Symptoms include burning, itching, foreign-bod y sensation, and crusting, particularly upo n awakening. Symptoms of irritation and burning te nd to peak in the
CLINICAL PRESENTATION
144 • Extern al Di se ase and Corn ea Table 5-3 Types of Blepharitis Sta phylococcal
Meibomi an Gla nd Dysfunction
Seborrheic
location
Ante rior eyeli d
Posterior eye lid
Anterio r eyelid
loss and w hitening of eyela shes Eyelid crust ing
Eyelid ulcerat ion Conjuncti vitis
Keratitis
Aqueous tear deficien cy Rosacea PEE
==
Frequent
(-)
Rare
Hard, fibrinous sca les; hard, matted cru sts (often accom pa ny ulcerat ive form ) Occasio nal Papillary (occasionally w ith muco purulent di sc harge ) Inferior PE E, ma rginal infilt rates, vasc ulariz ati on, phlycten ul osis Occasional
+/-
Oily or greasy
(-)
(-)
M ild to moderate injection , papillary ta rsal reaction Inf er ior PEE, marginal infil trates, vascular pa nnu s
(-)
Mild inj ect ion, fOllicu lar or pa pillary ta rsa l reaction Inferior PEE
Occasional
Occasiona l
34%-66%
0%-33%
punctate epi thelial erosi ons.
mo rning and improve as the day progresses, presu mably as the crusted material that accumulates on the eyelid margin overnight dissipates. Typical clinical manifestations incl ude hard, brittle fibrinous scales an d ha rd, matted crusts surrounding individual cilia on the anterior eyelid margi n (Fig 5-9). Small ulcers of the anterior eyelid margin may be seen when the hard crusts are removed. Injection and
Figure 5-9
Staphylococcal blepharitis wi th co llarettes surrounding eyelashes.
CHAPTER 5:
Infectious Diseases/External Eye: Microbi al and Parasitic Infections . 145
telangiectasis of the anterior and posterior eyelid margins, white lashes (poliosis), lash loss (madarosis), and trichiasis may be seen in va rying degrees, depending on the severity and duration of the blepharitis. Aqueous tear defiCiency is found in some patients with staphylococcal blepharitis. Excessive secretion of bacterially modified lipid products into the tear film can increase instability and accentuate evaporative losses, thus further compounding any associated dry-eye state. (See additional dry-eye discussion in Chap ter 3.)
Chronic conjunctivitis A unilateral or bilateral conjunctivitis that persists for 4 or more weeks is considered chronic. When conjunctivitis accompan ies blepharitis, as it frequently does, the condition is known as staphylococcal blepharocorljllrlctivitis. This association is marked by a chronic papillary reaction of the ta rsal conju nctiva, particularly the inferior tarsal conjunctiva near the eyelid margin, as well as injection of the bulbar and tarsal conjunctivae. Chronic conjunctivitis tends to be associated with mild conjunctival injection and scant mucopurulent discharge. Specific clinical signs are common ly seen in patients vvith chronic conj unctivitis caused by certain bacterial species. S aureus is often associated with matted golden crusts and ulcers on the anterior eyelid margin, inferior punctate keratopathy, marginal corneal infiltrates, and, in rare cases, conjunct iva l or corneal phlyctenules. Moraxella lacunata may produce a chronic angular blepharoconju nctivitis, with crusting and ulceration of the skin in the lateral canthal angle and papillary or follicular reaction on the tarsal conjunctiva. Moraxella angular blepharoconjunctivit is is frequ ently associated with concomitant S aureus blepharoconjunctivitis. Conjunctival swabbings for culture and sensitivity should be performed in cases that do not respond to initial empiric antibiotic therapy. In cases of persistent chronic unilateral conjunctivitis refractory to therapy, masquerade syndrome (conjunctival malignancy) and factitious illness should be ruled out.
Keratitis Several forms of keratitis may develop in association with staphylococcal blepharoconjunctivitis. PUrictate epithelial keratopathy manifests as erosions that stain with fluorescein. Freque ntly, the distribution of the keratopathy is mostly inferior, and it sometimes coincides with the contour of the eyelids across the corneal surface. Occasionally, a diffuse pattern may be observed, and asymmetric or unilate ral keratopathy is not uncommon. The degree of corneal involvement can be markedl y disproportionate to the severity of the eyelid disease, a circumstance that can lead to diagnostic confusion. Marginal corneal infiltrates may be the most distinctive clinical finding (Fig 5-10). Phlyctenufosis is a local corneal and/or conjunctival inflammation that is believed to represent a cell -mediated, or delayed, hypersensitivity response induced by microbial antigens such as the cell wall components of staphylococcus. Phlyctenulosis is frequently associated with S aureus in developed countries and is claSSically associated with Mycobacterium tuberculosis in malnourished children in areas around the vIOrld with endemic tuberculosis.
146 • External Disease and Cornea
Figu re 5-10
Staphylococcal ma rgi nal cornea l in fil trate.
Phlyctenules typically present unilaterally at or near the limbus, on the bulbar conjunctiva or cornea, as one or more small, ro unded, elevated, gray or yellow, hyperemic, focal inflammatory nodules accompanied by a zone of engorged hyperemic vessels (Fig 5-11). They typically become necrotic and ulce rate centrally and then spontaneously involute over a period of2-3 weeks. With resolution of corneal phlyctenules, wedge-shaped fibro vascular scars form along the limbus. Conjunctival phlyctenules do not lead to scarring. Bilateral limbus-based fibrovascular corn eal scarring, which tends to be greater inferiorly than superiorly, may indicate previous phlyctenulosis. Corneal involvement is recurrent, and centripetal migration of successive inflammatory lesions may develop. Occasionally, such inflammation leads to corneal thinning and, in rare cases, perforation.
Figure 5-11
Confluent phlyctenu les second ary to staphylococcal bl epharitis.
CHAPTER 5:
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147
Eyelid and conjunctival cuitures can be performed in suspected cases of staphylococcal blepharoconjunctivitis with a doubtful clinical diagnosis or a poor response to emp iric treatment. If the infection is chronic or wo rsening, diagnostic cultures may be essential. If the patient is still on antibiotics or other topical therapeutic measures, then a brief washout period may be advantageous prior to culturing. The characteristic laboratory finding in staphylococcal blepharoconjunctivitis is a heavy, confluent growth of S aureus. Never theless, the finding of a light to moderate growth of bacteria and/or the isolation of staphylococcal species other than 5 aureus does not exclude the diagnosis, particularly if a predominant manifestation of the disease is punctate epithelial keratopathy, marginal infiltrates, or phlyc tenulosis. Susceptibility testing may be useful in gUiding treatment in cases that have been refractory to empiric antibiotic therapy.
LABORATORY EVALUATION
Treatment cons ists of antibacterial and anti-inflammatory measures. Eyelid hygiene, using either commercially available eyelid scrub kits or warm wate r with diluted baby shampoo, may help reduce bacterial colonization and the accumulation of sebaceous secretions. Patient education should emphasize treatment directed toward the base of the lashes with a moistened cotton-tipped applica tor or a small, soft facecloth sudsed with a dilute concentration of baby shampoo. Fo ll OW ing scrubs, a th in film of ant ibiotic ointment may be applied to the eyelid margins. Topical bacitracin, eryt hromycin and azithromycin are commonly used. In addition, aqueous tear defiCienc y and/or lipid-induced tear-film instability is freque ntly present, and the use of artificial tears or other dry-eye remedies may be beneficial. Cases with a prominent conjunctivitis component should be treated with an antibiot ic solution. Treatment for sta phylococcal blepharitis is frequently prolonged and repeated. This factors into the physician's selection of a topical antibiotic. To minimize toxicity and resistance, a well -tolerated, relatively narrow, spectrum antimicrobial agent effective against the majority of staphylococci should be selected. When possible, the agent should be shown to be efficacious by susceptibil ity testing data from the local or regional microbiology laboratory. Anti-inflammatory therapy consists of lim ited and judiciOUS use of mild doses of top ical corticosteroids in selected cases. Corticosteroids should be reserved for patients who have a strong inflammatory component with little active infection. Patients wit h routine staphylococcal blepharitis or blepharoconj unctivitis may obtain more rapid symptomatic relief with the use of adjunctive topical corticosteroids, but the potential risks include prolonging or worsening the infection or inducing corticosteroid-related side effects. Therefore, corticosteroid use in routine cases is strongly discouraged. Corticosteroids provide little therapeutic benefit for toxic-related punctate epithelial keratopathy. In contrast, margi nal infiltrates and phlyctenulosis have a strong immu nologic component and can thus respond to topical cort icosteroid therapy. In the case of phlyctenu losis. corticosteroids are usually necessary early in the course of treatment. Conversely, in the case of marginal infiltrates, eyelid hygiene and antibiotic therapy alone may be sufficient. If the therapeutic effect is inadequate after a few days (in the case of marginal infiltrates), a time-limited cou rse of low-dose corticosteroid can be prescribed. MANAG EMENT
148 • External Disease and Cornea If epithelial defects are noted over the infi ltrates, diagnost ic cultures should be obtained before instituting corticostero id treatment. Chronic or indiscriminate use of corticosteroids sho uld be avoided. Hordeolum
Hordeola are inflammatory or infectious nodules that develop in the eyelid. Most frequently, they res ult from inspissation and secondary infection of sebaceous glands. T hose occurring on the anterior eyelid in the glands of Zeis or lash follicles are called external hordeola, or styes. Hordeola occurring at the posterior eyelid from meibomian gland inspissation are termed internal hordeola. Either type is associated with a localized purulent abscess, usually caused by S aureus.
PATHOGENESIS
Hordeola present as painful, te nder, red nodular masses near the eyelid margin. They may rupture, prodUcing a purulent drainage. Hordeola are generally self-limited, improving sponta neously over the course of 1-2 weeks. Internal hordeola occaSionall y evolve into chalazia, which are chronic granulomatous nod ules centered around sebaceous glands, usually the meibomian gla nds. (Chalazia are discussed further in Chapter 3.) CLIN ICAL PRESENTATIO N
Cultures are not indicated fo r isol ated, uncomplicated cases of hordeolum. Warm compresses with light massage over the lesion can facilitate dra inage. Topically applied antibiotics are generall y not effective and, therefore, not indicated un less an accompanying in fectious blepharoconjunctivitis is present. SystemiC antibiotics are generally indicated only in rare cases of secondary eyelid cellulitis; however, if the patient has a prominent and chronic acco mpanying meibomit is, oral doxycycline may be necessary. For large or persistent lesions, incision and drainage may be required.
LA BORATORY EVALUATION AND MANAGEMENT
Fungal and Parasitic Infections of the Eyelid Margin Demodex is a genus of m ites that are normal commensal acarian parasites of humans (see "Demodex species" earlier in the chapter). The hum an foll icle mites, D fo lliculorum and D brevis, are obligate parasites that inhabit hair follicles and sebaceous/meibom ian glands, respectively. They are com monly seen by slit-lamp biomicroscopy as waxy sleeves around eyelashes or as cylinders extending from sebaceous gla nds of the eyelid margin. The role of these parasites in the pathogenesis of blepharitis is un clear. O ther o rga nisms that survive on lipids of eyelid glands, such as J\lIalassezia fUlf"'; have also been incriminated in certain types ofblepharitis. A foca l granuloma or de rm atitis affecting the eyelid or conjunctiva can be caused by very rare infections, including blastomycosis sporotrichosis rhinosporidiosis cryptococcosis leis hmaniasis ophthalmomyiasis
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Lice in festatio n of the eyelids and eyelashes, also known as phthiriasis palpebrum, is an unco mmon fo rm of conjun ctivitis o r bleph aritis affecting ado lescents and young ad ul ts an d is caused by the pub ic louse and its ova. In rare instances, pediculosis involves the ocular regio n by localized extension of head o r bod y lice (Pediculus humal1us capitis or Pediculus humanus corporis, respecti vely) . Mecha nical remova l of the lice and nits (eggs) can be perform ed with jewelers forceps, but pu bic hairs are usua Ll y treated with a pedi culicide. Any oint ment can smother th e li ce and should be app lied twice daily for at least [0 days, because th e incubation period (of the nits) is 7~ 10 days. Peri odi c reexaminatio n is recommended over 10- 14 days to detect rec urrence and remove any new nits. Bed linen, clothing, and an y items of close contact should be washed and dr ied at the highest temperatu re setting (at least SO'C) .
Bacterial Conjunctivitis in Children and Adults A bacteria l etiology is a less com mo n cause of conjuncti vitis ill adults. Bacterial conjunctivitis is th e res ult of bacterial overgrowth and infiltration of the conjun cti val epithelial layer and sometimes the substantia propria as well. T he sou rce of infection is either di rect contact with an infected individual's secretions (usuall y thro ugh eye-hand co ntact) or the spread of infection fro m the organ isms colo ni zing the pat ient's own nas al and sinus mucosa. In an adu lt with unilateral bacte ri al conjun cti vitis, the nasolacrimal system should be exam ined. Nasolacrimal duct obstructi on, d acryosystitis, an d canal ic ulitis may lead to unilateral bac terial conjunctivitis. Although usuall y self-li m ited, bacterial conjunctivitis can occasionall y be severe and Sight-th reatening when caused by vi rulent bacterial species such as N gonorrhoeae or S pyogenes. In rar e cases, it may presage life-threate ni ng systemic disease, as with conjun ctivitis caused by N m eningitidis. Direct infection and inflammation of the conjunctival su rface, bystander effects o n adjacent tissues such as the cornea, and th e host's acute inflam matory res ponse and long-term reparative response all contribute to th e pathology. PATHOGENESIS
Bacteria l conjunctivitis sho uld be suspec ted in patients with co njunctival infl ammation and a pur ulent disch arge. T he rapidity of onset and severity of conjunctival inflammation and discharge are suggestive of the possible causative o rganism. Table 5-4 shows th e cl inical classification of bacteri al conjunctivitis based on these parameters.
CLINICAL PRESENTATION AND MANAGEMENT
Acute purulent conjunctivitis Ac ute pu ru lent conjuncti vitis, a fo rm of bacterial conjunctivitis, is cha racteri zed by an acute (less than 3 weeks' duratio n), self-li mi ted in fecti on of the conjunctival surface th at evokes an acute inflamm ato ry response wi th pu rulent discharge. Cases may occur spontaneously or in epidem ics. T he most co mmon etiologic path oge ns are S pneu m oniae, 5 aure us, and H inJlucnzae. The relative freq uency with whi ch each of these organ isms is isolated depends in part o n the paHent's age and geographic locatio n. 5 plleumoniae is a common cause of acute purulent bacter ial conjun ctivitis. Moderate pur ulent discharge. eyelid edema. chemosis. conjunctival hemorrhages, and occasional inflammatory membranes on the ta rsal conjun cti va are often associated
150 • External Disease and Corne a Table 5-4 Clinical Classification of Bacterial Conjunctivitis Course of Onset
Severity
Common Organisms
Slow (days to weeks)
Mild-moderate
Acute or subacute (hours to days)
Moderate-severe
Hyperacute «24 hours)
Severe
Staphylococcus aureus Moraxella lacunata Proteus spp Enterobacte riaceae Pseudomonas Haemophilus influenzae biotype 111 * Haemophilus influenzae Streptococcus pneumoniae Staphylococcus aureus Neisseria gonorrhoeae Neisseria meningitidis
· Previously referred to as Haemophilus aegyptius.
with acute conjunctivitis caused by S pneumoniae. Corneal ulceration occurs in rare in stances. H inJluenzae conjunctivitis occurs in young children, sometimes in association with otitis media. and in ad ults. particularly those chronically colonized with H influenzae (for example, smokers or patients with chronic bro nchop ulmona ry disease). Acute purulent conjunctivitis caused by H influenzae biotype II I (p reviously called H aegyptius) resembles that caused by S pnewnoniae; however, conjunctival membranes do not develop, whereas peripheral corneal epithelial ulcers and stromal infiltrates occur more comm only. H influenzae preseptal cellulitis may predispose children to a fulminant meningitis in which up to 20% of patients who recover have long-term neurologic sequelae. The incidence of infection has been reduced by a vigorous program of vaccination against Hib. S "ureus may produce an acute blepharoconjunctivitis. The discharge tends to be somewhat less purulent than th at seen in pneumococcal conjunctivitis, and the associated signs are generally less severe. Gram-stained smears and culture of the conjunctiva are not necessary in uncompli cated cases of suspected bacterial conjunctiviti s but should be performed in the fo llowing situations: certain compromised hosts, such as neo nates or debilitated or immunocomprom ised individuals severe cases of pu rulent conjuncti vitis, to differentiate it from hyperpurulen t conjunctivitis, which general ly requires systemic therapy cases unresponsive to initial therapy MANAGEMENT Most cases of acute pu rul ent conjunctivitis can be managed with empiric antibiotic th erapy. Uncomplicated cases that are equivocal or cases likely to rep resent a viral conjunctivit is should not be routinely treated with empiric antibiotics. Initial medical therapy fo r acute nonsevere bacteri al conju nctivitis includes the following topical agents: polym ixin combi natio n drops. am inoglycosides or fluoroq uin olone (ciprofloxacin, ofloxacin, levotloxacin, moxitloxacin, or gatifloxacin) drops, or bacitracin
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or ciprofloxacin oin tment. The dosi ng schedule is 4 times d aily for approxi mately 5- 7 days unless oth erwise indicated. Cases with gram -negative coccobaci lli on gram-stained smears are probably caused by Haemophilus species and should be treated with polymyxin B- tri methop rim. Supplemental oral antibiotics are recommended for patients with acute purulent conj unct ivitis associated with pharyngitis, for conjunctivitis-otitis syndrome, and for Haemophilus conjunctivitis in child ren. When empiric broad- spectrum anti biotic therapy is prescribed in cases of hyperac ute conj un ctivitis, the initial treat ment sho uld be weighted towa rd the resu lts of th e gramstained morphology of the conju nctival smear, if available. Definitive treatment should be based on the culture results, if available, as smear results may so metimes be inconclusive as to th e predom inant category of orga nism responsible for the infection. Cultures of the nose or th roat may be performed if an associated sinusitis or pharyngitis is present. Even if no overt sinusiti s, rhinitis, or pharyngitis is present, nasal or throat swabs should be considered in cases of relapsing conju nctivitis, because the persistence of o rganis ms coloni zing the respiratory mucosa may be t he source of infection.
Gonococcal conjunctivitis Gonococcal co njunctivitis prese nts with explosive onset of severe purulent conj un ctivitis: massive exudation; severe chemosis; and, in untreated cases, cor neal infiltrates, melting, and perforat ion. T he organism most com mon ly respo nsible for hyperp urulent conjunctivi tis is N gonorrhoeae (Fig 5-12). Gonococcal conjunctivitis is a sex ually transmitted disease res ulting fro m direc t genital-eye trans mission , genital- hand- oc ula r contact, or maternal- neonate transmission dur ing vagi nal delivery. The disease is cha ra cterized by rapid p rogression, copious purulent conjunctival discharge, marked conjunctival hyperemia and chemosis, and eyelid edema. Gonococcal co njun ctivitis may be associated with preaur icular lyrn phadenopathy and the forma tion
Figure 5-12 Peripheral corneal ulceration and perforation occurring several days after onset of hyperacute conju nctivitis cau sed by N gonorrhoeae,
152 • External Disease and Cornea
of conjuncti val membranes. Keratitis, the principal cause of sight-threateni ng complications , has been reported to occur in 15%-40% of cases. Corneal involvemen t may consist of diffuse epithelial haze, epithelial defects, marginal infiltrates, and peripheral ulcerative infectious keratitis that can rapidly progress to pe rforation. LABORATORY EVA LUATION
N gonorrhoeae grows well on chocolate agar and Thayer-Martin
media. Gonococcal conjunctivitis should be treated with systemic ant ibiotics. Topical ocular antibiotics can supplement but not replace systemic th erapy. Current treatment regimens for gonococcal conjunctivitis reflect the in creasing prevalence of penicillinresistmll N gonorrhoeae (PRNG) in the United States. Ceftriaxone, a third-generation cephalosporin, is hi ghly effective aga inst PRL'
Preferred Practice Patterns Committee, Cornea/External Disease Panel. Conjllnctivitis. San Fra ncisco: American Academy of Ophthalmology; 2008 .
Bacterial conjunctivitis in neonates N gonorrhoeae causes the most severe neonatal conjunctivitis. Fortunately, N gonorrh oeae is currently responsible for fewer than I% of aU cases of neonatal conjunct ivitis in the industrialized countries. In order of decreasing prevalence, the causes of neonatal bacterial conjunct ivit is are as follows:
Chlamydia trachoma tis Streptococcus viridans Staphylococcus aureus Haemoph ilus inj1uenzae group 0 Streptococcus Moraxella catarrhalis Escherichia coli and other gram -negative rods N gonorrhoeae
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Ophthalmia neonatorum is discussed in more detail in BCSC Section 6, Pediatric Oph-
thalmology and Strabismus. Neonatal gonococcal conjunctivitis The infrequency of neonatal gonococcal conjunc tivitis has been attributed to effective prenatal screening for maternal go nococcal genital infection an d prophylact ic ant inllcrobial therapy fo r conjunctivitis in newborns. Infants with gonococcal conjunctivitis typically develop bilateral conjunctival discha rge 3-5 days after parturition. The d ischarge may be serosanguineous during the fi rst several days, and a copious purulent exudate may develop later. Corneal ulceration, corneal perforation, and endophthalmitis have been reported as complications of untreated neonatal gonococ cal co njunctivitis. Infected infants may also have other localized gonococcal infections, including rhinitis and proctitis. Disseminated gonococcal infection with arthritis, meningitis. pneumonia, and sepsis resulting in death of the illfa nt is a rare complication. v
v
MANAGEMENT Some strains of N gonorrhoeae are developing resistance to various antibi otics, including penicillin (PR NG), fluoroquin o lones (quinolone-resistant N gonorrhoeae, or QRNG), and tetracycline. The currentl y recommended first-line treatment for neonatal gonococcal conjunctivitis is ceftri axone. For l1ondissemil1ated infections, a Single intramuscu lar or intravenous ceftriaxone injection (up to 125 mg or a dose of 25-50 mg/kg ) or cefotaxime at a si ngle dose of lOO mg/kg IV or 1M is recommended. For disseminated in fection. treatment should be augmented accordin g to infectious d isease consultation. Either of these regimens should be combined with hourly saline irrigation of the COI1 jun ctiva until discharge is eliminated. If corneal involvement is suspected, application of topical er ythromycin or gentamicin ointment or frequent application of a topical tluoroquinolone should be considered. Topical cycloplegia may also prove beneficial. Systemic treatment is advised for infants born to mothers with active gonorrhea, even in the ab· sence of conjunctivitis.
Amer ican Academy of Pediatrics. Gonococcal infections. Ln: Pickering LK, Baker Cj. Kimberlin OW, LongSS, eds. 2009 Red Book: Report afthe Committee on infectious Diseases. 28th ed. Elk Grove Viltage, IL: Ame rican Academy of Pediatrics; 2009:305-313. Centers for Disease Cont rol and Prevention, Workowski KA, Berman SM. Sexua lly transmitted d iseases treatment guid el in es 2006. MMWR Recomm Rep. 2006;55(RR- ll ): 1- 94.
Neonatal chlamydial conjunctivitis Chlamydial conjunctivitis in neonates d iffers clini cally from adult chlamydial conjunctivitis in the following ways: • There is no foll icula r response in newborns. The amount of mu copurulent discharge is greater in newborns. Membranes can develop on the tarsal conjunctiva in newborns. Intracytoplasmic inclusions are seen in a greate r percentage ofG iemsa-stained con junctival specimens in newborns . • The infectio n in newborns is more likely to respond to topicaJ medi cations. Both Gram and G iemsa stains of conjunctival scrapings are reco mmended in neonates with conjunctivitis to identify C trachomatis and N gonorrhoeae. as well as other bacteria, as causative agents. Other Chlamydia -associated in fections, sllch as pneumoni tis and otitis media, can accompany inclusion conjunctivitis in the newborn. Therefore,
154 • Externa l Disease and Cornea
systemic erythromycin (12.5 mg/kg o ral or IV gid fo r 14 days) is recommended, even though inclusion conjunctivitis in th e newborn usuall y responds to top ica l erythromycin o r sulfacetamide.
Chlamydial Conjunctivitis PATHOGENESIS C trachomatis is an obligate intracell ular bacterium th at causes several different conjunctivitis syndromes; each is associated wit h diffe rent serotypes of C tra choma tis:
trachoma: serotypes A- C adult and neonatal inclusion conjunctiv it is: serotypes D- K lymphogra nuloma venereum: serotypes Lt, L2, and L3 Rare cases of keratoconjunctivitis in humans have been reported caused by Chlamydia species th at typically infect animals, such as C psittaci, an agent ge neraLly associated with disease in parrots, and the feline pneumonitis agent. LABORATORY EVALUATION
C trachomatis can be diagnosed by Giemsa stain, cell culture
isolation , and peR. Tracho ma and adult inclusion conjunctivi tis are discussed individually in th e fo llowing sections.
CLINICAL PRESENTATION AND MANAGEMENT
Trachoma Trachoma is an in fectio lls disease that occurs in communit ies with poor hygiene and inadequate sanitation. It affects approximatel y 150 million individ uals wo rl dwide and is the leading cause of preventable bli ndn ess. Tracho ma is currently endemic in the Middle East and in developing regions around the world. In the United States, it occurs sporadically among American Indians and in mountainous areas of the South. Most infections are transmitted from eye to eye. Transmission may also occur by fli es and other household fom ites. The fomites also spread other bacteria that calise secondary bacterial infectio ns in patients with trachoma. Solo mon AW, Holl and MJ, Alexander NO, et al. Mass treatment with Si ngle-dose azithromycin for trachoma. N Engl JOl/I"fJal Med. 2004;35 1( 19):1962- 1971.
The initial symptoms of trachoma include fo reign-body sensat io n, red.ness. tearing, and mucopu rulent discharge. A severe follicular reaction develops. most pronlinentl y in the superio r tarsa l conjunct iva but sometimes appearing in the superior and inferior forni ces, inferior tarsal conjunctiva, semilunar fold , and limbus. In acute tra choma, follicles on the superior tarsus may be obscured by diffuse papillary hypertrophy and inflammato ry cell infiltration. La rge tarsal follicles in trach oma may become necrotic and eventually heal wi th Signi ficant scarr ing. Linear or stellate scarring of the superior tarsus (A r/t line) typically occurs (Fig 5-13). Involutio n and necrosis of fo ll icles may resu lt in Iimbal depreSSio ns known as Herbert pils (Fig 5- 14) . Corn eal findings in trachoma include epithelial keratitis, fo cal and multifocal peripheral and central stromal infiltrates,
CLINICAL PRESENTATION
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Fi gure 5-1 3 Linear scarring of the superior tarsal conjunctiva (Arlt line) in a patient with old trachoma . (Courtesy of Vincenr P deLuise, MD.)
Fi gure 5-14 Trachoma exhibiting Herbert pits of the superior limbus (round to oval, relatively lucen t areas within pannus) .
and superficial fibrovascular pann us, which is most prominent in the superior third of the cornea but may extend cent rally into the visual axis (Fig 5- 15). Clinical diagnosis of trachoma requires at least 2 of the following clinical features:
conjunctival follicles on the upper tarsal conjuncti va limbal foll icles and thei r sequelae (Herbert pits) typical tarsal conjunctival scarring vascular pannus most marked on the superior limbus Severe conjunctival and lacrimal gland duct scarring from chronic trachoma can result in aqueous tear defici ency, tear drainage obstruction, trichiasis, and entropion.
156 • Exte rna l Disease an d Cornea
Figure 5·15
Superior corneal micropannus in a patient with adult chlamydial conjunctivitis.
The Wo rld Health Organization (WHO) has introd uced a simple severity grading system for trachoma based on the presence or absence of 5 key signs: I. 2. 3. 4. 5.
follicular conjunctival inflammation di ffuse conjunctival inflammat ion ta rsal conjunctival scarring aberra nt lashes corneal opacification
The WHO grading system was developed for use by train ed personnel other than ophthalmologists to assess the prevalence and severi ty of tracho ma in population-based surveys in endemic areas. Thylefors B, Dawson CR, Jones BR, West SK, Taylor HR. A simple system for the assessment of trachoma an d its complications. Bull World Health Organ 1987;65(4):477-483. MANAGEMENT Active tracho ma is treated with topica l and oral tetracycli ne or erythromycin. Topical tetracycl ine 1% or erythromycin ointment shou ld be adm inistered twice daily for 2 months. Oral tetracycli ne in a dosage of 1. 5-2.0 g daily in di vided doses should be ad min istered for 3 weeks. Oral eryt hrom ycin is reco mme nded for treatment of the rare cases of trachoma that are clinically resistant to tetracycline. A single dose of aZi thromycin , 1000 mg, is useful because of the long-term effectiveness of single doses. Management of the complications of trachoma may include tear substitutes for dry eye and eyelid surgery for entropion or trichiasis.
Adult chlamydial conjunctivitis Adult chlamydi al conjunctivitis is a sexually transmitted disease often fo und in conjun ction with chlam ydial urethri tis or cervicitis. It is most prevalent in sexually active ado lescents and young adults. Chlamydia is a systemic disease. The eye is usually in fected by di rect o r indirect contact with infected gen ital secretions, although other modes of
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1 57
transmission may incl ud e shared eye cosmetics and inadequately chlori nated swim m ing pools. O nset of conjunctivitis is typically 1- 2 weeks after oc ular inoculati on an d is not as ac ute as with aden oviral ke ratoconjunctivitis. Often patients may complain of mild symptoms for weeks to months. External signs of ad ult inc.Jusion conjunctivi tis include a follicu lar conjunctival response that is most prom inent in th e Imver palpebral conjunctiva and forni x, scant mucopurulent discharge, and palpable prea uricular adenopa thy. Follicles in th e bulbar conjunctiva and semilunar fold are freq uentl y present. and these are a helpful and specific sign in pat ients who have not been using topical med ications associated with deve lopment of bulbar fol licles. lnflanlmatory conjun ctival memb ranes do not develop in chlamyd ial keratoconju ncti vitis. Corneal involve ment may consist of fi ne o r coarse epithelial infiltrates, occasionall y assoc iated with subepithel ial infiltrates. T he kerat itis is more likel y to be fo und in the superio r cornea but m ay also occur centrall y and resemble adenovi ral kerati tis. A mic ropannus, usually extending less th an 3 111m from th e supe ri or cornea, may develop.
CLINICAL PRESENTATION
Left untreated, adult chlamydial conjun ctivitis often resolves spontaneously in 6- 18 months. Currentl y. one of the following o ral antibiotic regimens is recolllmended:
MANAGEMENT
azithrolllycin 1000 mg single dose • doxycycline 100 Illg bid for 7 days tetracycline 250 Illg gid fo r 7 days erythromyc in 500 Illg gid for 7 days Patients with laboratory-confirmed ch lamyd ial conjunctivitis and their sexual contacts shou ld be evaluated for coinfection with oth er sexually transmi tted diseases, such as syphi lis or gonorrhea, befo re antibiotic treatment is started. Sexual partners sho uld be concomitant ly treated to avoi d re in fection. Centers for Disease Control and Prevention, Workowski KA , Berman SM . Sexually transmitted d iseases treatment gU idel ines 2006. MMWR Recomm Rep. 2006;55( RR- ll): 1- 94.
Parinaud Oculoglandular Syndrome G ranu lomatous conjunctivitis with regional lymphade nopathy is an un common condi tion caLled Paril1aud oculoglnndular syndrome. Cnt-scratch disease (CSD), which causes most cases of th e synd rom e, is estimated to affect approxi mately 22,000 people an nually in th e United States, with about 10% developing conjunctivitis. The primary causative agent is B henselae. Other. in freque nt causes of Parinaud oc uloglandular syndrome include Afipia fe/is Bartonella clarridgeiae tularemia tuberculosis sporotrichosis
158 • External Disease and Cornea
syphilis coccidioidomycosis PATHOGE NESIS
B henselae lives on cats and their fl eas. Most cases are transmitted by a
scratch from a flea -infested kitten. Other modes of transmission include a eat's biting or licking the human skin . Local infection causes a granulomatous reaction. Unilateral granulomatous conjunctivitis with one or more raised or flat gelat inous, hyperemic. granulomatous lesions develops on the superior or inferior tarsal conjunctiva, forn ix, or bulbar conjunctiva about 3-10 days afte r inoculation. Either concurrently or 1-2 weeks later, unilateral firm and tender regional preauricu lar and submandibular lymph nodes, and occasionally cervical nodes, develop. Approximately 10%-40% of the nodes enlarge and become suppurative. Mild systemic symptoms of feve r, malaise, headache, and anorexia develop in about 10%-30% of patients, with severe, disseminated complications, including encephalopathy, encephalitis, thrombocytope nic purpura, osteolysis, hepatitis, and splen itis occurring in approx imately 2% of CSD patients. Optic neuritis and neuroretinitis have been reported. CLINICAL PRESENTATION
Serologic testing is the most cost-effective means for diagnosing typical CSD. Antibodies to B henselae can be detected by indirect fluorescent antibody testing or by enzyme immunoassay. The enzyme immunoassay for B henselae is mo re sensitive than the indirect fluorescent antibody test and is available from specialty laboratories. The skin test antigen for CSD is neither commercially available nor standardized. Atypical CSD is best approached by combining serologic testing with culture or PCR.
LABORATORY EVALUATIO N
The ideal treatment has not yet been determined. Various antibacterial treatment regimens have rep orted success. Suggested agents generally include azit hromycin, erythromycin, or doxycycline. Rifampin is often used as an adjuvant. Responses to trimethoprim-sulfamethoxazole and fluoroquinolon es have also been reported but appear to be inconsistent.
MANAGEMENT
Ormerod LD, Dailey JP. Ocular manifestations of cat-scratch disease. Curr Opin Ophthalmol. 1999; 10(3);209-216.
Microbial and Parasitic Infections of the Cornea and Sclera Bacterial Keratitis Bacterial infection is a common Sight-threatening condition. Some cases have explosive onset and rapidly progressive stro mal inflammation. Untreated, it often leads to progressive tissue destruction with corneal perforat ion or extension of infect ion to adjacent tissue. Bacterial keratitis is freq uently associated with risk factors that disturb the corneal epithelial integrity. Common predisposing factors include contact lens wear trauma contaminated ocular medications
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• impai red defense mechanisms • altered structure of the corneal surface
The most freq uent risk factor fo r bacterial keratitis in the United States is contact lens wear, which has been identified as such in 19%-42% of patients who develop cultureproven microbial keratitis. Epidem iologic studies have estimated the annual incidence of cosmetic contact lens-related ulcerative keratitis at 0.21 % fo r individuals using extendedwear soft lenses and 0.04% for patients using daily-wear soft lenses. The risk of developing microbial keratitis increases significantly (approximately IS times) in pat ients who wear their contact lenses overnight and is positively correlated with the number of consecutive days lenses are worn \vithout removal. Bacteria have multiple mechanisms of adherence. For example, S aureU5 uses adhesi ns to bind to collagen and other components of the exposed Bowman layer and stroma, whereas P aeruginosa can bind to molecular receptors exposed on injured epithelial cells. A clone of bacteria initially proliferates, then-within ho urs-invades the cornea between stromal lamellae. Corneal inflammat io n begins with the local production of cytokines and chemokines that enable diapedesis and migration of neut rophils into the peripheral cornea from the li mbal vessels. Some microorganisms produce proteases that disrupt the extracellular mat rix. Enzymes released by neutrophils and activation of corneal matrix metaLloproteinases exacerbate inflammatory necrosis. With antim icrobial control of bacterial replication, wound healing processes begin that may be accompanied by neovascula rization and scarring. Progressive inflam mation, however, may lead to corneal perforation.
PATHOGE N ESIS
Rapid onset of pain is accompan ied by conjunctival injection, photophobia, and decreased vision in patients with bacterial corneal ulcers. The rate of progression of these symptoms depends on the virulence of the infecting organism. Bacterial corneal ulcers typically show a sharp epithelial dema rcation with unde rl ying dense, suppurative stromal inflammation that has indistinct edges and is surrounded by stromal edema. P aeruginosa typically produces stromal necros is with a shaggy surface and adherent mucopurulent exudate (F ig 5-16). An endothelial inflammatory plague, marked anterior chamber reaction, and hypopyo n frequently occur. Infections caused by slow-growing, fastidious organisms such as mycobacteria or anaerobes may have a nonsuppurative infiltrate and intact epithelium. Infectious crystalline keratopathy, an example of th is type of infection, presents as densely packed, white, branching aggregates of organisms in th e virtual absence of a host inflammatory response. It is believed to occur when a sequestered colony of slow-growing organisms develops after midstromal implantation in a cornea with compromised inflammatory responses. Corticosteroid use, contact lens wear, and infected corneal grafts can all create a prediSposition to th is infection. Infectious crystalline keratopathy has been reported with a number of bacterial species, most commonly a-hemolytic Streptococcus species (Fig 5-17).
CLI NI CAL PRESENTATIO N
LABORATORY EVALUATION The prevalence of a particular causative organism depends on the geographic location and risk factors for the infection. Common and uncom mon organisms causing bacterial keratitis are listed in Table 5-5.
160 • Ext ernal Di sease and Cornea
Figure 5·16
Suppu rative ulce rative keratitis caused by P aeruginosa.
Fi gure 5·17 Infectious crysta lline ke ra topat hy in a corneal graft ca used by a-hemolytic Streptococcus species.
Table 5-5 Causes of Bacterial Keratitis Common Organisms
Uncommon Organisms
Staphylococcus aureus Staphylococcus epidermidis Streptococcus pneumoniae and other Streptococcus spp
Neisseria spp Moraxella spp Mycobacterium spp Nocardia spp Non-spore-forming ana erobes Corynebacterium spp
Pseudomonas aeruginosa (most common org anism in soft co ntact lens wearers) Enterobacteriaceae (Proteus, Enterobacter, Serratia)
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By appea rance alo ne, it can be diffic ult to determi ne whether a corneal ulcer has an infectious etiology. Before initiating antim icrobial therapy fo r cases of suspected bacteria l keratitis, a clinician should consider conducting m icrobiologic diagnostic tests. (See Chapters 3 and 4 in this volu me and SCSC Section 4, Ophthalmic Pathology and Intraocular Tumors, for specim en collecting, culturing, sta in ing, and interpretation.) If a patient has already been treated with to pical ant ibiotics and is unresponsive to them, some advocate stopping the medication 12-24 hours prior to culturing in order to enhance recovery of viable organisms. This is controversial. Anti microbial therapy should not be disconti nued in severe or rapidly progressive corn eal ulcers. In addi tio n to culturi ng the cornea, it may be helpfu l to culture contact lenses, contact lens cases, solutions, and any oth er potentially contaminati ng sources, such as inflamed eyelids, because any of these might provide a clue to the causative organism in the event that corneal cultures are negative. This approach can also help ide ntify the source of the infection. MA NAGEMENT Currently, no single ant ibiotic agent is effective aga inst all bacterial species causi ng m icrobial keratitis. Initial broad-s pectru m therapy is recom mended unt il the offendi ng m icroorganism is identified in culture. If 1 type of bacterium is prominently identified on a stained di agnostic smear, therapy may initiall y be weighted toward that class of microorganism . Broad-spectrum therapy, however, should not be eliminated, as cultures may reveal a different class of microorgan ism. Once the offending m icrobe is identified, or the clin ical response suggests the change, approp riate monotherapy may be co nsidered (Table 5-6). The route of antibiotic administration should be based on the severity of the keratitis. Frequent (eve ry 30- 60 minutes) fortified top ical antibiotics are now used for bacterial keratitis. Fortified anti biotic solutions produce therapeutic antibiotic concentratio ns in the corneal stroma, whereas commercially available antibiotic solutions may result in subtherapeutic concentrations. In severe cases, thera peutic stromal concentrations of an tibiotic may be achieved 1110re rapidly by initiall y ad m inisteri ng the antibiotic drop every 5 min utes for 30 m inutes as a loading dose. Oral antibiot ics, especially the f1uoroquin olo nes, wh ich have excellent ocular penetrat ion, and frequent use of topical ant ibiotics are indicated in cases with suspected scleral and/or in traocu lar extension of infec tion. Modification of initial antimicrobial therapy sho uld be based on cl inical response, not on the results of ant imicrobial sensitivity testing. Determi nation of ant ibiotic sensitivity or resistance in tradit ional antimicrobial sensitivity tests is based on antibiotic concentrations achievable in the seru m by oral or parenteral admin istration. Often, anti biotic concentrations greatly exceeding the mean inhibitory concentrat ions of bacteria are achieved in the corn eal stroma following frequ ent for tified ant ibiotic admi nistration. An alternate antibioti c regimen should be considered in patients who do not show clinical response or who develop toxicity from the agent(s) used initiall y. Modification of antibiotic therapy in these cases should be based on antimicrobial sensitivity testing. Several clinical parameters are useful to monitor clinical response to antibiotic therapy:
blunting of the perimeter of the stro mal infilt ra te decreased denSity of the stromal infilt rate
162 • External Disease an d Corn ea
Table 5-6 Initial Therapy for Bacterial Keratitis
-- -
Orga nism
Antibiotic
Top ica l Dose
Subconjunctiva l Dose
Gram-positive cocci
Cefazol in Vancomyci n* Moxifl oxac in or gatifloxac in Tob ramycin Ceftazid im e Fluoroqu inolones Cefazolin with To bramyci n or Fluoroquinolones Ceft riaxone Ceftazidime Moxifloxac in or gatifloxacin Clarithrom yci n Moxifloxac in or gati floxac in
50 mg/mL 25- 50 mg/mL 5 or 3 mg/mL, respectively 9- 14 mg/mL 50 mg/mL 3 mg/ mL 50 mg/mL
100 mg in 0.5 mL 25 mg in 0.5 mL
9-14 m g/mL
20 mg in 0.5 mL
3 or 5 mg/ mL 50 mg/ mL
Not available 100 mg in 0.5 m L
G ram-negative rods
No organism or multiple types of organisms
Gram -negative cocci
Mycobacteria
Not available
20 mg in 0.5 mL 100 mg in 0.5 m L Not avai lable 100 mg in 0.5 mL
50 mg/mL
5 or 3 mg/mL, respectively
10 mg/ m L 0.03% 5 or 3 mg/mL, respectively
*For resistant Staphylococcu s species. Notes for Table 5 -6: Preparation of topical antibiotics
Cefazo lin 50 mg/ mL 1. Add 9.2 mL of Tears Naturale arti ficial tea rs to a vial of cefazolin in , g (powder for injection ). 2. Dissolve. Take 5 mL of this solution and add it to 5 ml of artificial tears. 3. Refrigerate and shake well before instillation. Va ncomycin 50 mg / mL 1. Add 10 mL of 0.9% sodium chlor ide for injection USP (no pre servatives) or artific ial tears to a 500-mg vial of vancomycin to pro duce a solut ion of 50 mg/mL. 2. Refrigerate and shake well before insti llat ion. Ceftaz idim e 50 mg / mL 1. Add 9.2 mL of artificial tears to a vial of ceftazidime 1 9 (powder for injection). 2. Dissolve. Take 5 mL of this so lution an d add it to 5 mL of artificial tears. 3. Refrigerate and shake well before instill at ion. To bram ycin 14 mg / mL 1. Withdraw 2 mL of tobramycin injectable vial (40 mg/ ml). 2. Add 2 mL to a tobramycin opht ha lm ic sol ution (5 mL) to give a 14 mg/mL solution. 3. Refrigerate and shake well before instil lation.
reduction of stromal edema and endothelial inflammatory plaque reduction in ante rior cham ber inflam mation reepithelialization cessation of corneal thi nn ing The frequency of topical antibiotic administration should slowly be tape red as the stromal inflammation resolves. Combination therapy with an age nt active against gram-positive bacteria (eg, van comycin, bacitracin, Neosporin, cefuroxime, or cefazolin) and an agent active against gram-negative bacteria (eg, tobramycin, gentamicin, amikacin, ceftazidime, ciprofloxacin, levofloxacin , or ofloxacin) provides good initial broad-spectrum antibiotic coverage.
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Single-agent therapy with a fluoroquinolone may also be considered. These antibiotics should initially be given every 30- 60 minutes and then tapered in frequency according to the clinical response. Fortified antibiotics shou ld generally be continued until substantial infection control has been achieved. Thereafter, a broad -spectrum, nonfortified antibiotic may be given 3- 8 times daily according to the patient's clinical status. Disadvantages of fortified antibiotics include ocular irritation, cost, and the inconvenience of extemporaneously preparing a solution that is not commercially available. Their chief advantage is their potential to save vision in aggressive infections. When irritation secondary to epithelial toxicity becomes a concern, lower-strength concentrations (eg, 25 mg/mL vancomycin) may be better tolerated. An alternative to combination therapy is the use of fluoroquinolone monotherapy, which is most appropriate in compliant patients with less severe ulcers (eg, <3 mm in diameter, midperipheral or peripheral, and not associated with significant thinning). Fluoroquinolones (eg, levofloxacin, ciprofloxaci n, ofloxacin, moxifloxacin, and gatifloxacin) must be administered at least every hour to maximize therapeutic effect. Because secondgeneration fluoroquinolones such as ciprofloxacin and ofloxacin typically have variable activity against streptococci, documented streptococcal infections should be treated with a cell wall-active agent (eg, bacitracin, cefazolin, vancomycin, or penicillin G) rather than a second-generation fluoroquinolone, regardless of in vitro testing that may suggest susceptibility. The role of corticosteroid therapy for bacterial keratitis is controversial. It is well recognized that tissue destruction in microbial keratitis results from a combination of the direct effects of lytic enzymes and toxins produced by the infecting organism, as well as the damage caused by the inflammatory reaction directed at the microorganisms. An intense suppurative inflammatory reaction consisting predominantly of polymorphonuclear leukocytes causes significant tissue des truction by generating free radicals as well as liberating proteolytic enzymes, including collagenases and gelatinases. The rationale for using corticosteroids is to decrease this tissue destruction. Several studies using animal models of bacterial keratitis have demonstrated that concurrent use of topical corticosteroids does not impair the killing effect of bactericidal antibiotics against susceptible microorganisms. Clinical series evaluating the effectiveness of corticosteroids for treatment of human bacterial keratitis have reported either no treatment effect or more rapid resolution of stromal inflammation than resulted from antibiotic therapy alone. However, the use of topical corticosteroids following presumed resolution of gramnegative bacterial keratitis (especially that caused by P aeruginosa) has been documented to promote a relapse of the infection. If the immune system is impaired by administration of topical corticosteroids before complete clearance of virulent organisms, recurrent i nfection may result. Topical corticosteroids should therefore be used for treatment ofbacterial keratitis \vith extreme caution. Following are recommended criteria for instituting corticosteroid therapy for bacterial keratitis: Corticosteroids should not be used in the initial phase of the treatment until an etiologic organism has been identified and the organism shows in vitro sensitivity to the antibiotic(s) being used for treatment.
164 • Exte rn al Di se ase and Co rnea
The patien t must be able to return fo r frequ e nt fo llo\v-up exam inat io ns an d de m onst rate com plia nce with appropriate antibiotic therapy. No othe r associa ted virule nt o r diffi cu lt-to-eradica te orga nism is fo un d . In addit ion. a favorable clin ical response to antibiotic therapy is strongly advised befo re topical co rti cos teroids are initiated . Co rti cos teroid d rops may be started in moderate dosages (predni solone acetate or phosphate 1% every 4-6 hours), and the patient should be mo ni to red at 24 an d 48 ho urs after initiat ion of th erapy. If the patient shows no adve rse effects, the frequency of administration may be adjusted based on clinical respo nse. Penet rat ing keratoplasty (PI<) fo r t rea tm e nt of bacterial kera titis is in d icated if lhe di sease progresses despite therapy. descemetocele formation or perforation occurs, or the kerat itis is un respo nsive to ant im icrobial therapy. The invo lved area sho uld be ident ified preope rati ve ly. and an attempt should be made to circumscribe all areas of infection. Peri pheral iridecto mies are ind icated , because pati ents may deve lop seclusion of th e pupil from inflammatory pupillary membranes. Inte rrupted sutu res a re reco mm ended. The patie nt should be treated wi th app rop riate antib iotics, cycloplegics, and intense to pical corticosteroids postoperatively. See Chapter 16 for a more detailed disCllssion of P I<. Preferred Practi ce Patterns Comm ittee, Cornea/Exter nal Disease Pa nel. Bacterinl Kern/itis. San Francisco: American Academy of Ophthalmology; 2008 . Sc hein OD, Glynn RJ, Poggio EC, Seddon JM , Kenyon KR. The relative risk of ulcerat ive ke raliti s alllong users of daily-wear and exte nded-wear soft contact lenses. A case-co nt rol study. Microbial Keratitis Study Group. N £/igi ] IVIed. 1989;321( 12):773-778.
Atypical Mycobacteria Atypical mycobacteria are important pathogens in post-LASIK infections. The most common pathoge ns are M Jortuitwn and M chelonei, wh ich may be foun d in soil and water. These organisms should be suspected in delayed-o nset postrefractive infections, cl assically \v ith recalcitrant, nonsupp urative infiltra tes. T he d iagnOSiS may be con firmed with acid -fast stai n o r culture on Lowenstein -Jensen media. Treatments include oral and topical clarithromycin, moxifloxacin . an d gatitloxacin. Am ikacin, previously the o nl y t reatment option, has been la rgely rep laced by these newer treat ment options. Chang MA, Jain 5, AZar DT.ln fecti ons fo llowi ng laser in situ keratomilellsis: an integratio n of the published literature. Sw'v Ophtfmlmof. 2004;49(3):269-280. Hyon IY, Joo MJ, Hose S, Sinha D, Dick JD, O'Brien TP. Comparative efficacy of topi cal gatifl ox acin with ciprofloxacin , amikacin, and clarithrom ycin in th e treatment of experimental Mycobacterium cheJonae keralitis. Arch Ophtlmfmof. 2004; 122(8): 11 66-1 169.
Fungal Keratitis Fungal keratitis is less common than bacteri al keratitis, generally rep resenting less tha n 5%- 10% of co rn eal infec ti ons in repo rted clinical se ries in th e Uni ted States. Filamentous funga l keratit is occ urs more frequentl y in warmer, more humid parts of the Un ited States th an in oth er regions of th e co untry. Traum a to th e corn ea with pla nt or vegetabl e mate rial is the leading ri sk facto r for fungal keratitis. Especially predisp osed PATHOGENESIS
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are gardeners who use weed trimmers or other similar motorized lawn care equipment without wearing protective eye wear. Trauma related to contact lens wear is another com ~ mon risk factor for the development of fungal keratitis. Topical corticosteroids are a major risk factor as \vell, as they appear to activate and increase the virulence of fungal organ~ isms by reducing the cornea's resistance to infection. Candida species cause ocular infec~ tions in immunocompromised hosts and in corneas with chronic ulceration from other causes. The increasing use of topical corticosteroids during the past 4 decades has been implicated as a major cause for the rising incidence of fungal keratitis during this period. Furthermore, systemic corticosteroid usage may suppress the host's immune response, thereby predisposing to fungal keratitis. Other common risk factors include corneal surgery (eg, PK, radial keratotomy) and chronic keratitis (eg, herpes simplex [HSV], herpes loster, or vernal/allergic conjunctivitis). In early 2006, an outbreak of contact lens- associated fungal keratitis was observed, fi rst in Singapore and the Pacific Rim and then in the United States. The epidemic occurred in association with the use ofRenu with MoistureLoc solution (Bausch and Lomb, Rochester, New York). Bausch and Lomb withdrew the solution from the world market on May 15, 2006. Chang DC, Grant GB, O'Donnell K, et a1; Fusarium Keratitis Investigation Team. Multistate outbreak of Fusarium keratitis associated with use of a contact lens solution. lAMA. 2006; 296 (8),953 - 963. CLI NICA L PRESENTATION Patients with fungal keratitis tend to have fewer inflammatory signs and symptoms during the initial period than those with bacterial keratitis and may have little or no conjunctival injection upon in itial presentation. Filamentous fungal kera~ litis frequently manifests as a gray-white, dry-appearing infiltrate that has irregular feathery or filamentous margins (Fig 5- 18). Superficial lesions may appear gray-white, elevate
Figure 5-1 8 Fungal ke ratit is caused by Fusarium so/ani with charact eri stic dry white stromal infiltrate with feathery edges.
166 • External Di sease and Cornea
the surface of the cornea, and have a dry, rough, or gritty texture de tectable at the time of diagnostic corneal scraping. Occasionall y. multifocal or satellite infiltrates may be present, although these are less common than previously reported. In addit ion, a deep stromal infiltrate may occur in the presence of an intact epithelium. An endothelial plaque and/or hypopyo n may also occur if the funga l infiltrate(s) is sufficiently deep or large. As the keratitis progresses, intense sup puration may develop and the lesions may resemble bacterial keratitis. At this point, rapidly progressive hypopyon and anterior chamber inflammatory membranes may develop. Extension of fungal infection into the anterior chamber is often seen in cases with rapidly progressive anterior chamber inflammation. Occasionall y, fungus may invade the iris or posterior cham ber, and angle-closure glaucoma may develop from inflammatory pupillary block. Yeast keratitis is most frequently caused by Cal1dida species. This form of fungal keratitis frequently presents with superficial white. raised colonies in a structu rally altered eye. Although most cases tend to remain superficial, deep invasion may occur with suppuration resem bling keratiti s induced by gram -positive bacteria. LABORATORY EVALUATION The fungal ce ll wall stains with Gomori methenamine silver but, except for Cal1dida, does not take up Gram stain. Blood, Sabouraud's, and brain-heart infusion media are preferred media fo r fungal culture. MANAGEMENT Natamycin 5% suspension is recommended for trea tm ent of most cases of filamentous fungal keratitis, particularly th ose caused by Fusarium species, which are the most commo n causative agents for exogenous fungal keratitis occurring in the humid areas of the southern United States. Most clinical and experimental evidence suggests that topical amphotericin B (0 .1 5%-0.30%) is th e most efficacious agent available to treat yeast keratitis; the majority of corneal yeast infections respond readily to the drug. Amphotericin B is also recommended for filamentous keratitis caused by Aspergillus species. Topical voricona zo le is effective in treating fungal keratitis that is not responding to traditional treatment. Oral ketoconazole (200- 600 mg/day) may be considered for adjunctive therapy in severe ftlamentous fungal ke ratitis and oral fluconazole (200-400 mg/day), for severe yeast keratitis. Oral itraconazole (200 mg/day) has broad-spectrum activity against all Aspergillus species and Candida but va riable activity against Fusarium. Oral voriconazole (200-400 mg/day) is rapidly replacing other oral antifungals because of its excellent intraocu lar penetration and broad-s pectrum coverage. Posaconazole may also be consid ered for treatmen t. In the presence of a negative smear when fungal infect ion is suspected. repeated scrapings or biopsy may be necessary to identify fungal material. Furthermore, mechan ical debridement may be beneficial for cases of superficial funga l keratitis. Fungal infiltration of the deep corneal stroma may not respond to topical antifungal therapy, because the penetration of th ese agents is reduced in th e presence of an intact epi th elium. Penetration of natamycin or amphotericin B has been shown to be Significantly enhanced by debridement of the corneal epithelium, and animal experiments indicate that frequent topical applicatio n (every 5 m in) for 1 hou r can read ily achieve therapeutic levels. Cases with progress ive disease despite maximal to pical and/or oral antifunga l therap y may require
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therape utic PK to prevent scleral or intraocular extension of the fungal infection. Both of these conditions carry a ve ry poor prognosis for salvaging the eye. Bunya VY, Hammersmith KM, Rapuano CJ, Ayres SD, Cohen EJ. Topical and ora l voriconazole in the treatment of fungal keratitis. Am J Ophthalmol. 2007;143( 1): 15 1- 153 . Loh AR, Hong K, Lee S, Man nis M, Acharya NR. Practice patterns in the management offungal corneal ul cers. Con/ea. 2009;28(8) :856-859.
Acanthamoeba Keratitis Acanthamoebae are free -living ubiquitous protozoa fo und in freshwater and soil. They are resistant to killing by freezing; desiccation; and the levels of chlorine rout in ely used in mun icipal water supplies, swimming pools, and hot tub s. They may exist as motile trophozoites or do rm ant cysts. The majority (70%) of repo rted cases of amebic kerat itis have been associated with contact lens use. Homemade saline solut ion prepared by dissolvi ng saline tablets in distilled water appeared to be a significant source of Acanthamoeba infection among contact lens wearers unt il saline tablets were take n off the US market in the 1980s. Over the past 5 years, an increased number of Acanthamoeba cases have been observed in the United States, particularly on the East Coast and in the Mid west. The CDC conducted a multistate, retrospective review of cases, which found an association between Acanthamoeba keratit is and soft contact lens users who used Complete MoisturePlus mu ltipurpose cleaning solution (Advanced Medical Optics; Santa Ana, CAl. The solution was voluntar ily removed from the market in May 2007. Unfortunately, initi al reports have not found a dramatic decli ne in these cases sin ce th e removaL
PATHOGENESIS
Joslin CE, Tu EY, McMahon rl~ Passaro OJ, Stayner L]~ Sugar J. Epidemiological characteristics of a Chicago-a rea Acanthamoeba keratitis outbreak. Am I Ophtlwllllol. 2006;142(2): 212- 217. Joslin C£, Tu EY, Shoff ME, et al. The association of contact lens solution use and Acanthamoeba keratit is. Am J Ophthalmol. 2007;1 44 (2) : \ 69-\80.
Patients with amebic ke rat itis com monly have severe ocular pain, photophobia, and a protracted, progressive course. Frequently, they have shown no therapeutic response to a variety of topical antimicrob ial agents. Acanthamoeba infection is localized to the corneal epithelium in early cases and may manifest as a diffuse punctate epitheliopathy o r de ndritic epithelial lesion. Cases with epithel ial dendrites are often m isdiagnosed as herpetic keratitis and treated with antiviral agents and/or corticosteroids. Stromal infection typically occurs in the central cornea, and early cases have a gray-white superfiCial, nonsuppurative infiltrate. As th e disease progresses, a partial or complete ring in filtrate in the parace ntral cornea is frequently observed (Fig 5- 19). Enlarged corneal nerves, called radial perineuritis, may be noted, as well as Iimbitis or foca l, nodular, or diffuse scleritis.
CLIN ICAL PRESENTATION
Diagnosis of Acanthamoeba kerati tis is made by visualizing amebae in stained smears or by culturing organisms obtained from corneal scrapings. The
LABORATORY EVALUATION
168 • External Disease and Cornea
Figure 5-19
Ring infiltrate in Acanthamoeba kerat itis.
highest diagnostic yield occurs relatively early in the course of the disease, when the organisms are localized to the epithelium. Later, the organisms penetrate into deeper layers and may be difficult to isolate from superficial scraping. Lamellar corneal biopsy may be required to establish the diagnosis in these cases. In contact lens-associated infections, the contact lenses and contact lens case can be examined. Amebae are seen in smears stained with Giemsa or with periodic acid- Schiff (PAS), calcofluor white, or acridine orange stains. Nonnutrient agar with E coli or E aerogenes overlay is the preferred medium for culturing amebae, although the organisms frequently grow well on blood agar plates and on buffered charcoal-yeast extract agar. Characteristic trails form as the motile trophozoites travel across the surface of the culture plate. Confocal in vivo microscopy can also be used to show organisms, particularly the cyst forms. MANAGEMENT Early diagnosis of Acanthamoeba keratitis is the most important prognostic indicator of a successful treatment outcome. Unfortunately, many cases are treated initially for herpetic keratitis. Not only is the delay in diagnosis detrimental, but the use of corticosteroids early in the disease may also be correlated with a poor outcome due to compromise of the host's inflammatory response against Acanthamoeba. Late immunoinflammatory responses after the amebae have been killed may be reduced by corticosteroids, but this is controversial and remains an area for further investigation. Clinical features that suggest a diagnosis of Acanthamoeba keratitis rather than HSV keratitis include
• noncontiguous or multifocal pattern of granular epitheliopathy and subepithelial opacities (unlike the contiguous, dendritic pattern in HSV keratitis) disproportionately severe pain, probably secondary to perineural inflammation (unlike hypoesthesia and disproportionately mild pain secondary to trigeminal nerve involvement in HSV)
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presence of epidemiologic risk factors such as contact lens use or exposure to possibly contaminated freshwater failure to respond to initial antiviral therapy Cases diagnosed during the early, epithelial stage of the disease respond well to epithelial debridement, followed by a relatively short (3-4 months) course of antiamebic th erapy. The prognosis for visual recovery wit h only mild residual stromal involvement is very good. Once stromal infiltrates appea r, however, eradication of organisms is more difficult, and treatment may be needed for 6- 12 months. A number of antimicrobial agents have been recommended for therapy of Acanthamoeba keratitis based on their in vitro amebicidal effects as well as their clinical effectiveness. Agents used for topical administration include
diamidines: propamidine, hexamidine bigual1ides: polyhexameth yle ne biguanide (polyhexanide), chlorhexidine aminoglycosides: neomycin, paromomycin imidazolesl triazoles: voriconazole, miconazole. clotrimazole. ketoconazole. itraconazole
Most of these agents are effective against the free-living trophOZOite form of the organiSl11 but have reduced efficacy in killing cysts. Although there is no consensus yet about the optimal therapeutic agent. successful resolution has been achieved with a biguanide with and without a diamidine. Recent repo rts favor the use of chlorhexidine 0.02% or polyhexamethylene biguanide (PHMB) 0.02% as initial therapy. Some specialists encourage the use of chlorhexidine or PHtvlB in combinat ion v'lith propamidine isethionate 0.1 %. Treatment with topical corticosteroids is of uncertain long-term benefit and may contribute to prolonged persistence of viable cysts or potentiate mixed infections when a virus is present. Penetrating keratoplasty is reserved for cases that are progressing despite maximal med ical therapy and shOWing evidence of severe stromal melting with threatened perforation. The risk for recurrence in this setting is very high. Even in apparently quiet, treated eyes, optical PK procedures are associated with a high risk of recurrence if performed within the first year after the onset of infection. The presumed pathogeneSiS of such recurrences is the persistence of an occasional residual viable cyst in an eye with compromised immunity as the result of the presence of an allograft and the use of topical corticosteroids postoperatively. Therefore, it is advisable to perform any elective PK procedure only after a full course of amebicidal therapy has been completed and a minimum of 3-6 months of disease-free follow-up thereafter has been documented. There is some controversy about the timing of corneal transplantation, with some favoring earlier intervent ion.
Corneal Stromal Inflammation Associated With Syste mi c Infections NOl1suppurative stromal keratitis can be caused by the following: reactive arthritis congenital or acquired syphilis
170 • Extern al Disease and Corn ea
Lyme disease tuberculosis Hansen disease (leprosy) onchocerciasis Most of these conditions are discussed in BCSC Section 9, Intraocular Inflammation and Uveitis.
Microsporidiosis Microsporida are intracellular protozoa that may cause ocu lar infection and have emerged in the literature because of their opportunistic nature in Lndividuals with AIDS. There are 2 distinct clinical presentations of microsporidi al infecti ons. depend ing on the immune status of the patient. In immunocom petent individuals, a corneal stromal keratitis may develop, and in AIDS patients, conj unctivitis and an epithelial keratopathy may be seen. The latter group may also have disseminated microsporidiosis involv ing th e sinuses, respiratory tract, or gastrointestinal tract. Patients present with symptoms that include ocular irritation, photophobia, vision decrease, and bilateral conj un ctival injection with little or no associated inflammation. Stromal keratitis is caused by agents of the Nosema genus, whereas th e Encephalitozoon and Septata genera have been associated with keratoconjunctivitis. In the keratoconju nctiv itis variant, corneal findings include superficial nonsta ining opacities described as "mucoid" in appearance, along with dense areas of fine punctate fluorescein stain ing. The corn eal stroma remains clear. with no or min imal iritis. Light microscopy usi ng the Brown and Hopps stain may identify small gram -positive spores in the epithelial cells of the conjunctiva. Transmission electron microscopy is a sen sitive means of identification. Tiss ue cultu re techniques may also be used, but im munofluorescent antibody techniq ues have greater cli nical utility. Some authors have discouraged corneal biopsy or scraping because of its potential for promoting additional corneal compromise. Although there is no definiti ve treatment, topical fumagillin has been used to successfully treat microsporidial kerato conjunctivitis with low toxicity. In severe cases of Vittaforma corneae, granulomatous inflammat ion may lead to necrotic th in ning and perforation. PK may then become the only ava ilable treatment for severe stromal thi nni ng. In ge neral, medical regimens requ ire lo ng- term use. and recur rence is com mon after treatment discontinuation. Joseph J. Sridhar MS, Murt hy S. Sha rma S. Cli nical and microbiological profile of microsporid ial keratoconjunctivitis in sOllt hern India. Ophthalmology. 2006;113( 4):531 ~537. Krachmer jH. Manni s MI, Holl an d El, eds. Cornea. 2nd ed. Vol 1. Philadelphia: Elsevier! Mosby; 2005. \"'ebec R, Canning EU. Microsporid ia. In: Murray PRJ Baron EJ. Jorgensen JH. Landry ML. Pfaller MA, eds. Malmo/ of Clinical Microbiology. 9th ed. Washington, DC: ASM Press; 2007.
Loiasis Loa loa and other filarial nematodes can cause conj unctivitis as well as dermatologic manifestations. After the bite of an infected vector, such parasites can bur row subcutaneously to reac h the eye area. The microfilarial stage is transmitted from human to human by
CHAPTER 5: Infectious Diseases/External Eye: Microbial and Pa rasitic Infections. 171 the bite of an infected female deer fly (genus Chrysops) indigenous to West and Central Africa. A migrating ,vorm moves under the skin at about 1 cm/min but is most conspicuous when it is seen or felt wriggling under the periocu lar skin or bulbar conjunctiva. Extraction of the filarial wOl'm cures the conjunctivitis; that is followed by antiparasitic treatment for widespread infestation. Diethylcarbamazine is generally given 2 mg/kg tid for 3 weeks and repeated as necessar y. Iver mectin 150 mg/kg may also be effective, but significant side effects have been reported in patients with prominent intravascular loiasis. Concurrent adm inistration of corticosteroids and/or antihistamines may be necessary to minimize allergic reactions.
Microbial Scleritis PATHOGENESIS Bacterial and fungal infections of the sclera are very rare. Most cases result from the extension of microbial keratitis involving the peripheral cornea. Trauma and contaminated foreign bodies (including scleral buckles) are possible risk factors. Bacteri al scleritis has also occurred in sclerae damaged by previous pterygium su rgery, especially when beta irradiation or mitomyci n has been used (Fig 5-20). Bacteria an d fungi can also invade tissue of the eye wall surrounding a scleral surgical wound, but endophthalmi tis is more likely in this setting. Scleral inflammation can also be a feature of syphilis, tuberculosis, nocardia, atypical mycobacteria, and leprosy. Diffuse or nodular scleritis is an occasional complication of varicella-zoster virus eye disease. LABORATORYEVALUATION Evaluating suppurative scleritis is similar to evaluating microbial keratitis. Smea rs and cultures are obtained before ant im icrobial therapy is begun. The wo rkup of nonsuppurati ve scleritis is guided by the history and physical examination, as described in Chapter 7. MANAG EM ENT Topical antimicrobial th erapy is begun just as for microbial keratitis. Because of the difficulty in controlling microbi al scleritis, subconjunctival injections and intravenous antibiotics may also be used. Long-term oral therapy shows promise.
Fi gure 5-20 Bacterial scleritis occurring 2 w eeks after pterygi um surge ry. he /mus, MD.)
(Courtesy of Kirk R. W i/-
CHAPTER
6
Ocular Immunology
Cellular Elements of the Ocular Immune Res onse For an in-depth discussion of the various features of the innate an d adaptive immune system, including the different types of hypersensitivity reactions with relevant ocular examples, see BCSC Section 9, Intraocular Inflammation and Uveitis. This chapter is an overvie\v of the ocular im mune response, which involves primarily the immune system
and the lacrimal functio nal unit (LFU): lacrimal gland, ocular surface (conjunctiva, cornea, and meibomian glands), tear film, eyelids, and the sensory and motor nerves that connect these structures. (See also Chapter 4.)
lacrimal Functional Unit In addition to the normal secretory tissue, whic h produces tears, the lacrimal gland contain s
a variety of lymphocytes (plasma cells, T cells, B cells), macrophages, and dendritic cells, as well as soluble "immune" factors produced by the epithelial cells. These soluble and cellular elements play an important role in the innate and adaptive arms of the ocular immune response. The lacri mal gland is also an important component of the mucosa-associated lym phoid tissue (MALT). The plasma cells of the lacrimal gland, which produce secretory IgA (SIgA), a component of the humoral (antibody-dependent) immune system, circulate throughout the MALT and arrive in the lacrimal gland through specific homing receptors.
The Ocular Surface The ocular surface compr ises the conjunct iva , corn ea, and meibomian glands. The normal, uninflamed conjunctiva conta in s immunoglobulins and a few polymor-
phonuclear leukocytes (neutrophils), lymphocytes, macrophages, plasma cells, and mast cells within the subepithelial tissue. In addition, the conjunctival stroma has its own endowment of dendr itic antigen-presenting cells (APCs). The epithelium contains a special subpopulation of dendr itic APCs known as Langerhans ce/ls, which are capable of both antigen uptake and priming (se nsitizing) of naive antigen-inexperienced T lymphocytes. Hence, these dendritic cells serve as the sentinel cells of the immune system of the ocular surface. In addition to the presence of immune cells, the conjunctiva has a plentiful supply of lymphatic vessels, which facilitate the trafficki ng of immune cells and antigens to the draining lymph nodes, where the adaptive immu ne response is generated. Table 6-1 summar izes the known distribution of certain imm une and inflammator y
cells in the ocular surface epithelium and substantia propria (stroma). 173
174 • External Disease and Corn ea
Table 6-' Immunologic Components of the Ocular Surface Ce ll Dendritic cells Helper T cells Suppressor T cells 8 cel ls and plasma cel ls Ne ut rophils Eosin ophils Mast cells
Epithe li um
Substantia Propria
+ + +
+ + + + +
+
+
The normal, uninflamed cornea, hke the conjunctiva, is endowed with dendritic cells. Like those in the conjunctiva, the dendrit ic cells in the corneal epithelium are also called Langerhans cells. They are located primarily in the corneal periphery and lim bus. These APes are in an activated, mature state (expressing class Il major histo compatibil ity complex [M HC] antigens an d costimulator y molecules) and hence capable of efficiently stimulating T cells. In addition to these dendritic cells (Fig 6-1), small numbers of lymphocytes are present in the peripheral epithelium and anterior stroma of the cornea. A highly regulated process, mediated by vascular endoth elial adhesion molecules and cytokines, controls the recruitment of the various leukocyte subsets from the intravascular compartment into the limbal matrix. Unlike the conjun ctiva, the normal cornea is considered to be an immunologically privileged site, so called because the generation of immune responsiveness to foreign
Figure 6-1 Langerhans cells represent a subpopula tion of dendritic antigen-presenting cells of the ocular surface epithelium . As the sentinel cells of the immun e system, they pick up, process, and present antigens to T cells. Th is micrograph shows the predominance of MHC class 11"- Langerhans cells in the limbus of the uninflamed eye. (Counesyof the laboratory of M. Reza Dana, MD.)
CHAPTER 6: Ocular Immunolog y . 175
(including transplantation) antigens is relatively suppressed. The normal cornea's im mune privilege is due to a multitude of factors, including absence of blood vessels, which impedes delivery of immune effector cells absence of lymphatics, which min im izes flow of antigens and APCs to the dra ining lymph nodes expressio n of immunosuppressive factors. including transforming gro\vth factor ~s (TGF-~s) and neuropeptides, such as a- melanocyte-stimulating hormone (a-MSH) expression of Fas ligand (CD95) by corneal cells, which is believed to playa critical role in inducing Fas-mediated apoptosis (programmed cell death ) of activated lymphocytes Hence, it has been postulated that the immune response generated to antigens located in the cornea and anterior chamber may lead to im mune unresponsiveness or even immunologic to lerance. The meibomian glands also contribute to the ocular inflammatory and immune response; these are regulated by a variety of local and systemic factors, includi ng Ci rculating androgens. Dana MR, Qian Y, Hamrah P. Twenty-five -year panorama of corneal immunology: emerging concepts in the immunopathogenesis of microbial keratitis, peripheral ulcerative keratitis, and corneal transplant rejection. Cornea. 2000; 19(5):625 -643. Streilein JW. Ocular immune privilege: therapeutic opportunities form an experimen t of nature. Na t Rev lmmtmol. 2003;3(I 1):879-889.
Soluble Mediators of the Ocular Immune Response Cellular elements of the ocular immune system function as a neuroregulatory unit comprising the ocular surface, the lacrimal gland, and the neuronal con nections between them (Fig 6-2). Regulation (up- or down-modulation) of the expression of many molecules is a critical facet of ocular surface immunoinflammatory responses. For example. many immunoglobulins (primarily dimeric IgA) are normally present in the tear film. However, antibody levels may drop significantly with lacrimal gland atro phy (as protein synthesis in the gland decreases) in severe exocrinopathy, as seen in Sjogren syndro me. In contrast, immunoglobulin levels increase in patients with allergic disorders of the external eye or with o ther disorders that activate the humoral arm of the immune system, such as infections.
Tear Film The normal tear film is a complex structure that contains a variety of elements, includ ing components of the complement cascade, proteins, growth factors, and a variety of cytokines (see Chapter 3 for discussion of tear-film phYSiology and BCSC Section 9,
Zierhut Diagram
Antiandrogen therapy
~
Androgen insensitivity
Neurotransmitters (substance P) Androgens
t
~
~
Age
Androgens ----j ~ ICAM-l
Slg A, IL-8 , PMN
Contact lens
~
Allergy
Thl , Th2
Infection of the ocular surface
--/ ~
Reduced function of the lacrimal gland
---
IL-l,IL-6, TNF-a ICAM-l ,I L-2 IL-l0
~t
Autoantibod ies
Autoimmune disorders
t
+
"
--"
-----~
t
--+-
Precursor
IL-8 EGF
Homing CALT
+
ICAM-l
~IL-la~, t~'~, ,,--"
Local autoimmu nity
MHC-II
Meibomian glands
Inflammation ! of the T ocular surface
Androgen
t
TGF-~
Lacrimal gland
+
+ t
T cells
+
CD80 CD86 ~
+
+
+
Antigen! presen ting cells T
Reduced fu nction 01 the meibomian glands
Figure 6-2 Th e lacrimal and meibomian glands might be in fluenced by various disorders, leading to stimulation of local autoimmunity, and activation of local antigen-presenting ce lis, followed by T-cell infiltration. This resu lts in inflammation of the ocular surface and glandu lar structure s with reduced exocrin e f unction. Various factors (cytokines, chemok ines, neurotransm itters, and androgen levels) can influ ence the intens ity of the inflammatory response, wh ich might result in blephariti s, co njunctivit is, ke rat itis, and th e dry-eye syndrom e. CALT = conju nctiva-assoc iated lymphoid ti ssue, EGF = epidermal growth factor, !CAM-1 = intercel lular adhesion molecule 1, !L = interleukin, MHC ~ major histocompatibil ity complex, PMN ~ polymorphonuclear leukocyte, TGF-{3 ~ transforming growth factor ~ s, TNF-a ~ tumor necrosis factor a. (Reproduced with permission from Zierhut M, Dana MR, Stern ME, and Sullivan DA. Immunology of the lacrimal gland and ocular tear film . Trends Immunol. 2002;23(7):333- 335.)
CHAPTER 6:
Ocular Imm unology.
17 7
IntraocuLar Inflammation and Uveitis, for more in-depth discussion and illustrations of the immune system). Cytokines such as interle uki n- l (IL-I) and tumor nec rosis factor u (TN F-u) are significantly up-regulated in a variety of corneal infl amma tory disorders, such as corneal graft rejection and dry eye. Similarly, an increased expression of growth factors. prostaglandins, neuropeptides, and proteases has been shown in a wid e array of im mune disorders of the cornea and ocular surface. Effective immu ne responses to foreign antigens require cells to "traffic" through tissues. Critical mediators that provide the trafficking Signals to immune cells are called chemakines (chemotactic cytokines) . These are small molecular-weight proteins, of which more than 50 have been identified to date; they have been classified into different subgroups based on th eir am ino acid sequence. Although there is some overlap in the function of these cytokine species, they can also be classified functionally into those that promote neutrophil recruitment (eg, IL-8), T helper-l (Th l) lymphocyte recruitment and activation (MIP-l ~), monocyte/macrophage recruitment (MCP- i), and eosinophil recru itment (eotaxin). As a better understanding of these critical mediators evolves, the possibility is emerging of molecularly targeting those chemokines that specifically regulate a pathologic funct ion (eg, eotaxi n, or its receptor CCR3, in allergy). To date, ma ny chemokines have been identified as playing important roles in corn eal inflam mation . A brief tabulation of some important soluble mediators involved in corneal and ocular surface immune and inflammatory responses is given in Table 6-2. Akpek EK, Gottsch JD. Immune defense at the ocular surface. Eye. 2003; 17(8):949-956. Zierhut M, Dana MR, Stern ME, Sullivan DA. Immunology o f the lacrimal gland and ocular tear film . Trends Immul1ol. 2002;23(7):333 -335.
Table 6-2 Soluble Mediators of Ocular Inflammation Group
Exa mp le
Exa mple of Action
Cell adhesio n mo lecu les Chemokines Clotting an d fibrino lyti c systems Complement Corneal prote ases Cytokines Eicosanoids
ICAM- 1 RANTES
Promotes leukocyte rec ruitmen t Directs leukocyte traffic Enha nces leu kocyte activity
Growth factors
VEG F
Fib rin
C5a Coll agenase Interl eukin-1
TN F-u Leukotriene B4 TGF-~ s
Kinin-formin g system Leukocyte oxidants Neuropeptides
Bradykinin Hydrogen pe roxide Substance P
u-M SH Vasoactive ami nes
Histamine
Prom otes leukocyte recruitment Degrades protein in stromal matrix Promotes leukocyte recruitment Promotes inflammation and breakdown of blood- ocular barriers Promotes angiogenesis and vascu lar permeability Inc reases vascular permeab il ity Ox idl zes free radicals Promotes inflammation and pa in Suppresses inflammation an d T-cell respon ses Dilates blood vessels
178 • Externa l Di sease and Corn ea
Hypersensitivity Reactions of the Ocular Surface Hypersensitivity responses typica lly involve normal adaptive protective mechan isms that, because of increased antigenic exposure and/or heightened im mu ne status, become so ampli fied that they lead to pathologiC changes. Hyperse nsitivity reacti ons are classified into several basic mechanisms grouped as types I - V (type V is not discussed in this Section; see BeSe Section 9, Intraocular Inflammation and Uveitis). Most clinically relevant ophthalmic diseases are probably not due exclUSively to a single type of hypersensitivity react ion. Nevertheless, a basic understa nding of the mechanisms of hypersenSitivity, as shown in Figure 6-3, can be useful in explaining the patho geneS iS of several im munemedi ated disorders of the cornea and ocular surface (Table 6-3). In the following sections,
C4 ~
CI .-.-
IgA
Type I
~
g'''"n
C2 - C3 - C5 \..
~
C3a ~. . • ';~ .- . .. . ,..,~ ..' ... . , .. .
Type II
Vessel
Target cell Type III
Type IV
Figure 6-3 Classifications of hypersensitivity reactions. Type I anaphylactic reactions are mediated by IgE antibodies bound to mast cells. Type II cytolytic or cytotoxic reactions are mediated by immunoglobulins against membrane antigens that activate complement. Type II I immune-complex reactions occur when antigen-antibody complexes accumulate in a tissue and activa te the complement cascade to attract leukocytes. Type IV delayed hypersensitivity immune reactions are med iated by T cells that re lease Iymphokines to attract macrophages. (Illustra tion by Christine Gralapp.)
CHAPTER 6: Ocular Immuno logy. 179
Table 6-3 Hypersensit ivity Reactions and Selected Ocu lar Disease Type II III IV
Ocular Di sease Allergic conjunctiviti s Ocular cicatricial pemphigoid Scleritis Stevens-Johnson syndrome Contact dermatitis Phlyctenulosis Corneal graft rejection
each type of hypersensiti vity response is put in the context of common corneal and ocular surface inflammatory pathologies. See BCSC Section 9, Intraocular Inflammation and Uveitis, for a full discussion of basic immunopathogenic mechanisms.
Anaphylactic or Atopic Reactions (Type I) The pathogenesis of allergic reactions begins with APCs interacting with CD4+ T helper-2 (Th2) cells that release interleuki n-4 (IL-4) and other Th2 cytokines. In type I reactions, antigens combine with IgE antibodi es bound to recepto rs on mast cells, resulting in the release of histamine and other preformed mediators, as well as a new synthesis of prostaglandins and leukotrienes (Table 6-4). Atopy is associated with an inherited mutation in the receptor for IL-4 that is associated with enhanced IgE production by B cells and increased numbers of T helper cells. Other features associated with atopy are decreased levels of putative suppressor (or regulatory) T cells. These cells play a ro le in down-modulating immune responses to common
Table 6-4 Selected Soluble Mediators Released by Mast Cells and Eosinophils Substance
Action
------------------~ Released by mast cells Histamine Heparin Tryptase Eosinophil chemotactic factor Neu t rophil chemotactic factor Platelet-activating factor Prostaglandin s (PGD 2 ) Leukotrienes (LTB 4 ) Released by eosinophils Major basic protein Cationic prote in Peroxidase Eotaxin Platelet-activating factor Leukotrienes (LTC4 ) Slow-reacting substance of anaphylaxis
Vasodilation and increased capillary permeabi lity Anticoagulation Complement activation Eosinophi l chemotax is Neutrophil chemotaxis Vasodilation and increased capillary permeability Vasodilation Leukocyte chemotaxis Mast cell degranulation Epithelial cytotoxicity Epithelial cytotoxicity Eosinophil chemotaxis Vasodilation and increased capillary permeability Increased capillary permeability Increased capi ll ary permeabili ty
180 • Externa l Disease and Cornea
antigens in th e environment. Treatment strategies include the use of topical mast-cell inhibitors, antihistamines, vasoconstrictors, cyclooxygenase inhibitors, and, occasionally, systemic corticosteroids in severe disease.
Cytotoxic Hypersensitivity (Type II) A type II reaction invo lves interactio n of immunoglobulins with foreign or autoantigens closely associated with cell membranes. Cell lys is may result from complement activation (and development of membrane attack complexes) and from recruitment of leukocytes. including neut rophils. lymphocytes. and macrophages. So-called killer lymphocytes may be involved in antibody-dependent. cell-mediated cytotoxicity (ADCC). In general, most investigators maintain that type II res ponses do not playa major role in corneal and ocular surface morbidities. However, one d isease in which type II responses are likely to be relevant is ocular cicatricial pemph igoid (discussed in Chapter 7). In this condition, severa l antigens along the conjunctival base ment memb ra ne zone can react with IgG or IgA antibodies. Treatment of type II respo nses usually requires systemic immunosuppression or immune modulation.
Immune-Complex Reactions (Type III) A type III re action results from the deposition of an tigen-antibody (immune) complexes in tissue with secondary complement and effector cell activation and recruitment. Immu ne complexes can fix complement that attracts polymorphonuclear leukocytes. The typical Arthus reaction involves vasc ulitis from im mune-complex deposition in small blood vessels. Similarly, the pathophysiology of scleritis and ocular syndromes seco ndary to vasculitis (eg. periphe ral ulcerati ve kerati tis) has been rel ated to immu ne-complex deposition. However, a basic understanding of mechanisms is still deficient, because the incit ing factors remain largely unknow n.
Delayed Hypersensitivity (Type IV) Type IV, or cell -mediated. im mu nity in volves sensitized CD4+ Thl lymphocytes. Antigens interact with receptors on the su rface of T lymphocytes. resulting in the release of Iymphokines. Contact dermatitis is a common delayed hypersensitivity response caused by lipid-soluble. low-molecula r-wei ght haptens. These penetrate the skin and gai n entry into the epidermal layer, where they may be picked up by Langerhans APCs. T hese cel ls can then process the antigen and pri me (s ensitize) naive T cells by coexpressing the processed antigen with the MHC class II an tigens to them. A similar process is thought to be responSible for corneal graft rejection.
Patterns of Immune-Mediated Ocular Disease Conjunctiva The conjunctiva is the part of the MALT that involves many mucosal tissues in the body, including the lacrimal gla nd. Humoral immunity in the conjunctiva la rgely involves [gA,
CHAPTER 6:
Ocular Immunol ogy .
18 1
and cellular immunity is dominated by CD4+ T cells. Serosal mast cells that contain neutral proteases are normally present in the conjunctiva, and mucosal mast cells with granules containing only tryptase are increased in the conj unctiva of atopic patients. Mast-cell degranulation produces conjunctival redness, chemosis, mucus discharge, and itching.
Cornea The normal cornea can have neithe r an ac ute allergic reaction (as it contains no mast cells) nor a typical Arthus reaction (as there are no blood vessels). However, the cornea does participate in immune reactions by way of humoral and cellular immune elements that enter the periphery from the limbal blood vessels. These anatomical features may explain why so many immune-mediated disorders of the corn ea occur primarily in the corneal p eriphery and limbus. Alternatively, ingress ofleuko cytes through the ciliary body/iris root and ingress of plasma proteins through breakdown of the blood- ocular barrier (as occurs in uveitis syndromes) are other internal pathways for im mune effectors to the cornea. The cornea can act as an imm unologic blotter, soaking up antigens from the ocular surface . This phenomenon was fi rst described by Wessely in 1911, when fo reign antigen was injected into the cornea of a previously sensitized animal and a ring-shaped infiltrate formed in the corneal stroma concentric to the injection site, much like an antige nantibody complex in an immunodiffusion test. Still called a Wessely immune ring, this infiltrate contains complement factors and/or neutrophils. Circulating antibodies are not required if sufficient local antibody production is stimulated by antigens deposited in the cornea . The antigen may be a drug, as in the peripheral corneal infiltrates associated with a neomycin reaction; a foreign body; or an unkn own substance, as in the corneal infiltrates that can occur in contact lens wearers. Wessely rings may persist in corneas traumatized with a foreign body for some time, even after the fo reign body is removed.
Sclera Nearly one half of patients with scleritis have an associated systemic immunologic or connective tissue disease. Immune-complex deposition, granulomatous inflammation , and occlusive vasculitis have been implicated in the pathogenesis of scleral inflammation.
Diagnostic Approach to Immune-Mediated Ocular Disorders Ma ny, but not all, immune-mediated ocular disorders are secondary to a systemic disease. As with most medical problems, diagnostic investigations need to begin with a complete history, including a revievv of systems, and a general physical examination, as indicated. Some of the more common laboratory diagnostic tests that are selected to further narrow the differential diagnos is are listed in Table 6-5. In general, except for rheumatoid arthritis, which has a strong predilection for scleral and corneal involvement, the workup for patients with immune-mediated corneal disease in whom an underlying disease is suspected is quite similar to that fo r the uve itis patient. Diagnosing systemic vasculitis in a patient presenting with ocular inflammation with tests, including ANCA (see Table 6-5), may have a profound effect in institut ing early life-saving therapy.
182 • Externa l Disea se and Cornea Table 6-5 Common laboratory Tests for Suspected Systemic Immune-Mediated Disease Test
Assay
Rheumatoid factor (RF )
Autoantibody (lgG, IgA, or IgM) against epitopes of the Fc portion of IgG Antibodies again st cell nu clear ant ig ens (DNA-histone, doubl estran ded DNA, single-stranded DNA, histone, RNA, nuclear ribonuc leoprotein, etc) c-ANCA generally se nsi tive for Wegen er gra nu lom atosis p-ANCA genera ll y i ndicative of small -vesse l vasculitis (microscop ic angiiti s), either genera li zed or related to inflam matory bowel disease, especially ulcerative co litis Ru le out active nephritis by checking fo r casts, red blood ce lls,
Antinuclear antibody (A NA)
Antine utrophil cytoplasmic antibodies (ANCA )
U rinalysis
etc Comp lete blood count Erythrocyte sedimentation rate or C-reacti ve protein
Abn orm ally high or low blood co unts are indicative of systemic di sease High va lues indicate system ic i nflamm ation
See BeSe Section 9, Intraocular Injlammation and Uveitis, for the diagnostiC workup of patients with uveitis. Table 6-6 provides the clinical interpretatio n of ocular surface cytology for imm une-mediated keratoconjunctivit is. Finally, it should be noted that corn eal and ocul ar surface morbidities may result from underl ying auto imm une disease. Generall y. when a systemic disease is suspected. it is also advisable to coordinate care with an internist or rheumatologist. especially if system ic immune suppression is contemplated. N iederkorn JY, Kaplan HJ, eds. Imnllllle Response and the l:.)e. 2nd, rev ed. Basel: Karger AG;
2007. Pfl ugfelder SC, Beuerman RW, Stern ME . Dry
eye and Ocular Surface Disorders. New York:
Tnfonna Healthca re; 2004. Zierhut M, Rammensee H -G, St rei lein JW. Antigen-Presentillg Cells and the Eye. New York: I nforma H ealthcare; 2007. Zierhut M, Stern ME, Su lli van DA. Imm unology of the Lacrimal Gland, Tear Film al1d Ocula r
Surface. New York: In forma Hea lthca re; 2005.
Table 6-6 Clinical Interpretation of Ocular Surface Cytology for Immune-Mediated Keratoconjunctivitis Finding
Examples
Sign ificant neutrophils Predom in an ce of lymphocytes and monocytes Eosinophi ls Baso phil s or mast ce ll s Keratinized epithelial cells
Severe acute/su bacute ocu lar surface inflammation Chronic toxic or alle rgic conjunctivitis Acute allergic co njun ctivit is Ve rnal conjunctivitis Ocula r cicatricial pemph igo id Stevens-Johnson syndrome Seve re ke ratoconjunct ivitis sicca Graft-vs-host disease
CHAPTER
7
Clinical Approach to Immune- Related Disorders of the External Eye
Immune-Mediated Diseases of the Eyelid Contact Dermatoblepharitis PATHOGENES IS
Topical ophthalmic medications, cosmetics, and environmental substances
can occasionally trigger a local allergic reaction. This may occur acutely as an anaphylactic reaction, which results from a type I IgE-mediated hypersensitivity reaction, or it may begin 24- 72 hours after exposure to the sensitizing agent, as with contact blepharocon junctivitis, a type IV T-cell-mediated, or delayed, hypersensitivity reaction. Type I immediate hypersensitivity reactions typically occur within minutes after exposure to an allergen. These reactions are associated with itching, eyelid CLIN ICAL PRESENTATION
erythema and swelling, and conjunctival redness and chemosis (Fig 7-1). In rare cases, patients may develop signs of systemic anaphylaxis. Ocular anaphylactic reactions can follow instillation of topical anesthetics and antibiotics such as bacitracin, cephalosporins, penicillin, sulfacetamide, and tetracycline but often resolve spontaneously. Delayed, type IV, hypersensitivity reactions to medications usually begin 24- 72 hours following instillation of a topical agent. Patients are often sensitized by previous exposure to the offending drug or preservative. An acute eczema with erythema, leathery thickening, and scaling of the eyelid develops (Fig 7-2). Sequelae of chronic contact blepharoconjunctivitis include hyperpigmentation, dermal scarring, and lower eyelid ectropion. A papillary conjunctivitis and a mucoid or mucopurulent discharge may develop. Punctate epithelial erosions may be noted on the inferior cornea. Medications that are commonly associated with contact blepharoconjunctivitis include cycloplegics such as atropine and homatropine aminoglycosides such as neomycin, gentamicin, and tobramycin antiviral agents such as idoxuridine and tritluridine
preservatives such as thimerosal and ethylenediaminetetraacetic acid (EDTA)
183
184 • External Dise.ase a nd Cornea
Figure 7-' Anaphylactic allergic reaction to topical ophthalmic medication with acute conjunctival hyperemia and chemosis.
Figure 7-2
Allergic contact dermatitis secondary to topical ophthalmic medication .
Treatm ent of hypersensiti vity reactions requires identi fying and discontinu ing the offendi ng age nt. Usually, the histor y provides the necessary clue to determine the offen ding agent, but sometim es a "rechallenge" is necessary to confirm a suspicio n. Rechallenges should never be done in patients with a known systemic allergy to a dr ug. Initial m anagement of type I hypersensitivity reactions includes allergen avo idance o r discontinuation. Adjunct ive th erapy may involve the use of cold compresses, artificial lubricants, topica l antihistamines, mast-cell stabili zers, and nonsteroida l antiin flam ma tory agents (NSA IDs) in the case of pain. Topica l vasoconstricto rs, either alone or in combinati on with antihistami nes, may provide acute symptomatic relief but sho uld not be used chronicall y. Delayed hypersensitivity reactio ns are also treated with allergen withd rawal. Tn severe cases, a brief (several-day) course of mild topical corticosteroids
MANAGEMENT
CHAPTER 7:
Cli nical Ap proach to Im mu ne-Related Disorders of the Exte rn al Eye.
1 85
applied to the eyelids an d periocular skin may speed resolution of eyelid and conjunctival inflammation.
Atopic Dermatitis PATHOG ENESIS Atopic dermatitis is a chronic condition in genetically susceptible individuals that usua ll y begins in infancy or childhood and may or may not involve the external eye. The pathogenesis of atopic de rmatitis involves increased IgE hypersensitivity. increased hista mine release from mast cells and basophils. and impaired cell -mediated im munity.
Diagnostic crite ria for atopic dermatitis include pruritus, lesions on the eyelid and other sites (eg. joint flexures in adolescents and adults. face and extensor surfaces in infan ts and young children). and a personal or fami ly history of other atopic disorders. such as asth ma. allergic rh in itis. nasal polyps. and aspirin hypersensitivity. There is an increased incidence of ectatic corneal diseases such as kerato conus and pellucid marginal degeneration as well as an increased incidence of staphylococcal and herpes Simplex infections. Other ocular find ings may include periorbital darkening. exaggerated eyelid folds. ectropion. and chronic conj unctivitis. The appearance of the skin lesions varies de pendi ng on the age of the patient. Infants typically have an erythematous rash; child ren tend to have eczematoid dermatitis with secondary lichenification from scratching; and ad ults have scaly patches with thickened and wrinkled dry skin. CLI NICAL PRESENTATION
MANAG EM ENT Allergens in the environment and in foods should be minimized whe never possible. In gene ral. the services of an allergist should be sought. Moisturi zing lotions and petrolatum gels can be useful for skin hydratio n. Acute lesions can be controlled with a topical corticosteroid cream or ointment (clobetaso ne butyrate 0.05%). but chronic use of such medications should be strongly d iscouraged to avoid skin thin ning. Topical tacrolimus is also effective and has fewer side effects. Oral antipruritic agents such as anti histamines and mast-cell stabilizers can alleviate itch ing but may exacerbate dry eye with their anticholinergic acti vity.
Ashcroft OM, Dimmock P, Garside R. Stein K, Williams He. Efficacy and tolerability of topical pimecrolimus and tacrolimus in the treatment of atopic dermatit is: meta-ana lysis of ran dom ised controlled trials. BMf. 2005;330(7490)5 16.
Immune-Mediated Disorders of the Conjunctiva Hay Fever Conjunctivitis and Perennial Allergic Conjunctivitis Hay feve r (seasonal) and peren nial allergiC conjunctivitis are largely IgEmediated immediate hypersensitivity reactions. The allergen is typ ically airborne. It enters the tear fil m and comes into contact with conjunctival mast cells that bear allergenspecific IgE antibodies. Degranulation of mast cells releases histamine and a variety of other inflammatory med iators that promote vasodilation, edema, and recruitment of
PATHOGENESIS
186 • Extern al Di sease and Co rn ea
other inflam matory cells sllch as eosinoph ils. The activatio n and degranulation of mast cells in a presensitized individual can be triggered within mi nutes of allergen exposure. Patients with hay fever conj unctivit is often suffer from oth er atopic conditions, such as allergiC rh in itis or asth ma. Symptoms deve lop rapidly after exposure to th e allerge n and consist of itching, eyelid swell ing, conj uncti val hyperemia, chemosis, and mucoid discharge. Intense itching is a hallmark symptom. Attacks are usua ll y sho rtli ved and episodic. Contr ibutin g fac tors, including contact lenses and d ry eye, should be ide ntified, as these can play an important role in fac ili tating allergen contact with the ocul ar surface. CLINICAL PRESENTATION
The diagnosis of hay fever conjunctivitis is generally made clini call y, alth ough conju ncti val scraping can be performed in order to observe th e characteristic eosinoph ils, which are not norm all y present on the ocular surface (see Chapter 6) . Challenge testing with a panel of all erge ns can be perfo rm ed.
LABORATORY EVALUATION
Effor ts should first be di rected at avoidance or abatement of allergen exposure. Tho rough cleaning (or changing) of unclean or old carpets, li ne ns, and bedding can be effect ive in removing accumulated allergens such as animal dander and house dust mites. Si mple measures such as wearing glasses or goggles can also serve as physical barriers. Treatme nt should be based on the severity of patient symptoms and consists of one or more of the following:
MANAGEMENT
Supportive • cold compresses • artific ial tears
Topical topical an tihistam ines and mast -cell stab ili zers topical NSA IDs judicious, selective use of topical corticosteroids topical vasoconstrictors
SystemiC • SystemiC an tihistamines may be effective for the short term and may be associ ated with increased dr y eye.
Artifi cial tears are beneficial in diluting and flus h ing away allergens and other inflammatory mediators present on th e ocula r surface. Topica l vasoco nstr ic tors, alone or in comb ination with antihistamines, may provide acute sym ptomat ic relief. However, th ei r use fo r more than 5-7 consecutive days may predispose to compensatory chronic vascular dilati on and rebound conju ncti val hyperem ia. Topical mast- cell stabili zing agents such as cromolyn sodium and lodoxamide trometham ine may be useful for treatin g seasonal allergiC conjun ctivitis, but their primary role is prophy lactic. Treatment effects usuall y require continued use over 7 or more days, and hence th ese agents are generall y in effecti ve in the acute phase of hay fever conjunctivit is. To pical cyclosporine and oral ant ihistam ines may provide symptomatic re lief in some pati ents. Hypose nsiti za tion injections (im munotherapy) can be beneficial if the offending allergen has been identified . Certain topical
CHAPTER 7:
Clinical Approach to Immune-Related Disorders of the External Eye. 187
NSAIDs have been approved by the Food and Drug Administration for use in ocular atopy, but their efficacy is highly variable. Reports of corneal perforations with the use of NSAIDs, especially the gene ric forms, suggest the need for careful monitoring. Refills shou ld be limited, and follow-up appointments need to be maintained. Topical corticosteroids are very effective in ocular allergy, but they should be used with caution except in very severe cases due to their toxicity. For associated dermatitis, topical tacrolimus appears to be a useful course of treatment.
Vernal Keratoconjunctivitis PATHOGENESIS Usually a seasonally recurring, bilateral inflammation of the cornea and conjunctiva, vernal (springtime) keratoconjunctivitis (VKC) occurs predominantly in male children, who frequently, but not invariably, have a personal or family history of atopy. The d isease may persist year-round in tropical climates. The immunopathogenesis appears to involve both types I and IV hypersensitivity reactions. The conjunctival inflammatory in filtrate in VKC consists of eosinophils, lymphocytes, plasma cells, and monocytes.
Abu El-Asrar AM, AI -Mansouri S, Tabbara KF, Missotten L, Geboes K. Immunopathogenesis of conjuncti val remodelling in vernal keratoconjunctivitis. Eye. 2006;20( 1):7 1-79. Baudouin C, Liang H, Bremond-Gignac D, et al. CCR 4 and CCR 5 expression in co njunctival specimens as di ffe rential markers ofT(H) II T(H )2 in ocular surface disorders. JAllergy elin Immu1/ol.2005; 11 6(3):6 14- 619.
Ono S, Abelson M. Alle rgic conjunctivitis: update on pathophysiology and prospects for future treatment. JAllergy Ciin Immunol. 2005; IIS( 1): 118- 122.
Symptoms consist of itching, blepharospasm, photophobia, blurred vision, and copious mucoid discharge. Clinicall y, 2 forms ofVKC may be seen: palpebral and Iimbal. The inflammation in palpebral VKC is located predominantly on the palpebral conjunctiva, where a diffuse papillary hypertrophy develops, usually more prominently on the upper rather than the lower region. Bulbar conjunctival hyperemia and chemosis may also occur. In more severe cases, giant papillae resembling cobblestones may develop on the upper tarsus (Fig 7-3). Limbal VKC may develop alone or in association with palpebral VKC. It occurs predominantly in patients of African or Asia n descent and is also more prevalent in hotter climates. The limbus has a thickened, gelatinous appearance, with scattered opalescent mounds and vascular injection. Horner- Trantas dots, whitish dots that represent macroaggregates of degenerated eosinophils and epithelial cells, may be observed in the hypertrophied limbus of patients with limbal VKC (F ig 7-4). Several types of corneal changes associated with upper tarsal lesions may also develop in VKC. Punctate epithelial erosions in the superior and central cornea are frequently observed. Pannus occurs most common ly in the superior cornea, but occaSionally 360· corneal vascularization may develop. Non infectious epithelial ulcers with an oval or shieldlike shape (the so-called shield ulcer) with underlying stromal opacification may develop in the superior or central corn ea (Fig 7-5). An association between VKC and keratoconus has been reported. CLI NICAL PRESENTATION
188 • Exte rnal Dise ase and Cornea
Figure 7-3
Figure 7-4
Palpebral vernal keratoconjunctivitis.
(Courtesy ofJames
J. Reidy, MD.)
Limbal vernal keratoconjunctivitis . Note the Horner-Trantas dots (arrow). (Courtesy of
Charles S. Bouchard, MD.)
Therapy should be based on the severity of the patient's symptoms and of the ocular surface disease. Mild cases may be successfull y managed with topical antihistamines. Climatotherapy, such as the use of home air-conditioning or relocation to a cooler environment, can promote improvement of the condition. Patients with mild to moderate d isease may respond to topical mast-cell stabilizers. In patients with seasonal exacerbations, these drops should be started at least 2 weeks prior to the usual time of symptomatic o nset. Patients with year-round disease can be maintained ch ron ically on mast-cell stabilizer drops. MANAGEMENT
CHAPTER 7:
Clinical App roach to Immune-Related Disorde rs of the External Eye.
Figure 7-5
Shield ulcer in vernal keratoconjunctivitis.
189
(Courtes yofJamesJ. Reidy, MD.)
Severe cases may require the use of topi ca l corticosteroids or top ical immunomod ulator y agents such as cyclosporine. Both have been shown to be effective in reducing innammation and symptoms. Because of the li kelihood that patients will develop corticosteroid-related com plicat io ns from chronic admi nistration, however, these drugs should be reserved for exacerbations with moderate to severe discomfort and/or decreased visual acuity. During th ese exacerbations, intermittent (pulse) th erapy is very effective; top ical corticosteroids are used at relatively high frequency (eg, every 2 hours ) for 5- 7 days and then rapidly tapered. Because of the propensity of particles of suspended corticosteroid (such as prednisolo ne acetate) to lodge between papillae, the use of less potent but soluble corticosteroids such as dexamethasone phosphate is preferred. Corticosteroids sho uld be discontinued between attacks. To discourage indiscrim inate use for relief of mild symptoms, the pat ient and family must be thorou ghly info rmed of the potential dange rs of chronic topical corticosteroid th erapy. Use of system ic anti -inflam matory therapy for severe VKC has been repo rted, but this should be reserved for very severe cases. Cooperative patients can be offered an alternative to topical deli very that avoids th e probJem of co ntinuing self-medication: supratarsal injection of corticosteroid. The supratarsal subconjunctival space is located superior to the upper border of the superior tarsus and is most eaSily reached by evertin g the upper eyelid. Th is space is free of the subepithelial adhesions that bind the superior palpebral conju nctiva to the tarsal plate. After the upper eyeLid is everted and the supratarsal conjunctiva has been anestheti zed, supratarsal injection of 0.5- 1.0 mL of either a relat ively short-ac ting corticosteroid such as dexamethasone phosphate (4 mg/mL) or a longe r-acting corticosteroid such as triam cinolon e acetonide (40 mg/mL) can be perfo rmed . Moni toring of intraocular pressure is mandatory, as corticosteroid -induced pressure spi kes are possible. Topical cyclosporine applied 2-4 times da ily can also be used to treat refractory cases of VKC. There are few data on exact dosing in VKC; success has been reported with 2% preparations in VKC treatment, but Significantl y lower concentrations (0.05%) have not
190 • External Disease and Co rn ea
been shown to be as effective. Reported side effects include punctate epithelial keratopath y and ocular surface irritation. Systemic absorpt ion after topical instiLlation is m inimal, but experience with this agent is li mi ted; therefore, ils use in VKC shou ld probably be reserved for the most severe cases. Dan iell M, Constantinou M, Vu H1: Taylor HR. Random ised controlled trial of topical ciclosporin A in steroid dependent allergic conju nctivitis. Br J Opht/wlmol. 2006;90(4): 461 -464. Heidemann DG. Atopic and vernal keratoconjunctivitis. Focal Poil/ts: Clillical Modules for OphtlJahnologists. San Francisco: American Academy of Ophthalmology; 200 l , module I. Tatlipinar S, Akpek EK. Topical cic\osporin in the treatm ent of ocular surface di sorders. Br J Oph"mlmol. 2005;89( I 0); 1363-1367.
Atopic Keratoconjunctivitis Keratoconjunctivitis may occur in patients with a history of atopic dermatitis. Approximate ly one third of patients with this condition develop one or more man ifesta tions of atopic keratocottjunctivitis (AKC). Atopic individuals show signs of type I immed iate hypersensitivity responses with seasonal va riatio n but also have depressed systemic cell -mediated ilnmunity. As a consequence of this alte red immunity, they are susceptible 10 herpes simplex virus keratitis and to coloni zation of the eyelids with StaphylococcLls aureus. Complications related to this predisposition to infection may contribute to) or compound, the prim ary imm unopat hogenic manifestations. AKC is primarily a type IV reaction; therefore, the use of mast-cell therapy may not be effective.
PATHOGENESIS
CLINICAL PRESENTATION
The ocula r findi ngs are similar to those of VKC, with the follow-
ing differences: Patients w ith AKC frequently have disease year- round ; seasonal exacerbation is minimal. Patients with AKC are older. The papillae are more apt to be small or med iu m-sized rather than giant. The papillae occur in the upper and lower palpebral conjunctiva. Mi lky conjun ctival edema, with va ri ab le subepithelial fi brosis, is often present (Fig 7-6) . Extensive corneal vasc ulari za tion and opacifi cat ion secondary to chronic epith elial disease (likely due to some degree of lim bal stem cell d ysfun ction) can occur (Fig 7-7). Eosinophils seen in conjuncti val cytology are less numerous and are less often degra nulaled. Conjunctival scarring often occurs and is sometimes so extensive as to produce symblepharon formation. Characteristic posterior sub capsular and /or multifaceted or shield-shaped an terior sub capsular lens opacities may occasionally develop.
Treatment of AKC involves allergen avo idance and the use of pharmacothe rap eutic agents similar to th ose used in the treatment of VKC. Cold compresses may
MANAGEMENT
CHAPTE R 7:
Figure 7-6 fibrosis.
Clini ca l A pproac h to Im m une-Re lated Disorde rs of t he Exte rnal Eye . 191
Atopi c keratoconjunctivitis demonstrating small papillae, edema, and subepithelial
Figure 7-7
Seve re corn eal vasc ularization and scarring wi th atopic keratoconj unctivitis.
also be of benefit. In addition, patients should be carefull y monitored for infectious disease complications that may wa rrant specific therapy, such as secondary staphylococcal infections. In the minority of patients in wh om th e disease takes a very aggressive and destructi ve course, local pharmacotherapies often fail to control the pathologic process. In these severe cases, the ind ications for system ic the rapy would include chronic ocular surface in fla mmation unresponsive to topical treatment, discomfo rt, progressive cicatrizatio n, and peripheral ulcerative kerata pathy. Systemic im mune suppression (eg, by oral cyclosporine 2.0-2.5 mgl kg daily) should be monitored with an intern ist. Systemic treatment of AKC may be benefi cial in suppressing the IL- 2 response, which promotes lymp hocyte proli feration. Topical therap y with tacro limus has been helpful far the dermatitis.
192 • External Disease and Cornea Ashcroft OM, Dimmock P, Garside R, Stein K, Williams HC Efficacy and tolerability of topical pimecrolimus and tacroHmus in the treatment of atopic dermatitis: meta-analysis of randomised controlled trials. BM]. 2005;330(7490):516.
ligneous Conjunctivitis PATHOGENESIS Ligneous conjunctivitis is a rare chronic disorde r characterized by the formation of firm ("woody"), yellowish fibrinous pseudomembranes on the conjunctival surface (Fig 7-8). These membranes are composed of an admixture of fibrin , fibrin-bound tissue plasminogen activator (tPA), epithelial cells, and mixed inflammatory cells that adhere to the conju nctival surface. Latent and activated form s of matrix metalloproteinase-9 (MMP-9) have also been reported. The cause of ligneous conjunctivitis has recentl y been linked to severe deficiency in type I plasmi nogen, with hypofib rinolysis as the primary defect. More than 12% of patients have severe hypoplasminogenemia. The genetic defect in the plasminogen gene (P LG) is located at chromosome 6q26.
Schuster V. Hogle B, Tefs K. Plasminogen deficiency. ] Thromb Hael1losf. 2007;5( 12}:2315-2322. Thachil], Reeves G, Kaye S. Ligneolls conj unctiviti s with plasminogen deficiency. Br J Haematal. 2009; 145(3):269. Watts P, Suresh p, Mezer E, et al. Effective treatment of ligneous conjunctivi tis with topical plasminogen. Am ] Ophthalmol. 2002; 133(4):451 - 455.
Ligneous conjunctivitis can affect all ages. Patients present with symptoms of ocular irritation and foreig n-body sensation. The card inal finding consists of yellowish, platelike masses that overlie one or more of the palpebral surfaces and are readily visible with eversion of the eyelid (see Fig 7-8). Ligneous conjuncti vitis is generally bilateral and can recur after excision. CLINICAL PRESENTATION
Figure 7-8 Ligneous conjunctivitis: papillary white-red lesions of firm consistency in both eyelids of the left eye. (Reproduced with permission from MiSSIon for Vision, 2005. Available at hrtp.1/Www.missionfor visionusa.org!ana tomy!2006/03/whal-is-ligneous-con/unctivitis,hlm!.)
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193
Cultures can be taken at initial diagnosis to exclude a bacterial pseudomembranous or membranous conjunctivitis. Surgical excision with or without adjunctive cryotherapy has been advocated. However, recurrences are frequent, and patients and their families should be informed about this possibility. Medical therapy by administration of purified plasminogen, fresh frozen plasma, heparin, corticosteroids, or azathioprine has been reported. Use of am niotic membrane has also been reported. No single treatment has been shown to be consistently effective or superior. Many cases of ligneous conjunctivitis eventually resolve spontaneously after several months to a few years.
MANAGEMENT
Barabino S, Ro lando M. Amniotic membrane transplantation in a case of ligneous conjunctivitis. Am J Ophthalmol. 2004;13 7(4P52- 753. Heidemann DG , \Villiams GA, Hartzer M, Ohanian A, Citron ME. Treatment ofligneous conjunctivitis with topical plasmin and topical plasminogen. Cornea. 2003;22(8):760- 762 . Schuster V, Seregard S. Ligneous conjunctivitis. Surv Ophthalmol. 2003;48(4):369-388.
Contact Lens-Induced Conjunctivitis
The pathogenesis of contact lens-induced conjunctivitis is not fully understood and may be multifactorial (allergic, dry eye, infectious). Patients with ocular prostheses and exposed monofilament sutures have shown reactions similar to those seen in patients with contact lens-induced conjunctivitis, suggesting that an immune-related response may result from a variety of ins ults, including repeated mechanical trauma of the superior tarsus by the sharp or rough surfa ce of a contact lens, prosthesis, or suture. A hypersensitivity reaction to the contact lens polymer itself (or to antigens or other foreign material adhering to it) has also been postulated but not formally demonstrated. Although most patients \\'ho develop contact lens-indu ced conj unctivitis do not have clinically significant dry eye, the latter condition is present in a significant minority (particularly because contact lenses diminish blinking and hence in crease evaporative loss of tears) and may facilitate adhesion of antigens to the surface epithelium. The histologic findings in contact lens-induced conjunctivitis are similar to those observed in YKC. An abno rmal accumulation of mast celis, basophils, and eosinophils is noted in the epithelium and/or the substantia propria of the superior tarsus . Abnormally elevated concentrations of immunoglobulins, specifically IgE, IgG, and IgM, and complement components have been found in the tears of affected patients. These findings suggest a combined mechanical and immune-mediated pathophYSiology for the condition. Surface deposits on worn contact lenses are a known risk factor for the development and persistence of contact lens-induced conjunctivi tis. PATHOGENESIS
Some patients who wear contact lenses, particularly extended-wear soft contact lenses, may develop infl ammato ry symptoms, including redness, itching, and mucoid discharge. One or more of the fo llowing signs may be seen during biomicroscopic examination of contact lens wearers with these symptoms:
CLINICAL PRESENTATION
mild papillary reaction (papillae <0.3 mm in diameter) on the superior tarsal conjunctiva punctate epithelial erosions peripheral corneal infiltrates and vasc ularization
194 • External Disease and Co rn ea
At the more severe end of the spectrum of contact lens- related inflammation is the entity known as giant papillary conjunctivitis (GPC). GPC te nds to develop earlier and more frequently in soft contact lens wearers than in hard contact lens wearers and may be recurrent. It may also be induced by other irritants, such as loose sutures or prosthetics. Symptoms include contact lens intolerance, itching, excessive mucus discharge, blurred vision from mucus coating of the contact lens, contact lens decentration, and conjunctival red ness. In rare instances, bloody tears and ptosis secondary to in flammation of the superior tarsal conjunctiva may be observed. The signs ofGPC consist of hyperemia, thickening, and abnormally large papillae (diameter >0.3 mm ) on the superior tarsal conju nctiva (Fig 7-9) due to disruption of anchoring septae. The morphologic appearance of the superior tarsal papillae may be variable in GPc. In some cases, the giant papillae cover the enti re central tarsus from the posterior eyelid margin to the upper border of the tarsal plate; involvement in other cases may be less extensive. Occasionally, only a few giant papillae appear, surrounded by smaller papillae. Long-standing or involuted giant papillae on the superior tarsus can resemble follicles. The symptoms of GPC ge nerally resolve when contact lens wear is discontinued. The tarsal conjunctival hyperemia and thickeni ng may reso lve in several weeks, but papillae or dome-shaped scars on the superior tarsus can persist fo r months to years. The goals of GPC treatment are to resolve the symptoms and enable patients to continue wearin g contact lenses, jf possible. Therapeutic strategies include discard ing the offending contact lenses, refitting the patient, improving lens hygiene, and treating conjunctival inflam mation with drugs. Simply fitt ing the patient with new con tact lenses frequently resolves GPc. Daily-wear rather than extended -wea r soft contact lenses should be encouraged, although GPC can also occur with dail y-wea r or even daily disposable contact lenses. Still, periodic planned replacement of soft contact lenses is often MANAGE MENT
Figure 7-9
Giant papillary conjunctivit is.
(Courtesy of Kirk R. Wi/he/mus, MD.)
CHAPTER 7:
Clinical Approach to Immun e- Related Diso rders of the External Eye.
195
beneficial and can easily be done by switching th e patient to disposable contact lenses that are used for daily wear and discarded eve ry day or every 2 weeks. Reducing daily-wear time and instituting a I-month contact lens holiday are other measures that can be helpful in many cases. Patients should be encouraged to clean their soft contact lenses daily using agents free of preservatives, particularly thimerosal, and to rinse and store lenses in appropriate lens storage solutions. Disinfection of contact lenses with a hydrogen peroxide system appears to be the method best tolerated by the inflamed conjunctiva . Regular enzymatic treatment of contact lenses may remove inciting contact lens deposits. It is also important to store contact lenses in cases that are routinely cleaned or sterilized; periodic replacement of contact lens cases is encouraged. If GPC persists, consideration should be given to changing the lens to a different polymer or to daily disposable lenses. Some patients do better with low-water-content lenses. Nevertheless, some patients continue to suffer from GPC as a result of soft contact lens wear despite these measures. In these cases, consideration can be given to fitting the patient with rigid gas-permeable (RGP) contact lenses, which are associated with a lower incidence of GPc. It should be noted that some patients have recurrences of GPC in spite of aggressive lens management and even RGP lens wear; these patients should be counseled about alternatives to contact lens wear. Pharmacologic therapy can be helpful in managing patients with GPc. Many practitioners recommend discontinuing lens wear for several (2- 3) weeks while treatment is initiated. Mast -cell stabilizers such as cromolyn sodium have been reported to improve early, mild GPC but have not been successful in advanced, severe cases. Howeve r, once advanced cases of GPC have been brought under control, maintenance therapy with topical mast-cell inhibitors may prevent further exacerbations. Topical corticosteroids, although effective in GPC, generally have a lim ited rol e because of their potential side effects. If used, they should be discontinued after a short peri od. Elhers WH, Donshik Pc. Giant papillary conjunctivitis. Curr Opin Allergy Clin lmmunol. 2008;
8(5H45-449.
Stevens-Johnson Synd rome and Toxic Epidermal Necrolysis Immune-complex deposition in the dermis and conjunctival stroma has been implicated in the pathogenesis of erythema multiforme. The most common inciting agents include drugs such as sulfonamides, anticonvulsants, salicylates, penicillin, ampicillin, and isoniazid; or infectious organisms, such as herpes simplex virus, streptococci, adenovirus, and occasionally mycoplasma. The distinctive pathologic changes of Stevens-Johnson syndrome are subepithelial bullae and subsequent scarring. The most severe fo rm of this condition is referred to as toxic epidermal necrolysis (TEN). TEN occurs more commonly in children and people with A IDS. It is characterized by keratinocyte apoptosis and epidermal necrolysis with minimal inflammatory infiltrate in the dermal stroma. See Table 7-1 for a comparison of StevensJohnson syndrome, TEN, and other oculocutaneous immune-mediated conditions. PATHOGENESIS
196 • External Disease and Cornea
Table 7- 1 Selected Oculocutaneous Immune-Mediated Reactions Condition
Causes
Eye
Skin
Oth ers
Angioedema
Drugs; foods; insect sting Unknown
Eye li d edema
Facial edema; urticaria Bull ous eruptions Pigm entary changes
Cardiorespiratory distress Lesions of oropharynx and genitalia Respiratory and gastrointestinal lesions Fever; respiratory lesions; se psis
Cicatricial pemphigoid Graft-vs- host diseas e StevensJohnson syndrome Toxic epidermal necrolysis
Bone-marrow transplant Drugs; infections Drugs; infections
Cicatrizing conjunctivitis Dry eye; conjunct ivitis Conjunctival erosion; con juncti vi ti s; episcleritis Blepharodermatitis; conjunctivitis; corneal exposure
Blisters
Blisters; necrosis
Fever; respiratory and gastrointestina l lesions
Albert OM , Miller JW, Azar DT, Blodi BA. Albert & Jakobiec's Principles and Practice ofOphthalmology. 3rd ed. Philadelphia: Elsevier/Saunders; 2008.
The term erythema multiforme refers to an acute inflammatory vesiculobuLlous reaction of the skin and mucous membranes. When these hypersensitivity disorders involve only the skin , th e term erythema mulliforme minor is used; when th e skin and mucous membranes are involved, the condition is knmvn as Stevens-Johnson sYl1drome. or erythema multiforme major. which accounts for 20% of all patients with erythema multi fo rme. The incidence of Stevens-Johnson syndrome has been shown to be about 5 cases per mi ll ion per year. Recent repo rts have suggested that patients with AIDS are at a higher risk of developing erythema multiforme. particularly patients treated for Pneumocystis carinii pneumonia. Stevens-Johnson syndrome occurs most commonly in children and young adults and in females more often than males. Fever, arth ralgia, malaise, and upper or lower respiratory symptoms are usually sudden in onset. Skin eruption fo11o\l/s within a few days with a classic "target" lesion consisting of a red center su rrounded by a pale ring and then a red ring, although maculopapular or bullous lesions are also common. The mucous membranes of the eyes. mouth. and genitalia may be affected by bullous lesions with membrane or pseudomembrane formation. New lesions may appear over 4-6 weeks, with approximate 2-week cycles for each crop of lesions. The primary ocular finding is a mucopurulent conjunctivitis and episcieritis. Bullae and extensive areas of necrosis may develop (Fig 7-10). Later ocular complications are caused by cicatrization resulting in conjunctival shrinkage, keratinization, trichiasis, and tear deficien cy. Patients with Stevens-Joh nson syndrome are at higher risk of infection due to loss of the epithelial barrier and hence may develop severe ocular infection concurrent with the ocular surface disease. Cicatricial pemphigoid has also been reported as a rare sequela of Stevens-Johnson syndrome (see the following section). CLINICAL PRESENTATIO N
ManagementofStevens-Johnsonsyndrome is mainly supportive. The mainstay of ocular therapy is lubrication with preservative-free artificial tears and ointments
MANAG EMENT
CHAPTER 7:
Clinical Approach to Imm une-Re lated Disorders of the External Eye. 197
Fi gure 7-1 0
Stevens-Johnson syndrome with associated ocular disease .
and vigilant surveillance for the early manifestations of ocular infections. Topical antibiotics are occasionally used as prophylaxis. Improved supportive therapy and, in some cases, administration of systemic corticosteroids have reduced the high mortality rate previously associated with this condition. However, the ro le of corticosteroids remains controversial. Some authorities recommend treating severe cases (Stevens-Johnson syndrome/TEN) with oral prednisone, starting with 1 mg/kg/day. Even when used for short periods of time, however, high doses of systemic corticosteroids (primarily when administered intravenously) can be associated with serious complications: gastrointestinal hemorrhage, electrolyte imbalance, and even sudden death. Moreover, they may increase the likelihood of infection. The efficacy of topical corticosteroids for the ocular manifestations of this condition has not been established and remains controversial. On the one hand, corticosteroids may decrease surface inflammation and corneal angiogenesis; on the other hand, they may contribute to corneal thinning and infection. Hence, aggressive lubrication with drops and ointment remains the mainstay of therapy and can prevent nosocomial complications in debilitated patients. Symblephara may form during the acute phase because the raw, necrotic palpebral and bulbar conjunctival surfaces can adhere to one another (Fig 7-1 1). Some authors recommend daily lysis of the symblephara and the use of symblepharon rings, but the longterm results of this therapy may be disappointing. In fact, some investigators discourage the use of these strategies, hypothesizing that repeated conjunctival lysis may exacerbate inflammation and surface morbidity. More recently, significant long-term benefit has been demonstrated from the early transplantation of amniotic membrane over the entire ocular surface, including the eyelid margins. This is one of the few potentially beneficial therapeutiC interventions for this devastating disease. A recent study also supported the use of high-dose IV corticosteroids during the acute phase, with improved ocular outcomes as well.
198 • External Dise,ase and Cornea
Figure 7-" Stevens-Johnson syndrome demon strating in feri or eyelid symblepharon as we ll as ocular surface keratin izati on. (Courtesy of Charles S. Bouchard, MD.)
Late eyelid sequelae, such as entropion, trichiasis, and keratinization result in chronic ocular surface inflammation that is difficult to manage. Attempts to reconstruct the symblepharon and eyelid margins with mucous membrane grafting may result in further inflammation and scarring. Therapeutic contact lenses may offer temporary help. Systemic immunosuppression is often required to suppress the severe inflammatory response in these cases. Eyelid reconstruction for severe disease needs to be performed prior to any ocular surface management such as limbal stem cell transplantation or penetrating kerato plasty (PK). Because of the altered ocular surface and the corneal neovascularization that frequently develops in these patients, PK has an extremely poor prognosis and is generally reserved for progressive thinning or perforation. Rare favorable results in desperate cases have been achieved with the use of a keratoprosthesis, although the long-term stability of such devices is poor. Unfortunately, many patients suffering from this condition are young and are left with lifelong ocular morbidity. Araki Y, Sotozono C, lnatomi T, et a1. Successful treatment of Stevens-Johnson syndrome with steroid pulse therapy at disease onset. Am J Ophthalmol. 2009; 147( 6): I004-1 011. Gregory DG. Th e ophthalmologic management of acute Stevens -Jo hnson syndrome. Ocul Su,! 2008;6(2);8 7-95. Nordlund ML, Brilakis HS, Holland EJ. Surgical techniques for oc ular surface reconstruction. Focal Points: Clinical Modules Jor Ophthalmologists. San Francisco: American Academy of Ophthalmology; 2006, module 12.
Ocular Cicatricial Pemphigoid The exact mechanism of ocular cicatricial pemphigoid (OCP), or mucous membrane pemphigoid (MMP), remains unknown, although it may represent a cytotoxic (type II) hypersensitivity in which cell injury results from autoantibodies directed against a cell surface antigen in the basement membrane zone (BMZ). Bullous pemphigOid
PATHOGENESIS
CHAPTER 7:
Cl inical Approach to Immune-Re lated Disorders of the External Eye.
199
antigen II (EPISO) and its soluble extracellular domains have been identified as possible auto antigens. Antibod y activates complement with a subsequent breakdown of the conjunctival memb rane. A number of proinflammatory cytokines such as 1L-1 and TNF- u are overexpressed. TNF-u has been shown to induce the expression of migration inhibitory factor, a cytokine found to have elevated levels in the conjunctival tissues of patients with OCP. Macrophage colony-stimulating facto r has also been shmo\fn to have an increased expression in the conjunctival tissue of patients with active OCP. Cellular immunity may also playa role. HLA-DR4, a special genetic locus in the major histocompatibility complex (MHC), has been associated with this condition, but not all affected individuals are positive for this background; hence, HLA typi ng is not useful. Pseudopemphigoid, which has a clinical picture similar to pemphigoid, has been associated with the chronic use of certain topical ophthalmic medications. Case reports have implicated pilocarpine, epinephrine, timolol, idoxuridine, echothiophate iodide, and demecarium bromide. The principal difference between pseudopemphigoid and true pemphigoid is that in the former, progression of the disease generally ceases once the offending agent is recognized and removed. The different ial diagnosis of cicatrizing conjunctivitis includes 4 major categories (Table 7 -2): 1. postinfectious conditions that follow severe episodes of trachoma, adenoviral conjunctivitis, or streptococcal conjunctivitis 2. autoimmu ne or auto reactive conditions such as sarcoidosis, sclerod erma, lichen planus, Stevens-Johnson syndrome, dermatitis herpetiformis, epidermolysis bullosa, atopic blepharoconjunctivitis, and graft-vs -host disease 3. prior conjunctival trauma 4. severe blepharokeratoconjunctivitis caused by rosacea or other disorders (eg, atopic keratoconjunctivitis) that are associated with conjunctival shri nkage The diagnos is of unilateral OCP should be made with caution, because other diseases, including many of those just listed, may masquerade as OCP. Finally, linear IgA dermatosis, a rare dermatologic condition, can result in an ocular syndrome that is clinically identical to cicatricial pemphigoid and requires similar treatment. Oyama N, Setterfield JF, Powell AM, et a1. Bullous pemphigoid antigen II (BP180) and its soluble extracellular domains are major autoantigens in mucous membrane pemphigoid: the pathogenic relevance to HLA class II alleles and disease severity. Br J Dermato/. 2006; 154(1):90-98.
Table 7-2 Differential Diagnosis of Cicatricial Conjunctivitis
Infectious
Allergic
Autoimmune
Miscellaneous
Trachoma Adenovirus Corynebacterium diphtheriae
Atopic keratoconjunctiv itis Stevens-Johnson syndrome
OCP Sarcoidosis Lupus Scleroderma Lichen planus
Ocula r rosacea Chemical burns Trau ma Medicamentosa Ra diation Neoplasia
200 • Exte rnal Disease an d Cornea
Cicatricial pemphigoid is a chron ic cicatrizing conjwlCtivit is of autoimmune etiology. Although it is a chronic vesiculobullous disease primarily involving the conjunctiva, it frequently affects other mucous membranes, including the mouth and oropharynx, genitalia, and anus. The skin is involved as well in approximately 15% of the cases. Pemphigoid should not be confused with pemphigus vulgaris, a skin disease that rarely affects the eyes and with rare exceptions does not cause conjunctival scarring. Cicatricial pemphigoid affects women more than men by a 2: I ratio. Patients are usually older than 60 and rare ly younger than 30. They frequently present with rec urrent attacks of mild and nonspecific conjunctival inflammation with an occasional mucopurulent discharge. In its earl y phases, OCP may present with conjunctival hyperemia, edema, ulceration, and tear dysfunction. Close examination of the conj unct iva in early stages of the disease (stage I) reveals subepithelial fibrosis (Fig 7- 12). Fine gray-white linear opacities, best seen wit h an intense but thin slit beam, appear in the deep conj unctiva. However, in many cases insidious disease in its early stages produces nonspecific symptoms with minimal overt physical fll1dings such as chronic red eye. Oral mucosal lesions may be a clue that can lead to early diagnosis. Transient bullae of the conjunctivae rupture, leading to subepithelial fibrosis. Loss of goblet cells, shortening of the fornices (stage II), symblepharon formation (stage Ill; Fig 7-13), and, on occasion, restricted ocular motility with extensive adhesions behveen the lid and the globe (stage IV) can follow. Ophthal mologists should attempt to diagnose this condition in its early stages and should therefore watch for an inferior forniceal depth ofless than 8 mm, which is abnormal and shou ld prompt further evaluation . Subtle inferior symblephara can be detected when the lower eyelid is pulled down while the patient looks up. Recurrent attacks of conjunctival inflammation can lead to destruction of goblet cells and eventually obstruction of the lacrimal gland ductules. The resultant aqueous and mucous tear defiCiency leads to keratini zation of the already thickened conjunctiva. CLINICAL PRESENTATION
Figure 7-12 Bouchard, MD.)
Ocular cicatrici al pemphigoid showing subepithelial scarring.
(Counesy of Charles
S
CHAPTER 7:
Figure 7-13
Clini ca l Approach to Immune-Related Disorders of the Externa l Eye.
20 1
Patient with OCP de monstrating s ub epit helial fibrosis, symblepharon, and short-
ening of the infer ior forn ix.
(Courtes y of Charles S. Bouchard. M D.)
Entropion and trichiasis may develop as scarring progresses, leading to abrasions, corneal vascul arization. further scarrin g, ulceration, and epidermalization of the ocular surface. Although the clinical course is variable, progressive deterioration usually occurs in un treated cases. Remissions and exacerbations are common. Surgical interve ntion can incite to furth er scarring but may be essential in manag ing entropion and trich iasis. Although ocr is a bilateral disease, I eye may be more severely in volved than the other. PathologiC support for a diagnosis of pemphigoid can be obtained from a conjunctival biopsy se nt for immunofluorescent or immunoperoxidase stain ing (see Table 7-2). False-negative results are not uncommon however. Biopsy specimens sho uld be obtained fro m an actively affected area of the conjunctiva or, if diffuse involvement is present, from the inferior conjunctival fornix. Oral mucosal biopsies may be useful, especially in the prese nce of an active lesion. Conjunctival biop sies mayor may not be positive for immunoreactants in pseudopemphigoid. Immunohistochemical staining techniques can demonstrate C3, IgG, IgM , and/or IgA localized in the BMZ of the conjunctiva in pemphigoid (Fig 7-14). Circulating anti- basement membrane antibody has been identified in the sera of some patients with pemphigoid. LABORATORY EVALUATION
Mihai S, Sitaru C. Immunopathology and molecular diagnosis of autoimmune bullous diseases. J Cell Mol M,d. 2007; II (3H62- 48I. MANAGEMENT A multidisciplinary approach is often required in the management of this disease, with the invo lveme nt of ophthalmologists, dentists, dermatologists, oral surgeons, primary care physicians, gynecologists, otolaryngologists, and gastroenterologists. Classifying patients into high-risk and low-risk groups is valuable when determining appropriate therapy. Patients with OCP involving ocular, genital, nasopharyngea l, esophageal, and laryngeal mucosae, as well as patients with ra pidly progressing disease, should be treated using th e high-risk algorithm. This consists of initial treatment with predn isone and
202 • External Disease and Cornea
Figure 7-14
Immunofluorescent staining of basement membrane in a patient wi th cicatricial
pemphigoid. cyclophosphamide (Cytoxan). Cyclophosphamide remains a mainstay of therapy in severe disease. The usual therapeutic dose is 1.5-2.0 mg/kg/day in divided doses. The therapeutic target is a reduction in white blood cou nt to the range of 2000-3000 cells/~L. Cytotoxic therapy can bring about disease rem ission. Consultation with an internist, dermatologist, or oncologist experienced in cytotoxic therapy is recommended when administering immunosuppressive agents such as cyclophosphamide. Etanercept may be an effective treatment option for OCP of the oral and ocular mucous membranes. This therapy should be considered an alternative treatment option for patients ""ho would require other aggressive systemic treatments, such as cyclophosphamide. corticosteroids. azathioprine. and intravenous immunoglobulin (IVIg). Low-ri sk patients include those with disease occurring only in the oral mucosa or oral mucosa and skin. These patients have a much lower incidence of scarring; thus, they can be treated more conservatively. Because progression is often slow, careful clinical staging of the disease and photodocumentation in differing positions of gaze are generally recommended in evaluating the disease course and response to therapy. Severity of pemphigoid can be judged by measuring the shortening of the inferior fornix depth (for stage ]] disease ) and the extent of symblepharon along the inferior fornix in quartiles (0%-25%. 25%-50%. 50%-75%. and 75%- 100% for stage II I-IV disease) (see Fig 7-13). Dapsone. a drug previously used to treat Hansen disease (leprosy) and dermatitis herpetiform is. has been advocated by most authorities as the initial drug of choice in mild cases. It must be avoided in patients with gl ucose-6-phosphate dehydrogenase (G6PD) defiCiency or sulfa allergy; therefore. testing for G6PD defiCiency is recommended before initiating treatment. However, even those without this enzymatic deficiency may develop hemolytic anemia. Topical vitamin A has been shown to reverse, to some extent, the keratinization resulting from the squamous metaplasia associated with this condition, but it is not currentl y commercially available as an ophthalmic preparation.
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203
Other measures, such as surgical correction of eyelid deformities or eyelash ablation for trichiasis, are occasionally required to achieve ocular surface quiescence. Intraocular surgery is best delayed until disease activity has been under control for an extended period of time. Hard palate and buccal mucosal grafting can be useful techniques in fornix reconstruction in severe cases. Puncta I occlusion, which may already have resulted from cicatrization, can be useful in managing any associated dry-eye condition. In general, patients with cicatrizing conjunctivitis have a higher rate of spontaneous extrusion of silicone punctal plugs, and thus permanent punctal occlusion with cautery is often required. Standard PK generally has a very guarded prognosis in patients who develop severe corneal disease in OCP, but keratoprosthesis surgery has been used with some success. Kheirkhah A, Blanco G, Casas V, Hayashida y, Raju VK, Tseng Sc. Surgical strategies for fornix reconstruction based on symblepharon severity. Am J Ophtha/mol. 2008;146(2):266-275 . Sami N, Letko E, Androudi S, Daoud Y, Foster CS, Ahmed AR. Intravenous immunoglobulin therapy in patients with ocular-cicatricial pemphigoid: a long-term follmv-up. Ophthalmology. 2004; III (7), 1380-1382. Saw VP, Dart JK, Rauz S, et al. Immunosuppressive therapy for ocular mucous membrane pemphigoid: strategies and outcomes. Ophthalmology. 2008; 115(2):253-26l. Tauber J. Ocular cicatricial pemphigoid. Ophthalmology. 2008;115(9):1639- 1640.
Ocular Graft-vs-Host Disease
Graft-vs-host disease (GVHD) is a relatively common complication of allogeneiC bonemarrow transplantation, performed most commonly for hematopoietic malignanCies. In this condition, the grafted cells can attack the patient's tissues, including the skin, gut, lungs, liver and gastrointestinal system, and eyes. Although GVHD can be acute or chronic (developing more than 3 months after bone-marrow transplantation), most ocular complications occur as a manifestation of chronic GVHD (cGVHD). Clinical features of ocular graft-vs-host disease (keratoconjunctivitis sicca [KCS], cicatricial conjunctivitis, scleritis, and others) mirror other inflammatory ocular conditions associated with autoimmune/co llagen vascular diseases. The pathogenesis of ocular surface disease in GVHD is multifactorial but has 2 main components: (1) conjunctival inflammation with or without subepithelial fibrosis, and (2) severe keratoconjunctivitis sicca from lacrimal gland infiltration by GVHD-effecting T lymphocytes. KCS occurs in 40%-60% of patients with cGVHD. Conjunctival inflammation in GVHD can be severe and even associated with limbal stem cell deficiency and secondary corneal scarring. Amniotk membrane transplantation and even autologous or allogeneiC stem cell transplantation may be used for more severe cases. Fortunately, the stem cell deficiency is rare. Aggressive lubrication and punctal occlusion are the mainstays oflocal therapy. A high incidence of fibrosis, which leads to extrusion of the punctual plugs, must be monitored closely. Severe filamentary keratitis can be treated further with mucolytic agents (10% acetylcysteine) or bandage soft contact lenses. Severe ocular surface disease in GVHD may be associated with active nonocular (often skin) GVHD and may require increased systemic immunosuppression by cyclosporine or tacrolimus (F KS06). Topical cyclosporine may also be useful in controlling the disease. Visual disturbances are due to su rface irregularity, and it is important to remember the high rate of posterior subcapsular cataracts, which
204 • Ext erna l Di sease and Cornea
B
A Figure 7-15
A, Patient with GVHD fitted with a therapeutic scleral contact lens. The infe-
rior paracentral cornea demonstrates subepithelial scarring. B. High magnification shows the space between the contact lens and cornea. (Courtesy of Charles S. Bouchard, MD.)
can cause dec reased vision. Gas-permeable scleral contact lenses provide an important management tool fo r patients with severe ocular surface disease (Fig 7-15). Kim SK. Update on ocular graft versus host disease. Curr Opin Ophthalmol. 2006;1 7(4) : 344-348. Nakamura N, lnatomi T, Sotozono C, et al. Transplantation of autologous serum-derived cultivated corneal epithelial equivalents for the treatment of seve re ocular surface disease. Ophthalmology. 2006;113 (10): 1765-1772. Takahide K, Parker PM , Wu M, et al. Use of flu id-ventilated, gas-permeable scleral lens for management of severe keratoconjunctivitis sicca secondary to ch ronic graft -versus-host disease. Bioi Blood Marrow Transplallt. 2007; 13(9): 10 16-1021.
Other Immune-Mediated Oiseases of the Skin and Mucous Membranes
Other im mune-mediated disorde rs that can, in rare cases, affect the conjunctiva include linear IgA bullous dermatosis, dermatitis herpetiformis, epidermolysis bullosa, lichen plan us, para neoplast ic pemphigus, pemphigus vulgaris, and pemphigus foliaceus (Table 7-3).
Immune-Mediated Diseases of the Cornea Thygeson Superficial Punctate Keratitis
The etiology ofThygeson superficial punctate keratitis (SPK) is unknown. Although many of the clinical features resemble those of a viral infection of the epithelium, attempts to confirm viral particles by electron microscopy or culture have been unsuccessfuL Confocal microscopy has demonstrated clumps of markedly enlarged epithelial cells and multiple highly reflective filamentary stru ctures in the deeper layers. Most of these lesions were linear, but some showed curled ends and others demonstrated branching lesions with "sprouts:' No inflammatory cells were evident. The rapid response of the lesions to corticosteroid therapy suggests that Th ygeson keratit is is largely immunopathogenically derived. PATHOG ENE SIS
CHAPTER 7: Clinical Approach to Immune-Related Disorders of the External Eye. 205
Tab le 7-3 Immunopatholog ic Featu res of Autoimmune Bullous Diseases Disease
Direct Immunoflu oresc ence
Indirect Immunofluorescen ce
Pem p higu s di sea ses Pemph igus vulgaris
Interce llular IgG and C3
Dsg 3, Dsg 1
Pemphigus foliaceus
Intercellular IgG and C3
Paraneoplastic pemphigus
IgG and C3 intercellularlyand at the dermalepidermal junction Intercellul ar IgA and C3
Intercellular IgG (monkey esophagus ) Intercellular IgG {monkey esophagus ) Intercellular IgG (monkey esophagus and rat bladder*) Intercellular IgA (monkey esophagus)
Dsc 1, Dsg 3
EpidermallgG (SSSt)
SP180, SP230
Epiderma l complement-fixing IgG (SSS) Epidermal or dermal IgG, IgA ISSS)
SP180 , SP230
BP180, Laminin 5, a6~4 in tegrin
EpidermallgA (SSS ) Derma l IgA (S SS I
LAD-I Type VII collagen
DermallgG (SSS )
Type VII collagen
Ant iendomysium IgA (monkey esophagus)
Transglutaminase
IgA pemphigus Pem p higoid di sea ses Bullous pemphigoid
Gestational pemphigoid Mucous membrane pemphigoid Linear IgA disease
Epidermolys is bullosa acquisita Dermatitis herpetiformis
Linear C3 and IgG at the dermalepidermal junction Linear C3 at the dermal- epidermal junction Linear IgG, IgA, and C3 at the dermalepidermal junction Linear IgA (and C3) at the dermalepidermal junction Linear Ig G, IgA, and C3 at the dermalepidermal junction Granular IgA deposits in the dermal papillae
Autoa ntigen s
Dsg 1 Dsg 3, Dsg 1, plakines
Dsc == desmocollin, Dsg == des moglein . *Rat bladder is a sensitive substrate for detection of circulating autoantibodies in para neoplastic pemphigus. tSSS is skin incubated with 1 M NaCI, as a substrate for detecting circulating autoantibodies in subepidermal blistering diseases. From Mihai S, Sitaru C. Immunopathology and molecular diagnosis of autoimmune bullous diseases. J Cell Mol Med. 2007 ;11(3):462-481.
Cheng LL, Young AL, Wong AK, Law RW, Lam DS. In vivo confocal microscopy of Thygeson's superficial punctate keratitis. Clin Experiment Ophthalmol. 2004;32(3):325- 327.
This condition, first reported by Thygeson in 1950, is characterized by recurrent episodes of teari ng, foreign-body sensation, photophobia, and reduced vision. It affects children to older adults and is typ ically bilateral, although it may develop initially in 1 eye or may be markedly asymmet ric in some cases. The hallmark finding is multiple (up to 40 but as few as 2-3) slightly elevated corneal epithelial lesions with "negative staining;' ·which are noted during exacerbations. The epithelial lesions are round or CLINICAL PRE SENTATION
206 • Externa l Disea se and Corn ea
oval conglomerates of gray, gra nular, or "crumblike" opacities associated with minimal conjun ctival reaction, in contrast to adenoviral keratoconjunctivitis. High magnificat io n reveals each opacity to be a cluster of multiple smaller pinpoint opacities (Fig 7- 16). A characteristic feature is the waxing and waning appea rance of individ ual epithelial opacities, which change in location and number over time. The greatest density of these lesions typ ically appears in th e central cornea. The raised punctate epithelial lesions themselves stain faintl y with fluorescein and rose bengal. No conjunctival infl ammatory reaction is noted dur ing exacerbatio ns, but occasionally patients wi ll have mild bulbar conjuncti val injection. In rare cases, a mild subepithelial opacity may de velop underlying the epithelial lesion-more common ly in patients who have received topi ca l antiviral therapy. The important facet of this condition is that the patient's symptoms may far exceed the apparent signs; frequently, patients complain bitterly of photophobia and foreign-body sensation in the setting of on ly a few cent ral epithelial lesions. MANAGEMENT Supportive therapy with artificial tears is often adequate in mild cases. Treatment altern atives for persistently symptomatic cases include topical corticosteroids and bandage soft contact lenses. Antiviral th erapy is not the standard of care at this ti me, as there are no firm data to associate th is condition with an active replicative vira l infection. If a topi cal corticosteroid is prescribed, only a very mild preparation is needed (eg, flu orometholone 0.1 %). Because th e lesions are quite responsive to corticosteroids, treatment will hasten their resolution, but they frequently recur in the same or di ffere nt locations on the cornea after the topi cal corticosteroids are stopped. Overall, the use of corticosteroids should be minimized in these cases and mo nitored closely. Topical cyclosporine 0.05% or tacroli mus given 2-4 times da il y is also effective in causing regression of the lesions. Although there is little to suggest that this treatment is superior to corticosteroid therapy, it is the preferred treatmen t over corticosteroids due to the higher safety profile.
A
B
Figure 7-16 A, Thygeson superficial punctate keratitis. B, At higher magnification, each lesion is seen to consist of several m in u~e dots .
CHAPTER 7:
Clinical Approach to Immune-Re lated Di sorders of the External Eye. 207
Connell PP, O'Reilly J, Coughlan S, Collum LM, Power \IVJ. The role of common ocular viral pathogens in Thygeson's superficial punctate keratitis. Br J Ophthalmol. 2007;91(8):1038-1041. Nagra PK, Rapuano CJ, Cohen EJ, Laibson PR. Thygeson's superficial punctate keratitis: ten years' experience. Ophthalmology. 2004; 111 (1) :34- 3 7. Tatlipinar S, Akpek EK. Topical ciclosporin in the treatment of ocular surface disorders. Br J Ophthalmol. 2005;89(10);1363 - 1367.
Interstitial Keratitis Associated With Infectious Diseases Interstitial keratitis OK) is a nonsuppurative inflammation of the corneal stroma that features cellular infiltration and usually vascularization without primary involvement of the epithelium or endothelium. Most cases result from a type IV hypersensitivity response to infectious microorganisms or other antigens in the corneal stroma. The topographic distribution (diffuse ve rsus focal or multi focal) and depth of the stromal infiltration, in addition to associated systemic signs, are helpful in determining the cause of IK. Congenital syphilis was the first infection to be linked with IK. Herpes simplex virus, which accounts for most cases of stromal ke ratitis, and varicella-zoster virus keratitis are discussed earlier in this volume. Many other microorganisms are much rarer causes of IK; these include PATH OG EN ESIS
lvIycobacterium tuberculosis M leprae Borrelia burgdolferi (Lyme disease) rubeola (measles) Epstein-Barr vi rus (infectious mononucleosis) Chlamydia trachoma tis (lymphogranuloma venereum) Leishmania spp Onchocerca volvulus (onchocerciasis)
Syphilitic interstitial keratitis Syphilitic eye disease is discussed further in SCSC Section 6, Pediatric Ophthalmology and Strabismus, and Section 9, Intraocular Inflammation and Uveitis. Systemic aspects of syphilis are discussed in BCSC Section 1, Update on General Medicine. Keratitis may be caused by either congen ital or acquired syphilis, although most cases are associated with congenital syphilis. Ma nifestations of congenital syphilis that occur early in life (within the first 2 years) are infectious. However, IK is an example of a later, immune-mediated manifestation of congenital syphilis. Affected children typically show no evidence of corneal disease in their firs t years; stromal keratitis lasting for several weeks develops late in the first decade ofHfe (or even later). These patients may also have other nonocular signs of congenital syphilis: CLINICAL PRESENTATION
dental deformities: notched (Hutchinson) incisors and mulberry molars bone and cartilage abnormalities: saddle nose, palatal perforation, saber shins, and frontal bossing
208 • External Disease and Cornea
cranial nerve VIII (vestibulocochlear) deafness rhagades (circumo ral radiating scars) mental retardation Congenital syphilitic keratitis is usuall y bilateral (80%). although both eyes mal' not be affected Simultaneously or to the same degree. Initial symptoms are pain. tearing. photophobia. and perilimbal injection. The inflam mation may last for weeks ifleft untreated. Sectoral superior stromal inflammation and keratic precipitates are typically seen earl y. As the disease progresses. deep stromal neovascularization develops. Eventually, the inflammation spreads centrally. and corneal opacification and edema may develop (Fig 7-17) . In some cases, the deep corneal vasc ularizat ion becomes so intense that the cornea appears pink-hence the term salmon patch. Sequelae of stromal keratitis include corneal scarring. thinning. and ghost vessels in the deep layers of the stroma . Visual acuity may be reduced because of irregular astigmatism and stromal opacification. Stromal keratitis develops only rarel y in acquired (as opposed to congenital) syphilis and. if it does. is typically unilateral (60%) . The ocular findings are similar to those seen in congenital syphilitiC keratitis. In genera l, uveitis and retinitis are much more common manifestations of acqUired syphilis than keratitis. The diagnosis can be confirmed serologically with the rapid plasmin reagin test and a treponeme-specific antibody test (FTA-ABS or MHA-TP). During the acute phase. ocular inflammation should be treated with cycloplegic agents and topical corticosteroids to li mit stromal inflammation and late scarring. The corneal disease can be suppressed effectively with topical corticosteroidsj however, even ifleft untreated. the disease typically burns out after several weeks. although it can lead to severe corneal opacification before doing so. Systemic syphilis (or neuroretinal manifestations) should be treated with penicillin or an appropriate alternative antibiotic according to the protocol appropriate for either congen ital or acquired syphilis. The necessity of LABORATORY EVALUATION AND MANAG EMENT
Figure 7-17
Active syphilitic interstitial kerati tis with sa lmon patch.
CHAPTER 7:
Clinical Approach to Immu ne-Related Disorders of th e External Eye . 209
lum bar puncture in syphilitic interstitial keratitis is uncertain. See BCSC Section 9. In traocular Inflamm ation and Uveitis, for a more in -dept h discuss ion of noncorneal syphilitic disease.
Reactive Arthritis Reacti ve arthritis (for merly Reiter syndrome) is a systemic disord er characterized by the classic triad of ocular (conjunctivitis/episcleritis. iridocyclitis. or kerati-
PATHOGENESIS
ti s), u rethral , and joint inflammation. The joint inflammati on is often highly asym metric and involves a few joints (o ligoart icular). These manifestations can appear simultaneously or separately in any sequence. Less common manifestations include kerato derma blen-
norrhagicum (a scaling skin eruption ). balanitis. aphthous stomatitis. feve r. lymphadenopathy. pneumonitis. pericarditis. and myocarditis. Attacks are self-limited. lasting from 2 to several months. but they may recur periodically over the course of several years. Reactive arthritis may occur after gram-negative bacterial dysentery (most frequently associated with Sa/morIella. Shigella, and Yersinia) or after nongonococcal urethritis caused by Ch lamydia trachomatis. More than 75% of patients with reactive arthritis are HLA-B27 positive. See BCSC Section 9. Intraocular Inflammation and Uveitis, for discussion of HLA- B27- related diseases and illustrations of nonocular manifestations of reactive arthrit is. A bilate ral papillary conjunctivit is with mucopurulent discharge is th e most com mon ocular finding in reactive arthritis; it has been rep orted in 30%-60% of
CLI NICAL PRESENTATIO N
patients. The conjunctivitis is self- limited. lasting for days to wee ks. Some patients present more wit h episcJer itis rathe r than with conjunctiviti s. Mild nongranulomatous iriti s has been reported to occur in 3%- 12% of patients. Various form s of keratitis may occur in rare
cases. includin g diffuse punctate epithelial erosions. superfi cial or deep focal infiltrates. and superficia l o r deep vascularization. Rea ctive arthrit is should be cons idered in any case of chronic, non follicul ar, mucopurulent conjunctivit is with negative cultu res. MANAGEM ENT
Treatm ent is mainly palliative. Corneal infiltra tes and vasc ularization often
respond to topical corticosteroids. Systemic antibiotic treatment of the related infection. if any. may be beneficial. Occasionally. the intraocu lar (uveitic) component of the disease can be ve ry severe and require sys temic immune suppress ion; see BeSe Section 9, Intraocular Inflammation and Uveitis.
Cogan Syndrome PATH OG ENESIS
Cogan syndrome is an autoimmun e disorder that produces stromal kera -
titis. ve rtigo. and hearing loss. The etiology of Cogan syndrome is obscu re, but the disease shares some cl in ico pathologic features with polyarteritis nodosa. CLINICAL PRESENTATION Cogan syndrome typically occurs in young adults. the majori ty of who m have had an upper respiratory infection 1- 2 weeks prior to the onset of ocular or vestib u]oauditory symptoms (vertigo. tinnitus. and hea ring loss). The earliest corneal findings are bi late ral faint white subepithelial inftltrates similar to those occurri ng in viral
210 • External Disease and Cornea
keratoconjunctivitis but located in the peripheral corn ea. Multifoca l nodular infiltrates may develop in the posterior cornea later in the course of this condition. Some patients develop a systemic vasc ulitis that presents as polyarteritis nodosa. When th e cause of stromal keratitis is not apparent, VDRL or RPR and FTA-ABS or M HA-TP are obtained (VDRL and RPR may become nonreactive in congenital syphilis). Other in fectious syndro mes sho uld also be considered. Because there are no specific labo ratory fi ndin gs, Cogan synd rom e is essentiall y a diag nosis of exclusion.
LABORATORY EVALUATION
The acute kerat itis of Cogan syndrome is treated with frequent topical corticosteroids. It is important to treat th is condi tion promptly because th e ocular and vestibular changes can proceed rapidly, and deafness is mo re likely if not treated early. O ral corticosteroids are recom mended for th e vestibuloaudito ry symptoms, because this treatment enhances the long-term prognosis and recovery of norrnal hearing. Cytotoxic agents may also have a therapeutic role but are reserved for severe and unresponsive cases.
MANAGEMENT
Gluth MB. Baratz KH, Matteson EL, Driscoll CL. Cogan synd rome: a retrospective review 0(60 patients throughout a half century. Mayo C/ill Proc. 2006;81 (4) :483-488.
Marginal Cornea l Infiltrates Associated With Blepharoconjunctivitis The lim bus plays an impo rtant role in immune-mediated corneal diso rders. As reviewed in Chapter 6, the limbus has a population of antige n-presenting cells that constituti vely express class I I MHC antigens and are capable of efficient m obi liza tion an d induction ofT-cell responses. Therefore, immun e- related cornea l changes often occur in a peripheral location adjace nt to the limb us. In addition, because the peripheral corn ea is adjacent to the vasc ulari zed (posterior) lim bus, circula ting immune celis, immune complexes, and complement facto rs tend to deposit adjacent to the term inal capillary loops of the limba l vascu lar arcades, thereby producing a varie ty of immune phenomena that manifest in the corneal periphery. Predisposing causes include
PATHOGENESIS
blepharoconjunctivit is contact lens wea r trauma endophthalmitis
Marginal infiltrates (also referred to as catarrhal infiltrates) usually occur where th e eyelid margins intersect with the cornea l surface : th e 10,2, 4, and 8 o'clock positions. Ma rginal infil trates in stap hylococcal blepharitis are typicall y gray-w hite, well circumscribed, and located ap proXimately 1 mm inside the limbus, with a characteristi c clear (in te rvening) zo ne of cornea between the infiltrate and the limbus (see Fig 5- I 0, in Chapter 5). In chronic disease, superfi cial blood vessels may cross the clear interval into th e area of corneal infiltration. The epithelium overl yin g marginal infiltrates may be in tact, show pu nctate epithelial erosio ns, or be ulcerated. Stromal opacification, peripheral corneal thinning, and lo r pannus may develop foll OWing resolution of the ac ute margi nal infiltrates.
CLINICAL PRESENTATION
CHAPTER 7:
Cli nical Approach to Im mune-Related Diso rders of the External Eye.
211
Perip hera l Ul cerative Keratitis Assoc iated With Systemic Immune-Mediated Di seases Autoimmune peripheral keratitis may develop in patients who have systemic immune-mediated and rheumatic diseases. Peripheral ulcerative keratitis (PUK) occurs most often in association with rheumatoid arthritis but may also be seen in Wegener granulomatosis, systemic lupus erythematosus, polyarteritis nodosa, ulcerative colitis, relapsing polychondritis, and other inflam matory diseases such as rosacea (Table 7-4) . Biopsy of conjunctival tissue adjacent to marginal corneal disease- although not a standard diagnostic procedure-typically shows evidence of immune-mediated vaso-occlusive disease. Central corneal melting in the setting of systemic collagen vascular disease may be due to a different mechanism associated with a T-lymphocyte infiltration. PATHOGENESIS
A history of connective tissue disease is often (but not invariably) present, although in some patients the ocular finding of peripheral corneal infiltration or
CLINICAL PRES ENTAT ION
Table 7·4 Differential Diagnosis of PUK Ocular Microbi al Bacteria l Viral Acanthamoeba Fungal Mooren ulce r Traumatic o r postsurgical Terrien marg inal degeneration Exposure keratopathy Rosacea System ic Microb ia l Bacterial Viral Helminthia si s Rheumatoid arthr itis Systemic lupus erythematosus Wegener granulomatosis Polyarteritis nodosa Relapsing polychondritis Progressive systemic sclerosis and scleroderma Sjogren syndrome Beht;et syndrome Sarcoidosis Inflammatory bowel disease (i 1-Antitrypsin deficiency Malignancy
Staphylococcus, Streptococcus, Gonococcus, Moraxella, Haemoph ilus Herpes simp lex, herpes zoster
Tuberculos is, syphil is, gonorrhea, borreliosis, bacillary dysentery Herpes zoster, AIDS, hepatitis C
Adapted with permission from Dana MR, Qian Y, Hamrah P. Twenty-five-year panorama of corneal immunology: em erging concepts in the iml n unopathogenesis of microbial keratitis, peripheral ulcerative keratitis, and co rn eal transplant rejection. Cornea. 2000;19(5):625-643.
212 • External Disease and Cornea
frank stromal melting may be the first sign of the tmderlying systemic illness. Autoimmune PUK generally correlates with exacerbations of systemic disease activity. Follow-up of these patients reveals that, if they are treated inadequately, a high proportion may suffer severe disease-related morbidity. The term keratolysis refers to the Significant (and often rapid) stromal melting seen in some cases of immune-mediated PUK associated with systemic autoimmunity. Although autoimmune PUK can sometimes be bilateral and extensive, it is usually unilateral and limited to 1 sector of the peripheral cornea (Fig 7-18). The initial lesions appear in a zone with in 2 mm of the limbus and are accompanied by varying degrees of vaso~occlusion of the adjacent lim bal vascular networks. In most cases, the epith e~ lium is absent in the affected area and the underlying stroma thinned; however, if the disease is detected early, epithel ial involve ment may be patchy and the stroma still of n ear~ normal thickness. Ulceration mayor may not be associated \vith a significant cellular infiltrate in the corneal stroma, and the adjacent conjunctiva can be minimally or severely inflamed. The goal of therapy is to provide local supportive measures to decrease melting. This is achieved through ma neuvers directed at (l) improving wetti ng, (2) promoting reepithelialization, and (3) suppressi ng the systemic-mediated inflammation. Maintaining enhanced lubrication of the surface is very important: first, because many rheumatoid patients have ke ratoconjunctivitis sicca as a manifestation of their secondary Sjogren syndrome; and second, because lubrication may help in diluting the effect of inflammatory cytokines in the preocula r tear film. Melting will stop or slow appreCiably if the epithelium can be made to heal by means of lubricants, patching, or a bandage soft contact lens. A number of topical collagenase inhibitors, such as sodium citrate 10%, Mucomyst 20%, medroxyprogestero ne 1%, o r tetracycline and systemic collagenase inhibi tors, such as tetracyclines (eg, doxycycline), are of possible value. Topical cyclosporine has been shown to be potentially effective in patients with central melting that is probably not due to occlusive vasculitis but is more likel y a T-cell~m ediated process. MANAGEMENT
Fi gure 7-18
Peri pheral ulcerative keratitis as a result of rheumatoi d disease.
CHAPTER 7:
Clinica l Approach to Immune-Related Disorders of the External Eye.
213
Topical corticosteroids, which also inhibit collagenase function, often have variable effects. Although they may suppress corneal inflammation when there is profound leukocyte infiltration in the cornea, they also may delay reepithelialization, predispose to superinfection, and even exacerbate melting by suppressing collagen production. In general, if the cornea has become significantly thinned, corticosteroid therapy is probably contraindicated. Excision or recession of adjacent limbal conjunctiva (as has been advocated for Moo ren ulcer; see the follOW ing section) is often followed by healing of the ulcer, presumably because the procedure elim inates a source of inflammatory cells and collagenolytic enzymes. Definitive management often cannot be achieved by local measures alone and re quires institution or escalation of systemic treatment, including immunosuppressive therapy using cytotoxic agents such as cyclophosphamide or immunomodulatory agents such as methotrexate or cyclosporine. Severe, rapidly melting cases may require intravenous therapy with high-dose cyclophosphamide, with or without corticosteroid therapy. Threatened perforation should be treated with temporizing measures such as cyanoacrylate glue and bandage contact lens placement until systemic therapy has been initiated, because lamellar or penetrating grafts are also susceptible to melting. Sometimes multiple tectonic grafts are required to preserve the globe while the systemic therapy is being adjusted. Once the underlying disease process has been controlled, reconstructive kerato plasty can be performed (see Chapters 15 and 16). Although conjunctival flaps can be very helpful for controlling the stromal melting in difficult-to -manage microbial keratitis, they are probably best avoided in immune-mediated disease. The melting could potentially be accelerated by bringing the conjunctival vasculature in even closer proximity to the area of corneal disease. Gottsch JD, Akpek EK. Topical cyclosporin stimulates neovascularization in resolving sterile rheumatoid central corneal ulcers. Trans Am Ophthalmol Soc. 2000;98:81-87. Perez VL, Azar DT, Foster CS. Sterile corneal melting and necro tizing scleritis after cataract surgery in patients with rheumatoid arthritis and collagen vascular disease. 5emin Ophthalmol. 2002;1 7(3 -4),124- 130.
Moore" Ulcer PATHOGENESIS Although the etiology of PUK is unknown, evidence is mounting that autoimmunity plays a key role. The follOWing have been found in patients with Mooren ulcer: deficiency of suppressor T cells • increased level of IgA increased concentration of plasma cells and lymphocytes in the conjunctiva adja cent to the ulcerated areas increased CD4+/CD8+ and B7-2+/antige n-presenting cell ratios as well as increased VCAM - I, VLA-4, and ICAM - I in the vascular endothelium of conjunctival vessels tissue-fixed immunoglobulins and complement in the conjunctival epithelium and peripheral cornea
214 • Exte rn.a l Disea se and Corn ea A significant nu mber of resi dent cells in Mooren ulcer specimens express MHC class II antigens, a reflection of the deg ree of immune-mediated inflarnmation in the tissue. It has been suggested that auto reactivity to a cornea-specific ant igen may playa role in the pathogenesis of th is disorder, and hu moral and cell-mediated immune mechanisms may be involved in the initiatio n and perpetuation of corneal destruction. T he proxim ity of the ulcerative lesion to th e limbus probably has pathophysiologic im portance (as discussed earlier in the sectio n on PUK) , because resection or recession of the limbal conjun ctiva can often have a beneficial therapeutic effect. Although the cause of Mooren ulcer is unknown, precipitati ng factors include accidental trauma or surgery and exposure to parasitic infection. The latter is of considerable importance, as the incidence of Mooren ulcer is parti cularl y high in areas where parasitic (eg. helmi nthic) infections are endemic. The principal hypotheses are that inflammation associated with previous injury or infection may alter the ex pression of corneal or con junctival antige ns (to which autoantibodies are then produced) or that cross-reactivity occurs between the i.m rnu ne effectors generated in response to infection and corneal autoantigens. The simultaneous presence of multiple types of inflammatory cell s. adhesion . and co stimulatory molecules in Mooren ul cer conjun ctiva suggests that their interacti on may contribute to a sustained immune activation as at least part of the pathogenic mechanism of this disorder. By definition, Mooren ulcer is of un known cause. Cases of PUK due to known local (eg. rosacea) or systemic (eg. rheu matoid arthritis) diseases should not be ca lled Mooren ulcer. Gottsch JD. Stark WJ. Liu SH. C loning and sequence analysis of huma n and bovine corneal antigen (CO -Ag) cDNA: identification of host-parasite protein calgranulin C. TrailS Am Dphthalmol Soc. 1997;95:111 - 125. Kafkaht C. Choi J. Za Cirakis p. et al. Mooren ulcer: an immunopathologic study. Comea. 2006; 25 (6):667-673. \'Vilson SE, Lee WM . Murakam i C. Weng J. Moninger GA. MOOl'en-type hepatitis C virus associated cornea l ulceration. Ophthalmology. 1994; I01 (4):736-745. Zelefsky JR. Srinivasa n M, Kundu A. et al. Hookworm in fes tati on as a risk factor for Mooren's ulcer in South India. Ophthalm ology. 2007;114(3):450-4 53.
Mom-en ul cer is a chronic, progressive, painful, idiopathic ulceration of the peripheral corneal stro ma and epithelium. Typicall y. the ulcer starts in the periphery of the corn ea and spreads circum ferentiall y and then centripetall y. with a leading underm ined edge of deepithelized tissue (Fig 7-19). A slower movement of ulceration proceeds toward the sclera. The eye is inflamed and pain can be intense. with photophobia and tea ri ng. Perforation may occur with m ino r trauma or during secondary infection. Extensive vasculari zation and fibrosis of the cornea may occur. In some patients. it may be ve ry diffi cult to distinguish Mooren ulcer from idiopathic PUK. An important distinguishi ng featu re is the purely corn eal in volvement of Mom·en; PUK has scleral involvement. Two clinical types of Mom·en ulcer have been described. Unilateral Mooren ulcer typically occu rs in an older patient population. Sex distribution is equal in this form , which is slowly progressive. A second type of Mooren ulcer is more common in Afri ca. T his fo rm
CLIN ICAL PRESENTATION
CHAPTER 7:
Clinical Approach to Immune -Re lated Diso rders of the Exte rnal Eye .
Figu re 7- 19
215
Moore n ulcer. (Courtesy of Vin cent P deLuise, MD.)
is usually bilateral, rapid ly progressive, and poorl y responsive to medical or surgical intervention (Fig 7-20). Corneal ulceration and perforation are frequ ent. Many of the patients with this form of Mooren ulcer also have coexisting parasitemia. It is possible that in this
subgroup of West African males, Mooren ulcer may be triggered by antigen- antibod y reaction to helminthic toxins or antigens deposited in the limbal cornea during the bloodborne phase of parasitic infection . M ANAGE M ENT
The multitude of therapeutic strategies used against Mooren ulcer un -
derscores the relative lack of effecti ve treatment. Topical corticosteroids, contact lenses, acetyleysteine (Mucomyst 10%) and L-cysteine (0.2 molar), topical cyciosporine, limbal
Fi gure 7-2 0
M oore n ulce r w ith severe superior limbal ulceration and thinning.
216 • External Disease and Cornea
conjunctival excision, and lamellar ke ratoplasty have all been described with variable success. More recently, topical IFN-a" and topical cyclosporine 2%, as well as infliximab, have also been reported as effective alternat ives. Systemic immunosuppressives such as oral corticosteroids, cyclophosphamide, methotrexate, an d cyclosporine have also shown promise in these cases. Hepatitis C-associated cases of "Mooren ulcer" -type PUK have responded to interferon therapy. Erdem U, Kerimoglu H, Gundogan F, Dagli S. Treatment of Mooren's ulcer with topical administration of interferon alfa 2a. Ophthalmology. 2007; 114{3}:446-449. Fontana L, Parente G, Neri p, Reta M, Tass inari G. Favourable response to inf1iximab in a case of bilateral refractory Mooren's ulcer. Cfill Experiment Ophthalmol. 2007;35(9) :871 -873. Tandon R, Chawla B, Verma K, Sharma N, Titiyal JS. Outcome of treatment of Mooren ulcer with topical cyclosporine A 2%. Cornea . 2008;27(8 ):859-861.
Immune-Mediated Diseases of the E isclera and Sclera Episcleritis Episcleritis is a self- limited, generally benign inflammation of the episcleral tissues. The pathophysiology of th is d isorder remains obscure. An underlying systemic cause is found in only a minority of patients. PATHOGENESIS
Episcleritis is typicall y a transient (usually days to weeks), selflimited disease of adults, usually 20-50 years of age. The chief complaint is usually ocular redness without irritation, which resolves spontaneously. Slight tenderness may be present. The disease occurs most commonly in the exposure zone of the eye, often in the area of a pinguecula, and it may recur in the same or different locations. About one third of patients have bilateral disease at one time or another. Episclerit is is diagnosed clinically by localizing the site of inflammation to the episclera. Unlike the deeper inflammation seen in scleritis (often with associated scleral edema clearly discernible on slit-lamp examination), episcleral inflam mation is superficial. The characteristic color in episcleritis is bright red or salmon pink in natu ral light, unlike the violaceous hue in most forms of scleritis. In addit ion, the redness in episcleritis (u nlike that associated with scleritis) will blanch with application of2.5% topical phenylephrine. Episclerit is is classified as simple (diffuse injection ) or nodular. In simple episcleritis, the inflammation is localized to a sector of the globe in 70% of cases, and to the entire episclera in 30% of cases. A localized mobile nodule develops in nodular episcleritis (Fig 7-21). Small peripheral corneal opacities can be observed adjacent to the area of episcleral inflammation in 10% of patients. The disease generally resolves wi thout producing any lasting destructive effects on tissues of the eye.
CLINICAL PRESENTATION
MANAGEMENT A workup fo r underlying causes (eg, autoimmune connective tissue disease such as Sjogren syndrome, rheumatoid arth ritis, or other conditions such as gout, herpes zoster, syphilis, tuberculosis, rosacea ) is rarely indicated except after multiple recurrences. Episcleritis generaliy clears without treatment, but top ical or oral NSAIDs may
CHAPTER 7:
Clinical Approach to
Im mu ne~ Rel a t ed
Figure 7-21
Diso rders of the External Eye. 217
Nodular episcleritis.
be prescribed for patients bothered by pain. Most patients simply need reassurance that their condition is not sight-threateni ng and can be treated with lubricants alone. The use of topical corticosteroids should be kept to a min imum in this benign, self-limited condition. However, in unusual cases of severe disease that does not respond to standard therapy with lubricants and NSAIDs, a short course of corticosteroids may be necessary. Jabs DA, Mudun A, Dunn JP, Marsh MJ . Episcleritis and scleritis: clinical features and treatment results. Am J Ophthalmol. 2000;130(4) :469- 476 . Vvilliams CP, Browning AC, Sleep TJ, Webber SK, McGill JI. A randomised, double-blind trial of topical ketorolac vs artificial tears for the treatment of episcleritis. Eye. 2005;19(7):739- 742.
Scleritis Scleritis is a much more severe ocular inflammatory condition than epi ~ scleritis. It is caused by an immune-mediated (typically immune-complex) vasculitis that frequently leads to destruction of the sclera. Scleritis is frequently associated with an underlying systemic immunologic disease; about one third of patients with diffuse or nodular scleritis and rno thirds with necrotizing scleritis have a detectable connective tissue or autoimmune disease. Scleritis causes Significant pain and may lead to structural alterations of the globe, with attendant visual morbidity. It is exceedingly rare in children, occurs most often in the fo urth to sixth decades of life, and is more common in women. About one half of scleritis cases are bilateral at some time in their course.
PATHOGENESIS
Watson PG. Scleral structure, organisation and disease: a review. Exp Eye Res. 2004;78(3): 609-623. CLI NICAL PRESENTATION The onset of scleritis is usually gradual, extending over several days. Most patients with scleritis develop severe boring or piercing ocular pain, which may worsen at night and occasionally awaken them from sleep. The pain may be referred
218 • Extern al Disease and Co rne a
to other regions of the head or face on the involved side, and the globe is often tender to touch. The inflamed sclera has a violaceous hue best seen in natural sunlight. Inflamed scleral vessels have a crisscross pattern . adhere to the sclera. and cannot be moved with a cotton-tipped applicator. Scleral edema, often with overlying episcleral edema, is noted by slit-la mp examination. Scleritis can be classified clinically based on the anatomical location (anterior versus posterior scleritis) and appearance of scleral inflammation (Table 7 -5). Diffuse versus nodular anterior scleritis Diffuse anterior scleritis is characte rized by a zone of scleral edema and redn ess. A portion of the anterior sclera «50%) is involved in 60% of cases. and the entire anterior segment is involved in 40% of cases (Fig 7-22). In nodular anterior scleritis, the scleral nodule is a deep red- pur ple color, immobile, and separated fro m the overlying episcleral tissue, which is elevated by the nodule (Fig 7-23). Necrotizing scleritis
Teeroti zing scleritis is the most destructive form of sclerit is. Of the patients affected, 60% develop ocular and systemic compl ications, 40% suffer loss of vis ion. and a significant minority may die prematurely as a result of complications of vasculitis.
Table 7-5 Subtypes and Prevalence of Scleritis l ocation
Subtype
Anterior sclera
Diffuse scleritis Nodula r sclerit is Necrotizing scleritis with inflammati on witho ut inflammation (scleromalacia perforans)
Posterior sclera
Figure 7-22
Diffuse ante rior scleritis. (Counesy of CharlesS. Bouchard, M D.)
Preva lence 40% 44% 14% ( 10%) (4%) 2%
CHAPTER 7,
Clinical Approach to Immune-Relat ed Disorde rs of the External Eye.
Figure 7·23
219
Nodular an terior scle ritis. (COUfresy of Charles S. Bouchard, MD.)
Necrotizing scleritis with inflammation
Patients with necrotizing scleritis with inflam -
mation typically present with severe pain. Most commonly, a locali zed patch of in fla mm ation is noted initially, with the edges of the lesion more inflamed than the center. In more advanced disease (25% of cases), an avascular edematous patch of sclera is seen (Fig 7-24). Untreated, necrotizing scleritis may spread posteriorly to the equator and circumferen-
tiall y until the entire anterior globe is involved. Severe loss of tissue may result if treatment is not intensive and prompt. The sclera may develop a blue-gray appearance (due to thi nning, which allows the underl ying choroid to show) and reveal an altered dee p episcleral blood vessel pattern (large anastomotic blood vessels that may circumscribe the involved area) after the inflammation subsides.
Figure 7-24
Diffuse anterior scleriti s with sa m ll area of necrotizing scleritis. Note also the
partially resolved sclerokeratitis (arrow).
(Courtesy of Charles
S.
Bouchard, MD)
220 • External Disease and Cornea
Necrotizing scleritis without inflammation This form of scleritis, also known as scleromalacia perforans, although undoubtedly due to inflammation, is said to be "without inflammation" because its clinical presentation is distinct from those of other forms of
anterior scleritis, in which typical signs (redness, edema) and symptoms (pain) of inflammation are readily apparent. Scleromalacia perforans typically occurs in patients with long-standing rheumatoid arth ritis. Signs of inflammation are minimal, and this type of scleritis is generally painless.
As the disease progresses, the sclera th ins and the underlying dark uveal tissue becomes visible (Fig 7-25). In many cases, the uvea is covered with only thin connective tissue and conjunctiva. Large abnormal blood vessels surround and cross the areas of scleral loss. A bulging staphyloma develops if intraocular pressure is elevated; spontaneous perforation is rare, although these eyes may rupture with minimal trauma.
Posterior scleritis Posterior scleritis can occur in isolation or concom itantly with anterior scleritis. Some in vestigators include posterior scleritis as an an terior variant of inflammatory pseudotum or.
Patients present with pain, tenderness, proptosis, visual loss, and, occasionally, restricted motility. Choroidal folds, exudative retinal detachment, papilledema, and angle-closure glaucoma secondary to choroidal thickening may develop. Retraction of the lower eyelid may occur in upgaze, presumably caused by infiltration of muscles in the region of the posterior scleritis. The pain may be referred to other parts of the head, and the diagnosis can be missed in the absence of associated anterior scleritis. Demonstration of thickened posterior
sclera by echography, CT scan, or MRlmay be helpful in establishing the diagnosis (Fig 7-26). Often, no related systemic disease can be found in patients with posterior scleritis.
Complications of scleritis Complications of scleritis are freque nt and include peripheral keratitis (37%), uveitis (30%), cataract (7%), glaucoma (18%), and scleral thinning (33%). Anterior uveitis may
Figure 7·25 Necrotizing anterior scleritis without inflammation (scleromalacia perforans) in a patient with rheumatoid arthritis. (Courtesy of Charles S. Bouchard, MO)
CHAPTER 7:
Clinical Approach to Immune-Related Disorders of the External Eye. 221
Figure 7-26 B-sca n ultrasound of a patient w ith posterior scleritis demonstrating local ized posterior sc leral t hickening , (Courtesy of James J. Reidy, MD.)
occur as a spillover phenomenon in eyes with anterior scleritis. Some degree of posterior uveitis occurs in all patients with posterior scleritis and may also occur in anterior scleritis when the overlying sclera is inflamed. Altho ugh one third of patients with scleritis have evidence of scleral translucency and/or thinning, frank scleral defects are seen only in the 1110st severe for ms of necrotizing disease and in the late stages of scleromalacia perforans. A wide variety of corneal findings may coincide with scleritis. In rare cases, corneas may develop central stromal keratitis in conjunction with scleritis, associated with heavy vascularizatio n and opacification in the absence of treatment. In diffuse or nodular scleritis, the corneal changes are usually localized to the area of infl am mation. In sclerokeratitis, the peripheral cornea becomes opacified by fibrosis and lipid deposition in conjunction with neighboring scleritis (v.. hich may be severe or ver y mild; Fig 7-27). The area of involvement may gradually move centrally, resulting in opacification
Figure 7-27
Sclerokeratitis.
222 • External Disease and Corn ea
of a large segment of cornea. This type of keratitis commonly accompanies herpes zoster scleritis but may also occur in rheumatic diseases. LABORATORY EVALUATION Sclerit is can occur in association with various systemic infectio us diseases, including syphilis, tuberculosis, herpes zoster, Lyme disease, cat-scratch disease, and Hansen disease. It is most fre quently seen, however, in association with auto immu ne connective tissue diseases such as rheumatoid arthritis, systemic lupus erythematosus, and seronegative spondyloarthropath ies (eg, anl-'ylosing spondylitis) or secondary to vascu litides such as Wegener granulomatosis, polyarteritis nodosa, or giant cell arteritis. Metabolic diseases such as gout may also, in rare instan ces, be associated '''lith scleritis. More than one half of patients with scleri tis have an associated identifiable systemic disease. The d ifferential diagnosis of scleritis is similar to that of PUK (see Table 7-4) . Because patients with certain fo rms of scleritis, especially necrotizing scleritis, have an increased rate of extraocular morbidity, its presence should be recogn ized as a manifestation of a potentially serious systemic disease. The workup of scleritis should therefore in clude a complete physical exami nation, with attent ion to the joints, skin, and cardiovasclilar and respiratory systems. Usually, this is best don e in conjunction with a rheumatologist or other internist with experie nce in diag nOS ing and managing these conditions. No Single approach can be used in the diagnosis of these patients' possible underlying illness, and laboratory studies should always be guided by the histo ry and physical examination . However, the following labo ratory tests are ge nerally recommended as an initial screening; other tests may then be ordered based on a more thorough rheumatologic (or infectious disease) examination:
complete blood count (CBC) with diffe rential erythrocyte sedimentation rate (ESR) or C-reactive protein (C R.P) serum autoantibody screen (antinuclear antibodies. anti-D A antibodies, rheuma toid factor, anti neutroph il cytoplasmi c antibodies) urinalysis serum uric ac id syphilis serology chest x-ray sarcoidosis screen (serum angiotensin -converting enzyme and lysozyme), as appropriate Topical corticosteroids may occasionaLly reduce ocular inflammation in mild cases of diffuse anterior and nodular scleritis, but in general the treatment of scleritis is systemic. For nonnecrotizing disease, es pecially diffuse disease, oral SA IDs may be effective. Some patients respond well to 600 mg of ibuprofen 3 times a day. Severe nodu lar disease and necrotizing disease al most always require more potent anti-in fl ammatory therapy. The use of tumor necrosis factor (TNF) inhibitors such as inflix.imab (Remicade) in rheumatoid arthritis-associated sclerit is has shO\vn promise in treating this difficult disease. Treatment is usually begun with oral corticosteroids. Although subconjunctival corticosteroids may be effective in redUCing scleral inflammation, they have been reported to cause scleral necrosis and exacerbate epithelial defects; therefore, use of depot corticosteroid injections in these cases is generall y contraindicated . MANAGEMENT
CHAPTER 7:
Clinical Approach to Immune-Related Disorders of the External Eye.
223
It is important to clearly define treatment goals: treatment failure may be considered
as progression of disease to a more severe form (eg, nodular to necrotizing) or failure to achieve response to treatment after 2-3 weeks of therapy, in which case an alternate therapeutic strategy will need to be instituted. Oral and/or high-dose (pulsed) IV corticosteroids may be effective for some cases of necrotizing scleritis or sclerokeratitis. If no therapeutic response is observed with corticosteroids, however, systemic immunosuppressive therapy with an antimetabolite (methotrexate), an immunomodulator (eg, cyclosporine), or a cytotoxic agent (eg, cyclo phosphamide) is recommended . Althoug h there is no consensus, most clinicians place rheumatoid arthritis patients on methotrexate and reserve more potent cytotoxic therapy for patients with active vasculitic disease such as '>\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%
Ocu lar (racia l) melanosis
Disc rete, brown or amelanotic, cysts Flat, patchy, brown Flat, gray- brown
Episcleral
<1%, uvea l melan oma
Flat, patchy, or diffuse
Conjunctival epithelium
50% with atypia
Conjunctival st roma
Brown or amelanotic, nodu lar, vascular, growth
Overa ll mortality 25%
Ocula r and oc ulodermal melanocytosis
Primary acqu ired mel anos is
Maligna nt me lanoma
Middle age, most often in Caucasians, unilateral Middle- to olde r-aged
Very rare
Multiple flat, brown patches of noncystic pigmentation appear within the superfiCial conjunctiva of 1 eye. Changes in size may be associated with inflammation or may be the result of hormonal influences. Presence or absence of cellular atypia withi n these lesions can be definitively established only by biopsy. Malignant transformation should be suspected when a lesion shows nodularity, enlargement) or increased vascularity. Pigmented lesions located on the palpebral conjunctiva, conjunctival forni x, plica, or caruncle should increase clinical suspicion and lead to a biopsy.
CLINICAL FINDINGS
All suspicious pigmentar y lesions of the ocular surface should be biopsied. If the lesions are multifoca\' then multiple biopsies should be performed in order to establish the presence of atypia and its location. If the diagnosis of PAM without atypia is made, then the lesion(s) may be followed every 6- 12 months. If atypia is present, then an excisional biopsy using the same techniques as for squamous neoplaSia of the conjunctiva should be performed. For lesions that show atypia or malignancy, topical mitomyci n C or interferon-a" may also be useful. Regional lymph nodes should be checked regularly.
MANAGEMENT
McLean IVV. Melanocytic neoplasms of the conjunctiva. In: Krachmer JH. Mann is MJ, Holland EJ, eds. Cornea. 2nd ed. Vol 2. Philadelphia: Elsevier/Mosby; 2005:571-578.
Malignant Pigmented Lesions
Melanoma With a prevalence of approximately 1 per 2 million in the population of European ancestry, conjunctival melanomas make up less than 1% of ocular malignancies. Conjunctival melanomas are rare in black and Asian populations. Although malignant melanoma of
CHAPTER 8:
Clinical A pproach to Neoplastic Disorde rs ofthe Conjunctiva and Cornea.
239
the conjunctiva has a better prognosis than cutaneous melanoma, the overall mortality rate is 25%. PATH OG EN ESIS Conjunctival melanomas may arise from PAM (70%) or nevi (2%), or be de novo (10%). Intralymphatic spread increases the risk of metastasis. In rare cases, an underlying ciliary body melanoma can extend th rough the sclera.
Although conjunctival melanomas can arise in palpebral conjunctiva, they are most com monly found in bulbar conju nctiva or at the limbus (Fig 8-12). The degree of pigmentation is variable; approximately 25% of conjunctival melanomas are amelanobe. Because heavy vascularization is common, these tumors may bleed easily. They grov,' in a nodular fashion and can invade the globe or orbit. Poor prognostic indicators include location in the palpebral conjunctiva, caruncle, or fornix; invasion into deeper tissues; thickness> 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 <10 mm or <9 mm in newborn; flat corneas with narrow AC; hyperopia Corneal diam. 13 mm or greater; typically seen in males
Persistent fetal vasculat ure; congenital cata racts; AC dysgenesis; optic nerve hypoplasia; cornea plana Iris hypoplasia; miosis; goniodysgenesis; cataract; ectopia lentis; arcus juvenilis; central cloudy dystrophy; glaucoma
Cataracts; anterior and posterior colo bomas; narrow angle; angle closure; microcornea Usually none
M yotonic dystrophy; fetal alcohol syndrome; achond roplasia; Ehlers-Danlos syndrome Craniosynostosis; frontal bossing; hypertelorism; facial anomalies; dwa rfi sm; facia l hemiatrop hy; mental reta rdati on; hypotonia; Down syndrome; Ma rfan syndrome; Alport synd rome; osteogenesis imperfecta ; muco lipidosis type II Ehlers-Danlos synd rome
Clinical Findings
Microcornea
Unilateral or bi latera l
Megalocornea
Bilateral
Cornea plana
Unilatera l or bilateral
Corneal curvature <43 D, typically 30-35 D. Cornea is clear; hyperopia is typical
Posterior embryotoxon
Usually bi lateral
Axenfeld-Rieger syndrome
Uni latera l or bilate ral
Peters anoma ly
60% bilateral
Th ickened, centra lly displaced Schwalbe line; seen in 8%-30% of normal eyes Anterior displaced Schwalbe line with attached iri s strands Central corneal edema present at birth; variable degrees of iridocorneal adhesion
Iris hypoplasia and atrophy; corectopia; pseudopolycoria; glaucoma Keratolenticular touch; cataract; congenital glaucoma; microco rnea; an iridia; persistent fetal vasculature
Inheritance
Gene Loci
Dominant> recessive
X-linked recessive
Xq21.3-q22
Dominant an d recessive Finnish ancestry
12q22 KERA gene
Alagille syndrome; X-linked ichthyosis; fam ilial aniridia
Usually dominant
Skeletal; cranial, facial, and dental anoma lies
Dominant or sporadic
6p25 forkhead genes
Developmental delay; heart defects; external ear anoma lies; hearing loss; eNS defic its; spinal defects; GI and GU anoma lies; facia l clefts; ske leta l anoma lies
Most cases are sporadic; however, both dominant and recessive inheritance have been reported
llp13: PAX6gene 4q25-26: PITX2 gene 2p22-21: CYP787 gene 6p25: FOXC7 gene
(Continued)
Table 9-1 (continued) Unilateral/ Anomaly
Bila te ra l
Clinical Findings
Associated Ocular Anomalies
Associated Systemic Anomalies
Inheritance
Posterior
Typically unilatera l
localized central or pericentra l
Astigmatism and amblyopia often present
Usua lly none
Sporadic
keratoconus
indentation of the posterior cornea with normal anterior topography; overlying stromal haze ; focal pigment
deposits and guttae often present at the margins of
t he opacity Sclerocornea
90% bi lateral
Nonprogressive, noninfl ammatory scleral ization of the cornea. May be partia l or complete. Limbus is ill-defined; vascularized
Cornea plana; angle anoma lies
Multiple system ic anomalies have been reported
Congenital ante r io r staphyloma
Typically
La rge, ectatic co rnea protruding forward between the eyelids at birth li ned by uveal tissue
Anterior segment anomalies; glaucoma; cataract
None
Most cases are sporadic; however, both dominant and recessive inheritance have been reported Sporadic
Keratectasia
Typically
Large, ectatic cornea
Anterior seg ment anomalies; glaucoma; cata ra ct
None
Sporadic
unilateral
unilateral
pro trud ing forward between the eyelids at birth
Gene Loci
CHAPTER 9:
Figure 9·9
Congen it al Ano mal ies of the Cornea and Sclera • 263
Congenital anterior staphyloma in Peters ano maly. (Courtes y of Wallace LM Alward, MD.J
thickening of Descemet's membrane may be seen, but no guttate changes are present. For further discussion, see Chapter 10. Ehlers N, M6dis L, Moller-Pedersen T. A morphological and functional study of congenital hereditary endotheli al dystrophy. Acta Ophthalmol Scand. 1998;76(3):314-318.
Congenital Corneal Opacities in Hereditary Syndromes and Chromosomal Aberrations Mucopolysaccharidoses (MPS) and mucolipidoses are disorders caused by abno rmal carbohydrate metabolism. Corneal clouding and haziness may be present in early li fe in varying degrees in many of these entities, including Scheie syndrome (M PS [ S) and Hurler syndrome (MPS I H). A more detailed discussion of these conditions appears in Chapter 11.
Secondary Abnormalities Affecting the Fetal Cornea Intrauterine Keratitis: Bacterial and Syphilitic Maternally tra nsmitted congenital infections can cause ocular damage in seve ral differe nt ways: through direct action of the infecting age nt, which damages tissue through a teratogenic effect resulting in malformation through a delayed reactivation of the agen t after birth, with inflammation that dam ages developed tissue A posterior corneal defect called von Hippe! internal corneal ulcer may follow int rauterine inflammation . Often, signs of inflammation may still be present after birth, including corneal infilt rates and vascu lari zation , ke ratic precipitates, and uveitis. Iris adhesions are extensive and may arise from areas apart from the collarette; the lens is usually involved .
264 • Externa l Disease and Cornea
Corneal ulce rs and endophthalmitis were cornmon complications of gonococcal ophthalmia neonatoru m before the widespread use of silver ni trate prophylaxis and an tibiotics. Neonatal conjunctivitis is disc ussed in Chapter 5. Congenitally acquired syphilis infections caused by the Trepoflema pallidum spirochete can lead to fetal death or premature delive ry. A variety of systemic manifestatio ns have been described. In terstitial keratitis can develop in the first decade of life in children with unt reated congen ital syph ilis. [t presents as a rapidly progressive corn eal edema followed by abnormal vascularization in the deep st ro ma adjacent to Descemet's membrane. The cornea may assume a salmon pink color because of intense vasc ul ari zation, givin g rise to the te rm salmon patch. Over several weeks to months, blood flow through these vessels gradually ceases, leaving empty "ghost" vessels in the corneal stroma. (See Chapter 7 for a more complete discussion of in terstitial keratitis.)
Congenital Corneal Keloid Corneal keloids are relatively rare lesions, most commonly described following corneal perforation or trauma. Congenital corn eal keloids, often bilateral, have been described in Lowe disease (oculocerebrorenal synd rome) and the ACL syndrome (ac romegaly, cutis gyrata, cornea leukoma syndrome). The y can be seen in association with cataracts, an iridia, and glaucoma and may represent a developmen tal anomaly with failure of normal differentiation of corneal tissue. Histopath ologic examination reveals thick collagenase bundles haphaza rdly arranged, with focal areas of myofibroblastic proliferation. Autosomal dominant in heritance has been observed in the ACL syndrome. Acqui red corneal ke loid is discussed in Chapter 12.
Congenital Corneal Anesthesia Congen ital corneal anesthes ia is a rare condition that is often misdiagnosed as herpes Simplex virus keratiti s, recurrent corneal erosion, and dry eye. Most cases are bilatera l and present with painless corneal opacities and sterile epithelial ulcerat ions during in fancy and childhood. Ros enberg classified the disorder into 3 distinct groups: group I is associated with isolated tr igeminal anesthesia, probably due to primary hypoplasia of the hindbrai n; group U is assoc iated with mesenchymal anomalies, which include Goldenhar syndrome, Mobius syndrome, and Riley-Day syndrome or fam ilial dysautonom ia (FD); gro up III is associated with foca l brainstem signs without evidence of mesenchymal dysplas ia. A thorough systemic examin ation, including neuroradiologic studies, should be performed to rule out associated systemic conditions. In family linkage studies, FD, also referred to as hereditary sensory and autonomic neuropathy type Ill, is an autosomal recessive disorder that maps to chromosome 9q3 1-q33. Treatment should include frequent topical lubrication, punctal occlusion, nighttime lid spli nt ing, lateral tarsorrhaphy, amniotic membrane tra nsplantation. scleral contact lenses and, in recalcitrant cases, conj unctival fl ap to stabilize the ocular surface. Mathen MM, Vishnu S, Prajna NV, Vijayalakshmi p, Srinivasan M. Congenital corneal anesth esia: a series of four case reports. Cornea. 2001 ;20(2): 194- 196.
CHAPTER 9:
Congenital Anomalies of the Cornea and Sclera •
265
Rosenberg ML. Congenital trigeminal anaesthesia: a review and classification. Brain. 1984; 107(Pt 4P073-1082. Verpoorten N, De Jonghe P, Timmerman V. Disease mechanisms in hereditary sensory and autonomic neuropathies. Neurobiol Dis. 2006;21(2):247-255.
Congenital Glaucoma Primary congenital glaucoma is evident either at birth or within the first few years of life. It is believed to be caused by dysplasia of the anterior chamber angle without other ocular or systemic abnormalities. Characteristic findings in the newborn include the triad of epiphora, photophobia, and blepharospasm. External eye examination may reveal buphthalmos, with corneal enlargement greater than 12 mm in diameter during the first year of life. (The normal horizontal corneal diameter is 9.5- 10.5 in full-term infants.) Corneal edema is present in 25% of affected infants at birth and in more than 60% by the sixth month. It may range from mild haze to dense opacification in the corneal stroma because of elevated lOP. Tears in Descemet's membrane called Haab striae may occur acutely as a result of corneal stretching. They are typically oriented horizontally or concentric to the limbus. BCSC Section 6, Pediatric Ophthalmology and Strabismus, also discusses pediatric glaucoma.
Birth Trauma Progressive corneal edema developing during the first few postnatal days, accompanied by vertical or oblique posterior striae, may be caused by birth trauma (Fig 9-10). Rup tures occur in Descemet's membrane and the endothelium. Healing usually takes place but leaves a hypertrophic ridge of Descemet's membrane. The edema mayo r may not clear; if it does clear, the cornea can again become edematous at any time later in life. High
Birth trauma demonstrat ing vertical ruptu res of Descemefs membrane secondary to traumatic de live ry. (Courtesv of Vincent P deLuise, MO,)
Figure 9-10
266 • Exte rna l Oi.sease an d Cornea
astigmatism and ambl yopia may be associated. Congenital glaucoma can present with similar fi nd ings and should be considered in the di fferential diagnosis.
Arcus Juvenilis Arcus juven ilis, a depos itio n of lipid in the peripheral corneal stroma, occasionall y occurs as a congenital anomaly. Usually the condition involves only a sector of the peripheral cornea and is not associated with abno rmalities of serum lipid.
CHAPTER
10
Corneal Dystrophies and Ectasias
Historically, corneal dystrophies are defined as bilatera l, symmetric, inherited conditions that appear to have little or no relationship to environmental or systemic factors. Dystrophies begin early in li fe but may not become clinically apparent until later. They tend to be slowl y progressive and more pronounced with age. Corneal dystrophies can be classified accordi ng to genetic pattern, severity, histopathologic features, biochemical characteristics, or anatomical location. The anato mical scheme that class ifies the dyst rophies according to the levels of the cornea that are involved is the one that has been used most often. However, there are exceptions to each part of the dyst rophy definition, as some dystroph ies are unilateral and/ or asymmetric, have no obvious he redity, and have associated
systemic fi ndings. In addition, dystrophies that appear the same phenotypically may map to diffe rent chromosomes, and dystroph ies that map to the same gene (eg, TGFBI) may have different phenotypes. In order to more accurately reflect the genetic, clinical, and histopathologic characteristics of the dystrophies, the International Com mittee for the Classification of Cornea l Dystrophies has revised the dystrophy nomenclatu re. The system is upgradable and can be retrieved at www.com easociety.org.
According to the new system , each dystrophy is sti ll organ ized according to the anatomica ll eve l affected, wit h a template summ arizing genetic, clin ical, and pathologic infor-
mation. Furthermore, each dystrophy is assigned a category num ber reflecting the level of ev id ence supporting its ex istence:
Category 1: A well-defined corn eal dystrophy in which the gene has been mapped and identified and specific mutat ions are known.
Category 2: A well-defi ned corneal dystrophy that has been mapped to one or more specific chromosomal loci, but the genets) remai ns to be identified. Category 3: A well-defined corneal dystrophy in wh ich the disorder has not yet been mapped to a chromoso mal locus.
Category 4: Reserved for a suspected new, or previously documented, corn eal dystrophy, although th e evidence for its being a distinct entity is not yet convincing. The category assigned to a corneal dystrophy may change with time as more informa tion abo ut it is obtai ned. Eventually, all valid corn eal dystro ph ies should attain category 1
267
268 • Externa l Di sease and Cornea
status. The new IC3D classification is summarized in Table iO- 1. The genetics of corneal dyst rophies is summarized in Table 10-2. Weiss JS, M01ler H, Lisch W, et al. The lC30 classification of the corneal dystrophies. Comea. 2008;27 ( IO:Suppl 2):5 1- 542.
Corneal Dystrophies Table 10-3 lists the M1M (Mendelian Inheritance in Man) numbers and abbreviations and the IC3D abbreviations.
Table 10-1 The IC3D Classification of Corneal Dystrophies Epithelial and Subepithelial Dystrophies 1. Epithel ia l basement membrane dystrophy (EBMD): majority degenerat ive, som e C1 2. Mutation in ke rat in genes: Meesmann co rn eal dy st rophy (MECD): C1 3. Lisch epithelia l co rn eal dystrophy (LE CD): C2 4. Gelatinous droplike cornea l dystrophy (G OLD): C1 Bowman Layer Dystrophies 1. Re is-Bu ck lers corneal dystrophy (RBC D), gran ula r co rn eal dystrophy type 3: C1 2. Th iel- Behnke co rn eal dystrop hy (TBCD): C1 ; potential va rian t: C2 Stromal Dystrophies 1. TGFBf cornea l dystrophies A. Lattice corneal dystrophy a. Lattice co rneal dystrophy, TG FB/type (LCD): cl assic lattice cornea l dystro phy (LCD1) : C1; variants (III, lilA, I/IIIA, an d IV): C1 b. Lattice corneal dyst rophy, gelsolin type (LCD2) : C1 (t his is not a true cornea l dystrophy but is in clu ded here for ease of differential diagnosis) B. Granu lar corneal dyst rophy: C1 a. Granu lar co rn eal dystrophy type 1 (classic) (GCD1 ): C1 b. Granul ar co rn eal dystrophy type 2 (granu lar-lattice) (GCD2): C1 c. Granular cornea l dystrophy type 3 (Reis-Bucklers, RBCD): C1 2. Non - TGFBf cornea l dystrop hies A. Macular co rn ea l dy strophy (M CD) : C1 B. Schnyder corneal dystrophy (SCD): C1 C. Congenital st romal corneal dystrophy (CSC D): C1 D. Fleck corneal dystrophy (FC D): C1 E. Poste rior amorphous co rneal dystrophy (PACO): C3 F. Central clo udy dystrophy of Fra nr;ois (CCOF ): C4 G. Pre-Oescemet co rneal dystrophy (POCO ): C4 Descemet Membrane and Endothelial Dystrophies 1. Fuchs endothe lial corneal dystrophy (FECD): Cl , C2, or C3 2. Poste rior polym orphou s cornea l dystrop hy (PPCD) : C1 or C2 3. Congenital he re dita ry en dothelial dystrop hy (C HED1): C2 4. Congenital hered itary endothelia l dystrophy (C HE02): C1 C "" category. Modified from Weiss JS, Moller H, Lisch W, et al. The IC3D classification of the cornea l dystrophies. Cornea. 2008;27(10:5uppl 2):51-542.
-----
Table 10-2 Genetics of Corneal Dystrophies Dystrophy
Gene locus
Gene
Category
Epithe li al base m ent membrane M eesmann
5q3 1
TGFBf in the min ority of cases
C1 (in a min o rity of cases); most are sporadi c
Ke ratin K3 (KRT3) Ke ratin K12 (KRT12) Unkn own
C1
Lattice type 1 Latt ice type 2 Granular type 2 Macular
12q13 17q12 Xp22.3 1p32 5q31 5q3 1 10q24 5q3 1 9q34 5q31 16q22
Schnyde r
1p36
Co ngenita l st rom al Fleck
12q21.33 2q35
Posterior amorpho us Central cl oudy dyst rophy of Fran.yo is Pre-D esce m et Fuchs
Unknown None
Unknown None
Unknown None (most co mmonly)
Unknown None
13pTel-13q 12. 13, 15q, 18q2 1.2 -q 21.32
Un kn own
Ea rly-onse t va riant: 1p34.3-p32
COL8A2
Lisch Gelatinous droplike Reis-Bu ckl ers Thie l-Behnke
---
TACSTD2 TGFBI TGFBI
Unknown TGFBI
Gelsol in (GSN) TGFBI
Carbohyd rate su lfotra nsferase 6
C2 C1 C1 C1 C2 C1 Cl (not a tru e dystrophy) Cl Cl
(CHST6)
UbiA prenyl transferase domain containing pro tein 1 (UB/AD1 ) Decori n (DeN) Pho sphatidyl i nosito l-3-phosphatel phos phatidylinositol5-kina se
Cl C1 C1
type 1I 11P1P5K3 )
Po sterior polymorphous
Congenital hereditary 1 Congenita l hereditary 2
PPCD1 : 20p 11 .2-q11.2 PPCD2: 1p34.3-p32.3 PPCD3: 10p1 1.2 20p 11. 2-q1 1.2 20p 13
Unkn own COL8A2 ZEB1
Un known SLC4A 11
C = category. From Weiss JS, M011er H, Lisc h W, et al. The IC30 classification of the co rn ea l dystrophies. Cornea. 2008;27(1 0:Suppl 2).
C3 C4 C4 C3 (Fuchs in patie nts w ith no known inh eritance) C2 (Fu chs with kn ow n genetic loc i but gene not yet loca lized ) Cl (early-o nset Fuchs)
C2 C1 C1 C2 C1
270 • Extern al Disease and Cornea
Table 10-3
The IC3D Classification-Abbreviations and MIM Number
Epithelia l basement membrane dystrophy Meesmann CD Lisch epithe li al CD Gelatinous dropl ike CD Reis-Bucklers CD Thiel-Behnke CD Classic lattice CD Lattice CD, gelso lin type Granular CD, type 1 Granular CD, type 2 (granular- lattice) Macular CD Schnyder CD Congenital stroma l CD Fleck CD Posterior amorphous CD Central cloudy dyst rophy of FranlV ois Pre-Descemet CD Fuchs endothelia l CD Posterior polymorphous CD Congenital hereditary endothelial dystrophy 1 Congenita l he red itary endothe lial dystrophy 2
MIM Abbreviation
le3D Abbreviation
MIM#
EBMD None None GDLD, CDGDL CDB1 , CDRB, RBCD CDB2, CDTB CDLl None CGDDl CDA,ACD MCDCl None CSCD None None None None FEC D1 PPCDl CHEDl CHED2
EBMD MECD LECD GDLD RBCD TBCD LCDl LCD2 GCD l GCD2 MCD SCD CSCD FC D PACD CCDF PDCD FECD PPC D CHEDl CHED2
121820 122100 None 204870 608470 602082 122200 105120 121900 607541 217800 121800 610048 121850 None 217600 None 136800 122000 121700 217700
CD = corn eal dystrophy, MIM = Mendelian Inheritance in Man. From OMIM (http://www.ncbi.nlm.nih.gov/omim) and from Weiss J5, M~lIer H, Lisch W, et al. The IC3D classification of the corneal dystrophies. Cornea. 2008;27 (1 0:5uppl 2):56.
Epithelial and Subepithelial Dystrophies
Epithelial basement membrane dystrophy (EBMO) Alternative names Map-dot-fingerprint dystrophy. Cogan microcystic epithelial dystrophy. anterior basement membrane dystrophy Inheritance May have dominant inheritance (often with incomplete penetrance) but is more often sporadic (ie. no documented inheri tance) Genetics cases
Loc us Sq3J; gene TGPBI (p reviously referred to as Big-H3) in a minority of
Category
Most cases are sporadic; some are category 1.
PATHOLOGY EBMD is an abnormality of epithelial turnover, maturat ion, and production of basement membrane. Histopathologic findi ngs include the following:
a th ickened basement membrane with extension into the epitheliu m abnormal epithelial cells with m icrocysts (often with absent or abno rmal hemidesmosomes) fibrillar material betvleen the basement membrane and Bowman layer
CHAPTER 10:
Corneal Dystrophies and Ectasias • 271
EBMD occurs in 6%-18% of the population, more commonly in women, with increasing frequency over the age of 50 years. Gray patches, micro cysts, and/or fine lines in the corneal epithelium are seen on examination. These are usu ally best seen with sclerotic scatter, retroillumination, or a broad tangential beam. Fo ur kinds oflesions are seen in the epithelium and its immediately subjacent basement membrane: CLINICAL FINDINGS
1. fingerprint lines 2. map lines 3. dots or microcysts 4. bleb or cobblestone-like pattern
These abnormalities occur in varying combinations and change in number and distribution from time to time. Fingerprint lines are thin, relucent, hairlike lines; several of them are often arranged in a concentric pattern so they resemble fingerprints. Map lines are the same as fingerprint lines except thicker, more irregular, and surrounded by a faint haze; they resemble irregular coastlines or geographic borders on maps (Fig 10- I). Maps and fingerprints consist of th ickened or multilaminar strips of epithelial basement membrane. Dots (in Cogan microcystic epithelial dystrophy) are intraepithelial spaces containing the debris of epithelial cells that have collapsed and degenerated before having reached the epithelial surface (Fig 10-2). The gray-white dots have discrete edges. Symptoms that are related to recurrent epithelial erosions and to transient blurred vision are more common in patients older than 30 but can be seen at any age. It is estimated that 10% of patients with EBMD will have corneal erosions and that 50% of patients with recurrent epithelial erosions have evidence of this anterior dystrophy. Both eyes must be examined because evidence of the dystrophy may be found in the uninvolved
Figure 10-1 Epithelial basement membrane dystrophy, shOWing thick geographic map lines, or "pu tty marks."
Epithel ial basemen t membrane dystrophy, showi ng microcysts and geographic map li ne areas. (Courtes y of Vincent P
Figure 10-2
deLuise, M O.)
272 • Exte rnal Disease and Cornea
eye. Uni late ral epithelial basement membrane changes may be related to localized trauma rather than a dystrophy. In some ci rcumstances, clinical find ings may rn imic corn eal in tfaepithelial dysplasia, and removed material should be submi tted for histopatho logy. Treatment may need to be extend ed for months. It consists of varying combinat ions of the following (see also th e discussion of recurrent corn eal erosions in Chapter 3):
MANAGEMENT
5% sodium chloride d rops or ointment vs. lubricating drops or ointment epithelial debri dement patching fitting of a thin, loose bandage (soft contact) lens Recalcitrant cases of rec urrent corneal erosion may benefit from anterior strom al puncture of the epithelium using a bent 20- to 25-gauge needle (0. 1 mm is sufficient depth). The visual axis shou ld be avoided. Multi ple small punctures dis tu rb the Bowman layer, thereby promoting a tighter adhes ion and stimulating the cornea to produce functi onal basement membrane complexes. The Nd:YAG laser and 5-mm diamo nd burr have also been reported to be effecti ve in creatin g anterior stromal distu rba nce as treatment of recurrent erosion. Removal of damaged epith elium alone may be very effective. Phototherapeutic keratectomy (PTK) with excim er laser into the ante rior 2- 4 flm of Bowman membra ne after removal of the epithelium may be used for central or recurrent erosions. Recurrence of erosive symptoms after PTK occurs in 13%-44% of patients and may require repetition of PTK. Boutboul S, Black GC, Moore lE, et al. A subset of patients with epithelial basement membrane corneal dystrophy have mutations in TGFB l/ SIGH3. Hum Mutat. 2006;27(6):553- 557.
Mutation in keratin genes: Meesmann corneal dystrophy (MEeD)
Alternative names Inheritance
Juvenile hereditary epithelial dystrophy; variant: Stocker- Holt
Autosomal dominant
Genetics Locus 12q 13; gene: keratin K3 (KRTJ); Stocker-Holt varia nt: locus 17q1 2, ge ne: kerat in KI 2 (KRT12) Category
I (including th e Stocker- Holt va ri ant)
In MECD, epithelial microcysts are seen that consist of dege nerated epithelial cell products (PAS- positive cellula r debris that fluoresces). The epith elial cells contain an electron-dense accumulatio n of granular and filam entary m aterial ("peculiar substance"). There are frequ ent mitoses an d a thickened basem ent membrane with projections into the basal epithelium; the basal epithelial cells have increased glycogen. On confocal microscopy, hyp oreflective areas are seen in the basal epithelium ran ging from 40 to I SO flm in diameter, with potential reflective spots inside.
PATHOLOGY
MECD appears very ea rl y in life. T iny epithelial ves icles are seenmost easi ly with retroillumination -extend ing out to the limbus. These appear as tiny.
CLINICAL FINDINGS
CHAPTER 10:
Figur. 10-3
Corneal Dy st rop hies and Ectasias •
273
Meesmann dystrophy, appearing as tiny, bubblelike blebs against the red ref lex.
(Courtesy of Vincent P deLuise. MD.)
bubblelike blebs and are most nu merous in the interpalpebra l area (Fig 10-3) . The surrounding epitheliu m is clear. Whorled and wedge-shaped epithelial patterns may be seen, The cornea may be slightly thinned and corn eal sensat ion may be reduced. Symptoms are usuall y limited to m ild irritation and a slight decrease in visual acu ity, Some patients complain of glare and light sensitivity. Painful recurrent erosions may occur. Most patients require no treatm ent, but soft contact lens wear may be helpful if patients show freque nt sym ptoms. In rare insta nces, sup erfi cial PTK may be useful for reducing symptoms,
MANAGEMENT
Tuft S, Bron AJ. Im aging the microstructural abnormalities of Meesmann corneal dystrophy by in vivo confocal m icroscopy. Cornea. 2006;25(7):868-870.
Lisch epithelial corneal dystrophy (LEeD) Alternative names epitheliu m
Band-shaped and whorled microcysti c dystrophy of the corneal
X-chromosomal dominant
Inheritance Genetics
Locus Xp22.3; gene unknown
Category
2
Diffuse cytop lasmic vacuolization of affected cells is seen in light and transmission electron microscopy. On immunohisto chemistr y, there is scattered staining on Ki67 without evidence of increased mitotic activity. Confocal microscopy shows many solitary dark rou nd and oval lesions (50- 100 ~m) . Some lesions show central reflective points (probably cell nuclei).
PATHOLOGY
O n di rect slit-lamp examination, gray, band-shaped, an d feat hery lesions appea r in whorled patterns. Retroillumination reveals intraepithelial, densely
CLINICAL FINDINGS
274 • Externa l Disease and Cornea
Lisch corne al dystrophy characterized by bands of gray, feathery opacities. Retroillumination shows clear, densely crowded microcysts. (Reproduced with permission from Lisch W, Figure 10-4
BUHner A, Geffner F, et al. Lisch corneal dystrophy is genetically distinct from M eesmann corneal dystrophy and maps to xp22.3. Am J Ophthalmol. 2000;130(4):461-468.)
crowded clear microcysts. The surrounding epithelium is clear (Fig 10-4). In Meesmann dystrophy, such band-shaped, feathery lesions in whorled patterns do not exist. Also, the intraepithelial cysts ofMeesmann are not as densely crowded as in Lisch dyst rophy but are isolated, with clear spaces between the cysts. Patients with Lisch dystrophy are pain -free. There may be an associated decrease in acuity. Corneal debridement may be attempted but often results in recurrence. Contact lenses may be helpful for more severe cases.
MANAGEM ENT
Alvarez-Fischer M, de Toledo JA, Barraquer RT. Lisch corneal dystrophy. Cornea . 2005;24(4): 494-495. Lisch ,<\r, Bi.ittner A, Oeffner F, et al. Lisch corneal dystrophy is geneticall y distinct from Meesmann corneal dystrophy and maps to xp22.3. Am J Ophthalmol. 2000;130(4):461-468 .
Gelati"ous drop like corneal dystrophy (GOLD)
Alternative names Inheritance
Genetics
Subepithelial amylOidosis, primary familial amyloidosis
Autosomal recessive Locus 1p32; gene: tumor-associated calcium signal transducer 2 (TACSTD2)
Category PATHOLOGY Light microscopy demonstrates subepithelial and stromal amyloid deposits. Disruption of epithelial tight junctions leads to abnormally high epithelial permeability. Amyloid deposition is noted in the basal epithelial layer on transmission electron microscopy.
CHAPTER 10:
Cornea l Dystrophies and Ectasias • 275
Onset occurs in the fi rst to second decade of life with subepithelial lesions that may appear similar to band ke ratopathy or with groups of small multiple nodules (mulberry configuration). The lesions show on fluorescein staining. There is a significant decrease in vision, with photophobia, irritation, and tearing, and a progression of protruding subeptheliallesions. Superficial vasculari zation is often seen . Stromal opacification or larger nodular lesions (kumquat-l ike lesions) may develop (Fig 10-5).
CLI NICAL FINDINGS
Recurrence within a few years occurs in all patients following superficial keratectomy, lamellar keratoplasty (LK), or penetrating keratoplasty (PK). Soft contact lenses are effective in managing the ab normal epithelial permeability to decrease recurrences. MANAGEM ENT
Ide T, Nishida K, Maeda N, et al. A spectrum of clinical manifestations of gelatinous drop-like corneal dystrophy in Japan. A m f Ophthalmol. 2004;137(6 );1081-1084 . Kinoshita S, Nishida K, Dota A, et al. Epithelial barrier funct ion and ultrastructure of gelatinous drop -like corneal dystrophy. Cornea. 2000;19(4):551 - 555 .
Bowman layer Corneal Dystrophies Reis-Biicklers corneal dystrophy (RBCO)
Alternative names Corneal dystrophy of Bowman layer type 1 (CDBl), geographic corneal dystrophy, superficial granular corneal dystrophy, atypical granular corneal dystrophy, granular corneal dystrophy type 3, anterior lim iting membrane dystrophy type 1 (ALMD 1)
A
B
Gelatinous droplike co rn eal dystrophy. A, Mulberry type . B, Band ke ratopathy type. C, Kumquat-like type. (Rewa-
Fig ure 10-5
duced with permission from Weiss JS, M @lIer H, Lisch W, e t al. The IC3D classification of the corn eal dys trop hies . Cornea. 2008;27(1 0:SuppI 2J:S 11.J
c
276 • Externa l Di sease and Corn ea
Inheritance Genetics
Autosomal dominant
Locus Sq31; gene TGFBI
Category
PATHOLOGY On light microscopy, Bowman layer is disrupted or absen t and replaced by a sheetlike connective tissue layer with granular Masson trichrome-red deposits. Transmission electron microscopy shows electron-dense, rod-shaped bodies. The rod-shaped bodies are immunopositive for the TGFBI (transforming growth factor ~-indu ced) protein keratoepithelin. Electron microscopy is needed to histologically d istinguish RBCD from TBCD (which has curly fib ers; see the next secti on). On confocal microscopy, distinct deposits are found in the epithelium and Bowman layer. The basal epithelial cell layer shows high reflectivity from small granular ma terial without any shadows. Bowman layer is replaced by highly reflective irreg ular mate ri al. Fine depOSits may be noted in the anterio r stroma. CLINICAL FINDINGS RECD appears in the first few years of life and mainly affects Bowman layer. Confluent, irregular, and coarse geogra ph ic opacities with varying densities develop at the level of Bowman layer and superficial stroma, mostly centrally. With time, the opac ities may extend to the lim bus and deeper stroma (Fig 10-6). The posterior cornea appears normal. In advanced cases, anterior scarring can lead to surface irregularity. Symptoms often begin in the first or second decade with painful
A
Figure 10-6
8
Reis-Bucklers corneal dystro-
phy. A, Coarse geographic opacity of the superficial cornea. B, Broa d, oblique illumination showing dense, retic ular, superficial
opacity. C, Slit-lamp view showing irregularities in Bowman layer. (Reproduced With permission from Weiss JS, Moller H, Lisch W, et al. The 1C30 class,ficarion of the corneal dystrophies. Cornea 2008,27(70.·SuppI2):S12.)
c
CHAPTER 10:
Cornea l Dystrophies and Ectasias •
277
recurrent epithelial erosions. Erosions are usuall y more severe and frequent than with TBCD. The recurrent erosions may resolve with time. Vision is redu ced by both anterior scarring wi th surface irregularity and anterior stromal edema. Initial treatment is aimed at the recurrent erosions. Superficial keratectomy, LK, PTK, or, in rare instances, PK may be performed. Recurrence in the graft is common.
M ANAG EM ENT
Kobayashi A, Sugiyama K. In vivo laser confocal microscopy findings for Bowman's layer d ystrophies (Thiel-Behnke and Reis-Bucklers corneal dystrophies). Ophthalmology. 2007;1 14(1}: 69-75. Laibson PR. Anterior corneal d ystrophies. In: Krachmer JH, Mannis MJ, Holland EJ, eds. Cornea. 2nd ed. Vol I. Philadelphia: Elsevier/ Mosby; 2005:897-906.
Thiel-Behnke corneal dystrophy (TBCO)
Alternative names Corneal dystrophy of Bowman layer type 2 (CDB2), honeycombshaped corneal dystrophy, anterio r limiting membrane dystrophy type 2 (ALMD2), curly fibers corneal dystrophy, Waardenburg-lonkers corneal dystrophy Autosomal dominant
Inheritance Genetics
Loci 5q31, 10q24; gene TGFBI (5q31), unknown ( IOq24 )
Category
1 (TGFBlvar iant), 2 (l Oq24 varia nt)
Light microsco py shows thickening of the epithelial layer, which allows for ridges and fur rows in the underl ying stroma and focal absences of the epithelial basement membrane. Bowman laye r is replaced by fibrocellular material in a pathognomonic wavy "saw-toothed" pattern. On electron m icroscopy, curly fibers (9- 15 nm) distinguish this dystrophy from RBCD. These curly fib ers are im munopositive for the TGFBI protein keratoepithelin associated with the 5q31 geneti c locus. On confocal microscopy, distinct depOSits are fou nd in the epithelium and Bowman layer. The depOSits in the basal epithelial cell layer show reflectivity, with round edges and dark shadows. Bowman layer is replaced with irregular reflective material that is less reflective than in REC D.
PATHOLOGY
Onset is in the first or second decade, with symmetric subepithelial reticular (ho neycomb ) opacities, sparing the peripheral cornea (Fig 10-7). Opacities may progress to deep stromal layers and corneal periphery. Clinically distinguishing TBCD from RECD is difficult. Recurrent erosions cause ocular discomfort and pain, with worsening of vision from corneal opacification. Erosions are less frequent an d severe than with RBeD and may resolve with time. Vision decreases secondary to increased corneal opacification. CLI NICAL FI NDINGS
MANAG EM ENT
Management is similar to that used in RB CD.
Kobayashi A, Sugiyama K. In vivo laser confocal microscopy findings for Bowman's layer dystrophies (Thiel- Behnke and Reis-Bucklers cornea l dystrophies) . Ophthalmology. 2007; 11 4( 1): 69-75.
278 • External Disease and Corn ea
Figure 10·7 Thiel· Behnke corneal dystrophy. (Reproduced with permission from Weiss JS, Moller H, Lisch \IV, et al. The IC3D classification of the corneal dystrophies. Cornea. 2008;27(10:SuppI2):S13.)
Kuchle M, Green W R, VoJc ker HE, Barraquer J. Reeva luation of corneal dystrophies of Bowman's layer and the anterior stroma (Reis-Bucklers and Th iel -Behnke types): a light and electron microscopic study of eight corneas and a review of the literatu re. Cornea. 1995; 14(4}:333-354 .
Stromal Corneal Dystrophies: TGFBI Dystrophies
Table 10-4 provides information on the histopathologic identification of the classic stromal corneal dystrophies. Lattice corneal dystrophy (LCD): classic lattice corneal dystrophy (LC01) and variants (the variants are multiple subtypes of lattice, which are not described here)
Alternative names Inheritance Genetics
Classic LCD, LCD type 1, Biber-Haab-Dimmer
Autosomal do minant Locus Sq31; gene TGFBI
Category Light microscopy of lattice dystrophy shows amyloid deposits concentrated most heavily in the anterior stroma. Amyloid may also accumulate in the subepithelial area, giving rise to poor epithelial-stromal adhesions. Epithelial atrophy and disrupti on, with degeneration of basal epithelial cells, and focal thinning or absence of Bowman layer increases
PATHOLOGY
Table 10·4 Histopathologic Differentiation of Granular, Macular, and Lattice
Dystrophies Dystrophy
Deposited Material
Granu lar Macular Lattice Avellino
Hyaline Mucopolysa cc haride Amyloid Hyaline amyloid
Masson
Alcian Blue
PAS
Amyloid*
Birefringence
+ +
+ +
+ +
+ + + +
* Sta ins for amyloid: Congo red, crystal violet, and thioflavine T.
CHAPTER 10:
Corn eal Dystrophies and Ectasias • 279
progressively with age. An eosinophilic layer between the epithelial basement membrane and Bowman layer develops, with stromal deposition of the amyloid substance distorting the corneal lamellar architecture. Amyloid stains rose to orange~red with Congo red dye and metachromatically with crystal violet dye, and it exhibits dichroism and birefringence. Electron microscopy reveals extracellular masses of fine 8- l0 - ~m fibrils that are electrondense and randomly aligned. In vivo confocal microscopy reveals characteristic linear im-
ages that should be differentiated from those seen in infection with fungal hyphae. Lattice dystrophy is relatively common and is characterized by typical glasslike branching lines in the stroma. The spectrum of corneal changes is broad, and the
CLINICA L FIN DI NGS
classic branching lattice figures may not be present in all cases. Refractile lines, central and
subepithelial ovoid white dots, and diffuse anterior stromal haze appear early in life. The refractile lines, so-called lattice lines, are best seen against a red reflex or with retroillumination (Fig 10-8). These lines start centrally and superficially and spread centrifugally and deeper. The stroma can take on a ground-glass appearance, but the peripheral cornea remains clear. Recurrent epithelial erosions occur often. Stromal haze and epithelial surface irregularity may decrease vision. MANAGE M ENT
Recurrent erosions are managed with therapeutic contact lenses, super-
ficial keratectomy, or PTK. Severe cases of lattice dystrophy with visual loss are treated with lamellar keratoplasty (DALK) or PK. Recurrence of this dystrophy may occur in the corneal graft. It is thought that lattice dystrophy recurs more frequently after grafting than does granular or macular dystrophy. One recent study suggested that granular dystrophy recurred more often than lattice; the study, however, had a S-year follow-up; the mean time of recurrence for lattice is 9 years (range 3- 26 years). Marcon AS, Cohen E], Rapuano C], Laibson PRo Recurrence of corneal stromal dystrophies after penetrating keratoplasty. Cornea. 2003;22( I): 19- 21.
Figure 10-8
Lattice corneal dystrophy.
(Courtesy of Vincent P deLuise, MD.)
280 • Extern al Disease and Cornea
Lattice corneal dystrophy (LCD): gelsolin type (LCD2)
Alternative names Familial amyloidosis, Finnish type (FAF); Meretoja syndrome; amyloidosis V; familial amyloidotic poly neuropathy type IV (FA P-IV) Autosomal dominant
Inheritance Genetics
Locus 9q34; gene: gelsolin (GSN)
Category
1 (Due to system ic involvement, th is is not a true corneal dystrophy.)
PATHOLOGY Light microscopy shows amyloid in the lattice lines as a discontinuous band under Bowman layer and withi n th e sclera. The amyloid in this condition is related to gelsolin and does not stain for type AA or AP. The mutated gelsolin is seen deposited in the conjunctiva, sclera, and Ciliary body, along the choriocapillaris, in the ciliary nerves and vessels, and in the optic nerve. Extraoc ul arl y, amyloid is detected in arterial walls, peripheral nerves, and glomeruli. On confocal microscopy, depOSits are seen along the basal epithelial cells and stromal nerves. CLINICAL FINDINGS This form of LCD comb ines lattice corneal changes with coexisting systemic amylOidosis and presents in the th ird to fourth decade. Patients have a characteristic facial mask; dermatochalasis; lagophthalmous, pendulous ears; cranial and peripheral nerve palsies; and dry, lax skin with amylOid deposition (Fig 10-9). The risk of open-angle glaucoma may be increased. The classic corneal lattice lines are less numerous and more peripheral, and they spread centripetally from the limbus. The central cornea is relatively spared; corneal sensation is reduced. Dry eye and recurrent erosions may occur late in life. Granular corneal dystrophy type I (GCDII
Alternative names Inheritance
Groenouw corneal dystrophy type I
Autosomal dominant
A ____ Figure 10-9 A, Diffuse lattice lines in lattice corneal dystrophy. gel50lin type (Meretoja). 8 , Typica l faci es of the Meretol a syndrome. (Reproouced with permission from WeissJS, Me/ferH, Lisch \IV, er at. The IC3D claSSification of rhe corneal dys trophies. Cornea 2008;27(10:SuppI 2):S I6.J
CHAPTER 10: Corneal Dystrophies and Ectasias • 281
Genetics
Locus 5q3 J; gene TGFBI
Category
1
Microscopically, the granular material is hyali ne and stains bright red with Masson trichrome stain. An electron -dense material made up of rod-shaped bodies im mersed in an amorphous matrix is seen on electron microscopy. Histochemically, the deposits are noncollagenous protein that may derive from the corneal epithelium and/ or keratocytes. Hyper-reflective opacities are seen on confocal microscopy. Although the exact cause is unknown, a mutation different from that of RBCD, LCD 1, and GCD2 has been identified in the TGFBI gene on chromosome Sq31, which is responsible for the formation of keratoepithelin.
PATHOLOGY
Onset occurs early in life with crumblike opacities that may broaden into a diskJike appearance as the patient reaches the teens. On direct illumination, the opacities appear white, but on indirect illumination, they are seen to be composed of small translucent dots with vacuoles and a glassy splinter or crushed breadcrumb appearance. The lesions do not extend to the limbus but can extend anteriorly through focal breaks in Bowman layer (Fig 10-10). The dystrophy is slowl y prog ressive, with visio n only rarely dropping to 20/200 after age 40. Patients complain of glare and photophobia. Recurrent erosions occur and vision decreases as the opacities become more confluent.
CLINICAL FINDINGS
Early in the disease process, no treatment is needed. Recurrent erosions may be treated with therapeutic contact lenses, superficial keratectomy, or PTK. When visual acuity is affected, DALK or PK has a good prognosis. Recurrence in the graft (anteriorly and peripherally) may occur after man y years as fine subepithelial opacities varying from the original presentation.
MANAGEMENT
Figure 10-10
Granular dystrophy type 1.
282 • Exte rnal Disease and Cornea
Granular corneal dystrophy type 2 (granular-lattice) (GCD2) Alternative names trophy Inheritance Genetics
Combined gra nular-lattice corneal dystrophy, Avell ino corneal dys-
Autosomal dominant Loc us Sq3l; gene TGFB I
Category
Pathologicall y, both the hyali ne deposits typ ical of gra nular dystrophy and the amyloid deposits typical oflatlice dystrophy are seen . These extend from the basal epitheliu m to the deep stroma. Individual opacities stain with either the Masson trichrome
PATHOLOGY
or Congo red stain . Rod -shaped bodies are seen on electron microscopy, as are randomly
aligned fibrils of amyloid. Findings on confocal microscopy are a combination of GCDI and LCD. Affected patients have a granular dystrophy both histologically and clinically, with lattice lesions in addition to the granular lesions. Cli nical fIndings differ from those of GCD 1. Stellate-sha ped, snowflake-like, and icicle-like opacities appear CLINICAL FINDINGS
between the superficial and mid stroma. Lattice lines are also seen deeper than the snow-
flake opacities. Older patients have anterior stromal haze between de posits, which reduces visual acuity. Pain may occur with mild corneal erosions (Fig 10-11). PTK, LK, or PK may be useful, depending on the depth of the deposits. LASIK and LASEK may result in increased opacification and are contraindicated.
MANAGEMENT
Holland Ej, Daya SM , Stone EM, et al. Avelli no corneal dystrophy. Clinical man ifestations and natural h istory. Ophthalmology. 1992;99( 10);1564-1 568. Kim TI, Hong JP, Ha BJ , Stulting RD, Kim EK. Determination of treatment strategies for granular corneal dystrophy type 2 using Fourier-domain optical coherence tomograph y. Br J Ophtlwlmol. 2010;94 (3) ;341-345.
Figure 10-11 Granular dystrophy type 2. (Reproduced with permission from Weiss JS, Mo//er H, Lisch W. er al. The IC3D classification of the corneal dysuophles. Cornea . 2008;27(70:$uppI 2):S I8.)
CHAPTER 10:
Corne al Dystrophies and Ectasi as • 283
Stromal Dystrophies: Non-TGFB/Dystrophies
Macu/ar corneal dystrophy (MCD) Alternative names Inheritance
Genetics
Groenouw corneal dystrophy type II, Fehr spotted dystrophy
Autosomal recessive
Locus 16q22; gene: carbohydrate sulfotransferase 6 (CHST6)
Category The deposits in macular dystrophy are glycosaminoglycans (GAGs; acid mucopolysaccharide), and they stain with colloidal iron and Alcian blue. They accumulate in the endoplasmic reticulum and not in lysosomal vacuoles, as seen in systemic mucopolysaccharidoses. Electron microscopy reveals keratocytes and endothelial cells that stain positive for GAGs, as well as extracellular clumps of fibrogranular material that also stains for GAGs. On confocal microscopy, blurred accumulations of light-reflective material are seen in the anterior corneal stroma.
PATHOLOGY
Macular dystrophy is the least common of the 3 classic stromal dystrophies (lattice, granular, and macular). Unlike most corneal dystrophies, it has an autosomal recessive inheritance, involves the entire co rneal stroma and periphery, and may involve the corneal endothelium.The corneas are clear at birth and begin to cloud at ages 3-9 years. The age of presentation of cli nical fmdings is youngest in macular dystrophy, followed by lattice dystrophy an d then granular dystrophy. Patients with macular dystrophy show focal, gray-white, superfiCial stromal opacities that progress to involve full stromal thickness and extend to the corneal periphery. Macular spots have indefinite edges, and the stroma between the opacities is diffusely cloudy (Fig 10-12). Involvement of Descem et's m embrane and the endothelium is indicated by the presence of cornea guttae. Epithelial erosions are possible, but symptoms usually involve a decrease in vision, between the ages of 10 and 30. Central corneal thinning and hypo esthesia have been noted. The 3 types of macular dystrophy are distinguished based on biochemical differences. Patients with type I macular dystrophy, the most prevalent form of macular dystrophy, lack antigenic keratan sulfate (AgKS) in their cornea, serum, and cartilage. These patients have a normal syntheSiS of dermatan sulfate-proteoglycan. Errors occur in the synthes is of keratan sulfate and in the activity of speCific sulfo transferases involved in the sulfation of the keratan sulfate lactose am ino glycan side chain. In type IA macular dystrophy, ke rato cytes manifest AgKS reactivity, but the extracellular material does not. There is no AgKS in the serum. Patients with type II macular dystrophy syntheSize a normal ratio of keratan sulfate and dermatan sulfate-proteoglycans, but total syntheSiS is 30% below normal. Moreover, the dermatan sulfate-proteoglycan chains are 40% shorter than normal. An enzyme-linked irnmunosorbent assay (ELISA) measures sulfated keratan sulfate. This test can help in the diagnosis of macular dystrophy, even in preclinical forms and carriers.
CLINICAL FINDINGS
284 • External Dise ase and Cornea
Figure 10-12
MANAGEMENT
Macular dystrophy, showing involvement to the limbus with diffuse haze.
Recurrent erosions are treated as for other stromal dystrophies, and pho-
tophobia may be reduced with tinted contact lenses. PTK may be used for symptomatic anterior macular dystrophy. Definitive treatment requires penetrating corneal transplan tation, altho ugh recurrences may be seen .
Schnyder corneal dystrophy (SeD) Alternative names Schnyder crystalline corneal dystrophy (SCCD), Schnyder crystalline dystrophy si ne crystals, hereditary crystalline stromal dyst rophy of Schnyder, crystalline stromal dystrophy, central stromal crystalline corneal dystrophy, corneal crystalline dystrophy of Schnyder, Schnyder corneal crystaUine of dystrophy Inheritance
Autosomal dominant
Genetics Loc us Ip36; gene: UbiA prenyltransferase domain-containing protein 1 (UBIADl) Category
This condition is thought to be a local disorder of corneal lipid metabolism. Pathologically, the opacities are accumulations of unesterified and esterified cholesterol and phospholipids. Oil red 0 stains the phospholipids red. In the normal process of em bedding tiss ue in paraffin, cholesterol and other fatty substances are dissolved; therefore, PATHOLOGY
the pathologist must be made aware of the requirements for special stains. Electron micros-
copy shows ab normal accumulation of lipid and dissolved cholesterol in the epithelium, in Bowman layer, and throughout the stroma. Confocal microscopy reveals disruption of the basal epithelial/subepithelial nerve plexus, with highly reflective intracellular and extracellular deposits.
CHAPTER 10:
Corneal Dystrophies and Ectasias • 285
Schnyder corneal dystrophy is a rare, slowly progressive stromal dystrophy that may become apparent as early as the first year of life. However, diagnosis is usually made by the second or third decade, although it may be further delayed in patients who have the acrystalline form of the disease. Central subepithelial crystals are seen in only 50% of patients and do not involve the epithelium. Vision and corneal sensation de-
CLINICAL FINDINGS
crease with age. Glare complaints increase due to progressive corneal haze.
Affected patients show predictable progressive changes on the basis of age, beginning with central corneal opacification (Fig 10-13): I. central corneal opacification (can affect the entire corneal stromal thickness) ±
subepithelial crystals (i n individuals younger than 23 years) 2. dense corneal arcus lipoides (third decade) 3. midperipheral corneal opacification (fourth decade; affects entire corneal stromal thickness) 4. decreased corneal sensation
Schnyder corneal dystrophy disproportionately reduces photopic vision (despite maintenance of excellent scotopic vision), leading to corneal transplantation in most patients over 50. The dystrophy can recu r after PK. PTK has been used to treat decreased vision fro m subepithelial crystals, but it does not treat panstromal haze. Abnormal serum lipids are managed by diet and/o r medication but do not affect the progression of the corneal dystrophy. A fasting lipid profile should be done for possible hyperlipoproteinemia (type lIa, III, or IV) or hyperlipidemia. Most patients have elevated serum cholesterol that often responds to diet or medication. Unaffected fam ily members may also have an abno rmal lipid prome.
MANAGEM ENT
'Weiss ]S. Visual mo rbidity in thirty-four families with Schnyder crystalli ne corneal dystro phy (an Amer ican Ophthalmological Society lhesis). Trans Am Ophthalmol Soc. 2007;105: 616-648.
B
A Figure 10-13
Schnyder crystalline dystrophy with (A) central subepithelial crystalline deposi-
tion and (8 ) central panstromal corneal opacity and arcus lipoides. No crystals are present. (Courtesy of Jayne S.
Weiss, MD.)
286 • Externa l
D i s~ ase
and Cornea
Congenital stromal corneal dystrophy (CSCD) Alternative names phy of th e co rnea
Autosomal dom inant
Inheritance Genetics
Conge nital hered itary st romal dystrophy, congenital stromal dystro-
Locus 12q2 1.33; ge ne: decorin (DeN)
Category PATHOLOG Y The stromal lamellae are separated from each other in a regular mann er, sometim es with areas of amorpho us depositio n. On electron microscopy, the collagen fib ril d iameter is abo ut half the no rmal size in all lam ellae. Ab normal lam ellar layers con sisting of thin filam ents arranged in an electron-lucent ground substance separates the lamellae of no rm al appearance. The keratocytes and endothelium are nor mal. T he absence of the anterior banded zone of Descemet's me mb rane has been reported. The epithelial cells are normal on co nfocal mic roscopy. Stromal evaluation is not possible due to increased refl ectivity.
Congeni ta l diffuse, bilateral cornea l clouding with tl akelike whitish opacities is fo und througho ut the stroma. The corn eas are th ickened . T he course is non prog ressive or slowly progressive, with moderate to severe vi sual loss (Fig 10-1 4) .
CLINICAL FINDING S
MANAGEMENT
PK is used in advanced cases.
Congenital stromal corneal dystrophy: diffuse bilateral clouding with flakelike opacities throughout the stroma. (Reproduced wirh permission from Weiss JS, Mo/fer H, Lisch \IV, et al. The
Figure 10·14
IC3D classification of the corneal dystrophies. Cornea 2008;27(10 ..SuppI 2!:S22.)
CHAPTER 10:
Corn eal Dystrop hies
and
Ectasias •
28 7
Bredrup C, Knap pskog PM, Majewski J, R0dah l E, Boman H. Congenital stromal dyst rophy of the cornea caused by a mutation in the decorin gene. Invest Ophthalmol Vis Sci. 200 5;46( 2) :420 - 426.
Fleck corneal dystrophy (FeD)
Alternative names Inheritance
Fran<;ois-Neetens speckled corneal dystrophy
Autos omal dom inant
Genetics Locus 2q35; ge ne: phosphatid yli nositol-3-phosphate/ phosphatidyli nositol 5-kinase type III (PIP5K3) Category Affected keratocytes are vacuolated and contain 2 ab normal substances: excess glycosam inoglyca n, which stains with Alcian blue and colloidal iron; and lipids, demonstrated by Sudan black B and oil red O. Transmissio n electron microscopy shows membrane-based inclusions with delicate gran ular material. Confocal microscopy shows an accu mulati on of pathologic material in stromal cells an d inclusions in th e basal nerves.
PATHOLOGY
Discrete, flat, gray-wh ite, dand ruff-like (someti mes ring-shaped) opacities appear throughout the stroma to its peripher y. T he epithelium, Bowman layer, Descemet's membrane, an d endotheli um are not involved. Sympto ms are m inimal, and vision is us ually not reduced. T he condition is no np rogressive and may be asym metr ic o r un ilateral. Fleck d ystro phy may be associated wi th decreased corn eal sensatio n, limbal dermoid, ke ratoconus, central cloudy dystrophy, punctate cortical lens changes, pse ud oxanthoma elasti cum, or atopy (Fig 10-15).
CLIN ICAL FINDINGS
MANAGEMENT
None is indicated
Purcell JJ Jr, Krachm er ]H, Weingeist TA. Fleck corneal dystrophy. Arch Oplithalmol. 1977; 95( 3) :440-444.
Figure 10-15 Dandruff-li ke opacities seen in Flec k co rneal dystroph y. (Reproduced with permission from Weiss JS, Moller H, Lisch W, et al. The IC3D classification of the corneal dystrophies. Cornea . 2008;27(IO:SuppI2J:S23)
288 • Exte rnal Di sease and Cornea
Posterior amorphous corneal dystrophy (PACDI Alternative names Inheritance
Posterior amorpho us stromal dystrophy
Autosomal dominant
Genetics
No identified gene locus
Category
3 (PACD may be a mesoder mal dysgenesis rather than a corneal dystrophy.)
Focal attenuation of endothelial cells and irregular stromal architecture anterior to Descemet's membrane are seen on light microscopy. On electron microscopy. there is diso rganization of the posterior st romal lamellae. A fibrillar layer interrupts Descemet's membrane. On confocal microscopy. there are microfolds and a hyperreflective layer in the posterior stroma.
PATHOLOGY
CLIN ICAL FIND INGS PACD presents in the first decade of life with a diffuse, gray-white, sheetlike opacity of the cornea, usually posteriorly. The condition is slowly progressive or nonprogress ive. The cornea is flat «41 D) and thill (as lowas 380 fun) and there is associated hypero pia. Descemet's membrane and the endothelium may be indented by opacities. Focal endothelial abnormalities have been observed, as have a prominent Schwalbe line, fine iris processes, pupilla ry remnant, iridocorneal adhesions, corectopia, pseudopolycoria, and anterior stromal tags. There is no associated glaucoma. Visual acuity is only mildly affected (Fig 10-16).
Figure 10· 16
opacity.
Posterior amorphous corneal dystrophy: central deep stroma l, pre-Descemet
(Reproduced with permission from Weiss JS, Molfer H, Lisch W, et al. The IC3D classification of the corneal
dystrophies Cornea. 2008;27(10:SuppI2):524.)
CHAPTER 10:
MANAGEMENT
Corneal Dystrophies and Ectasias •
289
Although usually no treatment is required, PK is sometimes performed.
Johnson AT, Folberg R, Vrabec MP, Florakis GJ, Stone EM, Krachmer JH. The pathology of posterior amorphous corneal dystrophy. Ophthalmology 1990;97(9):104- 109.
Central cloudy dystrophy of Fran/lois (CCDF) Alternative names
None
Inheritance Unknown (Autosomal dominant inheritance has been reported, but the condition may be a degeneration.) Genetics
No identified gene locus
Category
4 (most consistent with posterior crocodile shagreen, a degeneration)
In one case without known heredity, histopathologic examination showed folds of the deep stroma, with extracellular deposition of mucopolysaccharide and lipidlike materiaL Extracellular vacuoles, some with fibrogranular material and electron-dense deposition , are seen on electron microscopy. Endothelial vacuoles may have fibrogranular material. On confocal microscopy, small, highly refractile granules and deposits are seen in the anterior stroma.
PATHOLOGY
Opacities consist of multiple nebulous, polygonal, gray areas separated by cracklike intervening clear zones. Theses opacities are densest centrally and posteriorly and fade both anteriorly and peripherally (Fig 10-17). The epithelium, Bowman layer, stromal thickness, Descemet's membrane, and endothelium are normal. Vision is usually CLINICAL FINDINGS
A L-............:: Figure 10-17 A, Centra l cloudy dystrophy of Frangois . 8, Broad, obl ique Illumination demonstrating nebu lous, polygona l gray areas w ith cracklike intervening clear zones . (Reproduced with permission from Krachmer JH, Mannis MJ, Holland EJ, eds. Cornea. 2nd ed. Vol I. Philadelphia: Elsevier/Mosby: 2005:920,)
290 • Exte rna l Disea se and Corne a
not reduced. CCDF is phenotypically indistingu is hable from posterior crocod ile shagree n, which is a corneal degeneration.
None indicated
MANAG EMENT
De Sousa LB, Mannis MJ. The stromal dystroph ies. In: Krachmer JH, Mannis MJ , Holland £J, eds. Cornea. 2nd ed. Volt. Philadel phia: Elsevier/Mosby; 2005:907- 92 7.
Pre-Oesceme t corneal dystrophy (POCO) Alternative names
None
Inheritance No definite pattern of inheritance, although it has been described in fam ilies over 2-4 generations Genetics
No identified gene locus
Category
4 (may be a degeneratio n or associated with systemic diseases)
PATHOLOGY Large keratocytes are seen in the posterior stroma, with vacuoles and intracytoplasmic inclusions containing lipid -like material. On electron microscopy, there are membrane-bound intracellular vacuoles containing electron- dense mate rial suggesti ve of secondary Iysosomes an d inclusions consistent with lipofusCin-like lipoprotein, suggesting a degenerative process.
Focal, fin e, gray opacities are seen in the deep stroma anterior to Descemet's membrane. Onset is usually after age 30, but it has been reported in child ren as young as 3 yea rs. The rest of the cornea is normal. Vision is no rmal. Simila r opacities have been described in pseudoxanthoma elasticum, X-linked and recessive ichthyos is, keratoconus, PPCD, EBMD, an d CCDF (Fig 10-18) . CLI NICAL FIN DI NGS
MANAGEMENT
A
None indicated
B
Fi gure 10-1 8 Pre-Descemet corneal dystrophy: punctate opacities anterior to Descemet's membrane demonstrated wi th (A) indirect illumination and (B) slit-!amp beam. (Reproduced with permission from Weiss JS, Moller H, Lisch W, et al. The IC3D classification of the corneal dystrophies. Cornea. 2008;27(1 0:SuppI 2):S26')
CHAPTER 10:
Corneal Dystrophies and Ectasias • 291
Endothelial Dystrophies Fuchs endothelial corneal dystrophy (FEeD) Alternative names
Endoepithelial corneal dystro phy, endothelial corneal dystrophy
Inheritance Cases without known inheritance are most common; some cases wi th autosomal dominant inheritance have been reported Genetics Locus 13pTel- 13q 12.13, 15q, 18q21 .2 -q2!.32; early-onset varian t: Ip34.3-p32. Gene none (most commonly); early-onset variant: collagen type VIII alpha 2 (COL8A2) Category 3 (FEeD in patients with no known inheritance); 2 (FEeD with known genetic loci but gene not yet localized); I (early-onset FEeD)
Microscopically, the endothelial cells are noted to be larger (polymegathism) and more polymorphic (pleiomorphism) than normal and are disrupted by excrescences of excess collagen, a product of the stressed endothelial cells. Primary dysfunction of the endothelial cells manifests as increased corneal swelling and deposition of collagen and ex tracellular matrix in Descemet's membrane, which is thickened. There is a reduction in the number ofNa+I K+-ATPase pump sites or in pu mp function. It is not clear whethe r the reduction in the posterior nonbanded zone and the increase in thickness of the posterior banded zone (posterior collagenous layer) are pri mary effects of endothelial dysfunction or are secondary to chronic corneal edema.
PATHOLOGY
CLINICAL FINDINGS Findings vary with the severi ty of the disease. Cornea guttae are first evident centrally and sp read toward the periphery (F ig 10-19) . Descemet's membrane becomes thickened, and folds develop secondar y to stromal edema (Fig 10-20). Increased endothelial pigmentation may also be seen. As the endothelium fu rther decompensates, the central corneal thickness may approach I mm (0.52- 0.56 mm is normal). Epithelial edema develops, leading to microcystic edema; this later progresses to epithelial bullae, which may rupture. Subepithelial fibrosis occurs in later stages. Fuchs usually presents in the fifth or sixth decade (except for the early-onset variant, which may present in the third decade or earlier). Symptoms are rare before age 50 and are related to the edema, which causes a decrease in vision, as well as pain secondar y to ruptured bullae. Symptoms are often wo rse upo n awakening because of decreased surface evaporation during sleep. Painful episodes may subside once subepithelial fibrosis occurs.
Initial treatment is aimed at reducing corneal edema and relieVing pain. Use of sodium chloride drops and ointment (5%) and measures to lower [OP may temporaril y help the edema. A soft bandage lens may be useful in treating ruptured bullae. In advanced cases, anterior stromal puncture, amniotic membrane, or a conjunctival flap may be considered to relieve pain , but restoration of vision requires corneal transplantation. In the past, full-thickness (penetrating) keratoplasty was the standard procedure, but this has been replaced by endothelial keratoplasty, as the latter targets the pathologic endothelial ce lls. In advanced cases where there has been anterior corneal scarri ng, a full-thickness
MANAGEMENT
292 • Ext ern al Disea se and Corn ea
Fuchs endothelial dystrophy. Cor· nea guttae seen in retroillumination. (Reproduced
Figure 10·19
wirh permission from Krachmer JH, Mannis MJ, Holland EJ, eds. Cornea . 2nd ed. Vol 1. Philadelphia: Elsevier/M osb y;
2005:939.)
Figure 10·20 Fuchs endothelial dystrophy showing stromal edema, Descemet's folds, and endothelial guttae. (Courtesy of Vincent P deLuise, MD.)
CHAPTER 10:
Cornea l Dystrophies and Ectasias •
293
procedure may still be indicated. Prognosis for graft survival is good, especially if done before vascularization occurs. See Chapter 16 on corneal transplantation. Gottsch JD, Sundin OH, Liu SH, et a1. Inheritance of a novel COL8A2 mutation defines a distinct early-onset subtype of Fuchs corneal dystrophy. Invest Ophthalmol Vis Sci. 2005;46(6): 1934- 1939. Terry MA. Endothelial keratoplasty: history, current state, and future directions. Cornea. 2006; 25(8),873- 878.
Specular microscopy may be helpful in diagnosing Fuchs and following the clinical course for loss of endothelial cells. Corneal pachometry may indicate relative endothelial function and change with progression of the disease. Both procedures are useful in determining the relative safety of cataract or other intraocular surgery. Endothelial cell counts less than lOOO/m m', corneal thickness greater than 640 flm, or the presence of epithelial edema suggests caution and the possibility that the cornea may decompensate with any intraocular surgery (see Chapter 2).
COMMENT
Seitzman GD, Gottsch ]D, Stark W]. Cataract surgery in patients with Fuchs' corneal dystro phy: expanding recommendations fo r cataract surgery without si multaneous keratoplasty.
Ophthalmology. 2005:112(3)'441 - 446.
Posterior polymorphous corneal dystrophy (PPCD) Alternative names
Posterior polymorphous dystrophy (PPMD), Schlichting dystrophy
Autosomal dominant (Isolated unilateral cases with similar phenotype but no heredity have been reported.)
Inheritance
Locus: PPCDI: 20pl1.2-ql1.2; PPCD2: Ip34.3-p32.3; PPCD3: IOp11.2. Gene: PPCD I : unknown; PPCD2: coLlagen type VIII alpha 2 (COL8A2); PPCD3, ZEBl
Genetics
Category
PPCDI: 2; PPCD2: I; PPCD3: I
The most distinctive microscopic finding is the appearance of abnormal, multilayered endothelial cells that look and behave like epithelial cells or fibrob lasts. These cells
PATHOLOGY
• show microvilli stain positive for keratin show rapid and easy growth in cell culture have intercellular desmosomes manifest proliferative tendencies
A diffuse abnormali ty of Descemet's me mbrane is common, including thickening, a multilaminated appearance, and polymorphous alterations. Similar changes that are not limited to the cornea are seen in iridocorneal endothelial (ICE) syndrome (see Chapter 12) . ICE, however, is sporadic and unilateral. Specular microscopy may show typical vesicles and bands, in contrast to the involved cells in ICE syndrome, which appear as dark areas
294 • External Disease and Cornea
with central highlights and light peripheral borders. Opinion is divided on the value of relying on specular microscopy alone in making the diagnosis. Confocal microscopy reveals alterations in Descemet's membrane and polymegathism of the endothelial cells. CLINICAL FINDINGS Careful examination of the posterior corneal surface will show any or all of the folloWing:
isolated grouped vesicles geographic-shaped, discrete, gray lesions • broad bands with scalloped edges (Fig 10-21) Variable amounts of stromal edema, corectopia, and broad iridocorneal adhesions may also be seen (Fig 10-22). Fine, glasslike iridocorneal adhesions may be seen goni-
Figure 10-21
Posterior polymorphous dystro-
phy showi ng scal lop-e dged endothelial band (arrow) .
Figure 10-22
Poste rior po lymorphous dystrophy showing iri docorneal adhesion and corecto pia.
CHAPTER 10:
Corneal Dystrophies and Ectasias • 295
oscopically. Both angle-closure and open-angle glaucoma can occur, and 14% of patients have elevated lOP. MANAGEMENT Most patients are asymptomatic. Mild corneal edema may be managed as with early Fuchs dystrophy. To manage localized swelling, stromal micropuncture can be used to induce subepithelial pannus. With more severe disease, glaucoma must be managed, and corneal transplants may be required. Prognosis for PK is related to the presence of visible peripheral anterior synechiae and glaucoma. PPCD may recur in the graft. Endothelial keratoplasty is an alternative approach to targeting the abnormal endothelial cells in earlier cases without significant stromal opacification.
Weisenthal RW, Streeten BW. Posterior membrane dystrophies In: Krachmer JH, Mannis MJ, Holland EJ, eds. Cornea. 2nd ed. Voll. Philadelphia: Elsevier/Mosby; 2005:929-9 54.
Congenital hereditary endothelial dystrophy (CHEDt)
Alternative names
None
Autosomal dominant
Inheritance
Genetics
Locus 20pI1.2-qll.2 (pericentromeric region); gene unknown
Category
2
PATHOLOGY There is diffuse thickening and lamination of Descemet's membrane with sparse, atrophic endothelial cells. Parts of the endothelium are replaced by keratincontaining stratified squamous epithelium. Multiple layers of basement membrane- like material are seen on the posterior part of Descemet's membrane along with degeneration of endothelial cells with many vacuoles. On electron microscopy, stromal thickening is seen, with severe disorganization and disruption of the lamellae.
CHEDI occurs congenitally or during the first or second year of life and shows diffuse corneal clouding and thickening. Symptoms include blurred vision, photophobia, and tearing that is worse in the morning. Some patients have only irregular peau d'orange- like endothelial changes. Clouding progresses over 1- 10 years. Endothelial decompensation may occur over a prolonged period oftime (Fig 10-23).
CLINICAL FINDINGS
MANAGEMENT
PK is used in advanced cases.
Figure 10-23 CHED1, showing m ilky appearance of th e cornea with diffuse illumination. (Reproduced with permission from Weiss JS. Moller H, Lisch ltv, et al. The IC30 classification of the corneal dVstrophies. Cornea . 2008;27(10:SuppI2):S29.)
296 • External Disease and Corn ea
Figur. 10-24 CHED2, showi ng diff use stromal th ickening. (Reproduced with permission from Weiss JS, Meller H, Lisch IN. et al. The IC3D classification of the corneal dystrophies. Cornea. 2008;27f10:Suppl
2),529.)
Congenital hereditary endothelial dystrophy (CHED2) Alternative names Inheritance
Maumenee corneal dystrophy
Autosomal recessive
Genetics Locus 20pl3 (telomeric portion); gene: solute carrier fam ily 4, sodium borate transporter, member 11 (SLC4A l l) Category
1
PATHOLOGY There is diffuse thickening and la mination of Descemet's membra ne, with sparse atrophic endothelial cells. On electron microscopy, multiple layers of basement membrane- li ke material are seen on the posterior part of Descemet's membrane along with degeneration of the endothelial cells with many vac uoles. Stromal thickening with severe disorgani zation and disruption of the lamellar patte rn is evident.
CHED2 is conge nital and stationary but more severe than CH ED l. Corn eal clouding ranges from a diffuse haze to ground glass, with occasional focal gray spots. Thickening of the cornea (2- 3 times normal) occurs, with rare subepithelial band keratopathy and lOP elevation. Blurred vision and nystagmus occur with min imal to no tearing or photophobia (Fig 10-24) . CLINICAL FINOINGS
MANAGEMENT
Because corneal clouding is more com mon and severe, PK is usually
performed.
Ectatic Disorders Keratoconus Keratoco nus is a common disorder (prevalence of about 50 per 100,000) in which the central or paracentral cornea undergo es progressive thinning and bulging, so the cornea takes on the shape of a cone (Fig 10-25). The hereditary pattern is not prominent or predictable,
CHAPTER 10:
Figure 10-25
Corneal Dystrophies and Ectasias • 297
Kera tocon us.
but positive family histories have been reported in 6%- 8% of cases. Clinically unaffected first-degree relatives have a higher chance of showing subclinical topographic abno rm alities associated with keratoconus than does the general population. Multiple chromosomal loci have been reported, but the identification of specific genes remains elusive. The combination of genetic and environmental risk factors such as eye rubbing, inflammation, and oxidative stress all playa role in the onset and progression of keratoconus. McMonnies CWo Abnormal rubbing and keractectasia. Eye Contact Lens. 2007;33(6 Pt 1):
265 - 271. PATHOLOGY
Histopathologically, keratoconus shows the following:
fragmentation of Bowman layer thinn ing of the stroma and overlying epithelium folds or breaks in Descemet's membrane variable amounts of diffuse scarring Nearly all cases are bilateral, but I eye may be much more severely involved. Sometimes the less affected eye shows only high astigmatism, which may be considered the minimal manifestation of keratoconus. Alternatively, videokeratoscopy may show enantiomorphism (a mirror image) and reveal some mild steepening in the other eye. The disease tends to progress during the adolescent years and into the mid-20s and 30s, although progression can occur at any time. Early biomicroscopic and histopathologic findings include fibrillation of Bowman layer, leading to breaks and followed by fibrous growth and dysplasia through the break. As progression occurs, the apical thinning of the central cornea worsens, and extreme degrees of irregular astigmatism can develop. No associated inflammation occurs. Scissoring of the red reflex on ophthalmoscopy or retinoscopy is a very early sign of keratoconus. Rizzutti sign, a conical reflection on the nasal cornea when a penlight is
CLINICAL FINDINGS
298 • External Disease and Cornea
shone from the temporal side, is another early findi ng (Fig 10~26). Munson sign is evi dent as a protrusion of the lower lid upon downgaze (Fig 10-27). Iron deposits are often present withi n the epithelium around the base of the cone and constitute a Fleischer ring (Fig 10-28). This ring is brown in color and best seen with the cobalt blue filter using a broad, obli que beam. Fine, relucent, and rough ly parallel striations (VagI lines), or stress lines, of the posterior stroma can be observed. Focal ruptures and flecklike scars occur in Bowman layer. Spontaneous perforation in keratoconus is extremely rare. However, a tear can occur in Descemet's membrane at any time, resulting in th e sudden development of cornea l
Figure 10-26
Figure 10-27
Rizzutti sign (arrow).
M unson sign . (Courtesy of James R. Reidy, MD.)
CHAPTER 10:
Figure 10·28
Corn ea l Dystrophies and Ectas ias • 299
Keratoconus showing a Fleischer ring (arrow) . (CotJrresyofJamesJ. Reidy, MD.)
edema, or acute hydrops. Allergy and eye rubb ing are risk factors for the development of hydrops. The break in the posterior cornea usually heals spontaneously in 6-12 weeks; the corneal edema then disappears, but stromal sca rring may be left in its wake. Some patients regain good vision following the resolution of hydrops, depending largely on the extent and location of the scar. An increased prevalence of ke ratoconus has been reported in Down syndrome, atopy, Marfan syndrome, floppy eyelid syndrome, Leber congenital hereditar y optic neuropathy, and mitral valve prolapse. Keratoconus also occurs commonly in numerous congenital anomalies of the eye. Computerized videokeratography is helpful in detecting early keratoconus, in following its progression, and in helping to fit contact lenses. Placido-based topography shows inferior steepening in the power map, but pachometry mapping shows the thi n zone to be paracentral (Fig 10-29). Ul trasonic pachometry may be more accurate, however. Computeri zed videokeratography algorithms to diagnose forme fruste, or subclinical, keratoconus are continually being perfected to detect keratoconus suspects and screen them from prospective refractive surgery. Scanning slit and other elevation-based systems are being im proved to measure deviation above a "best-fit sphere:' (See Chapter 2 in this volume, as well as BCSC Section 3, Clinical Optics, and Section 13, Refractive Surgery.)
EVALUATION
Belin MW. Rodila JE Topographic analysis in keratorefractive s urgery. Ill: Krachmer JH, Mannis M], Holl and El, eds. Comea. 2nd ed. Vol 2. Philadelphia: Elsevier/Mosby; 2005:
1909-1922. Rao SN, Raviv 'r: l\flajrnudar PA ,Epstein RJ. Role of Orbscan II in sc reening keratoconus sus· pects before refractive corneal surgery. Ophthalmology. 2002;109(9): 1642-1646.
300 • External Disease and Co rn ea
,.
j,
,j,
••
t,
:.
/,
;"
'"
"
" ~ T
N '"
,.
",
"' ,., l"
B
A
t(nrn)SIep.0.Q10
'1'
-
'r
'1'
~
'"
'"
Figure 10-29 Keratoconus . A, Pla ci do disk co mpu terized videography showing inferior ste epening. B, Orbscan com puterized vid eography showing a pachom etry map of the sam e eye as in A . Note that the thin nest zone is near th e vi sual axis and not at the steepest point .
Some cases of keratocon us are mild enough. at least for a time, that vision can be corrected adequately with glasses. However, rigid or gas~permeable co n ~ tact lenses are far more helpful in all but the mildest cases. Their ability to neutralize the irregular corneal astigmatism often prod uces dramatic improvement in vision. The majority of patients with keratocon us without central corneal scarring can be fitted successfully with contact lenses using adva nced tech niques, and a central subepithelial scar can, on occasion) be removed (nodulectomy), allowing conti nued wear of contact lenses. Indications for PK include the following: MA NAGEMENT
contact lens intolerance even with good vision poor vision even with a comfortable contact lens fit (usually due to scarring) unstable contact lens fit (even with good vision and tolerance) progressive thinning to the periphery approaching the limbus, requiring a very large graft (with increased risk)
The prognosis for keratoplasty in ke ratocon us is excellent. Deep anterior lamellar kerato ~ plasty (DALK) has recently been reported as an alternate surgical modality. DALK leaves the host's endothelium untouched, thereby potentially decreasing rejection episodes. I n ~ trastromal rings and collagen cross~ lin kin g (presently being investigated with riboflavin and UV light) are additional modalities to stabilize keratoconus. (See also Chapter 16.) The disease is presently considered a contrain dication for refractive procedures, ex· cept for intracorneal rings, because of un predictability and the potential for poor results in either the short or long term in these patients. PK has been reported after LASIK in keratoconus patients because oflong~ ter m loss ofbest ~corrected visual acuity. Hydrops is treated conservatively with topical hy.pertonic agents and patching or a soft contact lens for several months. A cycloplegic agent may be needed for Ciliary pain. Aqueous suppressants may decrease the flow of fluid into the cornea. Hydrops is not an indication for immediate surgery.
CHAPTER 10:
Cornea l Dystrophies and Ectasias • 301
Pellucid Marginal Degeneration Pellucid marginal degeneration is somewhat uncommon, nonhereditary, and bilateral. Pellucid (ie, transparent) inferior, peripheral corn eal th inning takes place in the absence of inflammation. Etiology is unknown. CLINICAL FINDINGS Protrusion of the cornea occurs above the band of thinning. At times, a clear distinction between pellucid marginal degeneration and keratoconus is not possible. A cornea with keratoconus will show protrusion at the point of maximal thinn ing, but pellucid marginal degeneration can be superior or inferior and will show protrusion above the area of maximum thinning. No vascularization or lipid deposition occurs, but posterior stromal scarring has been noted within the thin ned area. Most patients are diagnosed between 20 and 40 years of age, and men and women are affected equally. Decreased vision results from high irregular astigmatism (Figs 10-30, 10-31) . Acute hydrops has been reported, and, although rare, spontaneous corneal perforation has also occurred.
Figure 10-30
Pellucid ma rgina l degeneration.
(Courtesy
of Vincent P deLuise,
MD.)
Topography of pellucid margina l degeneration. Note the inferior steepen ing and "lobster claw" pattern.
Figure 10-31
302 • Externa l Disease and Corn ea
Treatment consists of contact lenses early in the disease, although lens fitting is more difficult in pellucid marginal degeneration than in keratoconus. Hybrid (gaspermeable lenses with a soft lens "skirt") or scleral lenses may be options. Eventually, PK may be requ ired to restore vision. Because of the location of the th inn ing, the grafts tend to be large and close to the limbus, making surgery technicall y more difficult and the graft mo re prone to rejection. Wedge resection and lamellar tectonic grafts have been advocated as alternative or adjunctive procedures. MANAG EMENT
Rasheed K, Rabi nowitz YS. Su rgical treatment of advanced pellucid marginal degeneratio n.
Ophthalmology. 2000; 107(10);1836- 1840.
Keratoglobus
Keratoglobus is a ve ry rare, bilateral, no nin flammatory condition that differs from ke ratoconus and pell uCid marg inal degeneration in typically being present at birth (Table 10-5) . It is usually not hereditary. Keratoglobus is similar in appearance to keratoconus but manifests a globular rather than a conical deformation of the cornea (Fig 10-32). Keratoglob us is stron gly associated with blue sclera and Ehlers-Danlos syn drome type VI (see Chapter 9), and it may represent a defect in collagen synthesis. Histopathologically, it is characterized by an absent or frag mented Bowman layer, thi nned stroma with normal lamellar organi zation, and thin Descemet's membrane. Unlike keratoconus, keratoglobus is not associated with atopy, hard contact lens wear, or tapetoretinal degeneration.
PATHOLOGY
Both corneas have a globular shape with a very deep anterior chamber. The corneal cu rve may be as steep as 50- 60 D, and generalized thinning appears, espeCially in the midperiphery; this is in contrast to keratoconus, which has maximal th inning at or near the apex of the protrusion. Spontaneous rupture of Descemet's membrane and corneal hydrops can occur, but iron li nes, stress lines, and anterior scarring are not seen. The corneal dia meter may be slightly increased. Fleischer rin gs are usually not present, CLINICAL FINDINGS
Noninflammatory Ectatic Disorders Compared and Contrasted: Typical Clinical Presentation and Appearance
Table 10-5
Frequency Laterality Age at onset Thinni ng Protrusion Iron line Scarring Striae
Keratoconus
Pellucid Marginal Dege neration
Ke ratog lobus
M ost co mmon Usual ly bilateral Puberty Inferi or parace ntral Th inni ng at apex Flei sc her ring Comm on Comm on
Less common Bil ate ral Age 20- 40 years Inferior band 1-2 mm wid e Sup erior to band of thinning Sometimes On ly after hy drops Som etim es
Rare Bi lateral Usually at bi rt h Greatest in periph ery Generalized None Mild Somet im es
Modified fro m Krach mer JH, Mannis MJ, Holla nd EJ, eds. Cornea. 2nd ed. Vol 1. Philadelph ia: El sevie rl Mosby; 2005:9 55.
CHAPTER 10:
Corneal Dystrophies and Ectasias • 303
,,
,, ,
A
B
c
Figure 10-32 The presence of cornea l thinning and the type of co ntour abnorma li ty can be helpfu l in recog nizing the ty pe of ectatic disorder. A, Keratoconus . B, Pellucid marg inal degeneration . C, Keratog lobus. (Reproduced with permission from Krachmer JH. Mannis M), Holland EJ, eds. Cornea. 2nd ed. Vol 1. Philadelphia- Els evier/Mosbv; 2005:956.}
but prominent folds and areas of thickening in Descemet's membrane are common. Keratoglobus may be associated with blue sclerae, hyperextensibility of the joints, sensorineural deafness, fractures, and corneal perforation with minimal trauma (fragile cornea). MANAGEMENT Contact lenses, especially sderallenses, may be of benefit. Prognosis for successful PK is much poo rer in keratoglobus than in the other ectasias. A lamellar tectonic graft followed by PK could be considered in cases requ iring intervention to maintain functional vision. Spontaneous corneal rup ture has been reported, so patients must be counseled regarding the impor tance of protective eyewear. High myopia is treated with spectacles to prevent amblyopia.
Feder RS, Kshettry P. Noninflammatory ectatic disorders. In: Krachmer JH, Mannis MJ, Holland EJ, eds. Cornea. 2nd ed. VaIL Philadelphia: Elsevier/Mosby; 2005:955-974.
CHAPTER
11
Metabolic Disorders With Corneal Changes
Many of the co rneal man ifestations of systemic disease are alterations in corneal clarity caused by abnormal storage of metabolic substan ces within the epithelium, stroma, or
endothelium. Abnormal substances typically accumulate in Iysosomes or lysosome-like intracytoplasmic structures as a result of a single enzyme defect. Most of these disorders are autosomal recessive. with the notable excep tions of Hu nter syndrome (mucopolysac~
charidosis type 11) and Fabry disease, which are both X-linked recessive. Kenyon KR, Navon SE, Haritoglou C. Corneal man ifestations of metabolic diseases. In: Krach~ mer JH, Mannis M], Holland £J, eds. Cornea. 2nd ed. Vol I. Philadelphia: Elsevier/Mosby; 2005:749-776.
Disorders of Carbohydrate Metabolism M uco po Iysa cc ha ri doses Systemic mucopolysaccharidoses (MPSs) are rare, inherited lysosomal storage diseases that resu lt from the absence of lysosomal acid hydrolases, the enzymes that usually catabolize the glycosaminoglycans (GAGs) dermatan sulfate, heparan sulfate, and keratan sulfate. Although there are at least 8 separate syndromes, several features are common to all. Heparan sulfate, dermatan sulfate, and keratan sulfate, the GAGs normally present in highest concentration, are the accum ulated metabolites. All syndromes are au tosomal recessive, with the exception of the X-linked recessive Hunter syndrome, which rarely involves the cornea until old age, if at all . Hurler (MPS I H), Scheie (M PS I S), and the intermediate (Hu rler-Scheie, MPS I HIS) syndromes are all allelic for the enzyme
PATHOGENESI S
a-L-iduron idase, with different nucleotide substitutions leading to different amino aci d substitutions and markedly reduced enzyme activity «0.1 % of normal). Normally, GAGs constitute the ground substance of the co rn ea, but in th ese diseases, microscopic deposits of mucopol ysaccharide are found in the keratocytes and stroma and, in some cases, in the
corneal epitheli um and endothelium. CLINICAL FINDING S Differential findings are listed in Table 11 - 1. These various conditions are characterized by corneal clouding, retinopathy, and optic atrophy, although Sanfilippo
305
Table 11 -1 Clinical Features of Mucopolysaccharidosis I H: Hurler
VI: Marote aux-lamy
I S: Scheie
IV: Morquio
II: Hunter
III: Sanfilippo
A utosomal recess ive
Au tosoma l recess ive
Autosom al recess ive
Autosoma l recess ive
A utosomal recessive
Severe corneal clouding w ith in the first few yea rs
Seve re cornea l cl ouding w ithin the fi rst few years
Corneal opaciti es after' 0 yea rs ol d
Diffuse punctate st rom al opacities are present without invo lve m ent of the epith elium and endothel iu m
Narrow-ang le glau co ma ha s been repo rted
Sy ndrome: m ental retardati on, dwarfism, large head w ith abnormal appearin g face, enl arged abdome n, and contractu res of the joints Ot her abnorma lities: hepatos plen omegal y; thickening of the skin, li ps, an d tongue; chest enlargement ; hirsutism ; deafness; neurologic defects; and ca rdi ac defects Diagn os is co nfirmed by m easurin g the affected enzyme in peripheral leukocytes, cultured dermal fibroblasts, or amni ot ic ce ll s
Mild fac ial abnorma li ties and mu ltiple skeleta l changes, dwarfi sm, kyph osis, protubera nt stern um, and genu valg um
Corneal opaci fication from birth and slowly progresses to ca use decreased visio n by the second decade of life Cornea appears thickened or edema tous Co rneal changes may be more prominent in th e corn ea l periph ery Glau com a has also been reported Claw hand deformities, bony chang es in th e feet, and aortic va lve abnorma li ties may be prese nt
X-l inked recess ive trait Does not prese nt as a conge nital co rn ea l opacity Co rn ea l opaci ty may occur later in li fe in milder ph enotypes
Othe r abn orm alit ies: optic neuropathy, hy drocepha lus
Dwa rfi sm , ao rtic va lvular disease, and laxity of the joints
Clinica lly it appears simil ar to Hurl er sy ndrom e Deafn ess and hea rt defects are co m mon
Reproduced w ith pe rm ission from Krach mer JH, Mannis MJ, Holland EJ, eds. Cornea. 2nd ed. Vo l 1. Phil adel phia: Elsev ier/Mosby; 2005:320.
Co rn ea l opaci ty rarely develops
CHAPTER 1':
Metabolic Disorders With Corneal Changes. 307
syndrome only occasionally has corneal opacities, and Hunter syndrome only rarel y has corneal cloudi ng. Clouding generally involves the entire cornea and mayor may not be present at birth. It is often slowly progressive from the periphery toward the center and can cause serious reduction in visual acuity. Intracellular storage and extracellular accumulation of partially degraded GAGs are evident in tissues. The conjunctiva allows for a potential biopsy site. Numerous intracytoplasmic vacuoles in stromal fibroblasts and histiocytes contain fine fibrillogranular material. Vascular perithelial cells and lymphatic endothelial cells have similar inclus ions. Schwann cells of conjunctival nerves have numerous mem branous la mellar inclusions. Although conjunctival biopsy can confirm classic histopathology, specific diagnosis requires biochemical assay for enzymes in tears, leukocytes, cultured fibroblasts, or amniotic cells and for elevated urinary GAG levels. In the cornea, sim ilar fibrillogranular accumu lation is found in vacuoles of the basal epithelial cells, sub epithelial histiocytes, and keratocytes. The deg ree of corneal clouding appears proportional to the amount of GAG accumulation. Histiocytes laden with abnormall y acc umulated storage material (gargoyle cells) are found. Electron microscopic and x- ray diffraction studies show an abnormally large range of corneal stromal fibril size (2000-5200 angstroms [AJ, in contrast to a normal 2600-A size) with disruption of the extracellular matrix by sulfated GAG deposits. These factors cause significant light scattering and thu s the clouding.
LABORATORY EVALUATION
These conditions, as well as those discussed in the fo llowing sections, are sometimes amenable to penetrating keratop lasty (PK), un less impairment of the patient's rnental status or retinal or optic nerve abnormalities preclude visual improvement. The prognosis for successful keratoplasty is considered guarded, as the abn ormal storage material may acc um ulate again in the graft. Some regression of corneal clouding following successful donor stem cell bone-marrow transplantation occurs in about one third ofpatients. Enzyme rep lacement therapy is being used for Scheie and Hurler syndromes, an d gene transfer therapy is under investigation. MANAGEMENT
Diabetes Mellitus The most com mon disorder of carbohydrate metabolism, diabetes mellitus (DM), has nonspecific corneal manifestations of pu nctate epithelial erosions, basement membrane changes resembling epithelial basement me mbrane dystroph y, Descemet's folds, and decreased corneal sensati on. Diabetes is discussed at length in BCSC Section 12, Retina and Vitreous, although the emphasis is on retinal rather than corneal aspects of the disease. Patients with DM have ultrastructural abnormalities of the basement membrane complex that contribute to problems of epithelial-stromal adhesion. These abnormalities include thickening of the mu lt.ilaminar basement membrane, reduced hemidesmosome nu mber, and decreased penetrat ion of anchoring fibri ls. Accumulation of polyols such as sorbitol by the action of aldose reductase on excess glucose may contribute
PATHOGENESIS
308 • External
Di ~ease
and Cornea
to the alterations in the epithelium and endothelium and the corneal hypoesthesia seen in these patients.
Corneal epithelial surface changes and hypoesthesia occur with increasing severity (eg, type 1 diabetes, or insulin-dependent d iabetes mellitus, as opposed to type 2 diabetes, or non-insulin-dependent diabetes mellitus) and increasing duration of the disease. Removal of diabetic epitheli um at surgery results in the loss of the basal cells and basement membrane, often leadi ng to prolonged healing difficulties. Faint verti cal folds in Oescemet's membrane and deep stroma (Waite-Beetham lines) are not specific to OM but may represent early endothelial dysfunction and increased stromal hydration.
CLINICAL FINDINGS
Glycosolated hemoglobin is related to poor control of OM and may correlate with poor corneal healing in addition to progressive retinopathy.
LABORATORY EVALUATION
MANAGEMENT DM is not a contraindication to PK or other corneal surgery. Measures that can improve diabetic epitheliopathy include the following:
perioperative management of meibo mian gland dysfunction (increased cOl11 orbid-
ity with OM) minimizing epithelial debridement at surgery
increasing lubrication avoiding toxic medications
usi ng therapeutic contact lenses Bartow, RM. Endocrine disease and the cornea. In: Krachmer JH, Mannis MJ, Holland EJ, eds. Cornea . 2nd ed. Vol I. Philadelphia: Elsev ier/Mosby; 2005:831-839.
Disorders of Lipid Metabolism and Storage Hyperli poproteinemias Hyperlipoproteinemias are common conditions associated with premature coronary artery and peripheral vascula r disease. Recognition of the ocular hallmarks of these diseases, such as xanthelasma and corneal arcus, can result in early intervention and reduced morbidity. Extracellular deposits consist of cholesterol, cholesterol esters, phospholipids, and triglycerides.
PATHOGENESIS
Corneal arcus is a very common degenerative change of older patients and does not require systemic evaluation. However, corneal arcus in individuals younger than 40 years of age or corn eal arcus that is Significantly asym metric may suggest a lipid abnormality. These patients should have a systemic workup. Asym metry may be secondary to carotid atherosclerotic disease on the less affected side. Table 11 -2 gives the Fredrickson classification of 5 types of hyperlipoproteinemia. Types II and III are associated with earl y-onset xanthelasma and corneal arcus, or arcus juvenilis. Type III has been linked to 19q 13.2 (apolipoprotein E mutation). CLINICAL FINDINGS
CHAPTER 11: Metabolic Disorders W ith Corneal Cha nges. 309
Table 11-2 Genetically Determined Hyperlipoproteinem ias (Frederickson
Classification) Type
lIa lib III IV V
lipoprotein
Elevated Lipid
Clinica l Findings
Chy lom icrons
Trig lycerides
LDL LDL and VLDL Chylomicron and VL DL remnants VLDL Chylom icro ns and VLD L
Cho leste ro l Cho lestero l Cholestero l and t r iglycerides Triglyce ri des Cholestero l and trig lycerides
Xanthoma/ pancreatitis Xanthoma/CAD CAD Xanthoma/CAD
Mild CAD/PAD Xanthoma/ pancreatitis Mild CAD/ PAD
Oc ular Find ings
Inheritance
LR
AR
CA/XAN CA/XAN LR/CA/XAN
AD AD AR
LR
AD
LR
AD
AD = autosom al domi nant, AA '" autosomal recessive, CA '" cornea l arcus, CAD ", coronary artery d isease, LDL = low-density lipoprotein, LR == lipem ia retinalis, PAD == pu lmonary artery disease, VLDL very low-density li poprotein, XAN = xanthelasma.
=
Modified from Ha rri sons Online 2004-2005 ; and Bran AJ . Dyslipoprote inemias and their oc ular manifestations. Birth Defects Ori9 Artie Ser. 1976;1 2: 257-27 0.
Schnyder crystalline corneal dystrophy is thought to be a localized defect of lipid metabolism, but laboratory evaluation is needed to rule out concurrent systemic abnormality (see Chapter 10). A fasting and alco hol-restricted lipid proAie that includes cholesterol, triglycerides, and high- and low-density li poproteins (HDL and LDL, respectively) is required. Patients can then be classified phenotypically to assess their risk for atheroscle rotic disease.
LABORATORY EVALUATION
MANA GEMENT
Early de tection gives the patient time to be referred for diet or drug
treatment. Hypolipoproteinemias
Abnormal reductions in seru m lipoprotein levels occur in 5 diso rde rs: I. 2. 3. 4. 5.
lecithin-cholesterol acyltransferase (LCAT) deficiency Tangier disease fish eye disease fami lial hypobetalipoproteinem ia Bassen-Ko rn zweig syndrome
The last 2 disorders do not result in corn eal d isease; discussion here focu ses on the other 3 disorde rs. LCAT facil itates the removal of excess cholesterol from peripheral tissues to the liver, and a deficiency leads to accumulation of unesterified cholesterol in the
PATHOGENESIS
310 • External Disease and Cornea
tissues. This, in turn, leads to atherosclerosis, renal insufficiency, early corneal arcus, and nebular corneal clouding composed of m in ute focal lipid deposits. LCAT deficiency and fish eye disease are allelic variants of the same genetic locus on chromosome 16q22.1 , but fish eye disease has normal levels of LCAT that do not function to help HOL in esterifying cholesterol. Ta ngier disease has a complete absence of serum high-density a-lipoproteins and maps to 9q22-q31. All 3 cornea-affecting hypolipoproteinemias are rare, autosomal recessive conditions. Familial LCAT defiCiency is characterized by peripheral arcus and nebular stromal haze made up of myriad m inute focal deposits of lipid that appear early in childhood but do not interfere with vision. Fish eye disease has obvious corneal clouding from minute gray-white-yellow dots that progress from the periphery to decrease vision. Tangier disease, named after the Chesapeake Bay island, features very large orange tonsils; enlarged liver, spleen, and lymph nodes; hypocholesterolemia; abnormal chylomicron renmants; and markedly reduced HOL in the plasma. Corneas show diffuse clouding and posterior focal stromal opacities but no arcus. Neu ropathy leads to lagophthalmos and corneal sequelae.
CLINICAL FIN DINGS
The serum lipid profile shows characte ristic low levels of HDL. Recognition can allow the cl inician to make appropriate referra ls and encourage the patient to seek genetic cou nseli ng.
LABORATORY EVALUATION AND MANAGEMENT
Sphingolipidoses Sphingolipidoses are rare inherited disorders of complex lipids (gangliosides and sphingomyelin ) that involve the cornea in 3 condi ti ons: 1. Fabry disease (angiokeratoma corporis diffusum) 2. multiple sulfatase defiCiency 3. generalized gangliosidosis (G M , gangliosidosis type I)
These disorders oflipid storage are autosomal recessive, with the exception of Fabry, which is X-linked recessive. They principally affect the retina or optic nerve and may lead to CNS dysfunction. Fabry disease is again an important exception. It is caused by a defiCiency of a-galactOSidase A, leadi ng to the accumulation of ceramide trihexoside in the renal and cardiovascular systems. Multiple sulfatase deficiency combines features of metachromatic leukodystrophy and mucopolysaccharidosis. Affected children have subtle diffuse corneal opacities, macular cha nges, optic atrophy, and progressive psychomotor retardation. They die in the first decade. Generalized gangliosidosis is characterized by deficiencies of p-galactosidases and the accumulation of gangliosides in the CNS and keratan sulfate in somatic tissues. It has been linked to chromosome 3pI 2-3p13. Although Tay-Sachs disease (hexosam inidase A defiCiency with accumulation of GM 2 ganglioSide) primarily involves the retina, the corneal endothel ial cells can appear distended and filled with single membrane-bound vacuoles.
PATHOGENESIS
CLI NICAL FI NDI NGS In these conditions, the cornea exhibits distinctive changes consisting of whorl-like lines (cornea verticiLlata) in the basal layers of the epithelium that appear to now together to the inferior central corneal epithelium (Fig 11 - I).
CHAPTER 11:
M eta bo lic Disorders With Corneal Changes . 311
Fi gure 11-1 Whorl-like deposits of sphingolipid in the basal layer of the corneal epithelium in a patient with Fabry disease; identica l deposi ts occur in otherwise asymptomatic female carriers of this disease.
Periorbital edema occurs in 25% of cases, posterior spokelike cataracts in 50%, and conjunctival aneurys ms in 60%. Other ocular signs include papilledema, retinal or macular edema, optic atrophy, and retinal vascular dilation . The corneal changes resemble those seen in patients on long-stand ing oral chloroquine or amiodarone treatment. A careful drug history will help make th is diffe rentiation. Hemizygous males with Fabry disease are more seriously affected and show the typical corneal changes. A heterozygous female is us ually asymptomatic but still shows the same corneal changes. Fabry disease is also characteri zed by renal failure, peripheral neuropathy with painful dysesthesias in the lower extremities, and skin lesions. The skin lesions are small, round vascular eruptions that later become hyperkeratotic. They consist of an accumulation of sphingolipid with in the vascular endothelium. Corneal opacities have been reported in Gaucher disease, but thi s is a rare fi nding. In Fabry disease, a -galactosidase A is markedly decreased in urine and plasma. Conjunctival biopsy may be positive before cornea verticillata are apparent. Prenatal diagnosis can be perfo rmed with chorionic villus sampling.
LABO RATORY EVAL UATION
If a female patient is diagnosed as an asymptomatic heterozygous Fabry carrier, genetic counseling should be considered. The prognosis for successful PK in these conditions is generally poor. Enzyme replace ment with infusion of a -galactosidase A is a therapeutic option. MANAG EM ENT
Guemes A, Kosmorsky GS, Moodie DS, Clark B, Meisler D, Traboulsi EI. Corneal opacities in Gaucher disease. Am J Ophtha!mo!. 1998; 126(6):833-835. Masson C, Cisse I, Simon V, Insal2:co P, Audran M. Fabry disease: a review. Joint Bone Spine. 2004;71(5):381-383.
312 • Extern al Disease and Corn ea
Mucolipidoses Mucolipidoses (MLs) are autosomal recessive conditions that have features common to both MPSs and li pidoses.
These diseases are inherited defects of carbohyd rate and lipid metabolism combined. Consequently, they have someth ing in common with the MPSs as weLl as the sphingolipidoses. Mucopolysaccharides accumulate in the cornea and viscera. and sphi ngolipids are deposited in the retina and CNS. Currentl y recogn ized diseases in this class are the foLl owing:
PATHOGENESIS
ML [ (dys morph ic sialidosis) ML II (inclusion-cell disease) ML [[[ (pseudo-Hu rle r polydyst rophy) • ML IV Goldberg syndrome mannosidosis fucos idosis These conditions are all autosomal recessive. ML IV has been mapped to chromosome 19p. Histopathologic examination of corneal scrapin gs has revealed the accumulat io n of intracytoplasm ic storage material in the epitheli um . In fucosidosis, histopathologic study has revealed that, in spite of clinically normal corn eas, corneal endothelial cells show the presence of cyto pl asmic, mem brane-bound, confluent areas of Abrill ar, granular, and mu ltilaminated deposits. A retina l cherr y- red spot and retinal degeneration are also asso ciated wi th many of these disorders. All are caused by a defect in lysosomal acid hydrolase enzymes. With the exception of mannosidosis and fucosid osis, which are oli gosaccharidoses, all of these cond itio ns are characterized by varying degrees of corneal clouding. which can often be progressive.
CLINICAL FINDINGS
Plasma cells are vacuolated and plasma lysoso mal hydrol ases are elevated. In ML IV, with corn eal clouding from birth, conjuncti val biopsy shows fibroblas t inclusion bodies that are
LABORATORY EVALUATION
• Single membrane-li mited cytoplasm ic vac uoles containi ng both fib rillogranular material and membranous lamellae lamellar and concentric bodies resembling those ofTay-Sachs disease There is no evid ence of Illucopolysacchariduria o r cellu lar metachromasia. Chorio nic vi llus sampling has been reported in ML 11 fo r prenatal diagnosis.
Both PK and lamellar keratoplasty (LK) have been associated with ge nerall y poor results, probably because resurfac ing is impaired by the abnorm al epithelial cells. Altho ugh donor Ii mbal stem ceLl transplantation has been advocated, tissue matching may be req ui red, as graft rejection in these vascularized recipient beds is possible. Bone-marrow transplantatio n has been reported.
MANAGEMENT
CHAPTER 11:
Metabolic Disorders With Corneal Changes.
3 13
Bietti Crystalline Corneoretinal Dystrophy Bietti crystall ine corneoretinal dystroph y is a very rare autosomal recessive condition that is characterized by peripheral corneal opacities and tapetoretinal dyst rophy. It is presumed to be caused by a defect in lipid metabolism and has been mapped to chromosome 4q35-4qter.
Lysosomes of fibroblasts in the choroid and skin and circulating lymphocytes contain crystalline deposits, but no abnormal accu mulation of cholesterol or cholesterol esters has been documented.
PATHOGENESIS
Peripheral, sparkling, yellow-white spots are seen at the corneal limbus in the superficial stroma and subepithelial layers of the cornea in 75% of patients. These spots may fade with time. With progression, retinal crystals associated with retinal pigment epithelium atrophy and choroidal sclerosis result in nyctalopia, poor dark adaptation, peripheral visual field loss, or central vis ual acuity loss. CLINICAL FINDINGS
Visual fields, dark adaptation testing, and ERG may be normal in earl y cases, but advanced cases may have decreased ERG and retinal findings of atypical retinitis pigmentosa. No specific treatment is reported .
LABORATORY EVALUATION AND MANAGEMENT
Pa lay DA. Corneal deposits. In: Krachmer JH , Mann is MJ, Holland EJ, eds. Cornea. 2nd ed. Vol t. Philadelphia, Elsevie r/ Mosby; 2005,365 - 378.
Disorders of Amino Acid Metabolism Table 11 -3 summarizes the ocular and systemic findings in disord ers of amino acid metabolism.
Cystinosis Cystinosis is a rare autosomal recessive disorder characterized by the accumulation of the amino acid cystine within Iysoso mes. It affects 3.5 infants per 1 million births. Cystinosis has been mapped to chromosome 17p13; the defective gene is CTNS. PATHOGENESIS
A defect in transport across the lysosomal membrane leads to accumula-
tion of cystine. Cystinosis is a systemic metabolic defect that can present as an infantile, intermediate, or adult form. The age at diagnosis averages 1 yea r but can range into the teenage years. The infantile, or nephropathic, form features dwarfism and progressive renal dysfunction, with the deposition of fine polychromatic cystine crystals in the conjunctiva, corneal stroma, and other parts of the eye. The interm ediate, or adolescent, form has less severe rena] involvement. Systemic cysteamine treatment prevents or delays the negative consequences of the disease, which can include death. In the adult form, life expectancy is normal. Crysta ls can be seen in the corneal stroma on slit -lamp examination and in the trabecular meshwork on gonioscopy. These patients are often photophobic. The crystals, however, usually do not affect visual acuity. CLINICAL FINDINGS
314 • External Disease and Corn ea Table 11-3 Disorders of Amino Acid Metabolism Type
Heredity
Ocular Findings
Cystinosis
Rare autosomal recessive
Polychromatic cystin e crystals in conjunct iva, trabecular meshwork, and corneal stroma Photophob ia Photophobia; tearing; conjunctival injection; tarsal pap illa ry hypertrophy; pseudodendrites Epithel ial brea kdown with second ary corneal neovascularization and scarring Och ronos is (b rownish ) deposits of alkapton in corneal epith elium or in Bowman layer near limbus Rectus muscte tendons and adjacent sctera deve lop smudg elike pigmentation
Tyrosinemia
Autosomal recessive
Alkaptonuria
Rare autosomal recessive
LABORATORY EVALUATION
Ass oc iated Conditions
Genetic linkage
Dwarfism Renal dysfunction
Chromosome 17p13, gene
eTNS Hyperkeratotic lesions of palms, sales , and elbows Mental retardation
Gene locus at
Arthropathy, renal calculi, pigmentation of cartilaginous structures, inctuding earlobes, trachea, nose, and tendons
Gene locus at
16q22. 1-q22.3
3q21-q23
Cystine crystals may be seen in conjunctival biopsy, blood leu-
kocytes. or bone marrow. MAN AGEMENT Topical cysteamine drops reduce the density of the crystalline deposits and diminish corneal pain, possibly as a result of a decrease in the development of corneal erosions. Presumably, the topically adm inistered cysteam ine reacts with the intracellular cystine, forming a cysteine-cysteam ine disulfide that resembles lysine and is transported through the lysosome by the normal lysine transport system. The crystals have been observed to recur in patients who h'lVe undergone PK for clouding associated with the corneal deposits. These refractile polychromati c crystals are densest in the peripheral cornea but are seen throughout the anterior stroma, even within the central cornea (Fig 11-2). Posterior manifestations such as pigmentary retinopathy and optic nerve elevation may be treated with oral cysteamine_
Gahl WA, Kuehl EM, Iwata F, Lindblad A, Kaise r-Kupfer MI. Corneal crystals in nephropathic cystinosis: natural history and treatment with cysteamine eyedrops. Mol Gen.et Metnb. 2000;71 ( 1-2),100-1 20.
Tyrosinemia
Richner-Hanhart syndrome (tyrosi nem ia type II) is characterized by systemic findings, including hyperkeratotic lesions of palms, soles, and elbows, as well as eventual mental retardation.
CHAPTER 11 :
Figure " ·2
Metabolic Disorders With Corneal Ch ang es . 315
Cystinosis. Refractile polychroma tic crystals are clustered in the peripheral cornea.
This autosomal recessive disorder occurs secondary to an enzymatic defect of tyros ine ami notransferase that leads to excess tyrosine in th e blood and urine. The elevated tyros ine probably has a direct action on lysosomal membranes. leading to release of their enzymes with characteristic changes. The gene locus is at 16q22.1 -q22.3 .
PATHOGEN ESIS
CLINICAL FINDINGS Ocular changes include marked photophobia, tearing, conj unctival injection. and tarsal papillary hype rtrophy. Patients develop recurrent episodes of pseudodendrites. wh ich usually do not stain well with fluorescein or rose bengal. Continued episodes of epithelial breakdown can result in corneal va scular ization and scarring. It is important to consider this disorder in a you ng child who may carry a diagnosis of recurrent herpes Simplex virus keratitis. EVALUATION Hypertyrosinemia and tyrosinuria with normal phenylalanine level an d biopsy showing soluble tyrosine aminotransferase (TAT) deficiency are diagnostic.
LABORATORY
Restriction of dietary intake of tyrosine and phenylalanine can reduce both the corneal and system ic changes. including mental retardation . The institut ion of appropriate dietar y restrictions even later in life can improve the mental status. MA NAGE MENT
Alkaptonuria Alkaptonuria is a rare autosomal recessive disorder with a defect of tyrosine metabolism that maps to gene locus 3q21 -q23. An unus ually high frequency occurs in the Dominican Republic and Slovakia. Homogentisate 1,2 -dioxygenase. the enzyme necessary to degrade tyrosine and phenylalanine. is deficient. Phenylalan ine and tyrosine cannot be metabolized beyo nd homogent isic acid. which is oxidized and polymeri zed into alkapton. a brown-black material similar to melanin. Alkapton then deposits in connective tissues as dark pigment
PATHOGENESIS
316 • Extern al Disease an d Corne a
know n as ochronosis. Corneal lesions consisting of homogentisic acid are easily seen by light microscopy. Electron m icroscopic studies have shown extracell ular deposits of finely granular och ronotic pigment in and around collagen fibril s. Intracellular membranebound ochronotic pigment granules were observed in macrophages in fibroblasts, along with 2 other forms of extracellular ochronotic pigment.
Patients develop arthropathy, renal calculi, and pigmentation of cartilaginous structures, including earlobes, trachea, nose, tendons, dura mater, heart va lves, an d prostate. Eventually, medial and lateral rectus muscle tendons and the sdera adjacent to the tendon insertions develop smudgelike pigmentation. Darkly pigmented, dotlike opacities may appear in the corneal epithelium or in Bowman layer near the limbus.
CLIN ICAL FINDINGS
Urin e turns dark on standing and alkalinization. Homogentisic acid oxidase deficiency can be shown.
LABORATORY EVALUATION
No specific therapy is available, although high-dose ascorbic acid is reported to redu ce arthropathy in young patients. It is hoped that specific gene therapy will be available to treat this disorder in the future.
MANAGEM ENT
Cheskes ], Buettner H. Ocular manifestations of alkapton uric ochronosis. Arch Ophthalmol. 2000; 118(5),724 - 725.
Disorders of Protein Metabolism Amyloidosis The amyloidoses are a heterogeneous group of diseases characterized by the accumulatio n of amyloid in various tissues and organs. Table 11 -4 summarizes ocular find ings in the amyloidoses. PATHOGENESIS
AmylOid is an eosinophilic hyaline material with 5 basic stain ing charac-
teristics:
1. 2. 3. 4. 5.
positive staining with Congo red dye dichroism and birefringence metachromasia with crystal violet dye fluorescence in ultraviolet light with thioflavi ne T stain typical filamentous appearance by electron microscopy
Protein AP derives from a-globulin and is found in all amyloid fibrils. In addition, amyloid fibrils are composed of immunoglobulin light chains or fragments of ligh t chains (espeCially of the variable reg ion) and non immunoglobulin protein. AmylOid composed of immunoglobulin is deSignated AL for amyloid fibril protein and the L chain amyloid protein. Nonimmunoglobulin amyloid is deSignated AA for amyloid fibril protein and SAA, its serum-related protein. Protein AF has several subtypes found in the vario us dystroph ies. These noncollageno us proteins can be deposited in the cornea and conjunctiva and in intraocular or ad nexa l structures.
Table " -4 Amyloid in the Eye Type
Heredity
Ocular Distribution
Associated Conditions
Primary loca li zed amylo idosis
Nonfamilial
Conjunctival plaqu e Polymorphic amyloid degeperat ion Latti ce co rneal dyst rophy types I and II I Avel lino and granu lar dystrophy Gelatinous dropli ke dystrophy
None
Skin and co njunctiva (very rare) Ophtha l m oplegia (orbital and muscle infilt rates), ptosi s, vitreous veil s, dry eye, pupil abno rma li ties
Occu lt plasma ce ll dyscrasias Ca rd iomyopathy Peripheral neuropathy Gastrointesti nal disease Skin invol veme nt Meretoja syndrome (facial pal sies, skin nodul es, rarely renal involvement) Trachoma, psoriasis, trauma, ph lyctenulosis, retinopathy of prematurity, keratoconu s, bullous keratopathy, interstitial keratitis, leprosy, contact len s wear, trichiasis, tertiary syphil is, uveiti s, climatic droplet keratopathy
Famil ia l
Genetic linkage
5q3 1 (keratoepithelin gene)
lp32-q12 (M1Sl gene)
Primary systemic amyloidosis
Secondary localized amyloidosi s
Secondary systemi c amyloidosis
Nonfam il ia l Famili al
Nonfamilial
Familial Nonfamilial
Familial
Latti ce corneal dystrophy type II, crania l neuropathies Conjunctiva Skin Cornea
Non e Rare ly vitreous body (cornea l deposits are not amyloid ) Conjunctiva, skin (rare)
(Corn ea l nerve enlargement is not amy loid)
' 8ql'.2-q12 .' (transthyretin ge ne)
Many others 9q34 (gelsolin gene)
Mult iple myeloma Infectious diseases (tuberculosis, leprosy, syphilis) Inflammatory diseases (rh eumatoid arthriti s, other co nnective tissue disorders) Hodgkin di sease
MEN type 2A
lOq".2 (RET oncogene)
318 • External Disease and Co rnea
Ocular amyloidosis is classified as either primary (idiopathic) or secondary (to some chronic disease) and either localized or systemic. A useful classification of amyloidosis considers these 4 types. Each type will be discussed separately:
CLINICAL FINDINGS
1. 2. 3. 4.
primary localized amyloidosis primary systemic amyloidosis secondary localized amyloidosis secondary systemic amyloidosis
Primary localized amyloidosis is the most common form of ocular amyloidosis. Conjunctival amyloid plaques occur in the absence of systemic involvement (Fig 11 -3) . Primary familial amyloidosis of the cornea (gelatinous droplike dystrophy) , in which pudding-like translucent nodules occur as cobblestone masses on the central corneal surface (Fig 11-4), and lattice corneal dystrophy, a special form of primary localized
Figure 11·3
Figure 11·4
Conjunctiva l amyloidosis.
(Courtesy of Vincent
P. deLuise, MO)
Primary familial amyloidosis of the cornea (gelatinous droplike dystrophy).
CHAPTER 11:
Metabo lic Disorders With Corneal Changes. 319
amyloidosis, are discussed in Chapter 10. Polymorphic amyloid degeneration is discussed in Chapter 12. Primary systemic amyloidosis is a heterogeneous group of diseases in which waxy ecchymotic eyelid papules occur in association with vitreous veils and opacities as well as pupillary anomalies such as light-near dissociation. Orbital involvement, extraocular muscle involvement with ophthalmoplegia, and scleral infiltration with uveal effusion have been reported. The most common form of primary systemic amyloidosis is an auto somal dominant group of diseases linked to ISqI1.2 -qI2.1, with more than 40 different mutations of the transthyretin (TTR, prealbumin) gene described. Corneal involvement occurs in lattice dystrophy type II (Meretoja syndrome), as discussed in Chapter 10. Secondary localized amyloidosis is the most common form of amylOidosis of the cornea. It develops in eyes with long-standing chronic inflammatory disease such as trachoma; interstitial keratitis; tumors; or connective tiss ue disorders, usually rheumatoid arthritis. Corneal involvement may be seen in keratoconus, trachoma, phlyctenulosis, bullous ke ratopathy, interstitial keratitis, leprosy, contact lens wear, trichiasis, tertiary syphilis, uveitis, and climatic droplet keratopathy. Secondary deposition takes the form of a degenerative pannus, lamellar deposits in the deep stroma, or perivascular deposits. Deposits are typically yellOWish pink or yellow-gray, depe nding on the associated disease. Secondary systemic amylOidosis features amylOid AA and is seen in association with rheumatoid arthritis, Mediterranean fever, bronchiectasis, and Hansen disease (leprosy) . The eyelids can be affected but less commonly than with primary systemic amylOidosis. Amyloid does not deposit in the cornea in secondary systemic amyloidosis. Chang Rl, Ching SST. Corneal and conjunctival degenerations. In : Krachmer ]H, Mannis M], Holland E], eds. Cornea. 2nd ed. Vol I. Philadelphia: Elsevier/Mosby; 2005:987 - l004 .
Disorders of Immunoglobulin Synthesis The excess synthesis of immunoglobulins by plasma cells in multiple myeloma, Waldenstrom macroglobulinemia, and benign monoclonal gammopathy may be associated with crystalline corneal deposits. PATHOG ENESIS Monoclonal proliferation of plasma cells (B lymphocytes) leads to overproduction of both light (K or Ie) chains and heavy (Ct, y, e, 0, or ~) chains (together, M proteins), overproduction of light chains with or withou t production of heavy chains (Bence Jones protein), or overproduction of heavy chains without light chains (heavy chain disease) . PathogeneSiS is related either to direct tissue invasion, particularly of the bone marrow, or to hyperviscosity syndrome. Secondary hypercalcemia may occur. Deposition of paraproteins in the cornea is ve ry rare and is related to diffusion of the proteins, probably from the limbal vessels or, alternatively, from the tears or aqueous humor, followed by precipitation perhaps related to corneal temperature or local tissue factors. CLINICAL FINDINGS
Ophthalm ic findings include the following:
crystalline deposition in all)ayers of the cornea or in the conjunctiva copper deposition in the cornea
320 • Externa l Disease and Corn ea
sludging of blood flow in the conjunctiva and retina pars plana proteinaceous cysts infiltration of the sclera orbital bony invasion with proptosis Corneal deposits are nume rous, scintillating, and polychromatic. They are typical of IgG K chain deposition and possibly related to the size of the paraprotein and the chronicity of the disease. Waldenstrom macroglobulinemia is characterized by malignant proliferation of plasma cells generating IgM, causing hyperviscosity syndrome, principaLly in older men. It has been associated with needlelike crystals and amorphous deposits subepithelially and in deep stroma. Benign monoclonal gamm opathy is a frequent fi nding in people over age 60 (up to 6%). The systemic evaluation in these cases is negative. but a mild increase in paraprotein is detected «3 g/dL). Slit- lamp findin gs of iridescent crystals resemble myelo ma and are also very infrequent (abo ut 1%- 2% of affected patients). Cryoglobulins are proteins that precipitate on exposure to cold. They occur nonspecifically in autoimmune disorders. im munoproliferative disorders, or hepatitis B in fection. Ophthalmic findings include retinal hyperviscosity signs, occasional crystalline corneal deposits. amorphous limbal masses, and signs of autoimmune disease. LABORATORY EVA LUATION Corneal crystalline deposits have many causes, and eva luation depends on appearance and location in the cornea. Table 11-5 summarizes the differential diagnosis of corneal deposits based on the depth of corneal involvement, color and refractile cha racter. and conjunctiva l involvement. Serum protein electrophoresis, complete blood count (CBC), and general screen ing for albu min/globulin and calcium levels are performed when clinical suspicion of immunoglobulin excess arises. Further testing for systemic evaluation depends on clinical suspicion and the initial findings.
No ophthalm ic treatment is needed unless the amorphous depositions interfe re with vision and need to be removed with LK. Crystals will reso lve slowly after successful treatment of an underlying malignancy. MANAGEMENT
Noninflammatory Disorders of Connective Tissue Table 1l -6 summarizes the connective tissue disorders associated with corneal changes.
Ehlers-Danlos Syndrome Ehlers-Danlos syndrome (E DS), a heterogeneous group of diseases, is characterized by hyperextensibility of joints and skin, easy bruisability, and formation of "cigarette paper" scars. It was discussed briefly in Chapter 9 in connection with blue sclera. The many (more than 20) known types of Ehlers-Danl os syndrome are classified as autosomal dominant and recessive and X-linked recessive. Eight genetic loci
PATHOGENE SIS
Table 11 ·5 Corneal Deposits in Differential Diagnosis Type
Superficial
Stromal
Deep StromallEndothelial
Conjunctiva
Pigm ented
Cornea ve rticil lata (Fabry disease, amiod arone) Striate me lanoke ratos is Iron lin es Pigmented (nonca lcifi c) band keratopathy Spheroidal dege neration Adrenochrom e Alkaptonuria Subep ithelial muc in ous dystrophy Coats wh ite rin g Calci fi c band keratopathy Ciprofloxacin
Ph enothiazines Blood stain ing Bilirubin Sidero sis (iron) Corneal tattoo
M ercury Wi lso n di sease (cop per) Chal cos is (coppe r) Chry siasis (systemic gold ) Argyria sis (topi cal silver) Krukenb erg spindl e
Tetracyclin e
Gra nular dyst rophy Macular dystrophy Fleck dyst rophy Lipid deposition Muco po lysaccha ridoses Latt ice dystrophy Schnyder dystrophy Bietti crystalline corn eoretina l dyst rophy Immun oglob ulin dep os iti on Cyst inosis Infectio us crysta llin e keratopathy
Co rnea farin ata Pre-Descemet's dyst rophy X-lin ked ichthyos is Argy riasis (si lver)
Gout (urate)
Polymorph ic amy loid degenerati on
Cysti nos is
Nonpigm ented
Refractil e! crystalline
Meesmann dystrop hy Superficia l amyloid Tyrosinemia type II Intraepithel ia l ointm ent Gout (urate)
Adrenochrome Argyr iasis
From Palay DA. Cornea l deposits. In: Krachmer JH, Mannis MJ, Holla nd EJ, eds. Cornea. 2nd ed. Vol 1. Philadelphia: Elsevier/Mosby; 2005:365- 378.
Table 11-6 Skeletal/Connective Tissue Disorders of Interest to the Ophthalmologist Name (OMIM #)
Corneal Findings
Other Ocular Findings
Genetics/Map/Other Information
Albright hereditary
None
Zonular cataracts with multicolored flecks in 25% of patients Strabismus (exotropia with V pattern) Absence of extraocular muscles, proptosis, ocular hypopigmentation, optic atrophy Rare: nystagmus, ptosis, cataract, ectopia lentis, coloboma of iris Epicanthal folds, anti mongoloid slant, hyperor hypotelorism, optic atrophy, strabismus Rare: coloboma of the iris and choroid, congenital cataract, lens subluxation, nystagmus, ret inal detachment Cataracts, retina l dystrophy, nystagmus, iris atrophy, hyperopia, enophthalmos, strabismus
AD; sex-influenced 1 male:2 female AD Gene maps to 10q26 Mutations in FGFR2
AR Type I: Chromosome 5 Type II: 10q11
Strabismus (exotropia with V pattern) Exophthalmos, hypertelorism, optic atrophy in 30%
AD Gene maps to 10q26 Mutations in FGFR2
osteodystrophy (300800) Apert syndrome (1 01200)
Exposure keratitis with severe proptosis Keratoconus (very rare)
Megalocornea (very rare) Carpenter syndrome; ar.rocepha 10 polysyndactyly
type II (201000 )
Cockayne syndrome (Type I: 216400 Type B: 133540 Type III: 216411) Crouzon syndrome (123500)
Exposure keratitis secondary
to severe proptos is Microcornea (rare) Corneal leukoma (rare) Raised infe rio r corneal
les ion, band keratopathy, re curre nt erosions Exposure keratitis with
severe proptosis Keratoconus (ve ry rare ) Microcornea (very rare)
Ehlers-Danlos syndrome (EDS I: 130000 EDS II: 130010 EDS III: 130020 EDS IV: 130050 EDS V: 305200 EDS VI: 225400 EDS VII: AD-130060 EDS VII: AR-225410 EDS VIII: 130080)
Brittle cornea in type VI Keratoconus in types I and VI Keratoglobus in type VI
Rare: nystagmus, glaucoma, cataract, ectopia lentis, aniridia, anisocoria, myelinated nerve fibers Epicanthal folds, blue sclerae, retinal detachment, glaucoma, ectopia le ntis, angioid streaks (rare )
AR
See text
Goldenhar-Gor li n syndrome; ocu loauricu lovertebral sequence; hemifacia l m icrosomia (16421 0)
limbal dermoid
Halle r ma n n-St re iff -Fra ngo is syndrome; ocu lomandibu lodyscepha ly (234 100)
One case of sc lerocornea
Hypophosphatasia (Inf anti le: 241500 Ch il dhood: 2415 10 Adult ; 146300 )
Ban d kerat opat hy wit h con j unct iva l calc ificat io ns in in f ant ile fo rm
Marfan syndrome (154700)
Megalocornea Flat cornea Keratoconus (uncommon) M icrocornea
Na il -patella syndro m e; o nychoosteodysp las ia (161200) Ocu lodentoosseous dysp las ia (AD; 164200 AR; 257850) Osteogenesis imperfecta (Type I; 259400 Type II; 166200 Type III; 259420 Type IV; 166220)
Microcornea
Decreased central corneal th ickness Keratoconus Mega locornea (rare) Poste rio r embryotoxon (rare)
Upper > lowe r lid co loboma, strab ismus (25%)' Duane retraction syndrome, mic rophtha lmia, anophtha lmia, lacri ma l syste m d ysf unctio n, opti c ne rve hypoplas ia, tortuous ret inal vesse ls, mac u lar hypop las ia and hete rotrop ia, choro ida l hyperpigmentation, ir is and retina l co lobomas Congenital cataract s, sponta neous resorption of lens cortex w ith secondary membranous cataract fo r mation, glaucoma, uveitis, retinal fo lds, opt ic nerve dysplas ia, m icrophtha lmia Bl ue sc lerae, cataracts, optic atrophy sec o ndary to cran iost enos is, at ypica l retinit is pigmentosa; ocu lar comp li cat ions present on ly in i nfant ile and childhood forms, not in adu lt form Ectopia lent is, strabismus, cataracts, myop ia, retina l detachment, g laucoma Cataracts, micropht halm ia
Hypotelor ism, convergent strabismus, anter ior segment dysgenesis, g laucoma, cataracts, remna nts of the hya lo id system Blue sclerae Rare: congenita l g laucoma, cataract, choroidal sc leros is, subhya loid hemorrhage, hyperopia, ectopia lentis
Sporadic Rare ly AD and AR
Sporadic Ra r ely AD Increases anesthetic ri sk secondary to tracheomalac ia Infanti le: AR Ch i ldh oo d: AR, A D Adu lt: AD ALPL gene m aps to 1 p36-p34 AD Gene maps to 15q2 1.1 Mutations in FBN- 1 AD Gene maps to 9q34 .1 AD; m utat ions in con nex in-43 (GJA 1) gene on 6q2 1-23 .2 See text
(Continued)
Table 11 -6 (continued) Name (OMIM #)
Corneal Findings
Other Ocular Findings
Genetics/Map/Other Information
Parry-Romberg syn drom e; progressive facial hem iatrophy (141 300)
Neuroparalyti c keratiti s
Spo radic 5% bi late ral , left > 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
Peripheral cornea guttae Peripheral cornea guttae (Hassall-Henle bodies) are small, wartlike excrescences that appear in the peripheral portion of Descemet's membrane as a normal aging change. They occur on the posterior aspect of the membrane and protrude toward the anterior cham -
ber. With the slit lamp, Hassall -Henle bodies have the appearance of small, dark dimples within the endothelial mosaic; these are best seen by specular reflection. Rarely seen before age 20, they then increase steadily in number with age. They are pathologic when they appear in the central cornea and are then referred to as cornea guttae. Central cornea guttae associated with progressive stromal and eventually epithelial edema represent Fuchs endothelial dystrophy (see Chapter 10). They are the result of localized overproduction of basement membrane by endothelial cells and so have the same collagenous structure as does normal Descemet's membrane.
Melanin pigmentation Deposits of melanin on the corneal endothelium can be observed in patients with glaucoma associated with pigment dispersion syndrome. Typically, the cluster of ve rtically oriented pigments is known as Krukenberg spindle (see Table 12-2).
Scleral Degenerations Scleral rigidity increases in older people, and there is a relative decrease in scleral hydration and the amount of mucopolysaccharide. These changes are accompanied by subconjunctival deposition of fat, which gives the sclera a yellowish appearance. Calcium may also be deposited either diffusely among the scleral collagen fibers in granular or crystalline form or focally in a plague anterior to th e horizontal rectus muscle insertions. These senile
346 • External Disease an d Corne a
Figure 12-14
Senile scleral plaque anterior to horizon ta l rectus muscle insertions. (Courtesy of
Robert W Weisenrhal, MD.)
plaques are visible as ovoid or rectangular zones of grayish translucency (Fig 12-14). Histologically, the midportion of the involved sclera contains a focal calcified plaque surro unded by relatively acellular collagen. The plaques do not elicit inflammatio n and rarely extrude. If suffiCiently dense, they may be visualized on CT scan.
Drug-Induced Deposition and Pigmentation Ocular medications deposit within the cornea as a result of their concentration within the tear film , Iimbal vasculature, or aqueous humor; or due to a speCific affi nity of the chemical properties of the medication to corneal tissue. Specific drugs deposit in characteristic fashion and corneallayef. The deposition of the drug may reduce visual acuity, produce photosensitivity, or cause ocular irritation. Its cessation often eliminates the symptoms and resolves the drug deposits. Most drug-induced deposition is not symptomatic, however, and does not require cessation of the medication (Table 12-3).
Corneal Epithelial Deposits Corneal verticil/ala Corneal verticillata, or vortex keratopathy, manifests as a whorl-like pattern of golden brown or gray deposits in the inferior interpalpebal portion of the cornea in a clockwise fashion (Fig 12-15). A variety of medications bind with the cellular lipids of the basal epithelial layer of the cornea due to thei r cationic, amphiphilic properties. Amiodarone, an antiarrhythmic, is the most common cause of corneal vertic illata, followed by chloroquine, hydroxychloroq ui ne, indomethacin, and phenothiazines. A comprehensive list of systemic dru gs associated with corneal vertic illata is given in Table 12-3.
CHAPTE R 12: Depositio ns and Degeneratio ns . 347
Table 12-3 Systemic Drugs Associated With Corneal Deposits Cornea l Verticil lata
Stromal Deposits
Amin oquinolones (chloroqu ine, hydroxych loroquin e, am odiaqu in e) Am iod aron e Atova qu one Biaxi n (clarithromyci n) Clofazim ine Phenot hiazine (ch lorp romazine ) Gentami cin (subconjunctival) Gold Ibuprofen Ind om eth ac in M epa cri ne Mo nobenzone (topi cal skin oi ntm ent) Naproxen Perhex iline maleate Suram in Tam ox ifen Thi o xanthines (ch lorprothixine, thi othix ine ) nl o ro ne hyd rochl ori de
Antac id s Clofazimi ne Gold Imm unog lobulins Indometha cin Ph enothiazines Pheny lbutazon e Practo lo l Retinoid s (isotret inoin ) Si lve r
Adapted from Holl ander DA, Ald ave AJ. Dru g-induced corneal com pl icati ons. Curr Opin Ophtha/mol. 2004;15: 541-548; and Tyag i AK, Kaya rkar VV, McDon nell PJ. An unreported side effect of topica l cla rithromyci n when used successfully to treat Mycobacteriu m aviu m-i ntracellulare ke ratitis. Cornea. 1999;181510606-607 .
Figure 12-15
Corneal verticillata. (Courtesy of Robert W. Weisenthal, MD.)
It is unusual for these deposits to result in reduction of visual acuity or ocular symptoms, although this has occurred in some patients. The deposits typically resolve with disconti nuation of the responsible agents. If there is reduced vision with the use of amioda rone and tamoxifen , the possibil ity of optic neuropathy should be considered. Retinal toxicity associated with the chloroquine fami ly and tilorone hydrochloride can also reduce vision. The differential diagnOSiS of corneal vert icillata should also include Fabry disease, a disorder of sphingoli pid metabolism.
348 • External Disease and Cornea
Epithelial cysts Due to the rapid turnover of epithelial cells, drugs that inhibit DNA synthesis may be toxic to the epithelium when used in high doses systemically. Cytarabi ne (Ara-C), for example, may cause punctate keratopathy and refractile epithelial microcysts that are associated with pain, photophobia, foreign-body sensation, and reduced vision. Ciprof/oxacin deposits Topical ciprofloxacin therapy can result in the deposition within an epithelial defect of a chalky white precipitate composed of ciprofloxacin crystals. Although white plaques predom inate, a crystalline pattern may also be observed. The depos its resolve after discontinuation of the medication. Adrenochrome Long-standing administ rat ion of epinephrine compounds may lead to black or very dark brown deposits in the conjunctiva and cornea. Composed of adrenochrome, an oxidation product of the basic epinephrine compound, these melanin -like deposits can accumulate in conjunctival cysts and concretions in the conjunctiva (Fig 12- 16). They may discolor the cornea or contact lenses as weU. The deposits are harmless, although they are occasionall y misdiagnosed as conjuncti val melanoma o r other conditions. Arffa RC. Grayson's Diseases of the Cornea. 4th ed. St Louis: Mosby; 1997. Kaiser PK, Pineda R, Albert OM, Shore JW. "Black cornea" after long-term epinephrine use. Arch Ophthalmol. 1992;IIO(9P273-127S.
Stromal and Descemefs Membrane Pigmentation Chlorpromazine, a member of the phenothiazine family, may cause corneal pigmentation in 18%-33% of patients on chronic the rapy. It probably enters the cornea through the aqueous, and, therefore. the brown opacities are first found in the posterior stroma,
Figure 12-16 Adrenochrome deposits in inferior cul-de-sac.
CHAPTER 12:
Depositions and Degenerations.
349
Descemet's membrane, and endothelium; it later spreads to the anterior stroma and epi-
thelium. Chlorpromazine can also deposit on the anterior lens capsule. Clofazimine may produce anterior stromal opacities or crystalline deposition. Isotretinoin is typically associated with fine, diffuse gray deposits in the central and peripheral cornea. Certain classes of metallic compounds can produce characteristic deep stromal or Descemet ·opacities. Silver compounds were commonly used in the preantibiotic era to treat external infections. Their chronic use can result in a condition known as argyriasis, which
consists of a slate-gray or silver discoloration involving the bulbar and palpebral conjunctiva. Argyriasis can also occur after inadvertent excessive application of silver nitrate to the bulbar conjunctiva for the treatment of superior limbic keratoconjunctivitis. This condi-
tion can be permanent. Gold salts are used for the treatment of rheumatoid arthritis. With chronic usage and cumulative dosages exceeding 1 g, a high percentage of patients develop posterior stromal deposits that spare Descemet's membrane and endothelium.
Table 12-2 lists pigments that may be of diagnostic importance, with their locations and associated conditions. See also Chapter 11, Table 11-5.
Endothelial Manifestations Although rare, rifabutin has been described as causing stellate, refractile endothelial deposits initially in the periphery that may extend to the central cornea. Frauenfelder FT, Frauenfelder F\>\Z Drug-induced Ocular Side-Effects. 5th ed . Boston: Butterworth-Heinemann; 2001:647- 648. Hollander DA, Aldave AJ. Drug-induced corneal complications. Curr Opin Ophthalmol. 2004;
15(6):541-548.
CHAPTER
13
Clinical Aspects of Toxic and Traumatic Injuries of the Anterior Segment
Injuries Caused by Temperature and Radiation Thermal Burns Heat Rapid-reflex eyelid closure, Bell phenomenon, and reflex movement away from the source of intense heat usually limit damage to the globe from flames. Burns from molten metal that stays in contact with the eye are more likely to cause corneal injuries that result in permanent scarring. Heat is a major inducer of inflammation and stromal protease expression and can lead to collagen melt if severe. The major objectives of therapy for burns caused by heat are the following : Relieve discomfort. • Prevent secondary corneal infl am mation , ulceration. and perforation from infec-
tion or from exposure caused by eyelid damage. Minimize eyelid scarring and resultant malfunction.
A cycloplegiC agent can help relieve discomfort fro m secondary ciliary spasm or iridocyclitis. Prophylactic antibiotics (topical andlor systemiC) can help prevent infection of burned eyelids andlor reduce the chances of infectious corn eal ulceration. Limited debridement of devitalized tissues and granulation tissue, used with full-thickness skin grafts and tarsorrhaphy, helps minimize eyelid scarring and ectropion. Burned ocular tissue can be protected temporarily by covering the eye with a lubricant and a piece of sterile plastic wrap. Topical corticosteroids help suppress any associated iridocyclitis, but they can also inhibit corneal wou nd heali ng and must be used with caution and, in general, fo r short periods of time. Hair-curling irons are a common household cause of corneal burns. Fortunately, burns caused by curling irons are usually limited to the epithelium and generally require onl y a brief period of antibiotic and cycloplegiC therapy.
Freezing Transient corneal stromal edema induced by cold has been reported in a variety of settings, including individuals with Raynaud disease. Associated conjunctival vascular changes 351
352 • Externa l Disease an d Cornea
consistent with the Raynaud phenomenon have been documented under cold stress. Transient cold-induced corneal edema has also been reported in several patients with corneal nerve V (trigeminal) dysfunction. Research suggests that sensory denervation of the eye influences ocular temperature regulation, as well as altering the morphologic characteristics- and likely the function- of corneal cells, including the endothelium .
Ultraviolet Radiation The corneal epithelium is highly susceptible to injury from ultrav iolet (UV) radiation. Initially, there may be no symptoms; symptoms usually occur a few hours after exposure, when the injured epithelial cells are shed. The condition, although painful, is generally self-limited, and the epithelium heals within 24 hours. The most common causes of ocular UV inj uries are unprotected exposure to sunlamps, arc welding, and prolonged outdoor exposure to reflected sun light. Snoll' blindness, wh ich occurs in skiers and mOllntain climbers, is caused by UV light reflected fro m snow. Appropriate protection with UV-fiItering eyewear can prevent such injuries. Treatment consists of patching to minimi ze discomfort from eyelid movement, top ica l antibiotic ointment. and cycloplegia. If discomfort is severe, patients may require systemic analgesics.
Ionizing Radiation Exposure to ioni zing radiation may be associated with nuclear explosions, x-rays, and radioisotopes. The amount of exposure is related to the amount of energy, the type of rays em itted, and proxim ity to the ionizing source. Tissue destruction may be the result of direct killing of cells; cellular DNA changes that produce lethal or other mutations; or radiation damage to blood vessels, with secondary ischemic necrosis. Longer wavelengths penetrate less deeply, causing a more in tense reaction in superficial layers. Shorter wavelengths penetrate to deeper tissues and may not cause extensive dalllage to superfiCial tissues. Most cases of ocular exposure to ioni zi ng radiation involve both the conjunct iva and cornea and possibly the lacrimal glands. Conjunctival edema and chemosis occur acutely, often followed by scarring, shrinkage, loss of tear production, and alterations in conjunctival blood vessels with telangiectasia. Necrosis of the conjunctiva and underlying sclera can occur if radioact ive material (or rad iomhnetic chemkals such as mitomycin C) is embedded in the conjunctiva. Punctate epithelial erosions typify ac ute corneal changes. Explosions invo lving ionizing radiatio n may lead to perforation of ocular tissues with im mediate radiation necrosis. Management of acute problems includes removal of all foreign bodies. Depend ing on the severity of the injury, a bandage soft contact lens, tissue adhesive, or tectonic graft may be necessary. Poor wo und healing is a hallmark of ionizing radiat ion injuries. Late complications are related to lack of tears, loss of corneal sensation, loss of corn eal epithelium and its failure to heal, secondary microbial keratit is, vascula rizatio n, and keratit is. Manage men t of these sequelae includes the use of artificial tears and tarsorrhaphy. Late changes in the conjunctiva preclude its use for a conjunctival flap. If the fel low eye has not been
CHAPTER 13:
Clinica l Aspects of Toxic and Trauma tic Inju ries of the Anterior Segment . 353
injured, a contralateral autologous conjunctival flap may be helpful. The prognosis for penetrating keratoplasty in these situations is poor due to chronic ocular surface disease. Miller D, ed. Clinical Light Dam age to th e Eye. New York: Springer-Verl ag; 1987.
Chemical Injuries Chemical trauma to the external eye is a common problem that can range in severity from mild irritation to complete destruction of the ocular surface epithelium, corneal opacification, loss of vision, and even loss of the eye. The offending chemical may be in the form of a solid, liquid, powder, mist, or vapor. Chemical injuries can occur in the home, most commonly from detergents, disinfectants, solvents, cosmetics, drain cleaners, oven cleaners, ammonia, bleach, and other common household alkaline agents. Fertilize rs and pesticides are common offending agents in agricultural chemical injuries. Tn the workplace, plaster and cement products are frequent causes of alkali burns due to calcium hydroxide. Chemical injuries occurring in industry are usually caused by caustic chemicals and solvents. Some of the worst ocular chemical injuries result when strong alkalis (eg, lye) or acids are used for assault. Whenever possible, the offending chemical agent should be identified, because the severity of a chemical injury depends on the pH, the volume and duration of contact, and the inherent toxicity of the chemical. The most severe chemical injuries are caused by strong alkalis and, to a lesser extent, acids. These solutions cause damage by drastically altering the concentration of highly reactive hydrogen and hydroxyl ions in affected tissues. Alkali Burns Strong alkalis raise the pH of tissues and cause saponification of fatty acids in cell membranes and ultimately cellular disruption. Once the surface epithelium is damaged, alkaline solutions readily penetrate the corn eal stroma, where they rap idly destroy the proteoglycan ground substance and collagen fibe rs of the stromal matrix. Strong alkaline substances may also penetrate into the anterior chamber, producing severe tissue damage and intense inflammation. The visual prognosis is often determined by the extent of ocular surface injury (Table 13-1 ) and the presence and degree of skin burns and their effect on eyelid function.
Table 13-1 The Hughes Classification of Ocular A lkali Burns Grad e I
Grade II
Grade III
Grade IV
Cornea l epithelia l defect without limbal ischemia.
Corne al epithelial defect with stromal haze and ischemia affecting less than one third of t he limbus
Total cornea l epithe lial defect, with stromal haze obscuring iris details and ischemia affect ing one third to one half of the li mbus
Opaque cornea obscuring view of iris or pupil; ischemia of greater than one half of the limbus
354 • External Disease and Cornea
The most unfavorable vis ual prognosis is associated with extensive limbal epithelial damage and intraocular chemical penetration. The limbus contains corneal epithelial stem cells; hence, damage to this area can lead to a disruption in the normal repopulation of the corneal epithelium. Severe damage to the limbal area can be appreciated as limbal "blanching" -as the vascular supply to this critical area is disrupted via death of vascular endothelial cells. Resultant ischemia to the limbus and anterior segment can have dire consequences for eyes thus affected (Figs 13-1, 13-2, 13-3). Repopulation of the corneal
Figure 13·1 Mi ld. grade II alkali burn. Note inferior scleral ischemia. (Courtesy of James J Reidy, MO.)
Figure 13·2 Moderate, grade III alkal i burn wit h cornea l edema and haze.
Figure 13-3 Severe, grade IV alkali burn with epithelial loss and stroma l necrosis . (Courtesy of James J. Reidy. MO.)
CHAPTER 13:
Clinica l Aspects of Toxic and Traumatic In jur ie s of t he Anterior Segment. 355
surface epithelium with cells that do not have the proper degree of diffe rentiation leads to "conjunctivalization" of the cornea, which is associated with vascular izat ion, persistence of goblet cells in the corn ea (easily discern ible with PAS staining), poor epithelial adh esion and recurrent breakdown, and possibly chronic inflammation if the original traum a is severe. Intrao cular chemical penetration is often accompanied by cataract formation and secondary glaucoma; the latter is thought to result fro m damage to the outflow tract and co njunctival cicatr ization, which can affect outflO\v faci lity. In th e most severe cases,
ph thisis of the globe may occur. Colby KA. Chemical injuries of the eye. Focal Poillts: Clinical Modules for Ophthalmologists. San Francisco: American Academy of Ophthalmology; 2010, module 1.
Wagoner MD, Kenyon KR. Chemical injuries of the eye. In: Albert OM , Jakobiec FA, eds. Principles and Practice of Ophthalmology. 2nd ed. Vol 2. Philadelphia: Saunders; 2000:943- 959.
Acid Burns Acids denature and precipitate proteins in th e tissues they contact. Acidic solutions tend to cause less severe tiss ue damage than alkaline solutions because of the buffering capacity of tissues as well as the barrier to penetration formed by precipitated protein. Acids do not directly cause loss of th e proteoglycan ground substance in the cornea, although they too can in ci te severe inflam mat ion with secondary up· regulat ion in protease expression that can damage the corn eal matrix.
Management of Chemical Injuries Beyond the immed iate steps that need to be taken to minimize o ngoing exposu re to th e offending agent (see the following d iscussio n), there is no general consensus rega rdin g th e optimal management of chemical injur ies. Few clin ical trials have been perform ed in humans, and many of the c urrent recommendations fo r management are based on ani mal models of acute alkaline inju ry (Table 13-2). The most important step in the m anagement of chemical injuri es is immediate and copious irrigation of th e ocular surface with water or balanced saline solu tio n. If these liquids are not available, any other generally nontoxic and un polluted solutions (eg, carbonated beverages) can also be used to avoid delayi ng treatment. If possible, irrigation should be initiated at the site of the chemical inj ur y and continued until an ophthalmologist evaluates the patient. The eyelid should be im mobilized with a retractor o r eyelid speculum, and topical anesthetic sho uld be instilled. I rrigation may be accomplished using handheld int rave no us tubing, an irrigating eyelid speculum, or a Morgan medi -FLOW Lens (MorTan, Missoula, MT), a special scleral contact lens that connects to IV tubing. Irrigation should continue until th e pH of the conjunctival sac normali zes. T he conj un ctival pH can be checked easily with a urinary pH strip. If this is not available, it is better to "overtreat" for prolonged periods of irrigation than to "guess" that the pH has normalized. Because they can cont inue to release the tox ic chemical. particulate chemicals should be removed fro m the ocula r surface with cotton-tipped applicators and force ps. Eversio n of the upper eyelid sho ul,! be performed to search fo r materi al in the upper forni x (Fig 13-4).
Table 13-2 Management of Ocular Chemical Injuries Em ergent management Pain management Topical tetracaine Topical 2% lidocaine jelly Systemic analgesics Copious irrigation with 2- 3 liters of normal saline Morgan lens or by hand Removal of all particulate matter on the ocular surface Saline flush of fornices Gentle sweep of fornices with steril e Dacron swab Removal of adherent particles with jeweler's forceps Debridement of devitalized corneal epithelium Surgical sponge or Dacron swab Cyc loplegia Atropine l %/scopolamine 0.25% bid or homatropine 5% tid Control of lOP Mannitol 20% 1- 2 g/kg ideal body weight IV over 1-2 h Acetazolamide 5-10 mg/kg IV q 6-8 h Anterior chamber paracentesis Acute management (first 1-2 weeks) Antimicrobial therapy Pol ymyxin/bacitracin ointment q id or fourth-generation fluoroq uinolone qid Topical lubrication Preservative-free tears q 2 h Preservative-free ointment Ant i-inflammatory therapy Prednisolone acetate 1% qid to q 1 h for 7- 10 days with rapid taper thereafter Inhibitors of matrix metalloprotease (MMP) Doxycycline 50-100 mg PO bid Ascorbate 500-1000 mg q 12 h 10% sodium citrate qid (compounded) Cyc lop legia Atropine l %/scopolamine 0.25% bid or homatropine 5% tid Control of lOP Timolol 0.5% q 12 h Bri monidine 0.1 %-0.2% tid Dorzolamide/brinzolamide bid Di amox 250 mg PO q 12 h-q 6 h Methazolamide 25- 50 mg PO q 12 h Management of persistent epithe li al defect The rapeutic bandage contact lens Temporary lateral tarsorrhaphy Punctal occlusion Amn iotic membrane grafting fo r la rge, persistent epithelia l defects Chronic manag em ent (week 3 and beyond) Topical lubrication Preservative-free tears and ointment Anti-inflammatory therapy Id eally, corticosteroid use should be stopped or minimized Ant im icrobial therapy Continue qid and discontinue when suriace epithelium is intact Control intraocular pressure Inhibitors of matrix meta ll op rotease (MMP) Continue until suriace epithelium is intact Su rgical therapy Advancement of Tenon fascia limbal stem cell transplantation when inflammation is controlled Rotational tarsoconjunctival graft for scleral necrosis
CHAPTER 13: Clinical Aspects of Toxic and Trauma tic Inj uries of the Anterior Segment. 357
A
B
c
o
Figure 13·4 A, B, C, and D show steps in fashioning an eyelid retractor from a paper clip. E, Using the retractor for double eversion revea ls a foreign body on upper eyelid. (Courtesy of John
E_
_
E. Sutphin, MD.)
~.
The next phase of management should be directed at decreasing inflammation, monitoring lOP, limiting matrix degradation, and promoting reepithelialization of the cornea. An intense polymo rphonuclear (PMN) leukocyte infiltration of the corneal stroma has been noted in histologic sections of corneas subjected to acute alkali burns. PMNs may be a major source of proteolytic enzymes capable of dissolving corneal stromal collagen and ground substance. Corticosteroids are excellent inhibitors of PMN funct ion, and intensive topical corticosteroid administration is recommended for the acute phase (first 10-14 days) following chemical injuries. The dosage should be markedly reduced after 10-14 days, because corticosteroids can inhibit wound healing and pOSSibly exacerbate sterile stromal melting. Corticosteroids also increase the risk of secondary infection by means of inhibition of normal ocular surface imm une mechanisms; thus, their untoward side effects in the chronic phase may exceed the beneficial effects.
358 • External Disease and Cornea
A deficiency of calcium in the plasma membrane of PMNs inhibits their ability to degranulate, and both tetracycline and citric acid are potent chelators of extracellular calcium. Therefore, oral tetracyclines and topical 10% sodium citrate have theoretical benefits for inhibiting PMN-induced collagenolysis. In addition , topicall % medroxyprogesterone is effective in suppressing collagen breakdown. Topical cycloplegics are recom mended fo r patients with significant anterior chamber reaction. lOP is best controlled by use of oral carbonic anhydrase inhibitors in order to avoid toxicity from topical glaucoma medications. However, if the corneal epithelium is healing normally, topical therapies may be used as wel l. BeSe Section 10, Glaucoma, discusses medications for lOP control in depth. Measures to promote wound healing and in hibit collagenolytic activity may help prevent stromal ulceration. Severe alkali burns in rabbit eyes have been found to reduce aqueous humor ascorbate levels to one thi rd of normal levels. Redu ced aqueous humor ascorbate has been correlated with corneal stromal ulceration and perforation . SystemiC administration of ascorbic acid to rabbits with acute corneal alkaline injuries has restored the aqueous humor ascorbate level to normal and significantly reduced the incidence of ulceration. High-dose ascorbic acid is believed to promote collagen synthesis in the alkali-burned eye because ascorbic acid is requi red as a cofactor for this synthesis. There is cur rently no widely accepted standard fo r ad ministration of ascorbate to corneas after chemical injury, but one recommendation is for patients to receive 1-2 g of oral ascorbic acid (vitam in e) per day. However, because this therapy is potentially toxic to the kidneys, patients with compromised renal function are not good candidates for this approach. There are several strategies fo r promoting epithelial healing in acute and chronic chemical injury. Patients should be treated initially with intensive nonpreserved lubricants. Necrotic corneal epithelium should be debrided to minimi ze the release of in flammatory mediators produced by damaged epithelial cells and to promote reepithelialization. A bandage contact lens or temporary tarsorrhaphy may be beneficial for protecting ocular surface epithelium once it has begun to move onto the peripheral cornea. A tarsorrhaphy has the advantage of not increasing the risk of corneal infection, which is a concern with contact lens use in eyes with poor epithelium. Avascular sclera will usually not epithelialize until revascularization occurs. If scleral melting occurs, then a rotational tarsoconjunctival graft from the adjace nt eyelid can be performed to promote revascularization. Autologous conjunctival or limbal tra nsplants from a patient's uninvolved fellow eye may restore the integrity of the damaged corn eal epithelium. Am niotic membrane transplan tation may be helpful in suppressing inflammation and thereby promoting reepitheIialization and prevention of symblepharon formation. Limbal stem cell transplantation may be performed as soon as 2 weeks after chemical injury if no signs of corneal epithelialization have appeared. However, in general, the prognosis of limbal grafts is better when the eye is not very inflamed. Corneal transplantation is often delayed for years after a severe alkali injury to allow the surface inflammation to quiet down or until after the surface inflammation has qU ieted as a result of limbal stem cell grafting (ocular surface reconstruction). Even when there is no active inflammation in the ocular surface, stromal vascularization in the host bed is associated with a much higher risk of rejection in these keratoplasty cases. Keratoprosthesis surgery has also been used in eyes with a history of
CHAPTER 13:
Clinical Aspects of Toxic and Traumatic Injuries of the Anterior Segment . 359
chemical injury; as with other types of surgery in these eyes, the prognosis is best when the inflammation has been brought under control. Colby K. Chemical injuries of the cornea. Focal Points: Clinical Modules for Ophthalmologists. San Francisco: American Academy of Ophthalmology; 2010, module 1. Rao SK, Rajagopal R, Sitalakshmi G, Padmanabhan P. Limbal autografting: comparison of results in acute and ch ronic phases of ocular surface burns. Cornea. 1999;18(2): 164-171. Tejwani S, Kolari RS, Sangwan VS, Rao GN. Rol e of amniotic membrane graft for ocular chemical and thermal injuries. Cornea. 2007;26(1):2 1-26.
Toxic Keratocon'unctivitis From Medications A commonly encountered and freq uently unrecognized clinical problem is that of epithelial keratopathy secondary to topically app lied ocular medications. One of the most toxic ingredients in these preparations is the preservative, usually benzalkonium chloride. The corneal and conjunctival epithelium absorbs and retains preservatives. Residual amounts of preservatives are detectable in the epithelium days after a single topical application. Toxic effects on the epithelium include loss of microvillae, plasma membrane disruption, and subsequent cell death. Topical anesthetics have repeatedly been shown to be toxic if used for prolonged periods. Prolonged use can lead to frank epithelial loss, stromal edema, infiltration, and corneal opacities. However, sometimes even a single application of a topical anesthetic may cause transient epithelial irregularity. Med ical personnel with easy access to anesthetics are especially susceptible to this factitious disorder. Toxic conjunctivitis or keratoconjunctivitis may occur as a complication of exposure to various substances (Table 13-3). Topically applied ophthalmic medications can result in a dose-dependent cytotoxic effect on the ocular surface. The epithelium of the conjunctiva and cornea may show punctate sta in ing or erosive changes indicative of PATHOGENES IS
Table 13-3 Toxic Reactions Associated With Topical Ophthalmic Medications Toxic Keratoconjunctivitis
Toxic Follicular Conjunctivitis
Aminoglycosides Neomycin Gentamycin Tobramycin Antiviral agents Trifl uorothym id ine Antineoplastic agents Mitomycin C Topica l Anesthetics Propara caine Tetra caine Preservatives Benzalkonium chlo ride
Anti glau coma agents Miotics Pilocarp ine Carbachol Echothiophate iodide a-Agon ists Brimonid ine Apraclonidine Dipivefrin Epinephrine Cycl op legics Atropine Ho matropine
360 • External Disease an d Cornea
direct toxicity. A conjunctival reaction may be observed in the form of either a papillary reaction (vascular dilation) or a follicular response. An immune response can also produce sube pithelial corneal infiltrates. Although these reactions generally occur after long-term use (weeks to months) of a drug, they may take place sooner in individuals with delayed tear clearance from aqueous tear deficiency or tear drainage obstruction. Toxic reactions of the ocular surface can take different forms. A generalized injection of the tarsal and bulbar conjunctiva may be associated with a mild to severe papillary reaction of the tarsal conjunctiva, mucopurulent discharge, and punctate keratopathy. Occasionally, the discharge may be severe and mimic bacterial conjunctivitis. Infrequently, the reaction occurs in only 1 eye even though the medication has been applied to both. In its mildest form, toxic keratitis consists of punctate epithelial erosions of the inferior cornea. A diffuse punctate epitheliopathy, occasionally in a whorl pattern, may be observed in more severe cases. This pattern is sometimes called vortex or hurricane keratopathy. The most severe cases may involve a corneal epithelial defect of the inferior or central cornea, stromal opacification, and neovascularization. This severe typ e of corneal disease is seen with extensive damage to the limbal stem cells. A sign of limbal stem cell deficiency is effacement of the palisades ofVogt. Prolonged use of preservative-containing medications or administration of anti fibrotic agen ts (eg, topical mitomycin C drops, which have a radiomimetic effect on surrounding cells) may be the cause. Even when used in correct dosages for brief periods, mitomycin has been associated with prolonged, irreversible stem cell damage with resultant chronic keratopathy. Localized application of mitomycin using a cellulose surgical sponge to the surgical field (as in trabeculectomy or pterygium excision) is believed to incur a lower risk than more widespread topical administration and is the preferred method of antifibrotic therapy. A different type of toxic keratitis manifests as peripheral corneal infiltrates located in the epithelium and anterior stroma, leaving a clear zone behveen them and the limbus. Conjuncti val and/or corneal toxic reactions are typically seen following use of aminoglycoside antibiotics, antiviral agents, or medications preserved with benzalkonium chloride or thimerosal. Chronic follicular conjunctivitis is another manifestation of external ocular toxicity. Generally, the follicular reaction involves both the upper and lower palpebral conjunctivae, but the follicles are usually most prominent on the inferior tarsus and forn ix. Bulbar follicles are uncommon but highly suggestive of a toxic etiology when present (Fig 13-5). The medications most commonly associated with toxic follicular conjunctivitis include atropine, antiviral agents, miotics (particularly phospholine iodide), sulfonamides, epinephri ne (including dipivefrin), apraclonidine (Iopidine), u, -adrenergic agonists (eg, brimonidine ), and vasoconstrictors. Inferior punctate epithelial erosions may occasionally accompany toxic follicular conjunctivitis. With ongoing use of topical medications, the conjunctiva shows an increased num ber of chronic inflammatory cells and fibroblasts. Although any medication may potentially cause this low-grade in flamm atory response, it is most common with the chronic use of miotics for treatment 6f glaucoma. Asymptomatic subconjunctival fibrosis is not CLI NICA L PRESENTATI ON
CHAPTER 13:
Cl inica l Aspects of Toxic and Tra umati c Injuries of the Anterior Segment. 361
Drug-i nduced chronic fo llicular conjunctivitis induced by topical dipivefrin.
Figure 13-5
(Courtes y of James J Reidy, M D.)
uncommon with chronic topical drug use, but a small minority of affected patients will develop an insidiously progressive and more severe type of subconjunctival scarring that can lead to contraction of the conjunctival fo rnix, symblepharon formation, and corneal pannus format ion. This entity is called pseudopemphigoid, or drug-induced cicatricial pemphigoid. Treatment of toxicity requires discontinuation of the offending topical medications. Severe cases may take months to resolve completely; thus, the failure of symptoms and signs to resolve within a period of days to a few weeks is not inconsistent with a toxic etiol ogy. Patients who are experiencing Significant ocular irritation may find relief with nonpreserved topical lubricant drops or ointment. It is important to stress that toxic reactions to ocular medications can lead to irreversible changes, as may occur rarely with use of cholinergic (pilocarpine-like) and other medications. Pseudopemphigoid should be confirmed with a conjunctival biopsy, which often (but not always) demonstrates the characteristic diffuse, nonlinear immunofluorescent staining indicative of antibody deposition. Withdrawal of the medication is generally followed by a lag of weeks to months before progressive scarring can be stabilized. If clinical observation and photographic documentation demo nstrate clinical progression despite discontinuation of the medication, chemotherapy may be necessary (see Chapter 7).
MANAGE M ENT
Grant \'V M, Schuman IS. Toxicology of the Eye: Effects on the Eyes and Visual System from Chemicals, Drugs, Metals and Mi nerals, Plants, Toxins, and Venoms; Also, SystemiC Side Ef fects f rom Eye A1edications. 4th ed. Springfield, IL: Thomas; 1993. Liesegang T]. Conjunctival changes associated with glaucoma therapy: implications for the external disease consultant and the treatment of glaucoma. Cornea. 1998;17(6):574- 583.
Animal an d Plant Substances Insect Injuries Bee and wasp stings to the cornea and/o r conjunctiva are rare. Conjunctival hyperemia and chemosis usually occur acutely, sometimes associated with severe pain, corneal edema, and infiltration With subsequent decreased vision. The variability of the
362 • External Disease and Cornea
acute response is thought to reflect differences in the quantity of the venom injected and whether the reaction to the venom is primarily toxic or immunologic. In rare instances, other sequelae have been documented, includin g hyphema, lenticular opacities, iritis, secondary glaucoma, and heterochromia. Initial therapy with cycloplegics and topical, and occasionally systemic, corticosteroids has been beneficial. Removal of externalized stingers may be attempted. Afte r the acute episode, retained stingers may remain inert in the cornea for years. Caterpillar and tarantula hairs (urticating hairs) may also become embedded in the cornea and conjunctiva. These hairs are very fine and usually cannot be removed manually. Because of their str ucture, these urticating hairs tend to migrate more deeply into ocular tissues and elicit a localized granulomatous inflamm atory response (ophthalmia nodosum). Inflammatory sequelae usually respond to topical corticosteroids. Spraul CW, Wagner p, Lang GE, Lang GK. Ophthalmia nodosa caused by the hairs of the bird spider (family Theraphosidae) or hairy megalomorph (known in the US as tarantula): case report and review of the literature. Klin Monatsbl Augenheilkd. 2003;220(1-2):20-23.
Vegetation Injuries Ocular contact with the sap (latex) from a variety of trees can cause toxic reactions man ifested by acute keratoco njunctivi tis, epithelial defects, and stromal infiltration. The pencil tree and the manchineel tree, widely distributed in tropical regions, are known offenders. The dieffenbachia, which is a common houseplant, is known to cause keratoconjunctivitis and deposition of calcium oxalate crystals in the cornea. Corneal foreign bodies from coconut shell, sunfl ower stalk, and ornamental cactus have all been documented. Initial management for all such plant materials should include irrigation removal of fore ign bodies when possible and administration of topical cycloplegics with prophylactic ant ibiotic coverage, as indicated by the clinical situation. Corticosteroids are best avoided, as they suppress immunity to microbes in general and may promote fungal infection speCifically, which is of concern in all cases involvi ng vegetation matter. Surgical remova l of foreign bodies may be required in the setting of uncontrolled inflammatory response or associated secondary microbial infections. Cli nicians should be aware that plant sources are common causes of fungal keratitis. Hence, in a patient with a severe injury from plant sources or in cases that fai l to improve after supportive therapy, the possibility of infection should be entertained and appropriate workup (including culturing andlor biopsy) is indicated. For additional discussion of microbi al keratitis, see Chapters 4, 5, and 16.
Concussive Trauma Conjunctival Hemorrhage Blood under the conjunctiva creates a dramatic appearance that can alarm the patient. Most frequently, patients present with subconjunctival hemorrhage without a history of antecedent trauma. When trauma has occurred, damage to deeper structures of the eye
CHAPTER 13: Clinical Aspects of Toxic and Traumatic Injuries ofthe Anterior Segment. 363
must be ruled out. Subconjunctival hemorr hage is usually not assoc iated with an underl ying systemic disease and rarely has an identifiable cause. Occasionally, a history of vomiting , cough ing, or other form s of the Valsalva maneuver can be elicited. Most patients simply require reassurance that things are not as bad as they appear to be. However, if a patient suffe rs from repeated episodes of spontaneous subconjunctival hemorrhage or indicates the presence of a possible bleeding diathesis (easy bruising, frequent bloody noses), a careful medical evaluation may be warranted. Recurrent subconjunctival hemorrhages can be seen in association with systemic illness such as uncontrolled hypertension, di abetes mellitus, or a bleeding diathesis. No therapy is necessary for the hemorrhage, as it usually resolves in 7-12 days. Patients sho uld be warned that the hemorrhage might spread around the circumference of the globe before it resolves and that it may change in color fro m red to yellow durin g its dissolution.
Corneal Changes Blunt trauma to the cornea can result in ab rasions, edema, tears in Descemet's membrane, and corneoscleral lacerations, usually located at th e limbus. Traumatic posterior annular keratopathy or traumatic corneal endothelial rings have also been described. The rin gs, composed of disrupted and swollen endothelial cells, are whitish gray in appearance and occur directly posterior to the traumatic im pact. The endothelial rings ap pear within several hours of a contusive injury and usually d isappear within a few days.
Traumatic Mydriasis and Miosis Blunt injury to the globe may result in traum atic myd riasis or, less commonly, miosis. Traumatic mydrias is is often associated with iris sphincter tears that can permanently alter the shape of the pupil. Miosis tends to be associated with anterior chamber inflammation (traumatic iritis; see the follOWing section ). Pupillary reactivity may be sluggish in both situations. Cycloplegia is essential to prevent formation of posterior synech iae.
Traumatic Iritis Photophobia, tearing, and ocular pain may occur within the first 24 hou rs after injury. The in flammation of trau matic iritis is often assoc iated with diminished vision and perilimbal conjunctival injectio n. The anterior chamber reaction can be surprisingly min imal but is usuall y present if carefully sought. Treatment should consist of, at the very least, a topical cycloplegic agent to relieve patient discomfort. Topical corticosteroids may be used if Sign ificant inflammation is present and if compliance can be expected. Once the iritis has diminished, cycloplegia may be discontinued, and topical corticosteroids should be tapered off to prevent rebound iritis. See BCSC Section 9, i lltraocular Inflammation and Uveitis, for a more detailed discussion of uveitis. Rosenbaum JT, Tam maro J, Robertson JE Jr. Uve itis precipitated by nonpenetrati ng oc ular trauma. Am J Ophthalmol. 19?1 ;112(4j,392-395.
364 • Externa l Disease and Corn ea
Iridodialysis and Cyclodialysis Iridodialysis Blunt trauma maycause traumatic separation of the iris root from the ciliary body (Fig 13-6). Frequently, anteri or segment hemorrh age ensues, and the iridodialysis may not be recognized unt il the hyphema has cleared. A small iridodialysis requires no treatme nt. A large dialysis may cause polycoria and monocular diplopia, necessitating surgical repair. Cyclodialysis Traumatic cyclodialys is is characteri zed by a separation of the ciliary body fro m its attachment to the scleral spur, resulting in a cleft. Gonioscopicall y, this cleft appears at the junction of the scleral spur and the Ciliary body band. Sclera may be visible through the disrupted tissue. Ult raso und biomicroscopy is useful in identifying the location and extent of the cyclodialysis (Fig 13-7). A cyclodialysis cleft can cause increased uveoscleral outflow and aq ueous hyposecretion, leadin g to chronic hypotony and macular edema. If treatment with topical cycloplegics does no t suffice, closure may be attempted by using argon lase r, diat hermy, cryotherapy, or di rect suturing. If repai r is necessary, it should be done after the resolution of the hyphema.
Severe iridodia lysis resulting from blunt trauma. (Courtesy ofJames J. Reidy, MD.) Figure 13-6
Figure 13-7
Ultrasound biomicroscopy of cycl odia lysis.
(Courresy ofJames J. Reidy, MD.)
CHAPTER 13:
Clinical A!?pects of Toxic and Traumatic Inj uries of the Anter ior Segment. 365
Traumatic Hyphema Traumatic hyphema occurs most common ly in young males. It results from injury to the vessels o f the peripheral ir is or anterior ciliary body. Trauma causes posterio r displacement of the lens- iris diaphragm and scleral expansion in the equatorial zone, which leads to disruption of the maj or iris arterial circle, arterial branches of the ciliary body, andlor recurrent choroidal arteries and veins (Fig 13-8) . Anterior segment bleed ing can often be seen on penlight exam ination as a layeri ng of blood inferiorly in the anterior chamber (Fig 13-9). At other times, the bleeding is so subtle that it can be detected only as a few Circulating red blood cells on sli t-lamp examination (microscopic hyphema). At presentation, more than 50% ofhyphemas occupy less than one third of the height of the anterior chamber; fewer than 10% fill the whole chamber. The prognosis is good in patients who do not develop complications, but it is not dependent on the size of the hyphema itself. Even total, or "eight- ball;' hyphemas can resolve wi thout sequelae, unless secondary complications result (Fig 13-10). Hyphema is frequently associated with corneal abrasion, iritis, and mydriasis, as well as with significant injuries to th e angle structures, lens, posterior segment, and orbit. Spontaneous hyphema is much less com mon and should alert th e examiner to the possibility of rubeosis ir idis, clotting abnormalities, her petic disease, or intraocular lens (lOL) problems. Juven ile xa nthogranuloma, retinoblastoma, and leukem ia are associated with spontaneous hyphema in ch ildren.
Reb/eeding The maj or concern after a traumatic hyphema is rebleeding. Complications associated with secondary hemorrhage include glaucoma, optic atrophy, and corneal blood staining Force Dialysis of retina at vitreous base (ora serrata)
Hydraulic wedge
/
\ •
Vitreou s base fi rm ly attached
...
'----.i
Figure 13-8 Mechanism of hyphema and blunt force Injury to the eye. Blunt force applied to th e eye displaces the aqueous volume peripherally, causing an increase in hydraulic pressure at the lens, iris root, and trabecular meshwork. If this "wedge of pressure" exceeds the tensile strength of ocular structures, the vessels in the peripheral iris and face of the ciliary body may rupture, leading to hyphema . The force may cause scleral ruptures, typically at the lim bus and posterior to the muscle insertions, wh ere the sclera is t hinner and unsupported by the orb ital bones . Severe trauma leads to subluxation of the lens, retinal dialysis, opt ic nerve avulsion, and/or vitreous hemorrhage. (IIlusrra rion byCH Woole y.)
366 • Externa l Di sease and Cornea
Figure 13·9
Layered hyphema from blunt trau ma .
Figure 13·10
Total, or "e ight-ball," hy phe ma.
(Fig 13 -11). The rate of rebleeding reported in different studies va ri es; however, most studies report an incidence of less than 5%. Rebleeding may complicate any hyphema, regardless of size, and occurs most fre quently between 2 and 5 days after injury. The timi ng of the rebleeding may be related to the lysis and clot retraction that occur during this period. Numerous studies have docum ented the importance of rebleeding as a prognostic factor for poor visual outcome, ApprOXimately 50% of patients with rebleeding develop elevated lOP. The combination of elevated lOP, endothelial dysfunction, and anterior chamber blood predisposes the eye to corneal blood staining, which is difficult to detect whe n blood is in apposition to the endothelium. Red blood cells within the anterio r chamber release hemoglobin
CHAPTER 13:
Fi gure '3-"
Clinical Aspects of Toxic and Traumatic Injuries of the Anterior Segment. 367
Dense corneal blood staining after a traumat ic hyphema.
(Courte sy of Vincent
P.
deLuise, MD.)
that penetrates into the posterior corneal stroma, where it is absorbed by keratocytes. Hemoglobin is converted to hemosiderin within the keratocytes, which in turn causes keratocyte death. On slit-lamp examination, early blood staining is detected by yellow granular changes and reduced fibrillar defi nition in the posterior corneal stroma. Blood staining leads to a reduction in corneal transparency that may persist for years and can lead to the development of amblyopia in children. Histologically, red blood cells and their breakdown products can be seen with in the corneal stroma. Corneal blood staining often slowly clears in a centri petal pattern starting in the periphery.
Medical management The overall treatme nt plan for traumatic hyphema should be directed at minimizing the possibility of secondary hemorrhage. Elevated lOP may require treatment in order to reduce the chances of corneal blood staining and optic atrophy. Specifics of medical management remain controversial; however, most patients are treated with the followi ng: protective shield over the injured eye restriction of physical activity elevation of the head of the bed freque nt observatio n Analgesics that do not contain aspiri n should be used for pain relief, because aspirin has been demonstrated to increase the risk of rebleeding due to its antiplatelet effects. Nonsteroidal anti -inflammatory medications can also increase the risk of rebleeding. Hospitalization often facilitates daily examination and is necessary if satisfactory home care and outpatient observation cannot be ensured. Most ophthalmologists administer long-acting topical cycloplegic agents initially for comfort, to facilitate posterior segment evaluation, and to eliminate iris movement. Topical corticosteroids are benefiCial in controlling anterior chamber inflammation and
368 • External Disease and Corn ea
preventing synechiae for mation, and they may playa role in preventing rebleed ing. Oral cort icosteroids may be used to facilitate the resolution of severe inflammation and/or to prevent rebleeding. Topical antihype rtensives W-bloekers and a -agonists) are the mainstay of therapy, although occasionally intraveno us or oral hyperosmotic agents may be required. Prospective studies have supported the efficacy of antifibrinolytic agents (a minoeaproic acid [Am icar]; tranexamic acid; prednisone) in redu ci ng the incidence of rebleeding; however, these studies have failed to show an y statistical improvement in visual outcome. It is postulated that these agents in hibit fibrino lysis at the site of the injured blood vessel.. Significant side effects are associated with some of these agents, including nausea, vom iting, postural hypotens ion, muscle cramps, conjunctival suffusion, nasa l stuffiness, headache, rash, pruritus, dyspnea, toxic confusional states, and arrhythmias, as well as the risk of increased lOP on discontinuation. Patients on aminocaproic acid should be hospitalized; but patients using oral corticosteroids, which may also reduce the rate of rebleeding, may be treated as o utpatients. Ami nocaproic acid is used in an oral dosage of 50 mg/kg every 4 hou rs for 5 days (up to 30 g/day). Studies have suggested that a topical preparation containing 30% aminocaproic acid is equall y effective as systemic Amicar, with a much better side-effect profile. Unfortunately, a commercial preparation is not currentl y available. Evidence-based medical analysis would argue against the rout ine use of these agents due to potential adverse side effects, medical risks, cost, and lack of evidence for improved visual outcomes. Surgery Surgery (to evacuate blood) may be required to prevent irreversible corneal blood staining and optic atrophy from persistently elevated lO P. The timing of surgery is controversial, but surgery is ge nerally recom mended at the earl iest definitive detection of blood stain ing. Some authors suggest that surgery may be indicated if the lOP averages greater than 25 mm Hg for 5 days wit h a total hyp hema. Surgical intervention should be considered when the lOP is greater than 60 mm Hg despite maximal medical management for 2 days to prevent optic atrophy. Patients with preexisting optic nerve damage or hemoglobinopathies may require earlier interventio n. Table 13-4 has guidelines on surgical intervention. Surgical techniques are multi ple and varied. The Si mplest techn ique is paracentesis and anterior charnber irr igation with balanced salt solution. The goa l is to remove circu lating red blood cells that may obstruct the trabecular meshwork; removal of the entire clot is neither necessary nor wise. This procedure can be repea ted. If the patient is being treated with aminocaproic acid, then clot disso lut io n will not occur until the med ication is discontinued. Large lim bal incision techn iques with clot expression, if necessary, are best performed 4-7 days after the initial injury, when clot consolidation is at its peak. Automated cutting/aspiration instruments can be used to remove blood and debu lk clots through small incisions. Care must be taken to avoid damage to the iris and le ns, as well as the corneal endotheli um, when using automated cutting devices. In traocular dia thermy may also be used to control active intraoperative bleeding. Iris damage, lens injury, and additional bleed ing are the major complications of surgical interve ntion.
CHAPTER 13: Clinica l Aspects of Toxic and Traumatic Injuri es of the Anterior Segment. 369
Table 13-4
Guidelines for Surgical Intervention in Traumatic Hyphema To prevent optic at rophy lOP averages >60 mm Hg fo r 2 days lO P averages >35 mm Hg for 7 days To prevent corneal blood staining lOP averages >25 mm Hg for 5 days Evidence of early corneal blood staining To prevent peripheral anterior synechiae Total hyphema that pe rsists for 5 days Any hyphema fail ing to resolve to a volume of less than 50% by 8 days In hyphema patients with sickle hemog lobinopathies lOP averages 2:25 mm Hg for 24 hours lOP has repeated trans ient elevations >30 mm Hg for 2-4 days
Adapted with permission from Deutsch TA, Goldberg MF. Traumatic hyphema: medical and surgical management. Focal Points; Clinical Modules for Ophthalmologists. San Francisco: American Academy of Ophthalmology; 1984, module 5.
Sickle cell complications When an African-American patient develops a traumatic hyphema. a sickle cell workup should be performed to evaluate the patient for the possibility of sickle cell hemoglobinopathy. Sickle cell patients and carriers of the sickle cell trait are predisposed to sickling of red blood cells in the anterior chamber. Sickle cells are restricted in their outflow through the trabecular meshwork and may raise the lOP dramatically. In addition. the optic nerve appears to be at greater risk for damage in sickle cell patients. even with m odest lOP elevations (p resumably due to decreases in blood flow to the optic nerve ). All efforts must be made to normalize [OP in th ese patients. Carbonic anhydrase inhibitors and osmotic agents must be used with cautio n because of their tendency to reduce pH and lead to hemoconcentration. both of which may exacerbate sickling of red blood cells. Surgical intervention has been recommended if the average [OP remains 25 mm Hg or higher after the first 24 hours or after repeated. transient elevations greater than 30 mm Hg for 2-4 days. despite medical intervention. Campagna JA. Traumatic hyphema: current strategies. Focal Points: Clinical Modulesfor Oph-
thalmologists. San Francisco: American Academy of Ophthalmology; 2007, module 10. Walton W, Von Hagen S, Grigorian R, Zarbin M. Management of traumatic hyphema. Surv
Ophthalmol. 2002;47(4) ,297-334.
Nonperforating Mechanical Trauma Conjunctival Laceration In managing conjunctival lacerations associated with trauma, the physician must be certain that the deeper structures of the eye have not been damaged and that no foreign body is present. It is often useful to explore the limits of a conjunctival laceration using sterile forceps or cotton-tipped applicltors. The slit lamp is used following the instillation of a
370 • External Disease and Cornea
topical anestheti c. If any qu estion re mains as to whether the globe has been penetrated, cons id eration must be given to performing a peritomy in the operating room to better explore and exam ine the injured area. In general. conjunctival lacera tions do not need to be sutured.
Conjunctival Foreign Body Foreign bodies on th e conjunctiva l surface are best recogn ized with slit -lamp examinati on. Foreign bodies can lodge in the inferior cul -de-sac or can be located o n the conjunctival surface under th e upper eyelid (Fig 13-12). It is imperative to eve rl the upper eyelid to examine the super ior tarsal plate and eyelid margin in all patients with a histo ry th at suggests a foreign body. If several foreign bodies are suspected or particulate matter is present. doub le eversion of the eye lid with a Desma rres retracto r o r a bent papcrd ip is advised to allow the exam in er to effecti vely sea rch th e entire arc of the superior cui-dc -sac (see Fig 13-4). Following eve rsion of th e upper eyeli d, cop io us irrigatio n shou ld be used to clea nse the forni x. This procedure should th en be repeated us ing a Desmarres retractor for the upper and lower eyelids. Glass particles. cactus spin es. and insect hairs are often diffi cu lt to see, but a ca reful search of the cu l-de-sac wit h high magnificati on aid s in ident ifi cation and remova l. \I\'ith sli t- lamp mag nificat io n. the clin ician can gen tl y use a moistened co tton-tipped applicator to remove superfic ial fo reig n material. Occasionall y, salin e lavage of the cornea or cu l-de-sac washes o ut d eb ris that is not embedd ed in ti ssue. Whe n a patient co mplains of foreign-body sensati on, topical fluorescein should be instilled to check for thc fin e, lin ear. vertical corneal abras ions that are cha racteristic of retain ed foreign bodies on the eyelid margin or superior ta rsal plate. Foreign matter embedd ed in tissue is removed with a sterile, disposabl e hypoderm ic needle. Glass or particulate matter may be rem oved with a fine-tipped jeweler's forceps or blunt spatula. If a fore ign body is suspected but not seen, th e cul -de-sac sho uld be irrigated and wi ped wi th a moistened cotton-tipped applicator.
Figure 13·1 2
Foreign bodies seen on the
everted surface of the upper eyelid.
CHAPTER 13:
Clinical Aspects of Tox ic and Traumati c Injuries of the Anterior Segment. 371
Corneal Foreign Body Identifying the probable composition of a foreign body based on a detailed history is important due to the increased risk of infection associated \vith vegetable matter. Occult intraocular foreign bodies must be identified when there is a history of exposure to highspeed metallic foreign bodies, most commonly produced by high-speed grinding tools and metal-an-metal hammering. Corneal foreign bodies are identified most effectively during slit-lamp examination. Before removing the corneal foreign body, the clinician should assess the depth of corneal penetration. If anterior chamber extension is present or suspected, the foreign body should be removed in a sterile operating-room environment with sufficient microscopic magnification and coaxial illumination, adequate anesthesia, and appropriate instruments. Overly aggressive attempts to remove deeply embedded foreign bodies at the slit lamp may result in leakage of aqueous humor and collapse of the anterior chamber. If such a leak occurs and cannot be adequately tamponaded with a therapeutic bandage contact lens, tissue adhesive and/or urgent surgical repair is required. If several glass foreign bodies are present, all of the exposed fragments should be removed. Fragments that are deeply embedded in the cornea are often inert and can be left in place. Careful gonioscopic evaluation of the anterior chamber is essential to ensure that the iris and the angle are free of any retained glass particles. When an iron foreign body has been embedded in the cornea for more than a few hours, an orange-brown "rust ring" results (Fig 13-13). Corneal iron foreign bodies and rust rings can usually be removed at the slit lamp under topical anesthesia with a disposable (25- or 26-gauge) hypodermic needle, resulting in minimal tissue disruption. A battery-powered dental burr with a sterile tip may also be used; however, caution must be taken to cause minimal tissue disruption and thus minimize scar formation. A metallic foreign body that enters the corneal stroma beyond the Bowman layer always results in
Figure 13-13
Cornea l ru st rin g and multiple reta in ed iron foreign bodi es.
372 • Externa l Dis ea se and Cornea
some degree of scar formation. When they occur in the visual axis, th ese scars may result in glare and decreased visual acu ity from irregular astigmatism. Corneal perforation is a rare complication of foreign-body removal. Judicious decision making is mandatory; if multiple, very small foreign bodies are seen in the deep stroma (as may occur after an explosion) with no resultant inflammation or sign of infection, the patient may be monitored closely, because aggressive surgica l manipulation of the cornea in search of the very last particle may be unnecessary. Therapy following the removal of a corneal foreign body includes top ical antibiotics, cycloplegia, and occaSionally the application of a firm pressure patch or bandage contact lens to help the healing process. Close observatio n is usually indicated. If the residual corneal abrasion does not heal or if additional curettage is needed to remove a rust ring, cycloplegic and antibiotic drops are instilled before a new pressure patch is applied.
Corneal Abrasion Corneal abrasions are usually associated with im mediate pain, foreign-body sensation, tearing, and discomfort with blinking. Abrasions may be caused by contact with a finger, fingernail, fist, or even the edge of a piece of paper. The abrasion can also be caused by a propelled foreign body or by contact lens wear, because of either improper fit or excessive wear. OccaSionally, a patient may not recall a definite history of trauma but still present with signs and symptoms suggestive of a corneal abrasion. Herpes simplex virus keratitis m ust be excluded as a possible diagnosis in such cases. A slit -lamp examination is essential in determining the presence, extent, and depth of the corneal defect. It is very important to make a distinction between a "clean" corneal abrasion, which generally has sharp ly defined edges and little to no associated inflammation (when seen acutely), and a true corneal ulcer, which is characterized by an inflammation-mediated breakdown of the stromal matrix and possible th inning. Foreignbody sensation is an exceedingly specific localizing symptom for a corn eal epithel ial defect. It is important to evert the upper eyelid and examine the superior cul-de-sac to rule out a retained fore ign body. Patching is not necessary for most abrasions; many patients find patches uncomfortable. Abrasions may be managed with antib iotic ointment in combination with topical cycloplegia alone. Topical nonsteroidal anti-inflammatory agents have anesthetic properties and may be used for the first 24- 48 ho urs for pain relief in selected patients. In addition, oral pain management for the first 24- 48 hours can be helpful for many patients. Alternatively, a therapeutic contact lens in conjunction with antibiotic prophylaxis is also very effective, but this should be reserved for eye care professionals and patients being closely followed. Abrasions caused by organic material require closer follow -up to monitor fo r infection. Patients with contact lens- associated epithelial defects should never be patched because of the possibility of promoting a secondary infection. These patients should be treated with topical antibiotic drops or ointment.
Posttraumatic Recurrent Corneal Erosion A corneal abrasion can precipitate future recurrent corneal erosions. See Chapter 3 for a discussion of the pathogenesis, diagnosis, and treatment of recurrent corneal erosions.
CHAPTER 13:
Clinica l Aspects of Toxic and Trauma tic Injuries of the Anterior Segment. 373
Perforating Trauma It is important to differentiate a penetrating wound from a perforating wou nd. A penetrating wound passes into a structure; a perforating wound passes through a structure. For example, an object that passes through the cornea and lodges in the anterior chamber perforates the cornea but penetrates the eye.
Evaluation
History If a patient presents with both eye and systemic trauma, diagnosis and treatment of any life-threatening injury take precedence over evaluation and management of the ophthalmic injury. Once the patient is medically stable, the ophthal mologist should elicit a complete presurgical history (Table 13-5). Even though the diagnosis of perforating injury in many cases may be obvious from casual eye examination, a detailed history of the nature of the injury should include questions about factors known to predispose to ocular penetration so that this diagnosis will not be overlooked in more subtle cases. Such factors include metal-on-metal strike high-velocity proj ectile high -energy impact on globe sharp inj uring object lack of eye protection
Examination Evaluation of a patient with suspected perforating injury to the eye should include a complete general and ophthalmic examination. As soon as possible, the examiner should
Ta ble 13-5 Penetrating / Perforating Ocul ar Injury Hist ory Nature of inju ry Concomitant life-threatening injury Time and ci rcumstances of injury Suspected co mposition of intraocul ar foreign body (brass, copper, iron , vegetab le, soi l contaminatio n) Use of eye protectio n Prior treatment of injury Past oc ul ar hi story Refractive histo ry Eye diseases Current eye medications Previous surgery M edical history Diagnoses Current medications Drug allergies Risk factors for HIV/ hepatitis Currency of tetanu s prophylaxis Previous surge ry Recent food ingestion
374 • External Disease an d Cornea
determ ine visual acuity, which is the most rel iable predictor of final visual outcome in traumatized eyes, and perform a pupillary examination to detect the presence of an afferent pupillary defect (includin g a reverse Marcus Gunn response). Busy emergency room staff may omit these "ocular vital signs"; therefore, it is incumbent on the ophthalmologist to check both visual ac uity and pupils, as well as educate nonophthalmologic practitioners about the importance of these assessments. The ophthalmologist should then look for key signs that are suggestive or diagnostic of perforating ocular injury (Table 13-6). If a significant perforating injury is suspected, forced duction testing, go nioscopy, tonometry, and scleral depression should be avoided. Ancillary tests that may be useful in this setting are summarized in Table 13-7. Regardless of the results of laboratory tests, all cases should be managed with safeguards approp riate for patients known to have bloodborne infections (see un iversal precautions, Chapter 2).
Management
Preoperative management If surgical repair is required, the timing of the operation is crucial. Although studies have not documented any disadvantage in delaying the repai r of an open globe for up to
Table 13-6 Signs of Perforating Ocular Trauma Sug gestive
Diagnostic
Deep eyelid laceration Orbital che mos is Conjunctival lacerat ion/hemorrhage Focal iris- corneal adhesion Shallow ante rior chamber Iri s defect Hypotony Lens capsu le defect Acute lens opaci ty Retinal tear/ hemorrhage
Exposed uvea , vitreous, retina Posit ive Seidel test Vis ualization of intraocular forei gn body Intraocular foreig n body seen on x-ray or ultrasonog raphy
Table 13-7 Ancillary Tests in Perforating Eye Trauma Useful in many cases (to assess extent of injury and provide needed inform ation for preoperative assessment of patient) CT scan Plain-film x-rays (ge nerally not as useful as CT scans) CBC , differential, plate lets Electrolytes, blood urea nitrogen, creatinine Test for HIV status, he patiti s Useful in selected cases MRI (es pec ially in cases of suspected organ ic fo reign objects in the eye or orbit; this should never be used if a metall ic foreign object is suspected) Proth romb in time, partia l thromboplastin time, bleeding time Sick le ce ll Drug and/or ethanol levels
CHAPTER 13:
Clinical Aspects of Toxic and Traumatic Injuries ofthe Anterior Segment. 375
36 hours, intervention ideally should occur as soon as possible. Prompt repair can help minimize nUlllerous complications, including pain prolapse of intraocular structures suprachoroidal hemorrhage microbial contamination of the wound proliferation of the microbes projected into the eye migration of epithelium into the wound intraocular inflammation lens opacity
The following temporizing m eas ures can be taken during the preoperative period: Apply a protective shield. Avoid administering topical medications or other interventions that require prying open the eyelids. Keep the patient on NPO status. Provide appropriate medications for sedation and pain control, as well as antiemetics. Initiate intravenous antib iotics. Provide tetanus prophylaxis. Seek anesthesia consultation . Injuries associated with soil contamination and/or retained intraocular foreign bodies require attention to the risk of Bacillus endophthalmitis. Because this organism can destroy the eye within 24 hours, intravenous and/or intravitreal therapy with an antibiotic effective against Bacillus species, usually fluoroquinolon es (such as levofloxacin, moxifloxacin, gatifloxacin), clindamycin, or vancomycin , should be considered. Surgical repair should be undertaken with minimal delay in cases at risk for contamination with this organism.
Nonsurgical options Some penetrating injuries are so minimal that they spontaneously seal prior to ophthalmic examination, with no intraocular damage, prolapse, or adherence. These cases may require only systemic andlor topi cal antibiotic therapy along with close observation. If a corneal wound is leaking (see Chapter 2, Fig 2-6), but the chamber remains formed, the clinician can attempt to stop the leak with pharmacologic suppression of aqueous production (topical leg, ~-blockerl or systemic), patching, andlor a therapeutic contact lens. Generally, if these measures fail to seal the wound in 2- 3 days, surgical closure with sutures is recommended.
Surgical repair The eye can sustain severe internal damage with even a small, seemingly insignificant wound. The management of a typ ical corneoscleral laceration with uveal prolapse generally requires surgery (Fig 13-14). The primary goal of initial surgical repair of a corneoscleral laceration is to restore the integrity of the globe. The secondary goal, which may be accomplished at the time of the primary repair or during subsequent procedures, is to restore vision through repair of both external and internal damage to the eye.
376 • External D.isea se and Corn ea
Figure 13·14
Scleral laceration with prolapse of uveal tissue secondary to blunt trauma.
If the prognosis for vision in the injured eye is ho peless and the patient is at risk for sympathetic ophthalm ia. enucleation must be considered. Primary en ucleation should be performed onl y for an injury so devastati ng that restoration of th e anatomy is impossible, when it may spare the patient another procedure. In the overwhel ming majority of cases. however, the advantages of delaying enucleation for a few days far outweigh any adva ntage of primar y enucleation. This delay (which should not exceed the 12- 14 days thought necessary for an injured eye to incite sympath et ic ophthalmia) allows for assessment of postoperat ive visual funct ion, vitreoretinal or o phthalm ic plastic consultation , and stabiliza tion of the patient's medical condition. Most important, delay in enucleatio n following unsuccessful repair and loss of light perception allows the patient time to acknowledge that loss and accompanyi ng disfigurement and to cons ider enucleation in a nonemer· gency setting. Castiblanco CP, Adelma n RA. Sympathetic ophthalmia. Graefes Arch C/ill Exp Ophtha/mol. 2009;247(3) ;289- 302.
Anesthesia General anesthesia is almost always req ui red for repair of an open globe because retrobulbar or peribulbar anesthetic injection increases orbital pressure, wh ich may cause or exacerbate the extrusion of intraocular contents. After the surgical re pair is complete, a periocular anesthet ic injection may be used to control postoperat ive pain. Steps in the repair of a corneosclerallaceration All attempts at repairing a corneoscleral lace ration should be performed in the operating room with use of the operating microscope and trained ophthalmic personnel. Table 13-8 sum mar izes the basic steps in restoring the integrity of the globe with a corneosclera l laceration. No attempt should be made to fixate an open globe with rectus muscle sutures. Repair of adnexal injury should follow repair of the globe itself because eyelid surgery can put pressure on an open globe and certain eyeLid lacerations may actually improve globe ex posure.
CHAPTER 13:
Clinical Aspects of Toxic and Traumatic Injuries of the Anterior Segment.
377
Table 13-8 Essential Steps in Surgical Repair of a Corneoscleral Laceration 1. General anesth esi a 2. Excision of anteriorly prolapsed vitreous, lens fragm ents, co rnea l fo rei gn bodies 3. Reposi ti oning of an teriorly prolapsed uvea, retina 4. Closure of corneal component of lace ration at limbu s, landmarks 5. Completi on of w ate rti ght cornea l clos ure (10-0 nylon) 6. Peri tom y as necessary fo r exposure of sclera l compone nt 7. Stepwise excisi on of poste riorly prol apsed vitreou s 8. Stepwise repositioning of posteri orly prola psed uvea, retina 9. Stepw ise closure of sc leral comp onent (9-0 nylon or silk) 10. Conjunctiva l closu re 11. Subco njunctival an tibioti cs, corti costeroi ds
a-a
The corn eal component of the injury is approached fi rst. If vitreous or lens fragments have prolapsed through the wound, these should be cut flu sh with the cornea, taking care not to exert traction on the vitreous or zonular fibers. If uvea or retina (seen as translu cent, tan tissue with extremely fine vessels) protrudes, it should be reposited using a ge ntle sweeping technique through a separate Iimbal incision, with the assistance of viscoelastic injection to temporarily re-form the anterior chamber (Fig 13-1 5) . If epithelium has obviously migrated onto a uveal surface or into the wound, an effort should be made to peel this tissue off. Only in cases of frankl y necrotic uveal prolapse should uveal tissue be excised. Points at which the lace ration crosses landmarks such as the limbus are then closed with 9-0 or 10-0 nylon suture, followed by closure of the remaining corneal com ponents of the laceration. It may be necessary to reposit iris tissue repeatedly after each suture is placed to avoid ent rapment of iris in the wou nd. Despite these efforts, uvea may still remain apposed to the posterior corneal surface. Many surgeons place very shallow sutures at this stage of the closure to avoid impali ng uvea with the suture needle. Then, after the closure is watertight, the uvea can be definitively separated fro m the cornea with viscoelastic injection, followed by replacement of shallow sutures with new ones of ideal, near-full thickness depth. Suture knots should be buried in the corneal stroma, not in the wound. If watert igh t closure of the wound proves difficult to achieve because of unusual laceration configuration or loss of tissue, X-shaped or "purse-string" sutures or other customized techniques may suffice. Cyanoac rylate glue or even primary lamellar keratoplasty may be required in extremely difficult cases. A conjunctival flap should not be used to treat a wou nd leak. When the anatomy of the wound allows, a topographic closure is best for redu cing long-term complications. Wider-spaced, longer sutures are used in the peripheral cornea to flatten locall y and steepen centrally. Closer, shorter sutures are used centrally, avoiding the visual axis, to close the wound withou t excessive flattening (Fig 13-1 6); however, care should be taken that sutu res are long enough to minimize their "cheese wiring" through the inflamed stroma. The scleral component of the laceration is then approached with gentle peritomy and conjunctival separatio n only as necessar y to expose the wound. Prolapsed vitreous is
378 • Exte rna l p isease and Corn ea Viscoelastic Prolapsed iris
Weck-Gel lifting vitreous
Top view
vitreous
B
A Ang le of lacerat ion
Li mbUs ~
~
~ c
Epithel ial pigm ent li ne
Side view
Vertical incisions ten d to open, so close them first.
\ I'
_ ---'I I<-_ _ \[ Shelved lacerations tend to stay closed.
=:::z:= \[
D
Restoring anatomical relationships in co rneoscl eral lace ration repa ir. A , Prolapsed vitreou s or lens fragments are excised. B, Iri s is repos ited by means of viscoelastic and a cannu la inserted throug h a sepa rate paracentesis . C, Lan dmarks such as limbus, laceration angles, or epithe lial pigment lines are clos ed. Vertica l lacerations are closed f irst to create
Fi gure 13- 15
a wate rti ght globe more qu ickly, followed by shelved lacerations. D, The scleral part of the w ound is exposed, prolapsed vitreou s is severed, and the w ound is closed from th e limbus, w orking posteriorly. (Reproduced with permission from Hamill M8. Repair of the traumatized anterior segment. Focal Points: Cl inical Modules for Ophthalmologists. San Francisco: American Academy of Oph thalmology; 1992. mod-
ule 1. Illustrations by Christine Gralapp.)
excised) and prolapsed non necrotic uvea and retina are reposited with a spatula or similar instrument (Fig 13- 17) . The scleral wo und is closed with 9-0 nylon or 8-0 silk sutures. Often , dissection of Tenon capsule and management of prolapsed tissue m ust be repeated incrementally after each suture is placed.
CHAPTER 13:
Clinical Aspects of Toxic and Traumati c Injuri es of the Anterior Segment.
379
A Steepening effect
I
I
: :;
I : it
:
B
Flattening effect
Figure 13·16 Restoring functional architecture in corneal wound closure. A, Laceration has a flattening effect on the cornea. B, Long, compressive su tures are taken in the periphery to flatten the peripheral cornea and steepen the centra l cornea. Subsequently, short, minimally compressive sutures are taken in the steepened central cornea to preserve sphericity despite the flattening effect of the sutures. (Reproduced with permission from Hamill MS. Repair of the traumatized anterior segment. Focal Points: Clinical Modules for Ophthalmologists. San Francisco: American Academy of Ophthalmology; 1992, module 1,)
-!I-- - Cyclodialysis spatula
Figure 13·17 Zippering technique of scleral wound closure. Assistant depresses prolapsed uveal tissue while the scleral wound is progressively closed, moving in an anterior to posterior direction. (Redrawn from Hersh PS, Shingleton BJ, Kenyon KR. Management of comeoscleral lacerations . In: Hersh PS, Shingleton BJ, Kenyon KR, eds. Eye Trauma. Sf Louis: Mosby-Year Book; 1991
Some posterior wo unds are more easily approached with lou pes and a headlight, because the open globe should not be rotated too far. If the lace ration extends under an extraocular muscle, the muscle may be carefully removed at its insertion and reinserted
380 • Ext ern al Disea se and Cornea
following repa ir. Closure of the laceration should continue posteriorl y only to the point at which it becomes technically difficult or requires undue pressure on the globe. Very posterior lacerations benefit from effective physiologic tamponade by orbital tissue and are best left alo ne. Once the globe is watertight, a decision must be made whether intraocular surgery (if necessary) sho uld be attempted immed iately or postponed. Subconjunctival injections of antibiotics to cover both gram-positive and gram-negat ive organisms are given prophylactically at the conclusion of primary repair. Intravitreal antibiotics such as vancomycin 1 mg and ceftazidime 2.25 mg should be conside red for contaminated woun ds involving the vitreous. Essex RW, Vi Q, Charles PG, Allen PJ. Post-traumat ic endophthal mitis. Ophthalmology. 2004; 1l 1(lIPOlS- 2022.
Secondary repair of intraocular trauma Following prinlary repair of a corneosclerallaceration , the fol.lowing secondary measures may be indica ted: removal of intraocular foreign bodies (eg, using forceps or rare earth magnet) iris repair cataract extraction mechan ical vitrectomy IOL insertion cryotherapy of retinal tears Deciding whether to pursue such intervention at the time of ini tial repair is a complex process. The expertise of the surgeon; the quality of the facility, tech nical equipment, and instruments; the adequacy of the view of the anterior segment structures; and issues of informed consent should be considered. In ge ne ral, it is recommended that if there are concerns regarding any of these parameters, the surgeon complete the closure of the laceration to maintain globe integrity, and postpone the secondary procedures until a later date. For example, the average anterior segment surgeon should not attempt automated vit rectomy with retina present in the anterio r chamber, and even the most expert cataract su rgeon might not attempt a lens extraction wit h limited visualization of the lens. However, intraocu lar in flammat ion may worsen, opportunity for placement of an IOL in the capsular bag may be lost, vitreoretinal compLica tions may worsen, and the patient may experience increased pain and expense if these procedures are delayed. As always, the welfare of the patient should determine the proper course. In gene ral, if a fo reign body is visible in the anterior segment and can be grasped, it is reasonable to remove it, either through the wound or through a separate limbal incision. If removal of opaCified lens material is attempted, it is helpful to know whether the posterior capsule has been violated and lens- vitreous adm ixture has occurred. BCSC Section 11 , Lens and Cataract, also discusses the issues of cataract surgery and IOL placement followi ng trauma to the eye. Iris repair can be undertaken either priJllarily or secondarily. Closure of iris lacera tions may keep the iris in its proper pla ne, decreasi ng the forma tion of anterior or posterior synechiae. The McCannei technique, using 10-0 polypropylene suture with long
CHAPTER 13:
Clinical Aspects of Toxic and Tra umatic Injuries ofthe Anterior Segme nt . 381
needles that may be passed transcamerally, requires only a small additionallimbal incision be made (Fig 13-18). Iridodialysis, usually resulting from blunt trauma, may cause monocular diplopia and an eccentric pupil if left unt reated. The McCannel technique can also be used to repair an iridodialysis (Fig 13-19). In the event that corneal opacity prevents safe repair of internal ocular inj ury, repairs can be combined later with penetrating keratoplasty or with placement of a temporary keratoprosthesis, if posterior segment repair is planned.
Postoperative management After primary repair of penetrating anterior segment trauma, therapy is directed at preventing infection, suppressing inflammation, controlling lOP, and relieving pain. Systemic antibiotics (moxifloxacin 400 mg PO daily) are usually continued for 3-5 days, and topical antibiotics are generally used for about 7 days or until epithelial closure of the ocular surface is complete. Topical corticosteroids and cycloplegics are slowly tapered, depending on the degree of inflammation. A fibrin ous response in the anterior chamber may respond well to a short course of systemic prednisone.
The McCann el tec hnique for repairing iri s lacerations. With large lacerations, multi pl e su tures may be used . A, A limbal paracentesis is made over th e iri s discontinuity. Th en a long Drew s need le w ith 10-0 polypropyl ene is passed throu gh the peri phera l corn ea, the edges of the iris, and the periph eral cornea opposi te, and the sut ure is cut. 8 , A Sinskey hook, introduced t hrough th e paracentesis an d around th e suture peri pherally, is drawn back out throu gh t he pa racentesis. C, The suture is secu rely ti ed. 0, After the suture is secure, it is cut, and the iris is allowed to ret ract. (Reproduced with permission from Figure 13-18
A
B
Paracentesis
Hamill MB. Repair of the traumatized anterio r segment. Focal Points Clinical Modules for Ophthalmologi sts. San Francisco: American Academy of Ophthalmology; 1992, module 1. Illustrations by Christine Gralapp.)
D
382 • Externa l Disease and Corn ea
B Figure 13-19
Repair of iridodialysis. A , A cataract surgery-type incision is made at the site of iridodialysis or iris disinsertion. A double-armed, 10-0 polypropylene suture is passed through the iris root, out through the angl e, and ti ed on t he surface of the globe under a part ial-thickness scleral flap. The corneoscleral wound is then closed with 10-0 nylon sutures. B, In an alternative technique, multiple 10-0 Prolene sutures on double-armed Drews needles are passed through a paracentesis opposite the site of iris disinsertion to avoid the need to create a large corneoscleral entry wound. (Reproduced wIth permission from Hamill MB. Repair of the traumatized anterior segment. Focal Points: Clinical Modu les for Ophthalmologists San Francisco: American Academy of Ophthalmology; 1992, module 1. Illustrations by Christine Gralapp.)
Corneal sutures that do not loosen spontaneously are generally left in place for at least 3 months and then removed incrementall y over the next few months. Fibrosis and vascularization are indicators that enough healing has occurred to render suture removal safe. Applying fluorescei n at each postoperati ve visit is mandatory to ensure that sutu re erosion through the epithelium has not occurred, as these eroded sutures can induce infection. Traumatized eyes are also at increased risk of retinal detachment, so frequent examination of the posterior segment is mandatory. If media opacity precludes an adequate fundus exam ination, evaluation for an afferent pupillary defect and B-scan ultrasonography are helpful in monitori ng retinal status, Refraction and correction with contact lenses or spectacles can proceed when the ocular surface and media permit. Because of the risk of amblyopia in a child or loss of fusion in an ad ult, visual correction should not be unnecessarily delayed. Barr Cc. Prognostic factors in corneoscleral lacerations. Arch Ophthalmol. 1983;101(6 ): 919-924. Brightbill FS, ed. Corneal Surgery: Theory, Technique, and Tissue. 4th ed. Philadelphia: Elsevierl Mosby; 2009. Spoor TC. An Atlas of Ophthalm ic Traul1Ia. St Louis: Mosby-Year Book; 1997.
Surgical Trauma Corneal Epithelial Changes From Intraocular Surgery The corneal epitheli um fu nctions as a barrier to corneal absorption of fluid from tears. including medication instilled topicall y and pathogens residing on the ocular surface.
CHAPTER 13:
Clinical Aspects of Toxic and Traumatic Injuries of the Anterior Segment. 383
Breakdown of the epithelial barrier function, resulting in epithelial edema and stromal swelling, can follow inadvertent intraoperative trauma to the epithelium by surgical instruments desiccation of the epithelium through inadequate intraoperative hydration toxic keratopathy resulting from excessive preoperative instillation of topical ophthamic preparations (and their preservatives) accidental instillation of preoperative periocular facial scrub detergents
Although epithelial damage allows fluid to reach the stroma, it is resisted by the lOP and pumped out by the endothelium. Thus, endothelial damage has a far greater effect on corneal edema than does epithelial damage. Intraoperative damage to the corneal endothelium and/or Descemet's membrane can result in a positive stromal fluid pressure and subsequent epithelial edema. Epithelial edema begins in the basal cell layers of the epithelium and spreads through the epithelium, occasionally resulting in subepithelial bullae. With epithelial edema, this layer loses its homogeneity, and the corneal surface becomes irregular, leading to symptoms of glare, photophobia, and halos around lights from light scattering. In bright light, edematous epithelium causes enhanced light scaltering and can have a marked effect on vision. Surface irregularities caused by epithelial edema are more damaging to vision than stromal edema or scarring. The influence of epithelial surface irregularities on visual acuity is often underestimated, \vhereas the role of stromal scarring and edema is overestimated.
Descemet's Membrane Changes During Intraocular Surgery The distensibility of Descemet's membrane allows stretching or distortion, followed by return to its original shape. When the stroma imbibes fluid and thickens, the increased volume is distributed posteriorly, producing bowing and folding of Descemet's membrane (striate keratopathy). Detachment of Descernet's membrane can occur when an instrument or IOL is introduced through the surgical incision or when fluid is inadvertently injected between the membrane and the corneal stroma, resulting in stromal s\velling and epithelial bullae localized in the area of detachment (Fig 13 -20). Particular care should be taken when clear corneal incisions are enlarged prior to lens implantation during cataract surgery, because Descemet's membrane can be eaSily stripped off the stroma during re introduction of the keratome through the incision during this step. The membrane can be reattached with air tamponade. Recurrence may require suturing after repositioning Descemet's membrane in its native position.
Corneal Endothelial Changes From Intraocular Surgery Normal functioning of the corneal endothelium is highly pertinent to retaining normal stromal and epithelial hydration. Corneal hydration involves the following factors: stromal swelling pressure barrier function of the epithelium and endothelium the endothelial pump evaporation from the corneal surface lOP
384 • External Disease and Cornea
Figure 13·20 Traumatic detachment of Descemet's membrane following cataract extraction accompanied by secondary corneal edema. (CourtesyofJamesJ. Reidy, MO.)
Corneal edema following surgical procedures often has many causes; these are related to the health of the patient's endothelium, as well as to iatrogenic factors such as su rgical technique, duration of surgery, and in traocular irrigating soluti ons. Patients with underly-
ing corneal endothelial dysfunction such as Fuchs corneal dystrophy are at risk to develop postoperative corneal edema, even afte r uncomplicated surgery.
Cataract surgery and 10L implantation Pseudophakic bullous edema is a leading indication for corneal transplantation, underscoring how surgical trauma can have profound consequences for the health of the endothelium. Manipulation of instru ments in the eye t'hrough a limbal or clear corneal incision during cataract surgery can impair th e funct ional reserve of an already partially
compromised endothelium (as in Fuchs dystroph y), leading to localized edema at the site. During phacoemulsification, heat transferred fro m the probe to the cornea (" phaco burn") can result in stromal shrinkage, persistent wound leaks, and thinning. A wound that is too tight to allow adequate irrigation fluid flow through the probe or the occlusion of irrigation or aspiration tubing can cause such heat transfer. Closu re and repair of phaco burns can be complicated; therefore, every effort should be made to avoid them. The ultrasonic energy of a phaco tip held too close to corneal endothelium during surgery can injure endothelial cells and lead to their loss. Corneal edema in these cases may appear on the first postoperative day or mo nths to years after surgery. Uncomplicated intracapsular cata ract extraction or complicated extracapsular cataract extraction may res ult in vit reous to uch to th e corneal endothelium. Persistent corneal
edema can occur in the region of vitreocorneal ad herence either early or late. Early recognition and treatment with anterior vitrectomy as soon as corneal edema develops can help
prevent irreversible corneal edema. Mo re advanced cases with prolonged corneal edema may requ ire endothelial or penetrating keratoplasty combined with vitrectomy. Current irrigating solutions are superior to those used in the past. Theyare pH-balanced with bicarbonate buffers, have no epinephrine, and contain glutathione. Endothelial cell
CHAPTER 13:
Clinica l Aspects of To xic and Traum atic Injuries ofthe Anterior Segment. 385
loss rates of 8% or less have been reported in multiple series. Preserved solutions either irrigated or inadvertently injected into the anterior chamber can be toxic to the corneal endothelium and cause temporary or permanent corneal edema. Subconjunctival antibiotic injections have been reported to enter the anterior chamber through scleral tunnel incisions or, potentially, by reversing flow throu gh the aqueous outflow tracts. The presence of iris-fixated or closed-loop flexible anterior chamber IOLs has historically been associated with significant chronic corneal edema and development of pseudophakic bullous keratopathy. Subsequent development of bullous keratopathy often results in reduced visual acuity, chronic foreign -body sensation, photophobia, and epiphora, and predisposes to the development of infectious keratitis.
Laser burns Endothelial damage occurs following argon laser procedures as a result of the thermal effects of iris photocoagulatio n. Endothel ial burns are usually dense white with sharp margins; they may result in focal endothelial cell loss. Increases in mean endothelial cell size and endothelial cell loss associated with the use of greater laser power have also been reported. In follow-up periods of up to 1 year, endothelial cell loss following laser iridectomy has not been found to be statistically significant, however.
Conjunctival and Corneal Changes From Extraocular Su rgery Conjunctival chemosis with prolapse may result from orbital surgery or trauma. Exposed conjunctiva should generally not be excised but rather repos ited and ke pt in place with patching or, if recurrent, mattress sutures. Orbital surger y and trauma can cause pro ptosis of the globe, leadi ng to exposure keratopathy. Therapy includes lubricants, eyelid patching or taping, moist-chamber dressings, and temporary tarsorrhaphy.
CHAPTER
14
Surgery of the Ocular Surface Introduction The term ocular surface describes the entire epi thelial surface of the external eye, encompassing th e corneal epithelium as well as the bulbar and palpeb ral conjunctival epith elium. Moreover, this term stresses the interdependence of the corn eal and conjun ctival epithelia in maintai nin g th e hea lth of the external eye. Initiall y, the ocular surface was considered as an a natom ical classification based solely on th e phys ical continuity of the stratified nonkeratini zing epithel iu m of th e conjunctiva, lim bus, and corn ea. More recently, clinical and resea rch insights have offered compelli ng evidence of important fun ctional relationsh ips with in this anatomical entity. T h is rethi nki ng of the ocular sur face as a functional unit has stim ulated a complete reorgan ization of th e cu rrent approach to the manageme nt of ocu lar surfa ce d isease (Table 14-1).
Corneal and Con junctival Epithelial Wound Healing Observatio ns of the norma l re place ment p rocess of corneal epitheliu m provid e va luable inSights into the rationale for va ri ous oc ular su rface replacement techniques. Nu merous stud ies have demonstrated that central corneal epith elial mass is main tained by continued Table 14-1 Indications for Ocular Surface Reconstruction Conjunctival Autograft
limbal Autog raft or Allograft*
Recu rrent pterygium Cicatricia l st rabis mus (b il atera l) Forn ix reco nstru ction (uni lateral) Postexcision of co njunctival tumor Symb le pharon repa ir
Che mical inju ry Therm al bu rn Contact lens ke ratopathy Persistent epithelial defect (various etio log ies) Post-m ultiple surgery limbal dep letion Chro nic medicati on tox icity Stevens-Johnson syndrome Ocu lar ci catricial pemph igo id Ani ridi a Atopy
Amniotict or Mucous Membrane Transplantation Fornix reconstruct ion (bilateral) Chem ical injury:!: Immune me lts Pte rygium surgery Stevens-Johnson syndrome Ocu lar cicat ricial pemphigiod
* Limbal autograft preferable in unilateral or asymm etric cases; limbal allograft reserved for bi lateral cases. tMay be used in con junction with l i ~ bal autograft or allograft. t lndicated for fornix reconstruction after cicatricizati on.
387
388 • External ,Disease and Cornea
centripetal movement of peripheral corn eal epithelium toward the visual axis, as well as by anterior movement from the basal epithelial cells. (The mechanisms of wound healing of the corn eal stroma and sclera are covered in BCSC Section 4, Ophthalmic Path ology and Intraocular Tumors.)
Role of Stem Cells Because the corneal epithelium is a highly di fferentiated cell type that is self-renewing, its stem cells are essential for epithelial replacement and migration. It is believed that the limbal basal layer contains the stem cells of the corneal epithelium that normally repopulate the corneal su rface. After severe injuries, this normal process is augmen ted appreCiably in eyes that have a normal reservoir of fun ct ioning stem cells. When there is concurrent damage to the limbal stem cells, the conjunctival cells also become involved in repopulating the corneal surface. However, th is is a pathologic process often associated with vascularization, su rface irregularity, and poor epithelial adhesion.
Conjunctival Epithelium Healthy conj unctival epithelium has the abi lity to directly replace damaged corneal epithelium, but, as noted in the preceding section, conjunctival epithelial cells cannot completely restore the func tion of the corneal epithelium because the y do not have the pluripotency of limbal stem cells and cannot differentiate into the corneal phenotype. Followi ng complete traumatic loss of corneal and limbal epithelium, the remaining conju nctival epithelium resu rfaces the corneal epithelium by an adva ncing wave of adjacent conjunctiva. Some of these cells demonstrate morphologic changes, but they do not acquire all the biochemical markers of mature corneal epithelia. It was long believed that conjunctival cells retained the capacity for phenotypic change into corneal epithelium, but we now know this is not the case. The absolute necessity of repopulating the corneal surface epitheliu m with stem cells forms the rationale for syngeneic or allogeneic limbal stem cell transplantation .
Maintenance of the Ocular Surface and Its Response to Wound Healing In the mechanically abraded cornea (eg, total epithelial debridement during vit rectomy surgery or follOWing photorefractive keratectomy), reepithelialization and restoration of a relatively normal corneal surface usually occur quickly. In eyes that have suffered severe chemical injury, however, where the insult is to a wide array of cells (corn eal, limbal, and conjunctival), the process of cell migration and differentiation may become defective. Consequently, the wave of cells that repopul ate the corneal surface often maintains conjunctival characteristics, with variable goblet cells and neovascularizatio n. Based on these observations, autologous conjunctival transplantation has limited value in repopulating the corneal surface unless associated limbal cells are also harvested for grafting. However, conjunctival grafting can be successful in suppressing inflammation and scarring in the trau matized conjunctiva, and thereby providing (indirectly) more support for the proliferating corneal cells. The success of th is procedure is contingent on procurement of normal or near-normal donor tissue.
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Surgery of the Ocular Surface.
389
If the goal of surgery is to restore a more functional conjunctival mucosal surface, as in bilateral conjunctival cicatricial disorders or in severe epitheliopathy in keratoconjunctivi ~ tis sicca (eg, Sjogren syndrome), then a buccal mucosal graft or amniotic membrane transplant may be employed. Such grafts can restore more normal forniceal architecture and reduce ocular surface inflammation and corneal damage resulting from abnormal eyelidglobe relationships (eg, entropion, trichiasis), chro nic exposure (lagophthalmos), and direct corneal trauma (palpebral conjunctival keratinization). In advanced cases of mucosal (conjunctival) disease, complications caused by recurrent corneal epithelial breakdown, secondary infectious keratitis, vasc ularization, and scarring may lead to corneal blindness. Mucosal membrane grafting is not, however, by itself effective in repopulating the cornea with normal cells. Rather, its contribution to the health of the corneal surface is indirect: it improves ocular surface wetting by narrowing the palpebral fissure, thereby reducing exposure and evaporation, and it enhances eyelid movement and distribution of the tear film over the cornea and may contribute to mucus formation from the trans ~ planted tissue. Preserved amniotic memb rane is another tissue that can be used for ocular surface reconstruction, either by itself, to prevent further stromal degradation, or in conjunction with a Iimbal autograft or allograft, to repopulate the corneal stem cells. More recently, stem cell expansion by means of cell culture has proven an effective means of cell surface repopulation. Corneal stem cells have been used for this purpose; however, the long-term survival of these grafts remains uncertain. The use of cultured epithelial stem cells present in the oral mucosa to repopulate the corneal surface has also recently been successful and may hold greater promise for ocular surface reconstruction in a severely damaged eye. At the present time, these approaches are experimental and available in few centers worldwide. Kinoshita S, Koizumi N, Sotozono C, Yamada J, Nakamura T, Inatomi T. Concept and clinical application of cultivated epithelial transplantation for ocular surface disorders. Ocul Surf 2004;2(1),21 - 33. Tseng SCG, Tsubota K Amniotic membrane transplantation for ocular surface reconstruction. In: Holland E], Mannis M], eds. Ocular Surface Disease: Medical and Surgical Management. New York: Springer-Verlag; 2002:226- 23 l.
Surgical Procedures of the Ocular Surface This section covers some of the common surgeries performed on the ocular surface, as well as nonsurgical techniques such as the use of bandage contact lenses and cyanoacrylate adhesives. Chapters 15 and 16 of this volu me discuss corneal transplantation, and BCSC Section 13, Refractive Surgery, covers refractive surgery. Conjunctival Biopsy
Indications A conjunctival biopsy can be helpful in evaluating chronic conjunctivitis and unusual ocular surface diseases, including the following: , squamous lesions of the conjunctiva (eg, conjunctival intra epithelial neoplasia) cicatrizing conjunctivitis
390 • External Disease and Cornea
• conjunctival lymphoid tumors lichen planus pemphigus vulgaris graft ~vs - host disease superior limbic keratoconjunctivitis
Surgical technique After a topical anesthetic agent is administered, a pledget wet with proparacaine or similar agent is applied to the lesion or site for approximately 30 seconds. Subconjunctival anesthesia can also be given but is usually unnecessary. A drop of topical phenylephrine can blanch the conjunctival vessels and reduce bleeding. The surgeon uses forceps and scissors to snip a conjunctival specimen. Lesions are completely excised (excisional biopsy), if possible. For a subepithelial lesion , a wedge or block is excised. Tissue crushing must be minimized by grasping only the edge of the biopsy specimen. Gentle cauterization can be used to facilitate hemostasis; however, it is best to cauterize after excision to minimize burning of the specimen, which severely hinders histologic evaluation.
Tissue processing The sample is pJaced in the proper anato mical orientation on a carrier template (eg, filter paper) and inserted into the appropriate fixative, such as formalin (for histology), glutaraldehyde (for electron microscopy), or transport media (Zeus or Michel's) for imm unofluorescence microscopy. Preferred Practice Patterns Committee, Cornea/External Disease Panel. Conjunctivitis. San Francisco: American Academy of Ophthalmology; 2008.
Tarsorrhaphy Tarsorrhaphy is the surgical fusion of the upper and lower eyelid margins. It is one of the safest and most effective procedures fo r healing difficult -to-treat corneal lesions. Tarsor rhaphy is most commonly performed to protect the cornea from exposure caused by inadequate eyelid coverage, as may occur in Graves disease or facial nerve (CN VII) dysfunctions such as Bell palsy. It can also be used to ai d in the healing of indolent corneal ulceration sometimes seen with tear-fil m deficiency, herpes simplex or zoster, stem cell dysfunction, or CN V dysfunction (neurotrophic lesions). Tarsorrhaphies may be tem porary or permanent; in the latter case, raw tarsal edges are created to form a lasting adhesion. They may be total or partial, depending on whether all or only a portion of the palpebral fissure is occluded. Tarsorrhaphies are also classified as lateral, medial, or central' according to the position in the palpebral fissure. BCSC Section 7, Orbit, Eyelids, and Lacrimal System, discusses eyelid anatomy and surgical procedures in detail. Note that the cosmetic effect of a lateral tarsorrhaphy is significant, and patients are often unhappy with the appearance afterward.
Postoperative care Antibiotic ointment is usually applied to the wound twice a day for the first 5 days. If anterior lamellar sutures are used over a pledget, ointment is applied until the sutures are
CHAPTER 14:
Surgery of the Ocular Surface. 391
removed 2 weeks later. Ointment containing corticosteroids should be avoided, because corticosteroids may interfere with rapid healing. A tarsorrhaphy can be released un der local anesthesia. A muscle hook is placed under the tissue, and a blade is used to incise the ta rsorrh aphy adhesion parallel to the upper and lower eyelid margins. Iris scissors can also be used to cut along the margin. If the status of the corneal exposure is uncertain, the tarsorrhaphy can be opened in stages, a few millimeters at a time. If the tarsorrhaphy has been performed properly, eyelid margin deformity will be minimal.
Alternatives to tarsorrhaphy Other therapeutic modalities can help protect the integrity of the ocular surface. Injection of botulinum toxin type A (Botox) into the levator palpebrae muscle, to paralyze the levator muscle, can cause pharmacologic ptosis and provide a temporary protective effecl. Applying cyanoacrylate tissue adhesive (discussed later in this chapter) to the eyelid margins may also provide temporary closure of the eyelids for therapeutic purposes. Plastic eyelid splints (Stamler lid splint; Eagle Vision, Memphis, Tennessee) may be placed on the upper eyelid to cause complete closure. If kept dry, these splints may last for a week or more. Tape may also be used for this purpose, but tape rarely lasts for more than 24 hours. As a temporary measure, moisture chambers may be used to protect the ocular surface. These are available commercially or may be constructed with plastic wrap.
Pterygium Excision A pterygium is an abnormal overgrowth of conjunctiva onto the cornea, almost always in the palpebral fissure (see Chapter 12). Indications for pterygium excision include persistent discomfort, vision distortion, significant (>3-4 mm) and progressive growth toward the corneal center/visual axis, and restricted ocular motility. The aim of microsurgical excision of a pterygium is to achieve a normal, topographically smooth ocular surface. A common surgical technique is to remove the pterygium using a flat blade to dissect a smooth plane toward the limbus. Although it is preferable to dissect down to bare sclera at the limbus, it is not necessary to dissect excessive Tenon tissue medially, as th is can sometimes lead to bleeding and later scarring from inadvertent trauma to subjacent muscle tissue and muscle check ligaments. After excision, light cautery is usually applied to the sclera fo r hemostasis. Options for wound closure include (Fig 14-1)
Bare sclera. No sutures or fine, absorbable sutures are used to appose the conjunctiva to the superficial sclera in front of the rectus tendon insertion, leaving an area of exposed sclera. (Note that this techn ique has an unacceptably high recurrence rate of 40%-75% and is thus not recommended.) Simple closure. The free edges ofthe conj unctiva are secured together (effective only when the conjunctival defect is very small). Sliding flap. An L-shaped incision is made adjacent to the wound to allow a conjunctival flap to slide into place.
392 • Ext ernal Disease and Cornea
A
IJ
B
c
o
E
Figure 14·' Surgical wound closu res following pterygium excision . A, Ba re scl era, although sutures can be placed to tack down conjunctival wound edges. B, Simple closure with fine, absorbable sutures. C, Sliding flap t hat is closed with interrupted and/or runn ing suture. D, Rotat ional flap from the superior bulbar conjunctiva. E, Conjunctival autograft that is secured with interrupted and/or running 'suture. (Reproduced with permission from Gans LA. Surgical treatment of pterygium. Focal POintS: Clinical Modules for Ophthalmologists. San Francisco. American Academy of Ophrhalmology; 1996, module 12. lI1usrration by Christine Gralapp.)
CHAPTER 14:
Surge ry of the Ocular Surface .
393
Rotational flap. A U ·shaped incision is made adjacent to the wound to form a tongue of conjunctiva that is rotated into place. Conjunctival graft. A free graft, usually from the superior bulbar conjunctiva, is excised to correspond to the size of the wound and is then moved and either sutured into place or fIxated with a tissue adhesive (eg, Tisseel VH; Baxter Healthcare, Deerfield, Illinois). This tech nique is described in more detail in the next section. Amniotic membrane. A free amniotic membrane graft has been shown to be a reasonable alternative to conjunctival autograft, particularly when there is a shortage of autologous conjunctiva. Results have generally been reported to be comparable to those of conjunctival auto grafts. These grafts may be most useful with large pterygia, where a wide excision is needed.
Conjunctival Transplantation
Conjunctival autograft transplantation (see Table 14·1) is appropriate only in cases in which conjunctival inflammation, scarring, or loss is not complicated by extensive damage or destruction of the limbal epithelial stem cells. This technique is essentially a con· junctival free graft deSigned to replace a focal or localized defect in the conjunctiva (eg, after pterygium excision) relieve the restriction of extraocular muscle movement caused by scarring of conjunctival and Tenon tissue (after pterygium removal, strabismus surgery, or bulbar tumor excision) eliminate problems of conjunctival fo rnix scarring Conjunctival transplantation for pterygium The most common indication for conjunctival transplantation is advanced primary and recurrent pterygium. This tech nique red uces the risk of pterygium recurrence to approxi mately 3%-5% and ameliorates the restriction of extraocular muscle function sometimes encountered after pterygium excision. Because the superior bulbar conjunctiva is usually normal and undamaged due to reduced exposure to ultraviolet light and chemical irritants, conjunctival autograft tissue can be obtained from this area in the same eye. Various techniques of conjunctival transplantation have been used to manage pterygium. The procedure is performed on an outpatient basis, using topical plus peribulbar or retrobulbar anesthetic, especially in recurrent cases complicated by scarring. A traction suture (eg, 6·0 on a spatulated needle) placed at the 12 o'clock position, which can then be clamped down in various positions to the surgical drape, facilitates maximal exposure of the pterygium and the graft site. The pterygium is usually excised with a #57 blade or an angled crescent blade. It is important to remove as much of the fibrovascular scar tissue as possible. If the medial rectus muscle is restricted, it must be isolated, preserved, and care· fully freed of all scar tissue. A smooth surface at the site of dissection is a desirable end· point. With the eye in abduction, the size of the defect is measured with calipers. It is best to allow a little extra tissue for grafting, so the harvested tissue should be approximately 0.5-1.0 mm la rger than the size of the defect. The eye is then turned dOW!l to expose the superior bulbar conjunctiva, and the area to be harvested is marked with multiple focal cautery spots or with a surgical pen. The most
394 • Externa l Di sease and Cornea
important aspect of the harvesting is to procure conjunctival tissue with only minimal or no Tenon included. This may be facil ita ted by injecting a small amoun t of anesthetic between the conjunctiva and Tenon fascia. Some surgeons make a special point of harvesting limbal stem cells along with the conjunctiva and orienting the donor mate rial in the host bed so that the stem cells are adjacent to the site of corneal lesion excision. The donor site is usually left bare. After the graft is freed, it is transferred to the recipient bed and secured to adjacent conjun ctiva (with or without incorporating episclera) with either absorbable (eg, 10-0 Vicryl or 10-0 Biosorb) or non absorbable ( 10-0 nylon) sutures or tissue adhesive. Postoperatively, topical antibiotic-corti costeroid oi ntment is administe red frequently for approximately 4-6 weeks, until inflammation subsides. The surgeon should emphasize to the patient that compliance with this regimen minimizes the chance of recurrence. If the defect created following dissection of scar tissue is conSide rably larger than what ca n be covered with an autologous conjunctival graft, then an amniotic membrane graft may be used in conjunction wit h a conjunctival graft to cover the entire area of resection. Several authors have noted that this decreases postoperative inflammation and speeds reepithelialization of the surface. Many auth ors have described the use of commercially available fi brin tissue adhesive (eg, Tisseel VH) to fixate the conjunctival autograft, thereby elim inating the need for suture fixation. Eli mination of sutures decreases postoperative pain and reduces surgical time as well as the recurrence rate, com pared with bare sclera techniques. Fibrin tissue adhesive mimics natural fibrin format ion, ultimatel y resulting in the formation of a fibrin clot. Currently, use of this product in pterygium surgery is not FDA approved; its use should be considered off-label. Also, because both pooled huma n plasma and bovine products are used to obtain some of its components, careful consideration should be given to the potential of the product for disease transmission. Kli~likerdonmez
C, Akova YA, Alti nors DO. Compariso n of conjunc tival autograft with am· niotic membrane transplantation for pterygium surgery: surgical and cosmetic outcome. Cornea. 2007;26(4):407-4 13. Ti SE, Tseng Sc. Management of primary and recurrent pterygium using amn iotic membrane transplantation. Curr Opin Ophthalmol. 2002;13 (4):204-21 2. Uy HS, Reyes JM, Flores Jo, Lim- Bon-Siong R. Comparison of fibrin glue and sutures for attaching conjunctival autografts after pterygium excision. Ophthalmology. 2005; 112(4):667-671 .
Complications The risk of recurrent pterygium following conju nctival autografting is very low-between 3% and 5%. Self-li mited problems include conjunctival graft edema, corneoscleral dell en, and epithelial cysts. Cases of recurrent pterygi um after conjunctival autograft transplantation may be substantially improved by either repeated conjunctival autog raft, modified limbal autografts, or lamellar keratoplasty. Most studies report that the rate of recurrence with MMC is sim ilar to that with conjunctival grafting. Diplopia resulting from severe scarring rarely occurs but can be most disturbing to the patient. Infections are rare, although Pseudomonas sclerokeratitis has been reported, with poor visual outcome. A large body of li terature supports the use of MMC in pterygium surgery to minimize recurrence rates. Although low concentrations of MMC used at the time of surgery
CHAPTER 14,
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395
(applied to the area of resection with a surgical sponge for up to 2 minutes, followed by irrigation with copious volumes of balanced saline solution) have been shown to be ef~ fective in reducing recurrence, it is important to note that any use of topical MMC can be toxic and may cause visually significant complications such as aseptic scleral necrosis and infectious sclerokeratitis. These complicat ions may occur many months, or even years, after the drug's use. If surgery is being performed in a case of recu rrent pterygium, and MMC use is contemplated, it is safer to apply it in traoperatively than to give it to the pa~ tient for topical postoperative use; in the latte r case, overuse may be a problem . Other indications for conjunctival grafting In rare cases, an enlarged pinguecula may cause chronic irritation, necessitating re moval combined with an autologous conjunctival replacement graft. Conjunctival autografts can also be used for fornix reconstruction ,vhen conjunctival fibrosis and cicatrization lead to fornix foreshortening, symblepharon formation, cicatricial entropion, trichiasis, and ocular surface keratini zation and vascularizati on. Occasionally, un ilateral fornix foreshorten ~ ing occurs after localized disease. retinal detachment surgery, or excision of ocular surface tumors or nevi. This foreshorteni ng can be remedied by plaCing a conjunctival autograft from the opposite eye. Usually, however, cond itions associated with fornix obliteration (cicatricial pemphigoid, Stevens~ Johnson syndrome) are bilateral, so uninvolved conjunc~ tiva is not available for grafting. Mucous memb ra ne transplantation using buccal mucosa or amniotic membrane has become the preferred ocular surface replacement technique in such instances. Koranyi G, Seregard S, Kopp ED. Cut and paste: a no suture, sma!! incision approach to pte rygium surgery. Br f Ophthalmol. 2004;88(7) ,9 11 -9 14 . Tan DTH. Conjunctival autograft. In: Holland E], Manni s MJ, eds. Ocular Surface Disease: Medical and Surgical Management. New York: Springer-Verlag; 2002:65-89.
Limbal Transplantation When stem cells are destroyed by disease or injury, the corneal surface becomes covered with conjunctival epithelium. which is less transparent, more irregular, and more prone to erosion and vascularization than normal corneal epithelium (see the discussion of this phenomenon earlier in the chapter). This condition can be diagnosed clinically by the absence of the limbal palisades ofVogt, abnormal epithelium on the cornea, and vascular~ ization, or cytologically with impression cytology or biopsy of the limbal region to show goblet cells. Loss of limbal stem cells is seen most often in chemical injury, but it can also occur as a result of contact lens overwear, multiple surgical procedures, la rge ocular surface abrasions, repeated infections, or use of topical medications, especially use of toxic chemotherapeutic agents like MMC. If total loss of limbal stem cells occurs unilaterall y, an autograft of limba! epithelium fro m the fellow eye can repopulate the diseased cornea with normal corneal epithelium (Fig 1 4 ~2) . In this procedure, corneal epithelium, conjunctiva, and superficial pann us are removed from within 2 mm outside the limbus of the recipient eye, and 2 th in limbal autografts from the fellow eye ~re then attached to the limbus and allowed to regenerate and proliferate.
396 • External Qisease and Cornea
B
c
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F
Surgery of the Ocular Surface.
397
Figure 14·2 Limbal autograft procedure. A, With disposable cautery, the area of bu lbar conjunct iva to be resected is marked approximately 2 mm poste rior to the limbus. B, After conjunctival resection , abnormal corneal epithel ium and fibrovascular pannus are stripped by blunt dissection using ce llulose sponges and tissue forceps . C, Add itiona l surface polishing smooths t he stromal surface and improves clarity. 0 , Superior and inferior limbal grafts are delineated in the donor eye with focal applications of cautery approximate ly 2 mm posterior to the limbus. The initial incision is made superficial ly wit hin clear cornea using a disposable knife. E, The bulbar conjunct ival portion of the graft is undermined and thinly dissected from its limbal attachment. F, The limbal grafts are transferred to the ir corresponding sites in the recipient eye and are secured wit h interrupted sutures, 10-0 nylon at the corneal edge and 8-0 Vicryl at the conjunctival margin . (Reproduced by permission from Kenyon KR, Tseng Sc. Limbal autograft transplantation for ocular surface disorders. Opht hal mology. 1989;96(5):709-723.)
398 • Extern al Disease and Corn ea
If total loss of li mbal stem cells occurs bilaterally, the options for ocular surface transplantation are more limited. The appropr iate selection of procedures depe nds on th e relative health of the stem cell population in th e prospective donor eye. A limbal stem cell allograft from a living related donor may be considered. A similar procedure, keratolimbal aUograft, uses corneolimbal rims from eye bank do nor eyes. Although host cells may eventu ally reject or replace such a tissue, good long-term res ults have been repo rted. Technical difficulties, poor epithelial Viability, and rejection problems necessitating system ic immu nosuppression have li mited the useful ness of th is modality, but dramatic success has been observed in selected desperate cases. In contrast, the use of cultured li mbal epithelium is still not routinely ava ilable, even th ough it is technicall y feas ible and has been used with success. For cases of bilateral stem cell loss, the most prom ising technique for transferr ing donor stem cells is limbal allograft transplantatio n. Use of allogeneic (cultured cell or tissue) grafts reqlliTes systemic immllne modll ia tion to minimize the chance of reject ion of the highly immu nogen ic li mbal tissue. Ang LP, Tanioka H. Kawasaki S, et al. Cultivated human conjunctival epithelial transplantation for total limbal stem cell deficiency. III vest Ophtlwlmol Vis Sci. 2010;5 1(2):758-764. Holland Ej, Schwartz GS. The evolution and classification of ocular surface transplantation. In: Holland EJ, Mannis Mj, eds. OCIlla,. Surface Disease: Medical and Su rgical Management. New York: Springer- Verlag; 2002: 149-157.
Conjunctival Flap
Indications The conjunct ival fl ap procedure covers an llnstable or painfll l cornea l sllrface with a hinged flap of m ore durable conjunctiva. Conjuncti val flap surgery is performed less frequently now than in the past because of broadened indications for penetrating keratoplasty (PK) (see Chapters 10 and 16), more effective antimicrobial agents, avai lab ility of bandage contact lenses, and improved management of corneal infl ammatory diseases. Nevertheless, this procedure remains an effect ive method for managing inflammatory and structural corneal di sorders when restoration of vis ion is not an imm ediate concern. It should not be used for active micro bial keratiti s or corneal perforation, because residual infectious o rganisms may proliferate under a flap if an ulcer is not sterilized first. Any corneal perforation must first be sealed, or it will continue to leak under the flap. The procedure is not meant to provide tectonic suppo rt to a very thin cornea. The prin cipal in dicat ions for this procedure are
chroni c steri le epithelial and stromal ulcerations (stromal herpes simplex virus keratitis, chemical and thermal burns. keratoconjun ctivitis sicca, postinfectious ulcers, neurotrop hi c keratopathy) closed but unstable corneal wounds painful bullo us keratopathy in a patient who is not a good candidate for PK a phthisical eye being prepared for a prosthetic shell Reduced visualization of the anterio r chamber and the creation of a potential barrier against drug penetration are among the disadvantages of conjuncti va] flap sllrgery.
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Surgery of the Ocular Surface. 399
However, a successful conjunctival graft, free of buttonholes, \vill thi n out and enable functional vision.
Surgical technique A complete (Gundersen) flap (Fig 14-3) is highly successful if attention is paid to several fundamental principles: complete removal of the corneal epithelium and debridement of necrotic tissue reinforcement of thin areas with corneal or scleral tissue creation of a mobile, thin conjunctival flap that contains minimal Tenon capsule absence of any conjunctival buttonholes absence of any traction on the flap at its margins that may lead to flap retraction Retrobulbar, peribulbar, or general anesthesia may be used. The corneal epithelium and all necrotic tissue are removed, and the eye is retracted inferiorly with an intracorneal traction suture at the superior limbus. Elevation of the flap with subconjunctival injection of lidocaine with epinephrine enhances anesthesia, facilitates dissection, and reduces
A
B
c
D
Figure 14-3 Surgica l steps for the Gundersen conj unct ival flap. A, Removal of th e cornea l epithelium. B, A 360 0 peritomy w ith relaxing incisions, placement of superior limbal traction suture, superior forniceal incision, and dissectio n of a thin flap. C, Positioning of flap . D, Suturing of flap into position with multiple interru pted sutures . (Reproduced bv permission from Mannrs MJ Conjunctival flaps. Int Ophthalmol Clin. 1988;28(2):1 65-168.)
400 • External Disease and Cornea
bleeding. The needle for this inj ection should not pierce the conj unctiva in the area to be used for the flap. The dissection may start from either the li mbus or superior fornix. Dissecti on of conjunctiva from underlying Tenon fascia must be perform ed carefully under direct visualization to preve nt conjunctival perforation, especially in eyes with previous conjunctival surgery. Once the fl ap has been dissected, a 360' peritomy is performed, followed by scraping of all remain ing lim bal and corneal epithelium. Additional undermining of the flap allows it to cover the entire cornea and to rest there without tractio n. Any residual tension may foster later retraction of the fla p. After the flap is positioned over the prepared cornea, it is sutured to the sclera just posterior to th e limbus superiorly and inferiorly with absorbable sutures (6-0 to 10-0, depending on surgeon preference). Partial conjunctival flap A partial, or bridge, flap may be used for tempora ry coverage of a peripheral wound or area of ulceration. Retracti on is common despite adequate relaxation of the base. The flap should be well underm ined to reli eve tension and decrease the chance of retraction. The flaps are fixated to the cornea with nonabso rbable suture (9-0 or 10-0 nylon). Bipedicl e flap This partial, or bucket handle, flap can be used fo r small central o r paracentral corneal lesions that do not require complete corneal coverage. It can be useful in a cornea with inferior exposure. The advantage is that the view of the anterior chamber and the remaining uninvolved cornea is not obstructed. The flap is fashioned similar to the Gundersen flap but with only enough d issection required to cover the lesion, plus a small margin (the width of the flap should be 1.3-1.5 times the width of the lesion). Subconjunctival anesthesia is administered, and th e epithelium beneath the site of the flap is removed. After marking the bulbar conjunctiva with methylene blue, the surgeo n can create the flap and mobilize it into position for suturing with interrupted nylon suture. Advancement flap Peripheral limbal or paralimbal corneal lesio ns can be covered with a simple advancement conjunctival fl ap. A limbal incision is created with relaxing components, an d the conjunctiva is simply advanced onto the corn ea to cover the defect. Scleral patch grafts and onlay grafts may also be used in conjunction with th is technique. T he disadvantage of this type of flap is a te ndency to retract with time. Single-pedicle flap Also known as a racquet flap, a Single-pedicle flap can be used for peripheral corneal lesions that are not large eno ugh to requ ire a total flap. Although a Single-pedicle fl ap is more difficu lt to d issect th an an advancement flap, it is less likely to retract.
Complications Retraction of the fl ap is the most common complication , occurring in about 10% of cases. Other complications incl ude hemorrhage beneath the flap and epithelial cysts. In some cases, inclusion cysts enlarge to th e poi nt of requ ir in g excision or marsupialization. Ptosis, usually due to levator dehiscence, may also occur postoperatively. Unsatisfactory cosmetic appearance can be improved with a painted contact lens. Progressive corneal disease under the flap is a concern with infect ive and autoimmune conditions.
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Surgery of the Ocu lar Surface. 401
Considerations in removal o( the flap If PK is to be performed in an eye with a conjunctival flap, the flap may be removed as a separate procedure or at the time of PK. Simple removal of the flap (without keratoplasty) is usually unsatisfactory in restoring vision, as the unde rl ying cornea is almost always scarred and/or thinned. Because the conjunctival flap procedure tends to destroy or displace most lim bal stem cells, a limbal autograft or allograft after removal of the flap may be necessary to provide a permanent source of normal epitheliu m before an optical corneal transplant. Abbott RL, Beebe WE. Corn eal edema . In: Abbott RL. ed. Surgical Intervention in Corneal and External Diseases. Orlando: Grune & Stratton; 1987:81 - 84. Macsai MS . Manni s MJ. Darlington JK. Surface stabili zation procedu res. In: Holland EJ . Man nis MJ. eds. Ocular Surface Disease: Medical and Surgical Management. New York: SpringerVerlag; 2002,137- 148. Man nis MJ. Conjunctival flaps. Int Ophtlwlmol Cli,1. 1988;28:165 -168.
Mucous Membrane Grafting Indications The goal of mucuous membrane grafting is to reconstruct a more functional conjunctival mucosal surface so as to ameliorate the fornix obliteration or eyelid margin keratini zation that usually occurs with bilateral cicat ricial conjunctival disorders such as StevensJohnson syndrome or ocular cicatricial pemphigoid (see Table 14-1). Buccal mucosa or preser ved amniotic membrane can be used. Mucous membrane grafti ng has rarely been used as a treatment for unilateral chemical injury and is performed only in desperate cases of bilateral injury where advancement of the Tenon capsule is not possible and allograft limbal tissue is not available. Nonetheless, this technique has long been a popular method of correcting eyelid position abnormalities caused by cicatrizing conjunctival disorders. Although good results have been reported in inactive cicatricial disorders such as latestage, nonprogressive Stevens-Johnson syndrome, there is some reluctance to apply this technique to advanced (stage III or IV) ocular cicatricial pemphigoid for fear of exacerbating this progressive infl ammatory disorder. However, advances in immunosuppressive treatment have brought promise that mucous membrane grafting for the eyelid abnormalities associated with late -stage ocular cicatricial pemphigoid can achieve some success. The purpose of grafting mucosal membra nes is to achieve better ocular surface wetting by improving eyelid movement and distribution of the tear film over the cornea, thereby reduci ng exposure and evaporation. This procedure also proVides favorable extracellular matrix substrate for better epithelial migration and adhesio n. However, mucous membrane grafting is not effective in replacing normal stem cells. In a small series of patients with advanced ocular cicatricial pemphigoid or Stevens-Johnson syndrome, combinations of allograft limbal transplantation , amniotic membrane transplantation . and tarsorrhaphy, followed by the use of seru m-derived tears and systemic immu nosuppression. were shown to reconstruct the ocular surface. These therapeut ic modalities appear to provide an alternative to, other difficult procedures, such as keratoprosthesis, for treating patients with desperate cicatricial keratoconjunctivitis (see Chapter 16).
402 • External Disease and Cornea
There are many surgical techniques for mucosal grafting, and the reader should consult a surgical textbook or video for specifics. Potential complications, regardless of the particular technique, include buttonholing, retraction, trichias is, surface keratinization of the graft, ptosis, phimosis, depressed eyelid blink, incomplete eyelid closure, subm ucosal abscess formation, and persistent nonhealing epithelial defects of the cornea. Fernandes M, Sridhar MS, Sangwan VS, Rao GN. Amn iotic membrane transplantation for ocular surface reconstruction. Cornea. 2005;24( 6):643- 653. Holland EJ. Epithelial transp lantation for the management of severe ocular surface disease. Trans Am Ophthalmol Soc. 1996;94:677- 743 .
Tseng SCG, Tsubota K. Amniotic membrane transplantation for ocular surface reconstruction. In: Holland El, Mannis MJ, eds. Ocular Surface Disease: Medical and Surgical Management . New· York: Springer-Verlag; 2002:226- 231.
Superficial Keratectomy and Corneal Biopsy
Indications Superficial keratectomy consists of excision of the superficial layers of cornea (epithelium, Bowman layer, or superficial stroma) without replacement of tissue. The primary indica tions are re moval of hyperplastic or necrotic tissue (eg, corneal dermoid, pterygium, Salzmann degeneration, epithelial basement membrane reduplication, degenerative calcification) excision of retained foreign material in the cornea need for tissue for diagnosis (histopathology or microbiology) excision of scarring or superficial corneal dystrophic tissue If corneal biopsy is performed for histopathology, preservation of tissue integrity and anatomical orientation is crucial. A small specin1en can be placed on a filter or thin card to maintain the tiss ue orientation before fixation or cryosection. For microbiology workup, the biopsied speci mens can be minced or homogeni zed prior to inoculation of the culture media or tissue smearing for histochemical staini ngs.
Surgical techniques Mechanical keratectomy If the corn eal lesion is superficial, it may be possible to scrape or peel it away without sharp dissection. W hen deeper dissection is required, the su rgeo n can mark the area freehand with an adjustable-depth blade or use a trephine. Care must be taken to maintain the surgical plane and to avoid inadvertent perforation; keeping the dissection plane dry can be ve ry helpful. A lamellar keratectomy can also be performed using a mkrokeratome, a diamond burr 011 a surgical drill, or an excimer or femto second laser. Phototherapeutic keratectomy The excimer lase r can remove tissue with much greate r precision than is possible with mechanical techn iques. One problem with phototherapeutic keratectomy (PTK), however, is that scar tissue may ablate at a different rate than normal tissue, which results in an uneven surface even if the original surface was smooth. Also, if the corneal surface is irregular to begin with and ab lates homogeneously, the
CHAPTER 14:
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irregularity will persist. Frequent application of viscous liquid to the corneal surface during ablation fills in the gaps and helps to achieve a smooth surface. Most patients experience a hyperopic shift afte r PTK from the corneal-flattening effect of the procedure. Nevertheless, PTK may produce marked improvement in vision in selected patients with superficial stromal scarring or dystrophies and obviate the need for corneal transplant surgery. Topical MMC applied to the corneal ablation zone for a brief period follo wing PTK has been shO\vn to decrease postoperative scar formation. Oral vitamin C has been used prophylactically to reduce haze formation in PTK. Ayres BO, Rapu ano CJ. Excimer laser phototherapeutic keratectomy. Owl Surf 2006;4 (4): 196- 206. Kim TI, Pak JH , Lee SY, Tchah H. Mitomycin C- induced reduction ofkeratocytes and fibroblasts after photorefractive keratectomy. Invest Ophthalmol Vis Sci. 2004;45(9) :2978 - 2984.
Management of Descemetocele. Corneal Perforation. and Corneal Edema Bandage contact lens
Applying a thin, continuous-wear soft contact lens as a therapeutic bandage can protect the loosely adherent remaining or regenerating epithelium from the "windshield wiper" action of the blinking eyelids. Use of bandage contact lenses has significantly improved and simplified the management of recurrent erosions and persistent epithelial defects. Continuous bandaging can reduce stromal leukocyte infiltration and ensure the regeneration of basement memb rane and restoration of tight epithelial-stromal adhesion without compromising the patient's vision and comfort. Frequent lubrication, prophylaxis with antibiotics, and close follow-up are crucial, especially in patients with decreased corneal sensitivity or dr y eye. The choice of a soft contact lens for patients with severe dry eye can be difficult. In general, patients with dry eye run a high risk of infection with soft contact lenses. Punctal occlusion can facilitate lens retention and comfort. High-water-content lenses usually are not appropriate because rapid water evaporation further compounds the hypertonicity-induced surface damage in dry eyes. Low-water-content lenses with high oxygen transmissibility (eg, HEM A-silicone polymer) would be the most appropriate choice in this setting. Lenses should be replaced every 2-4 weeks or as depOSits accumulate on the lens. The use of an acrylic scleral lens may circumvent the problems encountered with a hydrogel lens. Even though a hydrogel lens can actually cause corn eal hypoxia and increase corneal edema, continuous wear of this type of lens can provide symptomatic relief of painful bullous or filamen tary keratopathy. Mild corneal edema can often be managed with hypertonic saline solution and judicious use of topical corticosteroids. if indicated. Chronic use of a bandage contact lens can lead to corneal pannus and compromise the success of future PK for visual rehabilitation. Tarsorrhaphy should be considered for patients who have contact lens complications or a high risk of infection. Cyanoacrylate adhesive
Tissue adhesives, particularly ~utylcyanoacrylate, have been used widely as an adjunct in the management of corneal ulceration and perforation. Early application of tissue
404 • External Di sease and Cornea
adhesives in the management of stromal melting has greatly reduced the need for urgent surgical interventions such as therapeutic keratoplasty or co njunctival flap. Although cyanoacrylate tissue adhesives are not approved by the FDA for use on the eye, they have been employed extensively over the past 2 decades to seal perforations or near perforations. Some perforations are so minimal that they seal spontaneously prior to any ophthalmic examination. with no intraocular damage. prolapse. or adherence. These cases may require only treatment with systemic and/or topical antibiotic therapy, along with close observation. If a corneal wou nd is leaking but the chamber remains formed, leakage can be reduced or stopped with pharmacologic suppression of aq ueous production (topical or systemic), patching, and/or a bandage contact lens. Generall y, if these measures fail to seal the wound in 3 days, closure with cyanoacrylate glue or sutures is recommended. Perforations greater than 1~2 mm are usuall y not amenable to tissue adhesive and require a corneal patch graft. Cyanoacrylate tissue adhesive applied to thinned or ulcerated corneal tissue may prevent further thinning and support the stroma through the period of vascularization and repair. The adhesive plug is also thought to retard the entry of inflam matory cells and epithelium into the area, thus decreasing the rate of corneal melting. After the lesion has been sealed, new stromal tissue may be laid down, and accompanying corneal vasculari zation may help to ensure the integrity of the area by proViding nutrients and antiproteases.
Surgical technique Tissue adhesive can usually be applied on an outpatient basis using topical anesthetics. However, if adherent or prolapsed uvea in the leakage site or a flat chamber is encountered, the procedure should be performed in the operating room using air or hyaluronate to re-form the anteri or chamber. The adhesive is applied under slitlamp or microscopic observation using a topical anesthetic (eg, 0.5% proparacaine hydroch loride). An eyelid speculu m is useful. Before the adhesive is applied, any necrotic tissue and corneal epithelium should be removed from the involved area and a 2-mm surrounding zone. The area is then dried using a cellulose sponge, and a small drop of the fluid adhesive is applied with a 30-gauge needle or a 27-gauge anterior chamber cannula. The glue polymeri zes completely within 20-60 seconds and usually adheres well to the deepithelialized surface. The glue does not polymerize on plastic, so a simple way to handle it is to spread a small amount on a surface such as the inside of the sterile plastic wrapping of any medical product cut to a size slightly larger than the perforation. It should then be applied to the surface of the cornea in as thin a layer as possible using the plastic handle of a cellulose sponge or the wooden stick of a cotton-tipped applicator. The ad hesive plug has a rough surface and can be irritating, so a bandage contact lens is used to protect the upper tarsal conjunctiva and to prevent the plug from being dislodged by eyelid blinking. An alternative to applying cyanoacrylate is to use multiple layers of amniotic membrane that has been cut to the shape of the defect, placing a patch into the defect where the near perfo ration is located. This patch may be held in place wi th a larger amniotic membrane patch, nylon sutures, and a bandage contact lens, or by means of fibrin glue. With time, scar tissue will r~inforce the deficient area and may mitigate against the need for a corneal transplant.
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Chan SM, Bo isjoly H. Advances in the use of adhesives in ophthalmology. Curr Opin Ophthalmol. 2004;15(4);305-310. Kim HK, Park HS. Fibrin glue-assisted augmented amniotic membrane transplantation for the treatment of large noninfectious corneal perforations. Cornea. 2009;28 (2): 170- 176.
Reconstructive lamellar and patch grafts
See Chapter 16 for discussion and illustration of PK and lamellar keratoplasty.
Corneal Tattoo Indications and options
Corneal tattooing has been used for centuries to improve the cosmetic appearance of a blind eye with an unsightly leukoma. It has also been used occasionally in seeing eyes to reduce the glare from scars and to eliminate monocular diplopia in patients with large iridectomies, traumatic loss of iris, and congenital iris colobomas. Different techniques have been used. One involves applying a platinum ion solution to the cornea. When reacted with a second agent, a dark black precipitate is formed in the corn ea, producing a dark deposit that can simulate a pupil. A second tech nique involves using the standard methods used in skin tattooing: applying to the cornea a paste of colored pigment, either india ink or a metal oxide, and then using a hypodermic needle or angled blade to drive the pigment into the corneal stroma in the area that needs coverage. Multiple superficial punctures are made until enough pigment has been applied; multiple pigment colors can be used to give a more natural appearance. However, the method is time-consuming and often needs to be repeated if the pigment uptake is inadequate or the pigment migrates. Kim JH, Lee D, Hahn TW, Cho i SK. New surgical strategy for corneal tattooing using a femtosecond laser. Cornea. 2009;28(1) :80-84. Kymionis GD, Ide T, Galor A, Yoo SH. Femtosecond -assisted anterior lamellar corneal stain ingtattooing in a blind eye with leukocoria. Cornea. 2009;28(2):211 - 213 . Reed JW. Corneal tattooing to reduce glare in cases of traumatic iris loss. Cornea. 1994;13(4): 401 - 405 . Rocher N, Hirst L, Renard G, Doat M, Bourges JL, Mance! E. Corneal tattooing: a series of 14 case studies. J Fr Ophlalmol. 2008;31(10);968-974.
CHAPTER
15
Basic Concepts of Corneal Transplantation
Transplantation Immunobiology Histocompatibility and Other Antigens
Antigens found within the host are known as endogenous antigens. The most important group of endogenous antigens is the homologous antigens, which are genetically controlled determinants specific to a give n species. Histocompatibility antigens, homologous antigens found on the surfaces of most cells, are an expression of genetic material on human chromosome 6 in a region refe rred to as the major histocompatibility complex (MHC). In humans, the MHC is known as the human leukocyte antigen (HLA) system. Human leukocyte antigens are fo und on the surface of all nucleated cells. They are determined by a series of 4 ge ne loci on chromosome 6 known as HLA-A, HLA-B, HLA-C, and HLA-D. Each zone controls several d ifferent antigenic specificities, over 95% of which can be recognized by serologiC methods. The histocompatibility antigens are important clinically because they form the basis for graft rejection in organ transplantation and for sensitization to most antigens. It is possible that H LAs are ge netic markers rather than actual transplantation antigens and that strong transplantation antigens are closely linked with the HLA markers on the genetic material. Some grafts are rejected even when donor- reci pient pairs are HLA compatible. Although minor histocompatibility antigens such as ABO and Lewis antigens are less potent than major ones, they nonetheless add to the overall antigenicity of a graft. Little is known about the number of minor histocompatibility antigens or their importance in transplantation immunology. Immune Privilege
The cornea was the first successfully transplanted solid tissue. After other tissues had also been transplanted, it was soon observed that corneas were rejected less frequently than other transplanted tissues. The concept emerged that the cornea was the site of"immunologic privilege" and that corneal grafts were somehow protected from immunologic destruction. Early immunologists attributed ocular immune privilege to "immunologic ignorance" due to the absence of lymphatics draining the anterior segment. It is now evident that corneal grafts are not different from other tissue grafts and that the allogenic cells of the transplant elicit an imm une response, but the response is aberrant. There is 407
408 • External Disease and Cornea
a profound antigen-specific suppression of cell-mediated immunity, especially T-cellmediated inflammation, such as delayed hypersensitivity and a concomitant induction of antibody responses. Tolerance to a corneal graft is now recognized as an active process based on several features: absence of blood and lymphatic chan nels in the graft and its bed absence of MHC class W antigen -presenting cells (APCs) in the graft reduced expression of MHC-encoded alloantigens on graft cells replaced with minor peptides (nonclass ical MHC-Ib molecules) to avoid lysis by natural killer cells expression of T-cell- deleting CD95 ligand (FasL, or Fas ligand) on endothelium that can induce apoptosis in ki ller T cells immunosuppressive microenvironment of the aqueous humor, including TGF-P2' a -MSH, vasoactive intestinal peptide, and calcitonin gene-related peptide anterior chamber-associated immu ne deviation (ACA 10) involving the development of suppressor T cells. ACA 10 is a down-regulation of delayed-type cellula r immunity. Antigens released in to the aqueous humor are, presumably, recognized by dendritic cells of the iris and ciliary body. These APCs can then enter the veno us circulation and induce regulato ry T cells in the spleen, bypassing the lymphatiC system. For an immune response to occur, an antigenic substance is introduced and "recognized" (afferent limb), producing the syntheSiS of specific antibody molecules and the appearance of effector lymphocytes that react specifically with the immunizing antigen (efferent limb). Although antibodies to fo reign tissues are formed during graft rejection, they are not believed to be important in the us ual type of allograft rejection. Rather, extensive evidence indicates that allograft rejection is associated with cellular immune mechanisms. The term delayed hypersensitivity, or type IV, reaction is used to describe such T-lymphocyte-mediated responses. Other mechanisms are also probably involved. For the endothelial cells to be rejected, they must express MHC class II antigens. Streilein suggests that in the presence of inflam matory stress (including mediators TNF-a and lFN-y), the endothelial cells' endogenous mino r H antige ns, which are recognized by the CD4' T cells, lead to delayed hypersensitivity and graft rejection. See also the discussion of immu ne-mediated disorders in Chapters 6 and 7 of this volume. BCSC Section 9, Intraocular Inflammation and Uveitis, discusses and illustrates the principles of immunology in greater detaiL Niederkorn JY. Ocular immune privilege: Nature's strategy for preserving vision. Science and Medicine. 2003;9(Pt 6),320- 331. Streilein JW. New thoughts on the immunology of corneal transplantation. Eye. 2003;17(8):
943-948.
Eye Banking and Donor Selection Before reliable storage or preservation methods were available, it was imperative that corneas be transplanted immediately from do nor to recipient. The McCarey-Kaufman
CHAPTER 15:
Basic Co ncept s of Cornea l Transplantatio n . 409
tissue transport medium developed in the early 1970s sign ificantly reduced endotheli al cell attrition, allowing corneal buttons to be safely transplanted after being stored for up to 4 days at 4' C. Improvemen ts in storage media over the past 2 decades have extended the viable storage period to as long as 2 weeks, not only increasing the ava ilability of donor corn eas but also allowi ng penetrating keratoplasty to be performed on a less exigent basis. The most commonly used preservation medium in the United States today is Optisol-GS (Bausch & Lo mb, Irvine, CAl, which includes such components as 2.5% chondroitin sulfate, 1% dextran, ascorbic ac id. vitamin B I 2, adenosine triphosphate precursors, and the antibiotics gentamicin and streptomycin. Currently under investigation is the addition of insulin, epidermal growth factor, broader-spectrum antibiotics, and other components to storage med ia. These changes may furt her improve endothelial cell viability and function and enhance steri li ty in the futu re. Organ cultu re storage techniques are common ly practiced in Europe and have the potential to provide improved donor quality in the future. Organ culture offers a relatively long storage time, which allows optimal use of available donor corneas in areas where there is a relati ve shortage. An added benefit of organ culture is the delivery of a donor cornea with sterility control of the med ium prior to transplantation. Its disadvantages include increased complexity and cost as well as a thick, opaque cornea at the time of surgical transplantation. Some eye banks in the United States are now offering precut tissue for Descemet stripphlg automated endothelial kera toplasty (DSAEK), otherwise known as endothelial kerato plasty, and Intralase {Abbott Laboratories, Abbott Park, IL)-enabled keratoplasty (IEK). This means that donors arriving at an eye bank are screened and then cut with a microkeratome to produce a thi n posteri or lamella suitable fo r DSAEK or are cut in a preselected wound shape for IEK. Such shaped wounds include top hat, mushroom, and zigzag donor configurations. These open the door to more precise wound apposition wi th better wound-healing strength . The lo ng- term effect on transplant outcome and astigmatism still must be determined. In the United States, not all eye banks are membe rs of the Eye Bank Association of America (EBAA), but all eye banks must comply with US Food and Drug Administration regulatory requ irements (Good Tissue Practices) im plemented in 2005 to ensure the safety of human cells, tissue, and cellular- and tissue-based products.
Criteria Contrai ndi cating Donor Cornea Use The EBAA has developed extensive criteria fo r screening donor corneas pri or to distribu tion to avoid transmissi ble infections and other conditions. Contraindications include • death of unknown cause unknown CNS disease or certain infectious diseases of the central nervous system (eg, Creutzfeldt-Jakob disease, subacute sclerosing panencephali tis, progressive mult ifocal leukoencephalopathy, congenital rubella, Reye syndrome, rabies, act ive viral encephalitis, encephalitis of unknown origin, or progressive encephalopathy) ac tive septicemia (bacteremia, fu ngemia, viremia) • social, clinical, or laboratory evidence suggestive of HIV infection , syphilis, or ac tive vira l hepat it is
4 10 • Externa l Di sease and Cornea
• leukemias or active disseminated lymphomas active bacterial or fungal endocarditis active ocular or intraocular inflammation such as iritis, scleritis, conjunctivit is, vitritis, retinitis, choroiditis intrinsic malignancies such as malignant anter ior segment tumors, adenocarci noma in the eye of primary or metastatic origin , and reti noblastoma (eyes with posterior choroidal melanoma may be considered acceptable, but most medical eye bank directors decline their use) congenital or acquired eye disorders that wou ld preclude successful surgical outcome: any central donor corneal scar or pterygia involving the central 8-mm clear zone (optical area of the dono r button), keratoconus, keratoglobus, or Fuchs dystrophy prior refractive corneal surgery such as radial keratotomy (RK), photorefractive keratectomy (PRK), LASIK, and lamellar inserts, although for use in endothelial keratoplasty such as DSAEK, refractive laser surgery may not disqualify a donor hepatitis B surface antigen- positive donors, hepatitis C seropositive donors, HIV seropositive donors, H1V or high-risk-for-HI V patients meeting any of the EBAAs behavioral or history excluSionary criteri a (eg, inmates, drug users, homosexuals, or guidelines as prescribed by the CDC) Corneas from patients with prior intraocular surgery (cata ract, IOL impl ants, glaucoma filtration) may be accepted if endothelial adequacy is docume nted by specular microscopy and meets the local eye bank's prescribed standards; those fro m patients with prior laser surgical procedures such as automated lam ellar keratoplasty (ALT) and retinal photocoagulation may be used if clea red by the eye bank's medical director. Diseases known or suspected to be trans mitted by cornea l transp lantation are listed in Table 15-1.
Table 15· 1 Disease Transmission From Donor Corneas Proven transmission by corneal transplantation Rabies Hepatitis B Creutzfeldt-Jakob disease (previously diagnosed) Retinoblastoma Ba cte rial or fungal kerati tis Bacterial or funga l endo phthalmitis Possible transmission by corneal transplantation Human immunodeficiency virus (H1V) Herpes simplex virus (HSV) Prion diseases Other diseases that exclude co rneal donors Hepatitis C, HTLV·I or -II infection, ocula r adenocarcinoma , malignant tu mors of the ante rio r segment, Reye syndrome, subacute sclerosing panencepha litis, progressive multifocal leukoencephalopathy, leukemias, active disseminated lymphoma s, active infecti ous endocard itis, active sept icemias, variant CJD (vCJD), dementia of unknown cause, recip ient of nonsynthetic dura mater graft
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Basi c Concepts of Corneal Transplantation. 411
Even with these standards, the ultimate responsibility for accepting donor tissue rests with the surgeon. Other factors to be considered include the following: slit-lamp appearance of donor tissue specular microscopic data (generally, endothelial cell counts <2000 cells/mm' are not used) death-to-preservation time (optimal range <12- 18 hours) tissue storage time prior to keratoplasty dono r age Most surgeons do not use corneas from donors younger than 24 months, as these corneas are extremely fl accid and can result in high corneal astigmatism and myopia postoperatively. Most eye banks establish a lower age limit of24 months and an upper age lim it of70 years, as older corneas tend to have lower endothelial cell counts. The acceptable age of donors who provide tissue for transplantation is up to the individual surgeon. For various reasons, including the potential decline in suitable donor tissue because of widespread refra ctive surgery, the EBAA and National Eye Institute sponsored the Cornea Donor Study (CDS) in 1999. The st ud y completed enrollment in 2002 and has been extended from 5-year to 10-year follow-up. The 1100 patients, 40-80 years old, who had endothelial dysfunct ion as indication for the first graft in the study eye, were randomized to receive tissue from donors aged 10-64 or 65-75 years. The primary endpoint is graft failure for all causes. A secondary endpoint is the analysis of ABO mismatches in the rate of rejection and failures. The Specular Mic roscopy Ancillary Study (SMAS) is analyzing the loss of endothelial cells in a subset of the stud y population. The study showed no difference in transplant outcome at 5 years' follow-up between the groups. Cornea Donor Study In vestigator Group; Gal RL, Dontchev M, Beck RW, et al. The effect of donor age on co rneal transplantation outcome results of the cornea donor study. Ophthal-
mology. 2008;115(4j,620-626.e6. Cornea Donor Study Investigator Group; Lass JH, Gal RL. Dontchev M. et al. Donor age and corneal endothelial cell loss 5 years after successful corneal transplantation. Specular microscopy ancil!ary study results. Ophthalmology. 2008; 115(4):627-632.e8.
CHAPTER
16
Clinical Approach to Corneal Transplantation
Corneal Transplantation Corneal transplantation refers to surg ical replacement of a fu ll -thickness or lamellar portion of the host cornea with that of a don or eye. If the donor is another person, the procedure is called an allograft; use of donor tissue from the same or fellow eye is called an autograft (see Corneal Autog raft Procedures later in this chapter ). In 2007, there were 34,806 penetrating keratoplasties (PKs), accounting for approximately 68% of all corneal grafts. Descemet stripping automated endothelial keratoplasty (DSAEK) accounted for 28% of transplants, or 14,159 procedures in 2007, an increase of over 135% from the previo us year. In addition , as surgeons strive for select ive removal of pathologic tissue while
preserving the healthy cornea, the indicatio ns and use of superficial anterior lam ellar keratoplasty (SALK) and deep anterior lamellar keratoplasty (DALK) have expanded. See Tables 16-1 and 16-2.
Surgical Approach to Corneal Disease The re are many options for surgical intervention to treat the large spectrum of corneal
disease. If the pathology is limited to the supe rficial 50-75 ~m of the cornea, phototherapeutic keratectomy (PTK) may be the best choice (see also Chapter 15). For corneal scarring or disease confined to the anterior third of the cornea, SALK is an excellent option. In patients with more extensive stromal disease and a healthy endothelium, such as with keratoconus, postinfectious keratitis, and corneal dystrophy or scarring. DALK is increas-
ingly popular. In cases of primary endothelial dysfunction such as Fuchs corneal dyst rophy, pseudophakic bullous keratopathy (PBK), or a failed corneal graft, EK has become the procedure of choice. However, full-thickness PK is a viable alternative for any type of corneal pathology and is particularly useful in patients with combined epithelial, stromal, and endothelial disease or with a failed graft with high astigmatism; or in cases where the surgical plan requires extensive anterior segment reconstruction and corneal surgery si-
multaneously. In the subset of patients with severe ocular surface disease or multiple graft failures, a keratoprosthesis may be the best prognosis for visual rehabilitation. The discussion of corneal transplantation in this chapter is intended to provide a basic understanding of surgical techniques involved with the procedures and is not m ean t
to be comprehensive. Many excellent resources available for this purpose are listed in the 413
414 • External Disease and Cornea Table 16-1 Indications for Penetrating and Lamellar Keratoplasty by Frequency Indications
Penetrating keratoplasty Keratoconus Repeat graft Post- cataract surgery edema Cornea l dystrophies and degenerations Fuchs dystrophy Mechanical or chemical trauma Microbial/postmicrobial kerat itis Congenita l opacity Post refractive surg ery Other causes of co rneal opacification or distortion lamellar keratoplasty Unspecified anterior stromal scarring Keratoconu s Ulcerative keratitis or perforati ons Corneal degenerations Pte rygium Trauma Postkeratectomy Reis-Buckl ers dystrophy
Frequency (percent)
--
19.6 15.7 15.7 12.6 9.2 2.9 2.8 1.7 0.2 19.3 32.7 27 .6 16.2 14.3 4.3 3.2 1.4 0.3
From Eye Bank Association of America. 2007 Eve Banking Statistics Report. www. restoresight.org.
references. Although most ophthalmologists do not perform corneal transplantation, all should be familiar with the preoperative evaluation for appropri ate referral of patients and postoperative managment if problems should arise. Eye Bank Association of America [www.restoresight.orgJ. Statistical Report all Eye Bal/king
Activity for 2008.
Preoperative Evaluation and Preparation
A complete eye exam ination is necessary prior to corneal transplantation, including a detailed social history to help determine whether the patient will be compli ant with the postoperative regim en and repo rt quickly if problems arise. Si mple clinical tests, such as those for color recognition or an afferent pupillary defect, can be very important in evaluating patients with media opacity. Ocular surface problems such as dry eye, trichiasis, exposure, blepharitis, an d rosacea must be recogn ized and treated prior to tra nsplantation. In older patients, the increased risk of problems with anesthesia and the rare complication of expulsive hemorrhage must also be considered. In additio n, the postoperative course may be more problematic due to the increased incidence of chronic epithelial defects, poor bli nk rate, infections, and wound dehiscence or slippage associated wit h slower wo un d healing. The preoperative evaluation should also address any neurologic or intraocular factors that cou ld compromise the final visual result, such as other m edia opacity, un controlled glaucoma, amblyop ia, macular abnormalities, ret inal disease, or optic nerve damage.
Table 16-2 Comparison of Procedures for Penetrating and Selective Keratoplasty Descemet Stripping Automated Endoth eli al Keratoplasty (DSAEK)
Superficial Anterior Lamellar Keratoplasty (SALK)
Deep Anterior Lamellar Keratoplasty (DALK)
Any st romal or endot heli al corneal patho logy
Endoth elia l dystrophy Pseudo ph akic bullous keratopath y ICE sy ndrome Fa il ed co rn ea l grafts
Intr!l0perative comp lications
Hemo rrhage Damage to lens/iris Irreg ular t rep hinat ion Poo r graft ce ntrati on Iris or vit reo us incarce ration in th e wo und Damage to do nor end ot helium
Ke ratoconus In fecti ons Co rnea l stroma l dyst rophies not involving en dot hel i um Co rneal 1hinning Co rn ea l ectasia seco nd ary to LAS IK Cornea l perforat ion req uiring tra nsition to PK Descemet's membrane spli tt in g
Posto perative comp lications
Wound leak Flat c hambe r Glauco m a Endopthalmiti s Persisten t epith el ia l defect Rec urrent prim ary disease Prim ary graft fa ilure Eroded infected sutures Graft rejection Co rnea l asti gm at ism
Poo r mic rokera tome di ssect ion o f donor tissue Inabil ity to strip Desce m et's tissue Loss o f orientation of t issue Poor ce nt ration o f treph ination, leading to a th ick edg e an d possible epi thelia l in growth Int raocula r hem orrhage leading to hem e in t he interface Excess ive man ipu lation o f t iss ue, leading to ce ll loss Pupill ary block Dis location of lenticule Difficulty fo ll owing i ntraoc ul ar pressure Prim ary gra ft failure Epith eli al in grow th
Superfic ial stroma l dystrophies and degenerati ons Sa lzma nn nodular dege nerat ion Sca rs/tra u m a/de rm oids In fections Poo r m icrokeratome dissecti on Corneal perforat ion
Loss o f donor lent icule
Opac ifi cat ion an d vasc ul ar ization of interface All og raft rejection Inflamm atory nec rosis of the graft
Procedure
Penetrating Keratoplasty
Indications
(Continued )
Table 16·2 (co n t in ued) Oesce met Stripp ing Automated
Procedure
Penetrati ng Kerato pl asty
Endothe li al Kerato pl asty (DSAEK)
Advantages
Fu ll-thickness tissue elimin ates interfacerelated visual problem s
Rapid visual rehabilitation Ind ependent of ocu lar su rface wo un d hea lin g Stab le co rn ea l curvature for t ripl e procedures Tecton ica ll y stro ng Elim inates suture- rel ated problems
Disadva ntages
Difficult to dete rmin e ante rio r co rn ea l curvature, leading to significa nt refractive error Postoperative astigmat ism Ocular surface disease or
Sig nifica nt st romal ha ze, subepi th elial fibro sis, or ep ith elial irregu larity may require seco nd proced ure Possible highe r rate of end othelia l cell loss
neu rotroph ic cornea leads to prolonged hea ling or persisten t epithelial defect
Sup erficial Anterior Lame ll ar Keratopl asty (SALK)
Deep Ante rior Lamella r Keratopl asty (DALK)
Selective rem ova l of patho logic tissue More rapid visual rehabi litation Less need for sut ures Minima l requi rem ents for donor t issue Reduced risk fo r graft reject ion Reduced risk of penet ration into the anterior chamber Less risk for poorly co mpli ant pat ien t, eye rubb er Irregu lar interface Irregu lar surface if lenti cu le shifts Interface vasc ularizaton
Tectonica lly stronger wo und than in PK Early rem ova l of sutu res Less d ependence on topica l co rt icosteroid s M inim al req u iremen ts for don or ti ss ue
Irreg ul ar in terface
CHAPTER 16:
Cl inical Approach to Corneal Transplantation.
417
. Preexisting glaucoma or ocular inflammation should be controlled before transplantation is considered. Active keratitis or uveitis is treated medically if possible, and the eye should ideally remain quiet for several months prior to surgery. An inflamed eye at the time of surgery is associated with a higher incidence of postoperative complications, such as graft rejection and failure, glaucoma, and cystOid macular edema . For example, corneal perforations in an acutely inflamed eye should, if possible, be closed either with cyanoacrylate tissue adhesive fo r a small perforation or by means of a lamellar corneal graft in order to restore the integrity of the globe and allow the eye to become quiet. A vision- restoring transplant may then be undertaken at a later date. A lamellar graft should at least be considered in any case with normal endothelium. Fluorescein angiography or optical coherence tomograpy (OCT) can be helpful in detecting retinal problems such as cystoid macular edema and age-related macular degeneration. If the media are completely opaque, standard B-scan for evaluating the posterior segment or ultrasound biomicroscopy (UBM) for evaluating the anterior segment may reveal problems that could affect the visual prognosis after transplant. The potential visual acuity meter, laser interferometer, blue-field entoptic phenomenon testing, vis ual fields , color discrimination, 2 points of light separation, and visually evoked cortical potentials may also help in preoperative assessment of the afferent system. In general, deep corneal vascularization, ocular surface disease, active anterior segment inflammation, peripheral corneal thinning, previous graft failures, poor compliance, and increased lOP worsen the prognosis for transplantation and thus influence the appropriateness of th is procedure for the affected patient.
Surgical Technique for Penetrating Keratoplasty Preparation of donor cornea
Donor tissue is most commonly prepared by trephination of the tissue - that is, centering the previously excised corneoscleral donor tissue, endothelial side up, in the concave well of a cutting block apparatus that approximates the cornea's shape. Sharp d isposable blades are vertically advanced along a guiding shaft to punch the button in a precise, crisp, guillotine fashion . The main goal is to obtain a central donor button with smooth vertical side cuts. Currently, femtosecond laser technology allows for the creation of mushroom shaped or inverted mushroom- shaped side incisions, top-hat configurations, and zigzag shapes. These wo und configurations can also be fashioned with a manual lamellar dissection using an artificial anterior chamber for the donor tissue and a suction trephine for the host. The new side configurations are reported to produce more rapid wound healing, allow early suture removal, create a stronger and more stable graft-vs -host interface, and induce less astigmatism. At this point, however, there are no studies demonstrating the clinical superiority of the shaped incisions. Each of these techniques has advantages and disadvantages relative to experience, cost, convenience, availability, and clinical scenario. Most surgeons size the donor button 0.25-0.50 mm larger than the diamete r of the host corneal opening (eg, an 8.0-mm -diameter corneal button for a 7.S- mm wound ). This size disparity may reduce postoperative glaucoma, enhance watertight wound closure, prevent peripheral anterior synechiae formation and excessive postoperative corneal
418 • Externa l Disease and Cornea
flattening, and provide the recipient eye with more endothelial cells. In ke ratoconus, especially in eyes with high axial length, sizing the donor tissue to match the exact size of the wo und may flatten the corneal contour and thereby reduce postoperative myopia. Preparation of recipient eye For safety purposes, it is recommended that all donor preparations be completed before trephination of the recipient eye. For preparation of the host bed, use of the traditional handheld trephine is still one of the most common methods because it offers convenience and low cost, requires only sharp disposable blades, and has design simplicity. However, hand fixation and rotation may lead to tilting and irregularity of cut as well as to unanticipated anterior chamber entry. Corneal vacuum trephines offer improved accuracy and consistency of cut, depth control, disposability, suture placement marking points, and relatively low cost. Disadvantages include outward beveling of the posterior corneal edges in deep trephination, slightly reduced observation, and more complexity than with a traditional trephine. The Hanna Trephine System (I-Med Pharma, Quebec, Canada) offers the advantages of less recipient edge undercutting and precision of cut depth. Its disadvantages include cost, complexity, and the surgeon's reduced visualization of the cornea when applying the device. Femtosecond laser technology can also be used to prepare the host bed so it matches the shaped side incisions in the donor tissue. Difficulties encountered with the use of the femtosecond laser include limited accessibility, increased costs, and the possibility that the treatment must be performed at a different locati on or time from the rest of the procedure. After completion of the treph ination and excision of the diseased cornea, the donor corneal button is placed onto th e recipient's eye, endothelial side down. Use of viscoelastic material helps protect the donor endothelium during surgical manipulation, keeps the anterior chamber formed, and shields the iris while the donor button is being sutured into the wo und. Suture techniques The donor button is secured with at least 4 interrupted cardinal sutures. The second cardinal suture is the most important because a mistake at this stage in anchoring the button 180 away from the first suture has the greatest mathematical potential, in principle, for misalignment error and subsequent astigmat ism. Complete wound closure is achieved wi th interrupted sutures, 1 or 2 continuous sutures, or a combination. The suture knots may be positioned in either donor or host tissue and are buried in the corneal stroma, not left in the wound interface. Most corneal surgeons prefer deep partial- thickness corneal suture bites over full -thickness bites. Incorporati ng 95% of the donor's and host's relative corneal thickness avoids posterior wound gape. Full-thickness bites may be associated with a higher chance ofleakage along suture tracks and serve as a portal of entry for microo rgan isms or epithelial ingrowth. The adva ntages of deep sutu re placement with either technique are decreased posterior wound gape and enhanced wound stabilization and healing. A va riety of techniques are used to complete the suturing, depending on the clinical situation and preference of the surgeon. Vasc ularized, in flamed, or thinned corneas tend to heal unevenly and unpredictably. Interrupted sutures, usually 16- 24 in number, are the technique of choice in such corneas, as well as in pediatric keratoplasties, where wound 0
418 • Externa l Dis eas e and Cornea
fl atten ing, and provide the recipient eye with more endothelial cells. In keratoconus, especiall y in eyes wi th high axial length. sizing the donor tissue to match the exact size of the wo und may flatten the corneal contour and thereby reduce postoperati ve myopia.
Preparation of recipient eye For safety purposes. it is recommended that all donor preparations be completed before trephination of the recipient eye. For preparation of the host bed, use of the traditional handheld treph ine is still one of the most common methods because it offers conven ience and low cost, requ ires only sharp disposable blades, and has design simplicity. However, hand fixation and rotation may lead to tilting and irregularity of cut as well as to unantici pated anter ior chamber entry. Corneal vacuum trephines offer improved accuracy and consistency of cut, depth control, disposabili ty, suture placement marking points, and relatively low cost. Disadvantages include outward beveling of the posterior corneal edges in deep trephination, slightly reduced observation, and more complexity than with a traditional trephine. The Hanna Trephine System (I-Med Phann a. Quebec, Canada) offers the advantages of less recipient edge undercutting and precision of cut depth. Its disadvantages incl ude cost, compleXity, and the surgeon's reduced visual ization of the cornea when applying the device. Femtosecond laser technology can also be used to prepare the host bed so it matches the shaped side incisions in the donor tissue. Difficulties encountered with th e use of th e femtosecond laser include limited accessibility, increased costs, and the possibility that the treatment must be performed at a different location or time from the rest of the procedure. Afte r com pletion of the trephination and excision of the diseased cornea, the donor cornea l button is placed onto the recipient's eye, endothelial side down. Use of viscoelastic material helps protect the donor endothelium during surgical manipulation, keeps the anterior chambe r fo rm ed, and shields the iris while the donor button is being sutured into the wound. Suture techniques The donor button is secured with at least 4 interrupted cardinal sutures. The second cardinal suture is the most important because a mistake at this stage in anchoring the butto n 180' away from the ftrst suture has the greatest mathematical potential, in principle. for misalignment error and subsequent astigmatism. Complete wound closure is achieved with interrupted sutures, 1 or 2 continuous sutures, o r a combination. The suture knots may be positioned in either donor or host tissue and are buried in the corneal stroma, not left in the woun d interface. Most corneal surgeons prefer deep partial-thickness corn eal suture bites over full -thickn ess bites. Incorporating 95% of the donor's and host's re lative corneal thickn ess avo ids posterior wound gape. Full-thickness bites may be associated with a higher chance of leakage along suture tracks and serve as a portal of entry for microorganisms or epitheli al ingrowth. The advantages of deep suture placement with either techniq ue are decreased posterior wound gape and enhanced wound stabilization and healing. A variety of techn iques are used to complete the suturing, depend ing on the clinical situation and preference of the surgeon. Vascu lar ized, inflamed, or thinned corneas tend to heal uneve nly and un predictably. Interrupted sutures, usuall y 16-24 in number, are the technique of choice in such corneas, as well as in ped iat ric keratoplasties, where wound
CHAPTER 16:
Figure 16·1 place.
Clinica l Approach to Corneal Transp lantation . 419
PK for syphilitic interstitial keratopa thy, with 24 interrupted 10-0 nylon sutures in
healing is rapid (Fig 16- 1). The tension of each interrupted suture acts as an independent vector, generating central steepening and local flattening. Sutures may be removed selectively in the presence of sufficient donor-recipient interface healing if they attract blood vessels or if they loosen because of wound contraction. Astigmatism may be reduced postoperatively by selective removal of sutures in the steep corneal meridian, although premature removal risks wound dehiscence or slippage. In the absence of vascularization, foca l inflammation, or thi nning, single or double continu ous sutures or combin ed interrupted and continuous sutures can be used to secure the PK (F igs 16-2, 16-3). If properly placed, continuous sutures may allow more even distribu tion of tension and healing around the wound. Suture passes may be placed radially to the donor- recipient wound or be placed torque-free. The advantages of running sutures include their ease of removal postoperatively. Disadvantages include sectoralloosening. o r cheese wiring. which may compromise the entire closure. The combined interrupted and continuous suture technique offers several of the advantages of both methods. The interrupted sutures may be removed earlier after PK in order to reduce corneal ast igmatism, whereas the continuous suture remains to protect against wound dehiscence. There is no consensus as to whether the combined technique or the running techniques produce less astigmatism. Many variables contribute to astigmatism, but the key suturing principle is uniform placement to minimize uneven suture tension, t.issue torque, and distortion, thereby achieving secure closure without override or posterior wound gape.
Combined Procedures Penetrating keratoplasy may be combined with other procedures such as cataract extraction, primary or secondary IOL implantation, IOL removal or exchange, glaucoma surgery, vitrectomy, and ret inal procedures. Synechiolysis can be performed with caution- excessive
420 • External Disease and Cornea
Figure 16·2
PK for pseudophakic cornea l edema, wi th si ngle continuous 10-0 nylon su t ure in
place.
Figure 16·3 Combin ed sut uring tec hnique employs both in terrupted and continu ous 10-0 nylon su tures. (Courtes y of Robert W. Weise nthal. M O.)
bleeding, tearing, or tissue and inflammatory exudation must be avoided. Iris defects may be repaired with 10-0 Prolene sutures to achieve pupil constriction, eliminate monocular diplopia, improve spectacle acuity, reduce glare, and minimize chances of iridocorneal adhesion. Iris segments and combined iris and IOL prostheses (eg, devices by Marcher and Ophtec) may be available un der a Humanitarian Device Exemption application (see BCSC Section 13, Refractive Surgery). In eyes at risk for postoperative uveitis (eg, those with herpes simplex or interstitial keratitis), a peripheral iridectomy may reduce the chance of postoperative pup,illary-block glaucoma.
CHAPTER 16:
Clinica l App roach to Corneal Transplantation . 421
Intraoperative Complications Complications that can occur dur ing PK include the following: damage to the lens and/o r iris from the trephine, scissors, or other instruments irregular trephination inadequate vitrectomy resulting in vitreous contact \vith graft endothelium poor graft centration on the host bed excessive bleeding from the iris and wound edge (in vascularized host corneas) choroidal hemorrhage and effusion iris incarceration in the wound damage to the donor endothel ium duri ng trephination and handling In severely edematous corneas, rec ipient Descemet's membrane may be inadvertently left behind after corneal excision, as it is eaSily stripped completely from the stroma. Thus, the recipient eye must be carefully examined fo r retained Descemet's membrane; donor endothelium resting against host Descemet's membrane may severely compromise the graft.
Postoperative Care and Complications The postoperative care of a corneal transplant is far more complex than that fallowing cataract surgery. The long-term success of a PK depends on the quality of the postoperative care as much as on the performance of the operative technique. Routine postsurgical care-use of topical antibiotics, tapering topical corticosteroids, and frequent office visits-is directed at prevention and earl y recognition of the myriad complications that can occur after PK, as well as optimizing postoperative wound healing and facilitating rapid visual rehabilitation. This section covers some of the more common postsurgical complications. Astigmatism and graft rejection are discussed separately.
Wound leak The wound is always checked carefully fo r leakage at the end of surgery. Small wound leaks that do not cause anterior chamber shallowing freq uently close spontaneously. Patching, th erapeutic contact lenses, and use of aqueous prod uction inhibitors may hasten wound closure. Resuturing is advised for leaks lasting longer than 3 days.
Flat chamber/iris incarceration in the wound Both flat chamber and iris incarceration in the wo und imply either poor wound integrity or excessive posterior pressure. and early surgical intervention is advised.
Glaucoma High lOP may occur at any time after PK. Often, the first clinical sign is the loss of folds in Descemet's membrane, usually seen in the earl y postoperative period. Glaucoma should be treated aggressively with medical, laser, or su rgical intervention as indicated. Unusual causes include epithelial downgrowth or fi brous ingrowth. (See BCSC Section 10,
Glaucoma.)
422 • External Disease. and Cornea
Endophthalmitis
After PK, endophthalmitis may arise from intraoperative contamination, donor button contamination, or postoperative invasion by organisms. Aggressive intervention can save the eye and vision in some cases. (See BCSC Section 9, Intraocular Inflammation and Uveitis.) Primary endothelial failure When a graft is edematous from the first postoperative day and remains so without inflammatory signs, a deficiency of donor endothelium is presumed (Fig 16-4). Most surgeons allow at least 4 weeks and up to 2 months for spontaneous resolution of edema and only then consider a regraft. Persistent epithelial defect
Large epithelial defects are common after PK, but they should heal within 14 days. After this time, irreversible scarring and ulceration may occur. Ocular surface disease (such as dry eye, exposure, rosacea, blepharitis, or trichiasis) should be ruled out or treated. Lubrication, patching, therapeutic contact lenses, punctal occlusion with plugs or cautery, and tarsorrhaphy may be helpful in difficult cases. If these are not successful, herpetic keratitis should be considered in the differential diagnosis, even in cases where this was not the un derlying reason for the graft (Fig 16-5). Oral antivirals may be used as a therapeutic trial. Otherwise, management is similar to that used in treating neurotrophic keratitis. Recurrence of primary disease Bacterial, fungal, viral, and amebic keratitis can recur in a graft. Medical treatment directed at the causative agent in recurrent infections is the initial form of therapy. In patients with superficial recurrent corneal stromal dystrophies such as granular or lattice dystrophy, PTK can be used to remove visually significant lesions (Fig 16-6).
Figure 16-4
Primary endothelial fa il ure after PK.
CHAPTER 16:
Figure 16-5
Clini cal Appro ac h to Corneal Transplanta tion .
423
Herpes simplex vi rus keratitis recurring in a graft.
Recurrence of granular cornea l dystrophy after cornea l transplantation. Arrowhigh lights deposition of new granular material within suture tract . (Courtesy of Robert W Weisenthal, MD.)
Figure 16-6
Suture-related problems Postoperative problems related to sutures include the following: excessive tightness loosening (usually as a result of wo und contraction, resolution of graft- host junction edema, suture breakage, or suture cheese wiring) (Fig 16-7) breakage of running suture infectious abscesses (usually localized around loose, broken, or exposed sutures~ Fig 16-8) noninfectious (toxic) suture infiltrates (Fig 16-9) • giant papillary conjunctivitis from exposed knots vascularization along sut,ure tracks
424 • Exte rnal .Disease and Corn ea
Figure 16·7 Broken running suture after PK. It should be removed to avoid further vasculariza· tion, infection, and graft rejection. (Courtesy of Robert W Weis8nthal. MD.J
Figure 16·8
Suture abscess caused by Streptococcus pneumoniae, 2 years after PK.
Figure 16·9
Deep, noninfectious tox ic suture infiltrates aher PK.
CHAPTER 16:
Clini cal Approach to Corneal Transplantation.
425
Loose and broken sutures do not contri bute to wo und stability and, therefore, should be removed as soon as possible. Totally buried interrupted suture fragments may be left. Vascularization along the suture indicates that the wound is adequately healed in the vicinity and that sutures may be removed safely. Vascularized sutures are also prone to loosening and may increase the chance of graft rejection. If only a small segment of the running suture is eroded, it is possible to remove th is portion while leaving the remainder intact, especially if no Significant corneal astig matis m is present. Patients should be warned to return if a foreign -body sensation is noted, as contiguous portions of a running suture may loosen and erode at a later date. After the sutures are removed, there may be a dramatic shift in refractive error or astigmatism, so the patient should be seen for followup to ensure wound stability and to recheck refrac tion. Microbial keratitis The use of topical corticosteroids, the presence of epithelial defects or edema, and exposed sutures predispose the PK patient to infectious keratitis, sometimes with unusual organisms. Decreased corneal sensation and topical corticosteroid use may also delay presentation. Lesions must be scraped immediately fo r diagnosis, and broad-spectrum antibiotic therapy initiated, in order to preserve the graft. A peculiar form of keratitis, infectiOUS crystalline keratopathy, is seen in grafts and nther immu nocompromised corneas (Fig 16-10). Branching colonies of organisms prolife rate in the deep corneal stroma with no visible inflammatory response. Many organisms have been implicated, but Streptococcus viridans is seen most frequently. Late nonimmune endothelial failure When a graft becomes edematous after months to years without inflammatory signs, 2 causes are possible. First, the tissue might have originally possessed a marginal number of endothelial cells, and the normal spreading of these cells has resulted in inability to maintain graft clarity. Alternatively, Significant loss of endothelial cells might have
Figure 16-10
Infectious crysta lline keratopat hy after PK.
426 • External Disease and Cornea
occurred later in the postoperative period; possible causes of such a loss include successfully treated rejection episodes, retention of an intraocular lens that caused endothelial damage, or persistent loss due to periphera l anter ior synechiae.
Control of Postoperative Corneal Astigmatism and Refractive Error A corneal transplant was once considered successful merely if the graft remained clear. Only later in the refinement of surgical procedu res was the vex.ing and relatively common problem of high corneal astigmatism after surgery seriously addressed. Severe astigmatism may be associated with decreased visual acui ty, anisometropia, aniseikonia, image distortion, and monocular diplopia, thus renderi ng an otherwise successful operation in-
effective. Astigmatism is the most frequent complication of PK. It may result in anisometropic asthenopic symptoms or in the inabiLi ty to wear contact lenses. Many methods have been used to reduce the occurrence, includ in g varying suture techniques making intraoperative adjustments improving trephines and use of new technology, such as the femtosecond laser, to
better match donor and host selective suture removal or adj ustment of the running suture using computerized
videokeratography and wavefront analysis for postoperative management The primary method to minimize astigmatism in the corneal graft postoperatively is to readjust or remove the sutures. If a Single running suture technique has been used, the surgeon may redistribute the suture tension at I month postoperatively using cornea] to -
pography as a guide. Alternatively, if th ere is a combination of running and interrupted sutures, the interrupted sutures can be removed starting at 1 month. If the patient has only interrupted sutures, then suture removal should begin at a later stage to avoid wound
slippage or dehiscence. Clinicians must be especially careful with older patients placed on long-term topical corticosteroid therapy, as the wou nd healing may be even slower. Managing astigmatism is similar with any type of suturing technique. The most critical step is to identify the steep ax.is using corneal topography, handheld keratoscopy, photokeratoscopy, or man ual kerato metry. For example, in Figure 16-11 the SIM K readi ngs show the steep axis of 49.93 at II and the fl at axis of 44.06 at 101. The photokeratoscopy shows clear rings that are ovalized, with the shorter axis horizontally corresponding to the steep axis. The presence of distinct rings demonstrates the smooth surface indicative of regular astigmatism. Rings that are very irregular or indistinct indicate irregular astigmatism. In the latter case, caution or delayed suture removal or adjustment is required.
A manifest refraction is helpful to confirm the steep axis (positive cylinder). The auto refraction in Figure 16-11 is - 9.00 + 6.75 at 4°. The manifest refraction is -7.00 + 5.00 at 4°, providing 20/25 acuity; the good visual ac uity confir ms the presence of regular astigmatism . Removin g the interrupted sutures at the 4° meridian or adjusting the runn.ing
suture will compensate for the induced astigmatism. After manipulation or removal of the sutures, the patient is placed on a topical anti biotic for 4 days, and a return visit scheduled for 1 month for repeat corneal topography and manifest refraction.
CHAPTER 16:
Clinica l Approach to Cornea l Transplantation.
427
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RelaXing incisions are used to reduce astigmatism if a large amount of res idual astigmatism is present after all sutures have been removed. Incisions are placed either in the
donor cornea anterior to the graft-host junction or in the graft- host interface at the steep (plus cylinder) meridian in an arcuate manner for maximum effect (astigmatic keratot· amy [AKJ). The effect can be augmented by suture placement at the flat meridian. LASIK, photo refractive astigmatic keratectomy, and femto second laser- assisted astigmatic keratoplasty have also been used to manage astigmatism (see BCSC Section 13, Refractive Surgery).
All of these procedures are associated with the potential for micro- or macroperforation. infection. rejection. under- and overcorrections, chronic epithelial defects, and worsening of irregular astigmatism. Bahar J, Levinger E. Kaiserman 1. Sansanayudh W, Rootman DS. Intra lase enabled astigmatic keratotomy for postkeratoplasty astigmatism. Am J Ophthnlmol. 2008; 146(6):897-904. Speaker MG, Haq F, Latkany R, Reing CS. Postkeratoplasty astigmatism. In: Krachmer JH, Mannis MJ, Holland EJ, eds. Cornea. 2nd ed. Vol 2. Phlladelphia: Elsevier/Mosby; 2005,1527- 1539.
Diagnosis and Management of Graft Rejection Corneal allograft rejection rarely occurs within 2 weeks, and it may occur as late as 20 years after PK. Fortunately, most episodes of graft rejection do not cause irreversible graft failure if recogni zed early and treated aggressively with corticosteroids. Early recognition is the key to survival of ap affected corneal graft. Corneal transplant rejection takes
42 8 • Exte rnal Disease and Corne a
4 clinical forms, descri bed in the following sections, which may occur either singly or in combination.
Epithelial rejection The immu ne response may be directed entirely at the donor epit heliu m (Fig 16-12). Lym phocytes cause an elevated, linear epithelial ri dge that advan ces centripetally. Because host ceUs replace lost donor epitheliu m, this form of rejectio n is problematic o nl y in that it may herald the onset of endothelial rejection. Epithel ial rejection has been reported at a rate of 10% of those patients experiencing rejection, and it is usually seen earl y in the postoperat ive period (1 - 13 months).
Subepithelial rejection Corneal transplant rejecti on may also take the for m of subepithelial infil trates (Fig 16- 13). When seen alone, they may cause no symptoms. It is not known whether these lymphocytic
Figure 16-1 2
PK.
An epithelial rejection line (arrow) witt, subepithelial infiltrates (arrowhead) after
(CourTesy of Robert W. Welsenthal, MD.)
Figure 16-13 Bouchard, MO)
Corneal graft rejection manifested by subepithelial infiltrates. (Counesyof Charles S.
CHAPTER 16: Clinical Approach to Corneal Transplantation . 429
cells are directed at donor keratocytes or at donor epithelial cells. A cellular anterior chamber reaction may also accompany this form of rejection. Easily missed on cursory examination, subepithelial infiltrates can best be seen with broad, tange ntial light. They resemble infiltrates of adenoviral keratitis. Subepithelial graft rejection leaves no sequelae if treated, but it may presage the more severe endothelial graft rejection.
Stromal rejection Isolated stromal rejection is not common but can be seen as stromal infiltrates, neovascularization, or typicall y noninfiltrative kerato lysis within the graft- host interface not extending into the periph era.l recipient stroma. In very aggress ive severe or prolonged bouts of graft rejection, the stroma can become necrotic.
Endothelial rejection The most common form of graft rejection is endothelial rejection, with reported rates of 8%-37%. It is also the most serious form of corn eal transplant rejection, because endothelial cells destroyed by the host response can be replaced only by a regraft. Inflammator y precipitates are seen on the endothelial surface in fin e precipitates, in random clumps, or in linear form under an area of corneal edema (Khodadoust line; Fig 16- 14). Inflammator y cells are usually seen in the anterior chamber as well. As endothelial function is lost, the corneal stroma thickens and the epitheliu m becomes edematous. Patients have symptoms related to inflammation and corneal edema, such as photophobia, redness, irritation, halos around lights, and fogginess of vision .
Treatment Freq uent adm inistration of corticosteroid eyedrops is the mainstay of therapy for corneal aIlograft rej ection. Either dexamethasone 0. 1% or prednisolone 1.0% eyed cops are used as often as every 15 minutes to 2 hours, depending on the severity of the episode. Altho ugh topical corticosteroid ointments may be used on occasion, their bioavailability is not as beneficial as that of frequentl y applied eyedrops. Corticosteroids may be given by periocular injection (triamcin olon e acetonide 40 mg) for severe rejection episodes or noncompliant patients. In particularly fulminant cases,
•
Fig u r. 16· 14 Endothelial graft rejection with stromal and epithelial edema. Note the Khodadoust line (arrows). (Courtesy of Roben W Weisenthal. MD.)
430 • Ext ern al Disease and Corn ea
systemic corticosteroids may be adm inistered either orally (40-60 mg per day tapered as the graft rejection responds) or intrave nously (1 25-500 mg methylprednisolone as a I-time dose).
Prevention A number of practices will minimize or reduce rejection. Attention to surgical techn iques to avoid the peripheral cornea and ensure proper graft- host junction alignment will minimize rejection, for example, as will early attention to loosening sutures and infections. Chronic topical corticosteroids or immunosuppressi ng agents such as cyclosporine may reduce episodes of rejection as well. In high-risk cases, the use of various immunosuppressing agents, including oral cyclosporine, tacrolimus, and CellCept, have been reported, but these require very careful fo llow-up because of the na rrow therapeutic index of these medications. Topical tacrolimus has also been advocated in high-risk patients. Bahar I, Kaiserman 1, Srinivasan S, Va-Pi ng J, Siomovic AR, Rootman DS. Comparison o f three di fferent tech niques of corneal transplantation for keratoconus. Am , Ophtha/. 2008; 146(6) ;905-912. Dhaliwal IS, Mason SF, Kaufman Sc. Long-term use of topical tacrolimus (FKS06) in h igh. ri sk penetrating keratoplasty. Cornea. 2008;27(4):488 - 493. Krachmer ]H, Mannis M], Holland E], eds. Co rnea. 2nd ed. Vol 2. Part IX: Penetratin g Keratoplasty. Philadelphia: Elsevier/Mosby; 2005: l 4 13-1666.
Pediatric Corneal Transplantation Corneal transplantation in infants and children presen ts special challenges. The issues involved in preoperative evaluation and anesthesia concerns are summarized by Maxwell. Improvements in ped iat ric anesthesia and the recognition that development of amblyopia is a major impedi ment to useful vision have led to PK being performed in neonates as early as 2 weeks after birth. Increased understanding of the special problems associated with pediatric grafts and advances in surgical methods have im proved the outlook for corneal transplants in this group. However, the prognosis in pediatric transplantation is still guarded and, in many cases, dependent on the extent of coexisting ocular abnormalities. For example, the most common indication for pediatric keratoplas ty is Peters anomaly. In type I disease, with a central corneal opacity and a normal anterior segment, the survival rate fo r a clear graft ranges from 48% to 67%. In type 2 disease, characterized by adhesions among the cornea, iris, and lens; corneal neovascularization; glaucoma; cataract; and corneal staphyloma, more extensive surgery is required. Unsurprisingly, the survival rate of the transplant decreases to 0%-22%. The probability of a repeat graft surviving fo r 3 years is less than 10%. In addition , the success of the procedure is very depende nt on the dedication of the family to foll ow a ri gorous postoperative regimen , includ ing repeat examinations unde r anesthesia and compliance with medications. Postoperative glaucoma, strabismus, selfinduced trauma, and immune rejection are extremely common. Prior to surgery, the physician must reserve ti me to discuss with the fam ily the ma ny diffic ult issues associated with surgery, including Significant risks, guarded prognosis, high costs, loss of time from
CHAPTER 16:
Cl inical Ap proach to Corn eal Transplantatio n . 431
Table 16-3 Guidelines for Suture Removal in Pediatric Corneal Transplants Age of Child
liming of Suture Remova l
6-9 mont hs 12- 24 months 2-3 ye ars 4-6 years 10 yea rs unt il teens Teenage
Approxi ma tely 5 weeks postoperatively 6-8 weeks postoperatively 8-12 wee ks postoperatively 4 months postoperative ly 6 mont hs posto peratively Approximate ly 9 months postoperatively
work Cwith associated loss of income), the extensive ongoing care required by the child, disruption of home life, and less time to attend to other dependents. Corneal grafting in children under the age of 2 is associated with rapid neovascularization, especially along the sutures. As the wound heals, erosions may occur along the sutures, leading to eye rubbing, epithelial defects, vascularization, and mucus accumulation. Suture erosion has been reported to occur as early as 2 weeks postoperatively in infants, which necessitates suture removal. In general, suture removal is best performed in the operating room for pediatric cases. Table 16-3 lists guidelines for the timi ng of suture removal. Also, it must be stressed that until all sutures are removed in infants or young children, frequent examinations are required. Early fitting with a contact lens Cas early as the time ofPK) and ocular occlusive therapy are necessary to stem development of amblyopia in children with monocular aphakia. As lamellar surgery has become more popular in the adult population, DALK may be an option for certain pediatric patients with stro mal scarring without any other corneal pathology. If the disease is primarily endothelial, then EK may be a good alternative in the appropriate patient. Some surgeons favor the use of a keratoprosthesis in pediatric patients with previous graft failures, multiple surgeries, or inflamed eyes. Botelho pJ, Congdon NG, Handa JT, Apek EK. Keratoprosthesis in high-risk pediatric corneal transplantation: first 2 cases. Arch Ophthalmol. 2006;124(9 ):1356- 1357. Dana MR, Schaumberg DA, Moyes AL, Gomes JA. Corneal transplantation in children with Peters anomaly and mesenchymal dysgenesis. Multicenter Pediatric Keratoplasty Study. Ophthalmology. 1997:104(10): 1580-1586. M3X\vell, C . Age-associated issues in preoperative evaluation, testing, and planning: pediatrics. Anesthesiol Clin North America. 2004;22:27 - 43. Yang L1, Lambert SR, Lynn MJ, Stulting RD. Long-term results of corneal graft survival in infants and child ren with Peters anomaly. Ophthalmology. 1999;106(4):833- 848 .
Corneal Autograft Procedures The greatest advantage of a corneal autograft is the elimination of allograft rejection. Although cases with clinical circumstances appropriate for autograft are uncommon, an astute ophthalmologist who recognizes the possibility of a successful autograft can spare a patient the risk oflong-term topical corticosteroid use and the necessity of lifelong vigilance against rejection.
432 • External Di sease and Cornea
Rotational Autog raft A rotatio nal autograft can be used to repos it ion a localized corn eal scar that involves th e pupillary axis. By makin g an eccentric trephi natio n and rotati ng th e host butto n prior to resuturing, the su rgeon can place a paracentral zone of clear cornea in the pupillary
axis. The procedure is particularly useful in children, who have a poorer prognosis for PK, and in areas with tissue scarcity. Graft edema can still be a problem, because both the preexisting disease or scar and the rotational procedure usually cause endothelial cell loss. Residual postoperative astigmatism is also a problem because of the eccentric location of the graft. Wound leaks occur frequ entl y. Bourne WM, Brubaker RF. A method for ipsil ateral rotational autoke ratoplasty. Ophthalmol-
ogy. 1978;85(12):1312-1316. Murthy S, Bansal AK, Sridhar MS, Rao GN. Ipsilateral rotational autokeratoplasty: an alternative to penetrati ng keratoplasty in nonprogressive central corneal sca rs. Cart/ea. 200 1;20(5): 455 - 457.
Contralateral Autograft A cont ralateral au tograft is reserved fo r patients who have in 1 eye a corneal opacity with a favorable prognosis for visual recovery and in the other eye both a clear cornea and severe dysfunction of the afferent system (eg, retinal detachment, severe amblyopia). The clear cornea is transp lanted to the first eye, and the cornea fro m the second eye is replaced either with the diseased cornea from the fi rst eye or with an allograft, or the eye is eviscerated or enucleated. Such bilateral grafting ca rries the risk of bilate ral endophthalmitis.
Keratoprosthesis Some patients have an extremely guarded prognosis for corneal transplantation due to a history of multiple graft failures or associa ted ocular surface disease, as seen with chronic bilateral inflammation from Stevens-Johnson syndrome or pemphigoid. These patients may be good candidates for a synthetic ke ratoprosthesis. Claes Dohlman, a pioneer in the development of the keratoprosthesis, di vides these high-risk patients into 2 groups: those with a good blink and wet eye and those with Significa nt conjunctival scarr ing, dry eye, and exposure. In the fi rst group of patients, the Boston Keratoprosthesis (KPro) Type I (Massachusetts Eye and Ear Infi rmary, Boston), made of medical-grade polymethylmethacrylate, works well (Fig 16-15). Another option is the AlphaCor keratoprosthesis (Add ition Technology, Su nnyvale, CAl. The prognosis with a keratoprosthes is has improved dramat icall y due to innova-
tions in the design of keratoprostheses and a better understandi ng of the postoperati ve management of these patients. The use of a soft contact lens and long- ter m prophylac tic antibiotics have reduced the incidence of infec tion and breakdown of tissue around the
keratoprosthesis. For patients with end-stage dr y eye, the Boston Type 11 KPro is an excellent alternative. Other types of keratoprostheses are available fo r these high-risk patients, such as the TKPro, which uses tibia bone tissue, and the osteo-odonto-keratoprosthesis (OOKP), which uses den ti ~e and alveolar bone tissue.
CHAPTER 16:
Clinical Approach to Corneal Transplantation.
Figure 16-15
433
Bost on ke ratoprost hesis . (Cour-
tesy of Jam es J. Re idy, MD.)
The most common complications associated with keratoprosthesis implantation include necrosis of tissue around the synthetic device, postoperative inflammation producing retroprosthesis membranes, vitreous opacities, retinal detachment, and macular edema. There is also the risk of significant glaucoma and infection. However, in general, the success rate with keratoprostheses has improved significantly due to the evolution in design of the synthetic devices and better patient care postoperatively. Dohlman CH, Barnes S, Ma J. Keratoprosthesis. In: Krachmer JH, Mannis MJ, Holland EJ, eds. Cornea. 2nd ed. Vol 2. Philadelphia: Elsevier/Mosby; 2005:1719- 1728. Hille K, Hille A, Ruprecht KW Medium term results in keratoprostheses with biocompatible and biological haptic. Graefes Arch Clin Exp Ophthalmol. 2006;244(6);696-704. Nouri M, Terada H, Alfonso EC, Foster CS, Durand ML, Dohlman CH. Endophthalmitis after keratoprosthesis: incidence, bacterial causes, and risk factors. Arch Ophthalmol. 2001;119(4);484- 489.
lamellar Keratoplasty With advances in instrumentation and techniques, the selective removal of corneal tissue with lamellar keratoplasty (LK) has become a much more popular procedure. The general ophthalmologist should be familiar with the special indications and limitations of the major techniques of LK, including SALK, DALK, and EK.
Anterior lamellar Transplantation Lamellar corneal grafting may be indicated in patients who present with opacities or loss of tissue that, for the most part, does not involve the full thickness of the cornea (Fig 16-16). These conditions include superficial stromal dystrophies and degenerations Ceg, Reis-BiickJers dystrophy, Salzmann nodular degeneration, band keratopathy) superficial corneal scars multiple recurrent pterygium corneal thinning (eg, Terrien marginal degeneration, descemetocele formation, pellucid marginal degeneration)
434 • External Disease and Cornea
A, Descemetocele in a patient w ith rheumatoid arthritis. B, Same patient after lamellar keratoplasty.
Figure 16·1 6
superficial corneal tumors • congenital lesions (eg, dermoid ) corneal perforations that are not am enab le to resuturing or that occ ur in patients with ocu lar surface disease (eg. keratoconjun ctivitis sicca) keratocon us selective infections. including aca ntha moe ba
Advantages LK has the following advantages over PK: rn inimai requirements for donor material (as preservation of endothelium is not mandatory)
CHAPTER 16:
Clinical Approach to Corneal Transplantation. 435
reduced risk of entry into the anterior chamber (avoids risks of glaucoma, cataract, retinal detachment, cystoid macular edema, expulsive hemorrhage, and endophthalmitis) shorter wound healing time and convalescence reduced incidence of allograft rejection and, consequently, decreased need for topical corticosteroids
LK is less risky than PK in patients who have ocular surface disease, show poor compliance with medical instructions, or experience difficulty in obtaining frequent follow-up.
Disadvantages Anterior LK does not replace damaged endothelium, which severely restricts its indications. The procedure is technically more difficult than PK and more time-demanding, and it may cause opacification and vascularization of the interface, which may limit visual function .
Surgical Technique Superficial anterior lamellar keratoplasty SALK is most commonly performed in 2 stages. In the initial procedure, a lamellar flap that encompasses the corneal pathology is created using a micro keratome. The flap is lifted to ensure that the underlying stroma is clear and then replaced. After a 4- 6-week interval that allows the flap to stabilize and partially adhere, the second stage is performed. A trephine is centered over the pupil and used to incise the previously made flap to a depth slightly below the initial lamellar dissection, ideally leaVing a I-mm flap rim. A blunt spatula is gently introduced at the plane of the lamellar flap, and the abnormal tissue is separated and lifted off. The donor tissue is then prepared using an artificial anterior chamber and a microkeratome with the same thickness head as in the initial procedure. The superficial donor disk remains on the microkeratome and is transferred to a cutting block. A trephine of the same or slightly oversized (0.25 mm) diameter is used to excise the tissue. The donor disk is then transferred to the host bed and, if there is a good match, the donor tissue may adhere spontaneously without sutures, although several 10-0 nylon cardinal anchoring sutures can be used to ensure proper alignment. To avoid the creation of striae and irregular astigmatism, care must be taken not to suture too tightly. A bandage lens can also be placed to facilitate adherence. Using a 2-stage approach, the diameter of the host bed can be matched preCisely with the diameter of the donor tissue with nice vertical incisions from trephination. The femtosecond laser may also be used to perform the lamellar dissections of both the host and donor tissue, which may allow better matching of the thickness and diameter of the resection, in a I -stage procedure. Deep anterior lamellar keratoplasty In DALK, the objective is to remove the abnormal stromal tiss ue without inducing scarring or interface haze. The Anw~r big-bubble technique is the most popular method for
436 • Externa l Disease and Corn ea
consistently exposing Descemet's membrane to provide the best interface over the pupillary zone. Init ially, a disposable or suctio n trephi ne is used to make an approximate 3 00 - ~Lm depth incision. T he anterior stromal tiss ue is exci sed, deb ulkin g the cor neal scarring an d allowing better exposu re for the remain der of the procedure. The trephine incision is then slightl y deepened with a sharp blade. A 27-gauge needl e on a S-cc syringe is bent at a 60' angle, approximately 3 mm from th e tip, bevel facing down. The needle is inserted deep into the groove and advanced fo r 2-3 mill parallel to the surface of the corn ea to avoid perfo ration of Descemet's membrane. The air is then forcefully injected, producing a white and opaque stroma. The air enters the p re-Descemet's plane, causing th e sudden appearance of a big air bubble outlined by a circular wh ite band. A Iim bal paracentesis is made to drain aqueous from th e eye in order to reduce t1le pressu re and help prevent perforation of the cor nea while exposing Descemet's membrane. The anterior wall of the bubble is then entered with a sharp 15° blade to create a I-mm opening. Once incised, the bubble collapses; some surgeons then inject viscoelastic into the collapsed bubble to help with th e meticulous d issection. A spatula is used to enter th e pre-Descemet's plane an d advanced to th e 6 o'clock positio n. When the spatula is lifted ante ri orly, th e stroma on the top of the spatula is incised using a sharp blade. As the stroma is severed, Descemet's membrane is exposed. To improve visualization, air may be injected into the anterior chamber, highlighting Descemet's membrane. A similar maneuver is performed in th e opposite di rection. A 0. 12 forceps and blunt-pointed Vannas scissors are used to fashion 2 long perpend icular incisions, creatin g 4 quadrants of residual stroma; then each qu ad rant is excised, baring Descemet's membrane. On ly afte r recipient bed preparation is completed is the donor tiss ue prepared because inadvertent entry into the anterior chamber necessitates conversion to a full-thickness PK. In the early learn ing cur ve stages, such inadvertent ent ry is not infrequent. The dono r tiss ue is prepared by pu nching an appropriate-sized button with a trephine. Descemet's memb rane is teased off the donor graft with a 0.12 forceps or Weckeel sponge and th en sutured into position using 10-0 nylon in a ru nning or interrupted fashion.
Postoperative Care and Complications Opacification and vascularization of the interface Meticulous irrigation and cleaning of the lam ellar bed at the time of surgery may reduce opacification and vasc ul arization, which can occur despite corti costeroid th erapy. Postoperatively, best-corrected visual ac uity is us uall y li mited to 20/40 or wo rse. Allograft rejection Because the endothelium is not transplanted, endothelial rejection cann ot take place. Epithelial rejection , subepithelial infilt rates, and st romal reject ion occasionall y occur, but they respond to corticosteroid therapy. If graft edema occurs, anot her cause must be so ught for endothelial dysfuncti on. Inflammatory necrosis of the graft
Although inflammatory necrosis of th e graft has p revio usly been described as an allograft reaction , no immunoh istopathologic evidence has confirmed thi s, and recent series have
CHAPTER 16:
Clinical Approach to Corneal Transplantation.
437
not demonstrated this phenomenon. The mechanism probably relates to the preexisting corneal disease. Prognosis for retention of a clear graft is poor despite corticosteroid therapy. Anwar M, Teichmann KD. Big -bubble technique to bare Descemet's membrane in anterior lamellar keratoplasty. J Cataract Refract Surg. 2002;28(3):398- 403 . Anwar M,Teichmann KD. Deep lamellar keratoplasty: surgical techniques for anterior lamellar keratoplasty with and without baring of Descemet's membrane. Cornea. 2002;21(4): 374 - 383. Gorovoy MS. Advances in lamellar corneal surgery. Focal Points: Clinical Modules for Ophthalmologists. San Francisco: American Academy of Ophthalm ology; 2008, module 4. John T. Surgical Techniques in Anterior and Posterior Lamellar Keratoplasty. New Delhi, India: Jaypee Brothers Medical Publishers; 2006:L1-L687.
Descemet Stripping Automated Endothelial Keratoplasty Gerrit Melles in Holland introduced the technique of posterior endothelial lamellar keratoplasty in 1998. Since then, significant modifications in surgical tech nique have led to a new procedure called Descemet stripping automated endothelial keratoplasty (DSAEK) that has reduced the learning curve for surgeons and improved the outcome for patients. In this procedure, Descemet's membrane and endothelium are stripped in the host eye (descemetorhexis), producing a smooth posterior stromal bed in the host. Then an automated micro keratome is used to prepare the donor tissue, producing a smoother stromal bed and potentially less irregularity in the graft-host interface. DSAEK is now the procedure of choice for endothelial dysfunction, including Fuchs corneal dystrop hy, pseudophakic bullous keratopathy (PBK), and repeat corneal grafts due to endothelial cell failure. It has also been advocated for the treatme nt of iridocorneal endothelial syndrome (ICE) and posterior polymorphous dystrophy (PPMD) in the absence of visually significant corneal scarring. Gorovoy MS. Descemet-stripping automated endothelial keratoplasty. Cornea . 2006;25(8) : 886-889. Melles GR, Eggin k FA, Lander F, et al. A surgical technique for posterior lamellar keratoplasty. Cornea. 1998;17(6) ,618-626. Melles GR, Wijd h RH, Nieuwendaal CP. A technique to excise the Descemet membrane from a recipient cornea (descemetorhexis). Cornea. 2004;23(3):286-288. Price FW Jr, Price MO. Descemet's stripping with endothelial keratoplasty in 200 eyes: early challenges and techniques to enhance donor adherence. J Cataract Refract Surg. 2006;32(3): 411 - 418.
Advantages DSAEK has the following advantages over PK; better globe integrity and stability with a scleral or clear corneal incision, as compared to a full-thickness central corneal incision elimination of corneal suture- related problems increased accuracy in IOL power calculations when combined with cataract extraction, although the shape of the lenticule in DSAEK may produce hyperopic shift
438 • Extern al Disease and Cornea
less induced postoperative corneal astigmat ism more rapid visual rehabilitation with less concern for ocular surface disorders
Disadvantages In DSAEK, the best spectacle-corrected visual acuity may not be 20120, often ranging between 20/25 and 20/40. This may be from optical degradation associated with the . graft-host lamellar interface or persistent stromal haze. Evaluation of patients with Fuchs corneal dystrophy who underwent DSAEK revealed that corneal light scatler was still in creased as compared to the norm 6 months after the procedure and correlated with the
age of the recipient at the time of surgery. Also, ante rior lamellar keratoplasty or corneal epithelial debridement may be requ ired for full visual rehabilitation in the presence of anterior basement membrane dystrophy or subepithelial fibro sis. Long- term graft survival is unknown. Patel SV, Baratz KH, Hodge DO, Maguire LJ, McLaren JW. The effect of corneal light scatter on vision after Descemet stripping with endothelial keratoplasty. Arch Ophthalmol. 2009; 127(2), 153- 160.
DSAEK Surgical Technique Preparation of donor tissue
Corneal surgeons have the option of obtain in g precut tissue from an eye bank or preparing the tissue in the operating room using an automated microkeratome and artificial anterior chamber. Recent studies have shown that th ere is no clinical difference in outcomes
between tissue obtained from the eye banks and tissue prepared in the operating room. To prepare the donor tissue using an automated microkeratome for the lamellar dissection, the tissue is placed on an artificial anterior chamber. The epithelium may be removed prior to the lamellar dissection \\~th a Weck-Cel sponge. The corneal thickness can be measured using a pachometer to select the appropriate size microkeratome head,
250 ~m to 350 ~m, with a goal of leaving apprOXimately I00- 150 ~m of posterior stroma \vith Descemet's membrane and endothelium . The donor corneoscleral rim is then pres-
surized with balanced salt solution (BSS), optisol storage medium, or viscoelastic to ensure a deep and smooth dissection. After the lamellar dissection is performed, the corneal stroma may be marked with an outli ne of the area of the trephine cut to allow proper cent ration of the tissue. Gentian violet has been shown to produce endothelial toxicity, so the surgeon must be careful to limit the amo unt of ink used. The donor tissue, with or without the anterior stromal free cap, is then placed in a concave well. A trephine is used to create a disk-shaped lamella of donor tissue from 8 to 9 mm in diameter. Chen ES, Terry MA, Shamie N, Hoar KL, Friend DJ. Precut tissue in Descemet's stripping automated endothelial keratoplasty: donor characteristics and early postoperative complications. Ophtha lmology.2008;1 15(3jA 97-502. Price MO, Baig KM, Brubaker JW, Price FW Jr. Randomized prospective comparison of precut vs. surgeon-dissected grafts for Descemet str ipping au tomated endothelial keratoplasty. Am JOphthalmol. 2008;146(1)36-41.
CHAPTER 16:
Clinical Approach to Corneal Transplantation.
439
Terry MA, Shamie N, Chen ES, Phillips PM, Hoar KL, Friend OJ. Precut ti ssue fo r Oescemet's stripping automated endothelial keratoplasty: vision, astigmatism , and endothel ia! survival. Ophthalmalogy. 2009;116(2) :248 - 256.
Surgical technique for recipient eye Some surgeons perform DSAEK under topical anesthesia; however, many prefer a retrobulbar block. The surgeon decides whether the incision will be limbal, clear corneal, or scleraL The length of the incision varies from 3 to 6 mm. Several studies using vital dye staining of the endothelium after insertion of the donor corneal tissue have shown that placing tissue through a 3-mm incision causes 2- 4 times more acute damage to the endothelium than does us ing a 5-mm incision, regardless of the technique used to place the tissue. However, new methods of tissue insertion may eliminate the trauma associated with the use of a smaller incision size. If the surgeon prefers, Descemet's mem brane can be stripped (Fig 16-1 7A) using a variety of instruments, including a Sinskey hook (BD Visitec, Franklin Lakes, Nj), a specially designed Descemet stripper, or an irrigation- aspiration handpiece. The stripping can be performed under viscoelastic, air, or irrigation with BSS. Some surgeons feel that it is necessary to strip Descemet's membrane only in Fuchs dystrophy and not to do so in patients with failed PK or pseudophakic bullous keratopathy. Whether the retention of Descemet's membrane in these cases may predispose to dislocation of the graft is controversiaL Initially, the primary method for graft insertion was to fold the donor tissue into a 60/40 "taco" shape that required gently unfo lding within the anterior chamber. However, laboratory studies using vital dye staining, specular microscopy, and scanning electron microscopy have demonstrated a 30%- 40% endothelial loss with this technique. As a result, some excellent newer methods have been developed that are less traumatic to the endothelium. These include the Busin glide; Tan EndoGlide; modified lens cartridges, using an IOL sheet glide to push or pull the tissue into place; Neusidl injector; and a suture pull-through technique (Fig 16-17B). The object is to insert the tissue in a single plane, stromal side up, without having the endothelial cells touch each other, while also maintaining proper orientation of the tissue and reducing the need for intraocular manipulation to unfold it. After tissue placement in the anterio r chamber, air is injected to appose the donor graft against the host stromal bed (Fig 16-17C). It is not clear what factors are responsible for tissue adherence, but it is probably a combination of physical and physiologic factors . Intraoperative maneuvers to facilitate adhesion include scraping the peripheral recipient bed, draining fluid from the interface through vertical midperipheral vent incisions, sweeping the surface of the cornea with a roller, and presoaking the donor tissue in BSS. The requ ired duration and pressure of the air fill to ensure adherence of the tissue is controversial. Techniques var y from a full air fill in the operating room for 10 minutes followed by release and replacement with a partial air fill; a full air fill for up to 1 hour, with subsequent partial release at a slit lamp; and a complete air fill overnight, combined with an inferior iridectomy or use of acetazolamide (Diamox). If the air is removed at the slit lamp within the first hour, it must be released slowly to prevent sudden and dramatic loss of pressure in the eye. Patients are then advised to
440 • External Disease and Cornea
A
t
8
c Figure 16·17 A, Stripping Desce met's membra ne. B, Glide in sertion of donor tissue (left); Busin glide insertion of donor tissue (right!. C, Air is tamponaded to appose the donor graft to the host stromal bed. (Illus tra tion by Ch(Jsrine Gralapp.J
CHAPTER 16:
Cli nical Approach to Corneal Transplantation . 441
lie on their back for the first 24 hours to ta mponade the donor graft against the posterior stroma with the retained air bubble, although some surgeons have relaxed the positioning requirements. Placement of an inferior anchoring suture may prevent graft dislocat ion while minimizing the need for the patient to remain supine. Busin M, Bhatt PR, Scorcia V. A modified technique for Descemet membrane stripping automated endothelial keratoplasty to min im ize en dothelial ceUloss. Arch OphthalnlOl. 2008 ;
126(8H133-1137. Mehta IS, Por YM. Beuerman RW, Tan DT. Glide insertion technique for donor cornea lenticule during Desce met's stripping automated endothelial keratoplasty.
J Ca taract
Refract
Surg. 2007;33(11); 1846-1850. Mehta IS, Por YM, Poh R, Beuerman RW, Tan D. Comparison of donor insertion techniques for Descemet stripping au tomated endothelial keratoplasty. Arch Ophthalmol. 2008;126(10 ):
1383- 1388. Terry MA. Saad HA, Sham ie
T,
et al. Endothelial keratoplasty: the influence of insertion tech-
niques and incision size o n donor endothelial survival. Cornea. 2009;28(1 ):24-31.
Intraoperative complications Complications that can occur during DSAEK include the follo wing: poor microkeratome dissection, precludi ng use of the donor tissue incomplete removal of Descemet's tissue poor centration of the donor tissue duri ng trephi nation, leading to a th ick edge and possibly retained epithelial cells that could be implanted into the anterior chamber intraocular hyphema and blood in the interface (Fig 16-18) excessive manipulation of the don or tissue, risking endothelial cell loss posterior dislocation of the donor tiss ue disorientation during placement of the donor tissue, leading to placement of the endothelium against the host stromal cornea
Figure 16-18
Hemorrhage in the interface after DSAEK.
(Counesy of Roben W. Welsenrha(
MOJ
442 • Externa l Disea se and Cornea
Postoperative care and complications During this disc ussion the emphasis will be on issues specific to DSAEK. Problems common to PK and DSAE K, such as graft rejection, were covered earlier in the chapter. In a typical postoperative follow-up, the patient is seen on postoperative day 1 to ensure that the lenticule is in good position and th at no fluid is in the interface. Typically, there is about a 40% air bubble (Fig 16- 19). Over a 4-day period, the air bubble absorbs and the corn ea begins to clear. After 6 months, it is d ifficu lt to visualize the interface cen ~ trall y (Fig 16-20A, B). The postoperative med ication regimen is sim ilar to that of PK, although some surgeons recommend maintaining the patient on topical corticosteroids fo r a longer period of time. Chen ES, Terry MA , Sham ie N. Hoa r KL, Friend DJ. Descemet-stripping automated endothelial keratoplasty: six-month results in a prospective study of 100 eyes. COrr/ea. 2008;27(5): 5 14-520. Su h LH, Yoo SH, Deobhakta A, et aL Com pl ications of Descemet's stripping with automated en dothelial keratoplasty: survey of 11 8 eyes at one institute. Ophthalmology. 2008; II 5(9): 1517- 1524.
Pupillarv block Inadequate release of the intraoperative air fill may lead to pupillary block fro m migration of the air behind the iris, thus closing the angle. The acute rise in pressure produces pai n and can potentially exacerbate underlying gla ucoma. Pupillary dilation beyond the retained air bubble fo r the first 24 hours may reduce the incidence of this complication. An inferior iridectomy may also prevent pupillary block. Dislocation olthe donor graft See Figure 16-21. The rate of dislocation of the donor graft varies greatly in reported case series) from 4% wi th experienced surgeons up to 35%-40% with novice surgeons (those who have had fewer than 10 cases). Dislocation of the donor graft occurs primarily within the first 24 hours, although occasionally inadvertent trauma from eye rubbing or a sudden blow to the eye has caused the donor disk to be di splaced at a later time.
Figure 16-19 Weisenthal, MDJ
DSAEK postoperative day 1 showing a residua l air bubble. (Courtesy of Robert W
CHAPTER 16:
Clini ca l Approac h to Cornea l Transp lantati on.
443
A
B Figure 16·20
A, Slit-lamp picture of healed DSAEK. 8, Side illum ination. (Courtesv of Robert W.
Weisenthal, MD.)
Figure 16·21
Dislocated lenticule after DSAEK. (Courtesy of Robert W We/senthal,
MD.)
444 • Externa l Di sease and Cornea
Figure 16·22 Epithelial ingrowth in the interface after DSAEK (arrow). (Courtesy of Robert W . Weisenrhal, MDJ
Epithelial ingrowth Epithelial ingrowth may first be seen as a white deposit within the interface that can be relatively stable and asymptomatic (Fig 16-22). In rare cases, epithelial ingrowth may lead to graft failure that is missed on clinical examination but recognized on histologic examination of the tissue after a second procedure. The source of the ingrowth may be host surface epithelial cells implanted within the eye during placement of the donor tissue or do nor epithelial cells inadvertently left in place and implanted follOWing eccentric trephination beyond the microkeratome dissection. In early reports, the prognosis with epithelial ingrowth appears to be similar to that seen with epithelial seeding under the lamellar LASIK flap - that is, often limited and asymptomatic-as compared with the progressive and devastating course that is seen with the intraocular epithelial down growth associated with intracapsu lar cataract extraction or corn ea l transplantation. In reported cases of graft failure whe re epithelial ingrowth was noted only after histopathologic examination of the removed lenticule, the secon d procedu res have done well, without recurrence of the ingrowth. Koenig SB, Covert OJ. Epi thelial ingrowth after Descemet·stripping automated endoth elial keratoplasty. Comea. 2008;27(6):727- 729.
Primary graft failure The primary failure rate seen in published reports va ries between 3% and 12%, with higher numbers associated with surgeons in the early stages of the learning cu rve and lower numbers associated with more experienced surgeons. The im proved results probably reflect better surgical technique leading to less endothelial trauma as a consequence of less tissue manipu lat ion and a lower rate of dislocatio ns. Endothelial cell loss Additional manipulation of tissue risks endothel ial cell loss from microkeratome dissection, placement and orientation of the tissue within the anterior chamber, air tamponade, and additional exposure of the donor graft to air in rebubbling. In 2 different studies, mean endothelial cell loss at 6 months was 34%. However, in a 6-month to 3-year follow-up by Price and colleagues, further cell loss was only 8%, which compared favorably to the CDS PK study that showed 42% cell loss between 6 months and 3 years. Price attributed trese resu lts to the increased diameter of the DSAEK grafts (8.75 to 9 m m), which provided more surface area and thus more transplanted endothelial
CHAPTER 16:
Clinical Approach to Cornea l Transplantation. 445
cells than the traditional PK; to removal of a smaller area of endothelium on the recipient, which allowed for overlap of the donor tissue onto host endothelium; and to use of corticosteroids for a longer duration postoperatively. Long-term follow-up is necessary to confirm these results. Additional complications associated with DSAEK are similar to those seen in PK, including suprachoroidal hemorrhage, retinal detachment, cystoid mac ular edema, and graft rejection. The rate of graft rejection may be lower in DSAEK tha n in PK due to the absence of sutures, which reduces vascularization and reduces the incidence of both late suture erosion inciting inflammation and fewer donor epithelial cells stimulating an immune reaction. Long-term follow -up is necessary to confirm this observation. Cornea Donor Study Investigator Group; Lass JH, Gal RL, Dontchev M, et al. Donor age and corneal endothel ial celJ loss 5 years after successful corneal transplantation. Specular microscopy ancillary study results. Ophthalmology. 2008;115(4):627-632. Price FW Jr, Price Mo. Does endothelial cell survival differ between DSEK and standard PK?
Ophthalmalogy.2009;116(3):367- 368. Price MO, Jordan CS, Moore G, Price FW Jr. Graft rejection episodes after Descemet stripping with endothelial keratoplasty: part two : the statistical analysis of probability and risk factors.
Br J Ophthalmol. 2009:93(3):391 - 395. Terry MA, Chen ES, Shamie N, Hoar KL, Friend DJ. Endothelial cell loss after Descemet's stripping endothelial keratoplasty in a large prospective series. Ophthalmology. 2008; 11 5(3):
488-496.
Descemet's Membrane Endothelial Keratoplasty Another modification in EK, recently suggested by Melles, is to transplant only donor Descemet's memb rane and endothelial cells and not to include stromal tiss ue, as in DSAEK. This promising procedure has been named Descemets membrane endothelial keratoplasty (DMEK). At the time of this publication, there are only early reports on DMEK and its possible advantages and disadvantages. Ham L, van der Wees J, Melles GR. Causes of primary donor failure in Descemet membrane
endothelial keratoplasty. Am J Ophthalmol. 2008:145(4):639-644. Melles GR, Ong TS, Ververs B, van der Wees J. Preliminary clinical results of Descemet membrane endothelial keratoplasty. Am J Ophthalmol. 2008;145(2):222-227.
Basic Texts External Disease and Cornea Albert DM, Miller J, Azar D, Blodi B, eds. Albert & Jakobiecs Principles and Practice of . Ophthalmology. 3rd ed. 4 vols. Philadelphia: Elsevier/Saunders; 2008. Arffa RC, Grayson M, eds. Graysons Diseases of the Cornea. 4th ed. St Louis: Mosby; 1997. Brightbill FS, McDonnell P), McG hee CN, Farjo AA, Serdarevic O. Corneal Surgery: Theory, Technique, and Tissue. 4th ed. Philadelphia: Elsevier/Mosby; 2009. Catania LJ. Primary Care of the Anterior Segment. 2nd ed. Norwalk, CT.: Appleton & Lange; 1996. Corbett M, Rosen ES, O'Brart DP. Corneal Topography: Principles and Applications. London: BMJ Books; 1999. Coster D). Cornea. Fundamentals of Clinical Ophthalmology series. London : BM) Books; 2002. Foster CS, Azar DT., Dohlman CH, eds. Smolin and Thofts The Cornea: Scientific Foundations and Clinical Practice. 4th ed. Philadelphia: Lippincott Williams & Wilkins; 2004. Kaufman HE, Barron BA, McDo nald M, eds. The Cornea . 2nd ed. Boston: ButterworthHeinemann; 1998. Krachmer )H, Mannis MJ, Holland E), eds. Cornea . 2nd ed. 2 vols. Philadelphia: Elsevier/ Mosby; 2005. Krachmer )H, Palay DA. Cornea Color Atlas. St Louis: Mosby; 1999. Leibowitz HM, Waring GO III, eds. Corneal Disorders: Clinical Diagnosis and Management. 2nd ed. Philadelphia: Saunders; 1998. Murray PR, Baron E), Jorgensen )H, et aI, eds. Manual of Clinical Microbiology. 9th ed. 2 vols. Washington, DC: ASM Press; 2007. Ostler HB, Ostler MW Diseases of the External Eye and Adnexa: A Text and Atlas. Baltimore: Urban and Schwarzenberg; 1993. Pepose IS, Holland GN, Wilhelmus KR, eds. Ocular Infection and Immunity. St Louis: Mosby; 1996. Rapuano C), Luchs JI, Kim T. Anterior Segment: The Requisites. Requisites in Ophthalmology series. St Louis: Mosby; 2000. Seal DV, Pleyer U, eds. Ocular Infection: Investigation and Treatment in Practice. 2nd ed. New York: Informa Healthcare; 2007.
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· Related Academy Materials Focal Points: Clinical Modules for Ophthalmologists Colby KA. Chem ical injuries of the eye (Module 1,20 10). Duhn SI'. Iris repair: putting the pieces back together (Module 11 ,2002). Garcia-Ferrer FJ, Schwab I R. New laboratory diagnosti c technigues for corneal and external diseases (Module 9, 2002). Goins KM , Wagoner MD. Imaging the anterior segment (Module 11 ,2009). Gorovoy MS. Advances in lamellar corneal surgery (Module 4, 2008). Heidemann, DG. Atopic and vernal keratoconjunctivitis (Module 1,2001 ). Hirst LW Pter yg ium surge ry (Module 3, 2009). Koreishi AF, Karp CL. Ocular surface neoplasia (Module 1,2007). Mamalis N. Toxic anterior segment syndrome (TASS) (Module 10,2009). Mets MB, Noffke AS. Ocular infections of the external eye and corn ea in children (Module 2, 2002). No rdlund ML, Brilakis HS, Holland EJ. Surgical techn ig ues for ocular surface reconstructio n (Modu le 12, 2006). Pflugfelder Sc. Dry eye (Module 5, 2006). Schul tze RL, Singh GD. Ne urotrophic keratitis (Module 2, 2003). Tuli SS. Herp etic corn eal infections (Module 8, 2008). Zloty P. Diagnosis and management of fungal keratiti s (Mod ule 6, 2002).
Print Publications Arnold AC, ed. Basic Principles of Ophthalmic Surgery. (2006 ). Dunn JI', Langer PD, eds. Basic Techniques of Ophthalmic SUlgery. (2009). Parke DW II , ed. The ProfeSSion of Ophthalmology: Practice Management, Ethics, and Advocacy. (2005 ). Ro ckwood EJ, ed. ProVision: Preferred Responses in Ophthalmology. Series 4. Self-Assessment Program, 2-vol set (2007) . Wang MX. Corneal Dystrophies and Degenerations: A Molecular Genetics Approach (Ophtha lmology Mo nograph 16,2003). Wilson FM II , Blomguist PH, eds. Practical Ophthalmology: A Manual for Beginning Residents. 6th ed. (2009).
449
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Preferred Practice Patterns Preferred Practice Patterns are available at http: //one.aao.org/CE/PracticeGuidelines/ PPPaspx. Preferred Practice Patterns Committee, Corn ea/External Disease Panel. Bacterial Keratitis
(2008) . . Preferred Practice Patterns Committee, Corneal External Disease Panel. Blepharitis (2008). Preferred Practice Patterns Committee, Cornea/External Disease PaneL Conjunctivitis (2008). Preferred Prac tice Patterns Committee, Cornea/External Disease Panel. Dry Ey e Syndrome (2008).
Ophthalmi c Technology Assessments Ophthalmic Technology Assessments are available at http: //on e.aao.org/CE/ Practice Guidelines/Ophthalmic.aspx and are publis hed in the Academy's journal, Ophthalmology. Individual rep rints may be ordered at http://www.aao.org/store. Ophthalmic Technology Assessment Com mittee, Cornea Panel. Confocal Microscopy (2004; reviewed for currency 2009) . Ophthalmic Technology Assessment Committee, Cornea Panel. Corneal Endothelial Photography (1997; reviewed for currency 2008). Ophthalmic Technology Assessment Com mittee, Cornea Panel. Corneal Topography (1999; reviewed for currency 2008) . Ophthalmic Technology Assessment Committee, Cornea and Anterior Segment Disorders Panel. Descemets Stripping Endothelial Keratoplasty : Safety and Outcomes (2009 ). Ophthalmic Technology Assessment Comm ittee, Cornea and Anterior Segment Disorders Panel. Safety of Overnight Orthokeratology for Myopia (2008) .
COs /OVOs Basic and Clinical Science Course (Sections 1-13) (DVD-ROM, 2010). Johns KL, ed. Eye Care Skills: Presentations for Physicians and Other Health Care Professionals, version 3.0 (CD-ROM, 2009).
On line Materi als For Preferred Practice Patterns and Ophthalmic Technology Assessments, go to http: // one.aao.org/CE/PracticeGuidelines/defau lt.aspx. Basic and Cli nical Science Course (Sections 1-13); http: //one.aao.org/CE/Educational Products/BCSC.aspx
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Focal Points mod ules; http://one.aao.org/CE/EducationaIProducts/FocaI Points.aspx Maintenance of Certification Exam Study Kit, MOC version 2.0 (2007); http://one.aao. org/CE/MOC/default.aspx Maintenance of Certification Exam Study Kit, Compass version 2.0 (2008); http: //one.aao. org/CE/EducationalContent/ CompassExam.aspx Price FW, Baig K, Price MO. Descemet's Strip ping with Endothelial Keratoplasty (December 2008); http: //one.aao.org/CE/Ed ucational Content/Courses.aspx Rockwood EJ. ProVision: Preferred Responses in Ophthalmology. Series 4. SelfAssessment Program, 2-vol set (2007); http://one.aao.org/CE/ EducationaIProducts/ Provision.aspx
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Question
Cred it Reportin g Form . 455
Section Evaluation Please complete this e ME questionnaire. 1. To what degree will you use knowledge from BCSC Section 8 in your practice?
o o o
Regularly Sometimes
Rarely
2. Please review the stated objectives fo r BCSC Secti on 8. How effective was the material at meeting those objectives?
o o
All objectives were met. Most objectives were met.
D Some objectives were met.
o
Few or no objectives were met.
3. To what degree is BCSC Section 8 likely to have a positive impact on health outcomes of your patients?
o Extremely likely
o o
Highly likely
Somewhat likely
D Not at all likely
4. After you review the stated objectives for BCSC Section 8, please let us know of any additional knowledge, skills, or information useful to your practice that were acquired but were not in cluded in the objectives.
5. Was BeSe Section 8 free of comm ercial bias? D Yes
D No 6. If you selected "No" in the previous question, please comment.
7. Please tell us what might improve the appli cability of BeSe to your practice.
Study Questions Although a concerted effort has been made to avoid ambiguity and redundancy in these questions, the authors recognize that differences of opinion may occur regarding the "be~t" answer. The discussions are provided to demonstrate the rationale used to derive the answer. They may also be helpful in confirming that your approach to the problem was correct OI, if necessary, in fixing the principle in your memory. The Section 8 fac u ity"wuld like to thank the Self- Assessment Committee for working with them to provide these study questions and discussio ns. 1. Phlyctenular keratoconjunctivitis is an example of which type of hypersensitivity re-
sponse? a. type I
b. type II c. type III
d. type IV 2. Immune privilege in the cornea results in part from expression of which of the folJowing: a. interleukin-8 (Ii-8)
b. multi focal choroiditis and panuveitis syndrome-l(MCP-l} c. Fas ligand d. major histocompatibility complex (MHC) class I I 3. A soluble mediator of ocular inflammation in the tear film that promotes angiogenesis and vascular permeability is a. intercellular adhesion molecule I (ICAM-I) b. vascular endothelial growth factor (VEGF) c. substance P
d. interleukin - I (Ii-I) 4. The normal conjunctiva typically contains whi ch of the following cell types: a. plasma cells b. basophils
c. eosinophils d. killer lymph ocytes 5. The immunoglobulin involved in atopic keratoconjunctivitis is a. IgE
b. IgA c. IgG
d. IgM
457
458 • Study Qu estions 6. Ligneous conjunctivitis is treated with a. system ic antibiotics b. topical antibiotics c. topical plasminogen d. topical in terferon-a 7. Peripheral ulcerative keratitis (PUK), which is associated with system ic immune-mediated disease is typically caused by which of the following' a. type IV hype rsensitivity reac tions
b. vasc uli tis and immune-complex deposition c. contac t lenses d. staphylococcal blepharitis 8. In Mooren ulcer, which type of cells are present in increased concentration in the junctiva adj acent to the ulcerated area?
COI1-
a. suppresso r T cells b. plasma cells
c. dendriti c cells d . mast cells 9. Which of the following ocular structures produces mucin, which co ntributes to the stabilization of th e tear film?
a. conjun cti val epithelium b. tarsus
c. meibom ian glands d. glands of Moll 10. Which of the foll owing layers of the corn ea continues to thicken from birth to adulthood? a. epithelium
b. stroma c. Desce met's membrane d. endot heli um 11. The major refracti ve power of the eye comes from the
a. corn ea
b. lens c. vitreous
d. aqueous
Study Questions. 459 12. Which of the following metabolic disorders that affect the cornea is X-linked recessive? a. Sanfilippo syndrome b. Hurler syndrom e c. Scheie synd rome d. Hunter synd rome 1~.
Which of the following drugs is associated with corneal verticillata? a. metoprolol b. amiodaro ne c. erythromycin d. tetracycline
14. Prominent corn eal nerves may be see n in whi ch condition? a. multiple endocrine neoplasia (MEN) b. pulmonary adenocarcinoma
c. lattice corneal dystrophy type I d. macular corneal dystrophy 15. A slit-lamp finding of corneal protrusion superior to a band of thinning in the inferior cornea describes which of the following co nditions? a. keratoglobus
b. keratoconus c. polymorphic amyloid degeneration d . pellucid marginal degeneration 16. In which of the following corneal disorders are recurrent corneal erosions most likely to occur? a. pellucid marginal degeneration b. macular dystrophy c. lattice dystrophy d. keratoglob us 17. Slit-lamp findings of fingerprint lines. mapl ike li nes. and dots at the level of the corneal epithelial basement membrane are all associated with which of the foll owin g conditions? a. corneal th inn ing and protrusion b. polymo rphi c amyloid degeneration c. recurrent corneal erosion d. autosomal recessive disorder
460 • Study Questio ns 18. Which of the following conjunctival reactions is most commonly seen with a herpes sim-
plex vi rus (HSV) infection'
a. follicular response b. papillary response c. pseudom embrane formation
d. pyogenic granuloma formation 19. Papillary conjunctivitis is associated with which of the following con ditions?
a. herpes simplex (HSV) conjunctivitis b. atopic keratoconjunctivitis c. adult inclusion conjunctivitis d. molluscum conjunctivitis 20. Which exam inat ion technique uses the Placido disk?
a. specu lar mi croscopy
b. retinoscopy c. keratoscopy
d. wavefront analysis 21. Central corneal opacity present at birth, iridocorneal adhesions, cataract, elevated lOP, and cardiac abnormalities may be associated with which of the foll owin g disorders?
a. congenital hereditary endothelial dystrophy (C HED ) b. congenita l glaucoma c. Peters plus
d. Peters anomaly 22. Corneal changes due to birth trauma typically manifest as which of the following: a. ruptures of Descemet's membrane
b. breaks in Bowman layer
c. epithelial reduplication d. stromal thi nning 23. Whic h of the following is a typical corneal finding in congenital gla ucoma? a. small corneal diameter b. Haab stri ae c. Vogt striae
d. guttae
24. Which of the foUO\ving would render a donor cornea unsuitable for penetrating keratoplasty? a. cell cou nt of2500 cells/ mm' b. negative se rology for hfpatitis B c. positive serology for cytomegalovirus (CMV) d . previous LAS] K eye surgery
Study Questions. 46 1 25. Corneal transplant rejection is believed to be uncommon because a. the cornea has immune privilege b. the cornea has immune processing cells in the stroma only c. the human body has developed tolerance to corneal tissue d. there are no histocompatibility antigens in th e cornea 26. vVhich of the following characteristics of a progressive corneal infiltrate is a contraindication for corneal biopsy? a. located deep in the cornea b. unresponsive to appropriate antim icrobial therapy c. culture-negative on superficial scrapings d. atypical clinical course 27. Which technique should be avoided in pterygium excision surgery? a. excision with conjunctival autograft b. excision with sliding conjunctival flap c. simple excision with bare sclera
d. excision with amniotic membrane graft 28. Which of the following is the best technique for achieving a permanent fusing of the eyelids? a. taping the eyelid margins b. injecting botulinum toxin into the eyelid c. suturing the eyelid margins d. applying cyanoacrylate adhesive to eyelid margins 29. \Vhich of the following is an appropriate way to alleviate chronic pain associated with a postinflammatory corneal opacity in an eye with poor vision potential? a. performing a corneal tattooing procedure b. performing a conjunctival flap c. prescribing tinted glasses
d. prescribing a topical anesthetic agen t 30. Immediate surgical treatment is indicated for which complication following penetrating keratoplasty' a. choroidal detachment b. suture abscess c. primary graft failure d. wound leak with flat anterior chamber
462 • Study Questions 31. An 83-year-old woman with prominent corneal edema and central corneal scarring in both eyes has episodic foreign -body pai n 00. Her best-corrected visual acuity is finger counts at 5 feet 00 and 20/100 OS. Th ere is a slight cataract in the left eye only, and lOP is normal. Which is the best managemen t option to restore visual function to the right eye? a. anterior stromal puncture b. epitheli al debridement c. lamellar keratoplasty d. penetrating keratoplasty 32. Band keratopathy can be caused by the deposition of which of the fo ll owing materials?
a. calcium hydroxyapat ite b. hyaline c. amyloid d. calcium hydroxid e 33 . \·Vh ich of the following is an indication for surgery on a pterygium? a. induced myopi a
b. tear defici ency c. in duced ast igmatism d. macular degeneration 34. Which of the foll owing is the best initial management for irregular astigmatism postkeratoplasty' a. lamella r keratopl asty b. excirnerlaser c. astigmatic keratotomies d . rigid gas-permeable contact lens fitt ing 35. W hich of the follmving is the most serious complication associated with silicone punctal occlusion? a. dacryocystitis b. migration into the canaliculus c. loss of th e silicone plug d . epiphora 36. Aqueous tear defici ency may be treated with which of the following? a. 0. 2% brimonidine tartrate b. 0.15% hyaluronic acid c. 0.005% latanopro't d. 1% tr ifl ur idine
Study Questions. 463
37. Common clinical findings in aqueous tear deficiency include which of the following? a. rapid tear-film breakup time b. increased tear meniscus c. lack of debris in the tear film
d. increased Schirmer test 38. In order to establish a diagnosis of Sjogren syndrome, which of the following laboratory tests should be ord ered? a. anti-Ro/Sj6gren syndrome-A (SS-A) antigen b. p-antineutrophil cytoplasmic antibody (p-ANCA) c. c-antineutroph il cytoplasmic antibody (c-ANCA)
d. erythrocyte sedimentation rate (ESR) 39. What is the most common presentation of meibomian gland dysfunction? a. anterior uveitis b. central corneal ulceration c. posterior eyelid margin disease
d. anterior eyelid margin disease 40. ''''hat is the most common presentation of ocular rosacea? a. scleritis b. central corneal ulceration c. recurrent erosions
d. chronic eyelid margi n injection 41. A persistent epithelial defect is most commonly associated with which of the following conditions: a. pellucid marginal degeneration b. herpes zoster keratitis c. posterior polymorphous corneal dystrophy (PPCD)
d. superficial punctate keratitis (SPK) ofThygeson 42. Vvhich of the following dermatologic disorders is included in the differential diagnosis for persistent corneal epithelial defect? a. sebaceous cell carcinoma b. acne rosacea c. melanoma
d. basal cell carcinoma
464 • Study Questions 43. Dysfunction of the ophthaLnic bra nch of the trigeminal ganglion may result from a. aneurysm b. pituitary adenoma
c. myasthenia gravis (MG) d. prostaglandin analogue 44. Corneallimbal stem cells reside a. \vithin the superficial epithelial laye r of the corneal li mbus b. over the entire surface of the bulba r co njun ctiva c. in the central and paracentral corn ea
d. within the basal epith elial layer of the co rneal limbus 45. "\Thich of the following conditions may be associated with epiphora?
a. megalocornea b. sclerocornea c. conjunctivochalasis
d. pingueculul11 46. A major risk fac tor for the develo pmen l of bac terial keratitis is a. age b. contact lens wear
c. frequent use of nonpreserved tears d. systemic bacterial infection 47. Parinaud oculoglandular syndrome is most commonly caused by which of the follow ing organisms: a. Rhinosporidiu11l seeberi
b. Treponema pallidum c. Bartonella hel1selae d. Mycobacteria spp 48. Corneal signs typically associated wit h acanthamoeba keratitis include a. subepithelial infiltrates b. ring infiltrate
c. corneal neovascu larization d. crystalline midst romal infiltrate
Stud y Qu estions. 465 49. Which of the following is a type of intraepithelial neoplasia of the conjunctiva? a. vascular
b. actini form c. ulcerative d. leukoplakic
SQ. An elevated, vasc ular, darkly pigmented lesion at the interpalpebral limbus may represent which entity?
a. malignant melanoma
b. conjunctival intraepithelial neoplasia c. conjunctival papilloma
d. Iimbal dermoid
Answers I. d. Phlycten ular keratoconjun ctivi tis is a ty pe IV delayed hypersensitivity response. Type IV delayed hypersensitivity reactions are med iated by T cells (CD4+ Th I lymphocytes) that release lymphok ines in order to attract macrophages.
2. c. Th e co rnea's relative immune privilege is du e to many factors, including ex press ion of Fas ligand (CD95 ligand) by corneal ce lls, whi ch is thought to playa critical role in indu cing apoptosis (programmed cell death ) of act ivated lymph ocytes. 3. b. VEGF may be found in the tear film of infla m ed eyes. It acts by promoting the growth of new blood vessels and by increasing vascular perm eab ility. 4. a. Plasma cells are the only cells present in no rmal co njun ctiva. The other cells may be present in diseased co njunctiva. 5. a. IgE is th e immunoglobulin that med iates alle rgic reactions, in cl uding all ergic conjunctivitis and atopic keratoconjuncti vit is. 6. c. Ligneous conjunctivitis is thought to result fro m a defi ciency of type I plasminogen. Topical appl ication of plasminogen may be an e ffec tive th erapy. 7. b. Conjunctival biopsies from pat ients with P UK have shown va so~occl usi ve d isease. which supports this process as the et io logy for peripheral co rnea l ulceration. Type IV h y~ perse nsitivity reactio ns are associated wi th phlyctenular disease. Staphylococcal margi nal infiltrates are not associated with systemic vascu lit ic d isease. 8. h. Mooren ulcer is an examp le of immul1 e~ m ed i ated co rneal infl ammation, in which cor~ nea l autoantigens may be generated as a respo nse to injury or infection. An autoantibody respo nse may then be generated, presumably by plasma cell s. 9. a . Goblet cells, which account for up to 10% of the basal cells of th e conjunctival epithelium. produce mucin. Corneal epithelial cells also produ ce some mucin. 10. c. Desce met's membrane is the basement mem brane of the corneal endothelium (which comes from neural crest cells). It in creases in thi ckness from 3 f.1I11 at birth to 10- 12 ~n in ad ul ts. 11. a. The curvature of the central cornea contr ibu tes abo ut 74% o r 43.25 d iopters of th e total 58.6 dio ptric power of a normal human eye. 12. d. Most of th e metabolic d isorders tha t affect th e corn ea are autosomal recess ive. Two exceptio ns are Hunter syndrome and Fabr y disease. which are both X~ lin ked recessive. 13. h. Amiodarone, an antiarrhythmic agent. produces lysoso mal deposits in the basal cor~ neal epithelial layer, creating a whor l ~ like pattern, Th is pattern may also be seen in Fabry di sease an d has been associated wi th lon g ~ t e rm treatment with chloroquine, chlorprom· azin e, and indomethacin . 14. a. MEN type 2B has been associated with prominent co rn eal nerves. It is an autosomal dominant di sease characterized by med ullary ca rcin o ma of the thyroid, pheochromoc y~ toma , and mucosal neuromas. (So me patients with MEN type 2A also have en larged cor· neal nerves.) 15. d. Pellucid margina l degeneration is charac terized by a band of inferior thi nn in g an d protru sion of the cornea abpve it. Keratoconu s shows protrusio n at the point of maximal
466
Answers . 467 thinning. Polymorphic amyloid degen eration is characterized by stromal amyloid deposits. Keratoglobus is characterized by a globular deformation of the en tire cornea. 16. c. Lattice is often accompani ed by recurrent erosions. Erosions are less common in macular dystrophy and not characteri sti c of either pellucid marginal degeneration or keratoglobus. 17. c. Maps, dots, and fingerprints are typical for co rn eal epithelial basement membrane dystrophy (EBMD). Approximately 10% of patients with EBMD have recurrent erosions, and 50% of patients with recurrent erosions have evidence of this dystrophy. 18. a. Epithelial infections wit h HSV are associated with follicular reactions of the conjunctiva. They do not result in a papillary react ion, membrane or pseudomembrane fonnation, or a pyogenic granuloma. 19. b. Atopic keratoconjunctivitis results in a typical papillary reaction of the tarsal conjunctiva. HSV, adult inclusion co njunctivitis, and moll usc um all cause a follicular conjunctivitis. 20. c. In 1880, Antonio Placido developed a disk composed of a series of concentric circles that, when held in fron t of the cornea, are reflected off the tear film. The corneal surface affects the shape of the circles. Analysis of the corneal shape using this type of device is known as keratoscopy. 21. d. The appropriate anSwer is Peters anomaly. Peters plus refers to the same finding associated with limb dwarfism. CHED does not have elevated lOP. Corneal opacity and iridocorneal adhesions are not consistent wi th co ngenital glaucoma alone. 22. a. Progressive corneal edema developing duri ng th e first few postnatal days, accompanied by vertical or oblique posterior striae, may be cau.sed by birth trauma. Ruptures occur in Descemet's membrane. Healing usuall y takes place, often leaving a hypertrophic ridge(s) of Descemet's membrane. 23. b. Haab striae is correct. Vogt striae occur in keratoconus. A large corneal diameter wou ld be expected, but guttae are not typically prese nt. 24. d. Only a cell count of less than 2000 wou ld disqualify this donor. Negative serology for hepatitis B is a requirement. Serology that is positive for CMV will not disqualify the donor. Previous LASIK surgery will disquali fy the donor for full penetrating keratoplasty! as curvature of the cornea and bonding of the 2 layers cannot be ensured . 25. a. The cornea has a way of causing tolera nce in the body that can be called "immune pr i vilege~'
26. a. A corneal biopsy would not be done in a posterior lesion, as this would require a fullthickness removal of tissue that would leave a perforation requiring a corneal transplant. A biopsy is a good option when a keratit is has not responded to antimicrobial therapy, is culture-negative on usual scrapings, or is following an atypical cou rse. Fungal infections, acanthamoeba, and mycobacterial infections may elude routine scrapings. 27.
Co In pterygium surgery, the recurren ce rate with simple bare excision is quite common, often quoted at up to 75%. It is therefore not recommended and not justified unless no other means is available. The other methods of excision with cove ring of the bare sclera generally lead to an acceptable cosmetic and functional result with a small risk of recurrence.
28. c. For permanent closure of the eye fiss ure, suturing the eyelid margins. with removal of a small amount of the margin, will result in a perm anent closure of the eyelids. The other choices are good options when a temporary closure of the eyelids is required.
468 • Answers 29. b. In an eye with chronic ocular surface pain and poor visual potential, a Gunderson conjunctival flap that covers the cornea is the best option. One would never prescribe a topica l anest hetic agent, as it can be toxic and lead to ulceration and perforation. Tinted glasses will not remedy the pain, and corn eal tattooing is useful oilly in improving the cosmetic appearance of a scar and will not improve the pain associated with chronic corneal pain. 30. d . Small wo und leaks with a deep anterior chamber can be managed conservatively with a bandage lens and topical aqueous suppressants; however, a flat anterior chamber with a large wound leak should be managed acutely. Choroidal detachments may resolve without intervention, a suture abscess can be treated with topical antibiotics, and primary graft failure can be handled electively. 31. d. The co mbination of stromal scarring and corneal edema from endothelial dysfunction requires penetrating keratoplasty in order to address the pathology in both the stroma and endothelial layers. 32. a. Band keratopathy is caused by the deposition of calcium hydroxyapatite in the superficial corn ea. Amyloid deposition is seen vvi th lattice dystrophy; hyal ine deposition is associated with granular dystrophy; and calciu m h)fdroxide is seen in lime, which is very harmful to the cornea. 33. c. T he major indication for pterygium excision is induced or irregular astigmatism that reduces a patient's vision. Pterygia do not cause myopia or macular degenerati on. Tear deficiency may exacerbate the symptoms of the pterygium but is not related to its pathogenesis. 34. d. Regular astigmatism after corneal transpla ntation can be treated with astigmatic keratotomy or the excimer laser. However, irregular ast igma tism sho uld be primarily managed with a rigid gas-permeable contact lens. Ultimately, the best treatment is prevention, with meticulous surgical technique and sutu rin g. 35. a. Dacrocystitis is the most serious co mpli cation because it ca n require dacrocystorhinostomy, a major surgical procedure to remove the plug-effectively a foreign body-from the lacrimal drainage system. If severe enough, secondary infection co uld result in orbital cellulitis. 36. b. The addition of hyaluronic acid to topical tear replacement formula tions has been found to be helpful in the treatment of moderate to severe aqueous defic iency states. Trifluridine is a topical antiviral agent that has secondary epithelial toxic effects that will worsen the effect of aq ueous deficiency. Brimonidine and latanoprost are antigla ucoma preparations and are not indicated for the treatment of dry-eye syndrome. 37. a. Rapid tear-film breakup time is arguably the most sensitive test of tear-film deficiency. It is easily ca rried out and readily available. 38. a. The presence of Sjogren syndrome autoantibodies (SS-A and SS-B) has been correlated with th e severity of symptoms and ocular surface disease in patients with Sjogren sy ndrome. An elevated ESR is a nonspecific finding in many inflammatory disorders. Elevated ANCA autoantibodies are found in both Wegener granulomatosis and polyarteritis nodosJ, not Sjogren syndrome. 39. c. Posterior eyelid margin disease is co nsistent with the location of the meibomian glands and their ori fices.
Answers • 469
40. d. The association of rosacea with ocular surface disease is often missed, in part because of the variability of the severity of rosacea and the fact that it is not always obvious in dimly lit ophthalmol ogic offices. Hyperemia of th e eyelid margin is a co mmon early clinical findi ng. Corneal ulceration may occu r as a late fi nding in severe ocular rosacea. Scleritis may occur in association with rosacea, but it is uncommon. Recurrent erosion of the cornea is not a com mon feature of rosacea. 41. h. Herpes zoster keratitis is perhaps the 1110st common cause of neurotroph ic keratopathy leading to corneal ulceration. Pellucid marginal degeneration and PPCD do not lead to neurotroph ic kera topathy. SPK ofThygeson does not result in loss of corn eal sensiti vity. 42 . b. Rosacea has a number of ophthalmic mani festations, and this associa tion is importan t. 43. a. Although perh aps not the most commo n cause, a cerebral aneurysm within the cavernous sinus is po tentially life-threatening and therefore important in the d iffe rential. Pituitary adenoma, MG, and systemic prostaglan din ana logues do not cause selective dysfunction of the ophthalmic brmlch of the trigeminal ga nglio n. 44. d. Corn eal stem cells reside within the basal ep ithelial layer of the corneosclerallimbus. They are not present in the ce nt ral corn ea. Conj unctival stem cells are found throughout the bulbar conjunctiva but do not transform into the cornea phenotype. 45. c. Conjunctivochalasis is associated with ep ipho ra when redundant nasal bulbar conjunctiva occludes th e puncta. Megalocornea and sclerocornea are not typica ll y associated with epiphora. Unin flamed pingueculae are usually asymptomatic. 46. b. Contact lens wear is the most commo n risk factor for the development of bacterial keratitis because of presum ed microtrauma to the corneal epithelium combined with bacterial adherence fac tors. 47. c. Rhinosporidiosis is a rare cause of co njunctival granuloma but has not been reported to cause Parinaud oculoglandular syndrome. Bartonella henselae is the 1110st common causative age nt. 48. b. A ring infilt rate is often associated with acan thamoeba keratitis. Rad ial keratoneuritis, pseudodendrite(s) , and pain out of propo rtionlvith clinical findings are also typical findings. Subepitheli al in filtrates, crystalli ne infi lt ra tes, and corneal neovascularization are not characte rist ic of acanthamoebal keratitis. 49. d. The 3 types of conjunctival intraepithelial neoplasia are papillifo rm , le ukoplakic, and gelatinous. 50. a. Malignant melanoma of the conju nctiva is usually darkly pigme nted, elevated, and often vascular. Limbal dermoids are usually located inferotemporall y and are not pigmented. Co njunctival papilloma and int raepithelial neoplasia are no t pigmented.
Index (j = figure;
t = table)
Ablepharon, 249 ABO antigens, transplant rejection and, 40i, 411 Abrasions. corneal, 372 posttraumatic recurrent corneal erosion and, 372 Absidia, 140 AcalltiJamoeba, 140 keratitis/ocular infection caused by, 167-169, 168/ contact lens wear and, 167> 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
Burns, thermal, 351 - 352 Butylcyanoacrylate tissue adhesive, 403-404. See also Cyanoacrylate adhesives C5a complement, 177 t C5a peptidase, streptococcal production of, 133 C-reactive protein, in immune-mediated disease, 182t Calcific band keratopathy (calcium hydroxyapatite deposition), 328, 342 - 344, 343f in sarcoidosis, 73 Calcific plaques, senile scleral, 9, 345-346, 346f Canalicular plugs, for dry eye, 62 Canaliculi tis, lOlt Cancer. See also specific type or organ or structure affected corneal nerve enlargement and, 328-329, 328f, 329t Candida (candidiasis), 139 albicmls, 139, 139f adherence in virulence of, 98 keratitis caused by, 165, 166 as normal ocular flora, 97, 97t, 139 Canthoplasty, for persistent corneal epithelial defects, 87 Capillary hemangiomas, 240- 241 Capsaicin cream, for postherpetic neuralgia, 122 Capsid (viral), 104 Carbohydrate sulfotransferase 6 (CHST6) gene, in macular dystrophy, 269f, 283 Carbohydrates, corneal changes in disorders of metabolism of, 305-308, 306t mucolipidoses and, 312 Carbon, corneal pigmentation caused by, 337t Carbon ic anhydrase inhibitors dry eye and, 61 for intraocular pressure control in chemical injuries, 358 Carcinoma sebaceous,233,234f squamous celi, of conjunctiva, 226t, 231-232, 232f Carcinoma in SiIIJ, of conjunctiva, 228 Carpenter syndrome, 322t Caruncle, 4 Cat -scratch disease, 136, 157- 158 Cataract graft-vs-host disease and, 203-204 scleri tis and, 220 in Wilson disease, 327 Cataract surger}' corneal endothelial changes caused by, 384-385 in megalocornea, 254 in nanophthalmos, 252 pseudophakic bullous keratopathy after, 384- 385 Catarrhal (marginal corneal) infiltrates, staphylococcal blepharitis/blepharoconjunctivitis and, 145, 146j, 147,210 Caterpillar hairs, ocular inflammation caused by, 362 Cationic protein, 1791 Cats Bartonella henselae transmitted by, 136, 157, 158 toxoplasmosis transmitted by, 141 Cautery, thermal, for punctal occlusion, 61, 61f, 62 Cavernous hemangioma, 240-241 CCDF. See Central cloudy dystrophy, of Frano;:ois
476 • Index CD4' T cells in anaphylactic/atopic (type 1) reactions, 179 in delayed hypersensitivity (type IV) reactions, 180 in external eye defen se, 96 in herpetic stromal kerat itis. 114 in HI V infection/AIDS, 130 in Sjogren syndrom e, 63 CD8+ T cells
in external eye defense, 96 in herpetic stromal keratitis, 114
in Sjogren syndrome, 63 CD40, in Sjogren syndrome, 63 CD40 ligand, in Sjogren syndrome. 63 CDA. See Granular corneal dystrophy. type 2 CDSI (corneal dystrophy of Bowman layer type 1). See
Reis-Bucklers corneal dyst rophy CDB2 (corneal dystrophy of Bowman layer type 2). Sec Thiel-Behnke corneal dystrophy CDGDL. See Gelatinous droplike corneal dystrophy CDLt. See Classic lattice corneal dystrophy CORBoSee Reis-Biicklers corneal dystrophy CDS (Cornea Donor Study), 4 11 CDTB. See Thiel- Behnke corneal dystrophy Cefazolin, for bacterial keratitis, 1621 Ceftazidime, for bacterial keratitis, 1621 Ceftriaxone for bacterial keratitis, 1621 for gonococcal conjunctivit is. 152 in neonates, 153 Cell-adhesion molecules, 177t CelJ wall, bacterial, 131 - 132 Cellular immunity (cell -mediated immunity), 17Bf, 1791,180 in cicatricial pemphigoid, 199 in conjunctiva, 181 Cellulitis, preseptal, Haemopllillls causing, 150 Central cloudy dystrophy of Fran~ois, 2681, 270r, 289-290, 289f genetics of, 2691, 289 genetics of, 2691 Central corneal power, keratometry in measurement of, 38-39 Central zone, 37. 37j Ceramide trihexoside, in Fabry disease, 3 10 Ceruloplasmin , in Wilson disease, 327 Cevimeline, for dry eye, 60 CGDDI. See Granular corneal dystrophy, type 1 Chalasis, 201 Chalazion, 72-73, 72f, 148 internal hordeolum and, 148 in meibom ian gland dysfunction, 67 in rosacea, 69 Chalcosis, corneal pigmentat ion in, 3371 Chandler syndrome, 344 CHED1/CHED2 . See Congenital hereditary endotheli al dyst rophy Chelation therapy, for band keratopathy, 343 Chemical injury (burns), 353-359 acid burns, 355 alkali burns, 353-355, 353(, 354j limbal transplantation for, 94, 358 management of, 355 - 359, 3561, 3571 mucous membrane grafting for, 401
Chemokines, 177, 177t Chemosis. 20t, 21 extraocular surgery causing, 385 ionizing radiation caUSing, 352 Ch ickenpox. See Varicella CHIL D (congenital hemidysplasia with Ichthyosiform erythroderma and limb defects) syndrome, 74 Children bacterial conjunctivitis in, 149- 152 corneal transplantation in, 430-431, 431r preseplal cellulitis in, 150 Chlamydia,13i conjunctivitis caused by. 154 - 157, ISSf, 156j in adults, 156-157, 156j in neonales, 153-154 gonococcal coinfection and, 152 ocular infection/inflanlillalion caused by, 154-157, ISS/, 156/ persistence and, 99 psirtaci, 154 specimen collection/isolation techniques for diagnosis of, lOlt, 103 trachoma caused by, 154-156, ISSf, 156/ tracJlomatis, 154 Chlorhexidine, for Accl1lthamoeba keratitis, 169 Chloroquine toxicity, cornea vertici!lata and, 346 Chlorpromazine, corneal pigmentation caused b)', 348-349 Chocolate cyst, 243 Choristomas, 246-247, 247/ See also Dermoids complex. 246-247. 147j epibulbar, 245-247, 246f, 247/ neuroglial ,247 osseous, 247 phakomatous, 247 Chr ysiasis, corneal pigmentation in, 337t CH SD. See Congenital hereditary stromal dystrophy CHST6 gene. in macular dyst rophy, 269t, 283 Cicatricial (mucous membrane) pemphigoid, 180, 196t, 198-203, 199t, 200f, 20 II, 202j. lOSt drug-induced (pseudopemphigoid), 199, 361 mucous membrane grafting for, 40 1 Cilia (eyelashes), 4, 5f accessory. See Distichiasis disorders of, 89 lice infestation of, 149 misdirection of. See TrIchiasis in staphylococcal blepharitis, 1441, 145 Ciliary flush, 110 CIN. See Conjunctival inlraepilhelial neoplasia Ciprofloxacin for baclerial keratitis. 163 corneal deposits caused by, 348 for gonococcal conjunctivitis, 152 Citric acid/sod ium citrate, for chemical injuries, 358 Citrobacter, 135 Clarithromycin, for bacterial keratitis, 1621 Classic lattice corneal dystrophy, 268t, 270t, 278-279, 279/ genetics of, 2691, 278 Climatic droplet keratopathy, 334-335, 335f See also SpherOidal degene rat ion Climatotherapy, fo r vernal keratoconj unctivitis, 188
Index. 477 Clobetasone, for atopic dermatitis, 185 Clofazimine, corneal pigmentat ion caused by, 349 Coats white ring, 334, 335/ Coche -Bonnet esthesiometer, 31 Cockayne syndrome, 322t Coefficient of variation, specular photomicroscopy in evaluation of, 32 Cogan microcystic epithelial dystrophy. See Epithelial/ subepithelial dystrophies, basement membrane Cogan-Reese (iris nevus) syndrome, 345 Cogan syndrome, 209- 210 COUAl/COLlA2 genes, in osteogenesis imperfecta, 252
COL8A2 gene in Fuchs endothelial corneal dystrophy, 269t, 291 in posterior polymorphous corneal dystrophy, 269[,
293 Cold (temperature), anterior segment injuries caused by, 351 - 352 Collagen corneal, 7, 8, 9 in Ehlers-Danlos syndrome, 325 scleral, 9 stromal, 7, 8 Collagen plugs, for dry eye, 61 - 62 Collagen type VIII alpha (COL8A2) gene in Fuchs endothelial corneal dystrophy, 269(, 291 in posterior polymorphous corneal dystrophy, 269t, 293
Collagenase inhibitors, for peripheral ulcerative keratitis, 212 Collagenases,l77t in ocular infections, 98 Collagenous layer, posterior (retrocorneal fibrous membrane),29 Collimating keratoscope, 39 Colony-stimulating factors, in cicat ricial pemphigoid, 199
Combined granular-lattice corneal dystrophy. See Granular-lattice corneal dyst rophy Combined interrupted and continuous sutures, fo r penetrating keratoplasty, 419, 420/ Complement, 177t in external eye defense, 95 Complete blood count, in immune-mediated disease, 182t
Complex choristomas, 246- 247, 247/ Computerized corneal topography, 40- 45, 401, 411, 421, 431, 44f See also Cornea, topography of Concretions, conjunctival, 332- 333 Concussive trauma, anterior segment, 362- 369, 3641, 36Sf, 366f, 367f, 369, Confocal microscopy, 35- 36, 36/ in dry eye evaluation, 5S Congenital anomalies. See also specific type of anterior segmen t/cornea, 253- 266 of globe, 249- 253 of sclera, 249- 253 Con genital epithelial melanosis, 233 Congen ital glaucoma, 265 Congenital hemidysplasia with ichthyosiform erythroderma and limb defects (C HILD) syndrome, 74
Congenital hereditary endothelial dystrophy, 260- 263, 268t, 270t, 295- 296, 295/ CHED l, 260, 268(, 270t, 295- 296, 295/ CHED2, 260, 268(, 270t, 296, 296/ genetics of, 269t, 295, 296 Congenital hereditary stromal dystrophy, 260, 286. See also Congenital stromal corneal dystrophy Congenital keratitis-ichthyosis-deafness (KID) syndrome, 74 Congenital rubella syndrome, 130 Congenital stromal corneal dystrophy, 268(, 270t, 286- 287, 286/ genetics of, 269t, 286 Congenital syphilis, corneal manifestations of! interstitial keratitis, 207 - 209, 2081, 264 Conidia, 138 Conidiophores, 138 Conjunctiva. See also under Conjunctival age-relatedlinvolutional changes in, 331 amyloi d deposits in, 317t, 318, 318/ anatomy of, 4- 6 biopsy of, 389- 390 in cicatricial pemphigoid, 201 in mucopolysaccharidoses, 307 for ocular microbiology, 102 in pseudopemphigoid, 361 in superior limbic keratoconjunctivitis, 82 blood under, 75, 76, 76t, 362 - 363 bulbar, 4, 6 carcinoma of, squamous cell, 2261, 231-232, 232/ concretion s of, 332- 333 contact lenses causing injury to, 193- 195, 194/ cysts of, 225- 226, 226/ degenerations of, 331 - 333 development of, 4 discharge from, 20t disorders of, 20t contact lenses causing, 193- 195, 194/ immune-mediated, 180- 181 , 185-204, 1971 ioni zing radiation causing, 352- 353 neoplastic, 225- 247. See also Conjunctiva, tumors of epithelium of, 5 cysts of, 225- 226, 226/ im munologic features of, 173, 1741 tumors of, 226- 233, 2261 wound heali ng/repair and, 388 erosions of, 22t punctate epithelial, 20t in external eye defense, 96 extraocular surgery affecting, 385 folli cles of, 201, 24, 24/ fo reign body on, 370, 370/ granuloma of, 20t, 221, 241 - 242, 241/ in sarcoidosis, 73 - 74 hemangiomas of, 240- 241 hemorrhage of, 76, 761, 362- 363 in hereditary hemorrhagic telangiectasia, 76 immune response/immunologic features of, 173, 174t infectionlinflammation of, 20t, 21 - 24, 221, 22(, 23f, 24f, 143- 148, 149- 158, 150t. See also Conjunctivitis; Keratoconjunctivitis intraepithelial neoplasia of (CIN) , 226t, 228- 229, 229f, 230/
478 • Index laceration of, 369-370 lithiasis of, 333 lymphoma of, 244, 245/ melanoma of, 238-240, 238t, 239/ membrane of, 20t, 221 in epidemic keratoconjunctivitis, 124, 12 5, 125/ in ligneous conjunctivitis, 192, 192! nevus of, 236-237, 236f, 238t
normal nora of, 96-97, 97t palpebral, 4, 6 papillae of, 20t, 21-22, 22f, 221, 23f See also Papillae, conjunctival
papillomas of, 128, 129,226- 228, 226t, 227J pH of, chemical injury management and, 355
pigmented lesions of, 21St
benign, 233-237, 234t malignant, 234t, 238-240 preinvasive, 2341, 237-238
pseudomembrane of, 20t, 221 in epidemic keratoconjunctivitis, 124
scrapings/swabbings from, 47 specimen collection from for ocular cytology, 47-48 for ocular microbiology, 100- 102, lO lt stem cells of. 92 stroma of. See Substantia propria in superior limbic keratoconjunctivitis, 81, 82, 82f tarsal, 4 transplantation of, 94, 392j, 393- 395 for chemical injuries, 358 indications for, 387(, 395 for wound closure after pterygium excision, 392j,
393,393-395 tumors of, 225-247 epithelial, 226-233, 226t glandular, 233 human papillomaviruses causing, 128, 129, 226-227 inflammatory, 241-242, 24 1j, 24lt lymphatic and lymphocytic, 242- 244 malignant, 234f, 238-240 metastatic, 245 neurogenic and smooth muscle, 240 pigmented,238t benign, 233-237,234t malignant, 234f, 238-240 preinvasive, 234f, 237-238 vascular and mesenchymal, 240- 242 , 24 1( ulceration of. 22t vascular anomalies of, noninflammatory, 75-77 wound healing/repair of, 388 Conjunctiva-associated lymphoid tissue (CALT/ conjunctival MA LT), 3, 5, 180- 181 Conjunctival autograft , 94, 392j, 393- 395 fo r chemical injuries, 358 indications for, 387t, 395 for wound closure after pterygium excision, 392j, 393 ,
393-395 Conjunctival fl aps, 398-401, 399f for neurotrophic keratopathy, 88- 89 for wound closure after pterygium excision, 39 1-393,
392[ Conjunctival hyperemia, 20f, 75
Conj unctival inclusion cysts, 225, 226f Conj unctival intraepithelial neoplasia (CIN), 226f, 228-229, 229f, 230[ Conjunctival sac, 4 Conjunctivalization of cornea, 355 Conjunctivitis, 20t, 21-24, 22j, 22t, 23j, 24j, 10 1f. See also Keratoconjunctivitis acute hemorrhagic, 130 puru lent, 149-151 adenoviral, 124-127, 125f allergic perennial, 185-187 seasonal, 185-187 bac terial, 149-154, 1501 in children, 149-152 classification of, 149, ISOt in neonates, 152-154 in children, 149-152 preseptal cellulitis caused by, 150 chlamydial, 154- 157, 155j, 156f in adults, 156-157, 156f in neonates, 153-154 cicatricial, 196f, 198-203, 199f, 200j, 20 1j, 202f See also Ocular cicatricial (mucous membrane) pemphigoid di fferential diagnosis of, 199, 199t contact lens-induced, 193- 195, 194/ coxsackievi rus, 130 enterovirus, J 30 Epstein-Barr "irus causi ng, 122 - 123 follicular, 221, 24, 24f in acute hemorrhagic conjunctivitis, 130 adenoviral,124 in measles, 129 med ication toxicity causing, 359 t, 360, 36If in mumps, 129-130 RNA viruses causing, 129 giant papillary (contact lens- induced), 23j, 194- 195,
194[ gonococcal, 134, 15 J -152, IS If in neonates, 153 Haemopliilll5 causing, 150 hay fever, 185-187 hemo rrhagic, 130 herpes zoster causing, 106, J06f infectious. 101 t. See also specific type ligneous, 192- 193, 192f measles virus causing, 129 medication toxicity causing, 359- 36 1, 359t, 361f microsporidial, 170 mumps virus causing, 129- 130 neo natal, 152-154 papill ary, 221, 23f in Parin aud oculogland ular synd rome, 157- 158 in reactive arthritis/Reiter synd rome, 209 RNA viruses causing, 129 seasonal allergic, 185-187 staphylococcal/staphylococcal blepharitis and, 10 1(, 144f,145 in Stevens-Johnson syndrome, 196 streptococcal, 10lt, 149-150 subconjunctival hemorrhage caused by, 76t
Index. 479 toxic contact lens solutions causing, 92 medications causing, 359- 361, 3591, 361f varicella-zoster virus causing, 117- 119 Conjunctivochalasis, 21, 53, 53f, 333, 333f Connective tissue disorders corneal changes in, 320- 325, 322 - 324t peripheral ulcerative keratitis in, 211 - 213, 211t, 212f scleritis in, 222 Conradi syndrome, ichthyosis in, 74 Contact dermatitis/dermatoblepharitisl blepharoconjunctivitis, 180, 183- 185, 18'if Contact lens solutions allergic reactions to, 92 giant papillary conjunctivitis and, 195 for keratoglobus, 303 toxic conjunctivitis caused by, 92 Contact lenses Acanthamoeba keratitis associated with, 167, 168 bandage, 403 for chemical injuries, 358 contraindications to in exposure keratopathy, 80 for corneal abrasion, 372 for dry eye, 60t, 61 , 403 for graft-vs-host disease, 203 for perforating injury, 375 for peripheral ulcerative keratitis, 213 for recurrent corneal erosions, 84, 403 for Thygeson superficial punctate keratitis, 206 conjunctivitis caused by (giant papillary conjunctivitis) , 23f, 193 - 195, 194f in dry-eye patients, 61 keratitis associated with use of, 159, 165, 167, 168 for keratoconus, 300 for pellucid marginal degeneration, 302 problems/complications with, ocular surface, 91 - 92 scleral in dry-eye patients, 61 for graft-vs-host disease, 204, 20'if for trial fitting, disinfection of, 46 Contact specular microscopy/ photomicroscopy, 32- 33, 32f Continuous sutures, for penet rating keratoplasty, 419, 420f Contralateral corneal autograft, 432 Copper corneal deposition of, 327- 328, 327f, 337t Kayser-Fleischer ring caused by, 327, 327f, 337t in Wilson disease, 327- 328, 328f Cornea. See also under Corneal abrasions of, 372 posttraumatic recurrent corneal erosion and, 372 age-relatedlinvolutional changes in, 334 stromal corneal degenerations and, 336- 338, 338[' 339f amyloid deposits in . See Cornea, deposits in anatomy of, 6- 9, 7[,8f anesthesia of congenital,264- 265 herpes simplex epithelial keratitis and, 110 neurotrophic keratopathy/persistent corneal defects and, 86, 87 apex of, 37, 38f
apical zone of, 37 biomechanics of, 9 biopsy of, 402- 403 for ocular microbiology, 103 blood staining of, 3371, 366- 367, 367f Bowman layer/membrane of, 7, 7f dystrophy of, 268t, 275- 278 congenital/developmental anomalies of, 253- 266, 261 - 2621 . See also specific type secondary abnormalities causing, 263- 266 of size and shape, 253- 255, 254f, 261 - 262t of structure and/or clarity, 255 - 263, 256f, 257f, 259f, 260f, 261 - 2621, 263f conjunctivalization of, 355 curvature of, 37- 38. See also Cornea, topography of axial, 40, 41f in cornea plana, 254 mean , 41, 42f measurement of keratometry for, 38- 39 keratoscopy for, 39, 39f power and, 37- 38 radius of, 6, 39 in cornea plana, 254 instantaneous (meridiona1!tangential power), 40,41f keratometry in measurement of, 38- 39 degenerations/dystrophies of. See specific type and Corneal degenerations; Corneal dystrophies; Keratopathy deposits in, 32lt amyloid, 3171, 318- 319, 318! See also Amyloidosis/ amyloid deposits in gelatinous droplike corneal dystrophy, 274- 275, 275f, 317t, 318, 318f in lattice dystrophy, 278, 280 copper (Wilson disease) , 327- 328, 327f differential diagnosis of, 320, 321 t drug-induced, 346- 349 , 3471 immunoglobulin synthesis disorders and, 319 - 320 nonpigmented,321t pigment,321t drug-induced, 346- 349, 347t refractile/crystalline, 321 t Descemet's membrane of. See Descemet's membrane/ layer development of, 4 disorders of, 20- 2It blunt trauma causing, 363 contact lens- related, 91 - 92 ectatic, 296- 303, 302t immune-mediated, 181,204- 216 ionizing radiation causing, 352- 353 metabolic disorders and, 305-329 neoplastic, 225 - 247. See also specific tumor type in rosacea, 70, 70f scleritis and, 220, 221, 221 - 222, 2211 surgical approach to, 413-4 14 thermal burns causing, 351-352 ultraviolet radiation causing, 352 donor. See Donor cornea ectasia of. See Ectasia/ectatic disorders
480 • Index edema of, 29-30, 301 birth trauma causing, 265-266, 266f cold-induced,351-352 in Fuchs endothelial dystrophy, 291, 292f intraocular surgery causing, 383, 384 in keratoconus, 298-299, 300 management of, 403-405 endothelium of, 7f, 8-9 anatomy of, 7f, 8-9 development of, 4 dysfunction of, corneal edema and, 25 intraocular surgery causing changes in, 383, 383-385 epithelium of, 6, 7f anatomy of, 6, 7f cysts of, 348 defects/persistent defects of, 2It, 85- 87 ocular infect ion and, 99 after penetrating keratoplasty, 422, 423f drug-induced deposits in, 346-348, 347t, 348f intraocular surgery causing changes in, 382-383 metabolic damage in contact lens overwear syndromes and, 91 tumors of, 226-233, 2261 wound healingJrepair of, 387- 388 erosions of in epithelial basement membrane dystrophy, 83, 271,272 in herpetic keratitis, 117 punctate epithelial, 20t, 25, 26f, 27t in vernal keratoconjunctivitis, 187 recurrent, 83-85 , 85f eye pain and , 83 posttraumatic, 372 examination of, 11 - 46. See also Examination, ophthalmic in external eye defense, 96 extraocular surgery affecting, 385 farinata, 337- 338, 338f fetal, secondary abnormalities affecting, 263- 266 flat (cornea plana), 254- 255, 26lt sclerocornea and , 254, 255, 258 foreign body in, 371-372, 371f plant/vegetation, 362, 371 function of, 3 guttae/ guttata, 30, 345 age-related, 334 in Fuchs endothelial corneal dystrophy, 291, 292f peripheral (Hassall-Henle bodies/ warts), 334, 345 hydration of, 8 immune response/immunologic features of, 174-175, 174/ infectionlinflammation of, 20- 2lt, 24 - 25, 261, 271, 27t, 281, 158 - 171. See also Keratitis; Keratoconjunctivitis innervation of, 6. See also Corneal nerves intraepithelial neoplasia of, 226t, 229- 231, 231f keloids of, 341 congenital, 264 laceration of. See also Corneosclerallaceratioll Seidel test in identification of, 17, 19f marginal inmtrates of, staphylococc.al blepharitis/ blepharoconjunctivitis and, 145, 1461, 147,2 10
melting of (keratolysis) gonococcal infection and, 134 peripheral ulcerative keratitis and, 211,212, 213 multifocal, retillosCOpy in detection of, 45 neovascularization/vascularization of in atopic keratoconjunctivitis, 190, 191f contact lens wear causing, 92 inflammation and, 25 after lamellar keratoplasty, 436 after pediatric corneal transpl antation, 431 in stem cell deficiency, 93, 94 opacification of chromosomal aberrations and, 263 congenital, 260- 263 in hereditary syndromes, 263 inflammation causing, 25 after lamellar keratoplasty, 436 in Schnyder corneal dystroph y, 285, 285f perforation of. See also Corneosclerallaceration; Perforating injuries foreign -body removal and, 372 management of, 403- 405 surgical repair in, 377, 378f, 379/ See a/so Corneosc1eral laceration, repair of peripheral, degenerations of, 339-340, 340f pigmentation/ pigment deposits in, 3211 drug-induced, 346- 349, 3471 plana (flat cornea), 254 -2 55, 2611 sclerocornea and, 254, 255, 258 refractive index of, 6, 38 refractive power of, 37- 38 keratometry in measurement of, 38-39 sensation in, 6 measurement of (esthesiometr y), 30- 31 reduction of in diabetes mellitus, 308 in herpes simplex epithelial keratitis, 1 iO in neurotrophic keratopathy, 87 shape of, 6, 36- 37 curvature and power and, 36-37 disorders of, 253-255, 261 - 2621 size of, disorders of, 253 - 255, 254f, 261 - 2621 specimen collection from, IOlt, 102- 103, 102f staphyloma of, congenital, 258- 260, 2621, 263f stem cells of, 5, 6, 9, 92- 93, 389 stroma of, 7- 8, 7f, 8f anatomy of, 7-8, 7f, 8f development of, 4 inflammation of, 25, 27f, 271 in systemic infections, 169- 170 neovascularization of, contact lenses causing, 92 pigmentation of, 348- 349 subepithelial infiltrates of, 21t in epidemic keratoconj unctivitis, 124, 125/ surgery affecting extraocular procedures and , 385 intraocular procedures and, 382-385, 384f thicknesslrigidit)' of, 28 intraocular pressure measurement and, 8, 9, 30 measurement of, 28- 30, 291, 30t. See also Pachometry tonometry measurements affected by, 30
•
Index . 48 1 topography of, 36-45 astigmatism detection/management and, 43, 43f,
44 after penetrating keratoplasty, 426, 427/ computerized, 40-45, 40f, 4 If, 42f, 43f, 44/ corneal zonesand,36-37,37/ indications for, 43-44, 43f, 44/ limitations of, 44- 45 measurement of, 36-45 Placido-based, 39, 40, 40/ in keratoconus, 43-44, 44f, 299, 300/ refractivelkeratorefracti\"e surgery and, 43-44, 44/ transparency of, 8 transplantation of, 407-41 1, 413-445. See also Donor cornea; Keratoplasty autograft procedures for, 413, 431-432 basic concepts of, 407-411 for chemical injuries, 358 clinical approach to, 413-445 comparison of procedures for, 415-4161 donor selection and, 408-411, 4101 eye banking and, 408- 411, 4101 histocompatibility antigens and, 407 immune privilege and, 175,407-408 immunobiology and, 407-408 lamellar keratoplasty for, 413, 433-437, 434/ pediatric, 430-431, 431 ( penetrating keratoplasty for, 413, 415-416(, 417-430 preoperative evaluation/preparation and, 414-417 rabies virus transmission and, 130 rejection and, 407, 408, 427-430, 428f, 429f, 436. See also Rejection tumors of, 225-247. See also specific Iype vertex of, 37, 38/ verticillata, 310, 31 If, 346-348, 3471, 348/ wound healing/repair of, 387-388 zones of, 36-37, 37/ Cornea Donor Study, 411 Corneal allografts. See Corneal grafts Corneal arcus, 336-337, 338/ in dyslipoproteinemia/hyperlipoproleinemia, 308, 309t, 336 juvenilis, 266, 336 lipoides, in Schnyder corneal dystrophy, 28S, 285/ sen ilis, 336-337, 338/ Corneal cap, 6 Corneal degenerations, 334 - 345 dystrophies differentiated from, 334t endothelial, 344-345, 344/ epi thelial/subepithelial, 334-336, 335/ st romal age-relatedlinvolutional changes and, 336- 338, 338f, 339/ peripheral, 339-340, 340/ postinflammatory changes and, 340-344, 34 If, 342f, 343/ Corneal dystrophies, 167- 268, 268 - 296, 268t, 2691, 270t. See also specific type Bowman layer, 268t, 275- 278. See also Bowman layer corneal dystrophies classifi cation of, 267-268, 268t, 2691, 270t
definition of, 267 degenerations differentiated from, 334t Descemet membrane, 2681 endothelial, 2681, 291 - 296. See also Endothelial dystrophies epithelial/subepithelial, 2681, 270-275 . See also Epithelial/subepithel ial dystrophies genetics of, 2691 metabolic disorders and, 305-329 stromal, 2681, 278- 290, 278t. See also Stromal corneal dystrophies Corneal dystrophy of Bowman layer type I. See Reis-Bti ckJers corneal dystrophy Corneal dystrophy of Bowman layer type 2. See Thiel -Behnke corneal dystrophy Corneal elastosis, 334-335, 335f See also Spheroidal degeneration Corneal endothelial rings, traumatic, 363 Corneal grafts. See also Donor cornea; Keratoplasty allograft s, 413 autografts, 413, 431-432 disease recurrence in, 422, 423/ dislocation of, after Descemet strippi ng automated endothelial keratoplasty (DSAEK), 442, 443/ endothelial failure of late non immune, 425-426 primary, 422, 422/ after Descemet stripping automated endothelial keratoplasty, 444-445 inflammatory necrosis of, after lamellar keratoplasty, 436-437 rejection of, 407, 408, 427-430, 428f, 429f, 436. See also Rejection Corneal hysteresis, 9 Corneal intraepithelial neoplasia, 226t, 229-231,231/ Corneal light reflex, corneal vertex and, 37 Corneal melting (keratolysis) gonococcal infection and, 134 peripherallilcerative keratitis and, 211, 212, 213 Corneal nerves, 6 enlarged, 328-329, 328f, 329t in Acal1thnmoeba keratitis, 167 in mult iple endocrine neoplasia, 328-329, 329t Corneal nodu les, Salzmann, 340-341, 341/ Corneal pachometry. See Pachometry (pachometer) Corneal power maps, 40-43, 4 If, 42/ keratorefractive surgery and, 44 Corneal storage medium, 408 -409 Corneal tattoo, 337t, 405 Corneal transplant. See Cornea, transplantation of; Donor cornea; Keratoplasty Corneal ulcers, 21 t. See also Keratitis abrasions differentiated from, 372 in herpes Simplex keratitis, 110, 117 Mom·en , 213 - 216, 21S/ neurotrophic, herpetic keratitis and, 87, 88, 11 7 in vernal keratoconjunctivitis, 187, 189/ in vitamin A defiCiency. 78 von Hippel internal, intrauterine inflammation and, 263-264 Corneal vacuum trephines, for penetrating keratoplasty, 418
Corneoretinal dystrophy, Bietti crystalline, 313
482 • Index Corneosderallaceration. Sec also Anterior segment, trauma to; Perforating injuries repair of, 375-381, 376f anesthesia for, 376 postoperative management and, 381 - 382 preoperative management and, 374-375 secondary repair measures and, 380-38\, 38 11, 382/ steps in, 376-380, 377(, 378f, 379! Seidel test in identifkation of. 17, 19/ Corticosteroids (steroids) Acallthmnoeba keratitis treatment and, 168 for adenovirus infection, 125- 126 for allergi c conjunctivitis. 187 for atopic dermatitis, 185 for bacterial keratitis, 163- 164 for chalazion, 73 fo r chemical injuries, 355
for Cogan syndrome, 210 fo r contact dermatoblepharilis. 184- 185 fo r corneal graft rejection, 429-430
for dry eye, 60, 601 for epidemic keratoconjunctivitis, 125- 126 fungal keratitis associated with use of, 165 for giant papillary conjunctivitis, 195 herpes simplex keralitisand, 113, 115-116 fo r herpes zoster, 121 fo r hyphema, 367-368 for meibomian gland dysfunction, 68 for ocular al lergies/inflammation, 184-185, 185, 187 for peripheral ulcerative keratitis, 213 for recurrent corneal erosions, 84 for rosacea, 70 for scleritis, 222, 223 for seborrh eic blephariti s, 72 for staphylococcal blepharitis/blepharoconjunctivitis, 147 for Stevens-Johnson syndrome, 197 (or stromal keratitis, 1081, 115- 116 for T hygeson superficial punctate keratitis, 206 for traumatic iritis, 363 for vernal keratoconjunctivitis, 189 wound healing affected by, 39 1 CorynebacteriulII, 134 diph theriae, 134 as normal ocular nora, 971, 134 ocular infection caused by, 134 xerosis, 77, 134 Coxsackievirus conjunctivitis, 130 Crab louse (PhlilirZls pubis), 142, 1421 ocular infection caused by, 142, 149 Cranial nerve V (trigem inal nerve) in herpes simplex infection, 106 in herpes zoster, 118, 119- 120 neurotrophic keratopathy caused by damage to, 87 Crc utzfeldt-Jakob disease, corneal transplant in transmission of, 14 3 Crocodile shagreen, 337 Cromolyn for allergic conjunctivitis, 186 fo r giant papil la ry conju nctivitis, 195 C rouzon syndrome, 3221 C ryoglobulins, precipitation of, ophthalmic findings • and, 320
Cryotherapy for conjunctival intraepithdial neoplasia, 229, 230j for conjullctival papillomas, 228 fo r corneal intraepirbcliai neoplasia, 230-23 1 for ligneous co njunctivitis, 193 for squamous cell carcinoma of conjunctiva, 231 for trichiasis, 89 CryprococClis neojorm(llls (cryptococcosis), 139 C ryptophthalmos. 249-250, 2491 C rystalline corneal dystrophy, Schnyder, 2681, 270l,
284 - 285,285/ geneti cs of, 2691, 284 Crystalline dystrophy, Bietti corneoretinal, 3 13 Crystalline keratopa thy, infect iolls, 159, 160j after penetrating keratoplasty, 425 , 425/ CSCO. See Congenital stromal corneal dystrophy CSD. See Cat-sc ratch disease CTNS gene, in cyst inosis, 313, 3 141 Cult ured epithelial stem cells. for transplantation, 389,
398 Curly fibers corneal dystrophy. See Thiel -Beh nke corneal dystrophy Curvature, corneal, 37-38 axia l, 40, 411 in cornea plana, 254 keratometry in measurement of, 38-39 keratoscopy in measurement of, 39, 39/ mean, 41, 421 power and, 37-38 radius of, 6, 39 in cornea plana. 254 instantaneous (meridional/tangential power), 40, 4 1f keratometry in measurement of, 38-39 Cllrvu/a ria, 139
Cutaneous leishmaniasi s, 14 1 Cyanoacrylate adhesives, 403-404 fo r corneal perforation/corneosclerallaceration, 377,
404 for peripheral ulcerative keratitis, 213 as tarsorrhaphy alternative, 391 Cyclodialysis, 364, 3641 Cyclophospham ide for cicatricial pemphigoid, 202 for peripheral ulcerative keratitis, 213 for scleritis, 223 Cyc1oplegia/cycloplegics for chemical injuries, 358 for corneal abrasions. 372 for herpes zoster, 121 for hyphema, 367 for recurrent corneal erosions, 84 for thermal burns, 351 for traumatic iritis, 363 Cyc1osporine/cydosporinc A for allergic conjunctivitis, 186 for atopic keratoconjunctivitis, 191 for corneal graft rejection, 430 for dry eye, 60, 601 for graft-vs-host disease, 203 for peripheral ulcerative kerat itis, 212 for scleritis. 223 for T hygeson superficial punctate keratitis, 206 for vernal keratoconjunctivitis, 189- 190
Index. 483 CYP1 81 gene, in Peters anomaly, 258 Cysteamine, for cystinosis, 313, 314 Cyslicerws celllliosae (cyst icercosis), 142 Cystine accumulation/crystals, in cystinosis, 313, 314, 3141,3 15f Cystinosis, 314-315, 314t, 315f corneal changes in, 314-3 15, 3 14/, 315f Cystoid macu lar edema, in sarcoidosis, 74 Cytarabine, epithelial cysts caused by, 348 Cytobrush,47 Cytokines, 177, 1771 in external eye defense, 95. 96 in Sjogren syndrome, 63 Cytology (ocular). 47-48 in immune-med iated keratoconjunctivitis, 182t impression. 47- 48 in Sjogren syndrome diagnosis, 57 in stem cell deficiency, 94 interpretation 0(, 48 specimen collection for, 47-48 Cytolysin , en terococci producing, [34 Cytotoxic hypersensitivity (type II ) reaction, 178f, 179/, 180 Cytotoxic T lymphocytes, in external eye defense. 96 Cytotoxicity, antibody-dependent, 180
Dacryoadeniti s,IO lt Epstein-Barr virus causing, 122- 123 mumps virus causing, 129 Dacryocyst itis,IO It DALK. See Deep an terior lamella r keratoplasty Dapsone, for cicatricial pemphigoid, 202 Dark-field illumination, for Treponema pal/idum visualization, 137 DCN gene, in co ngenital stromal corneal dystrophy,
286 Debridement for Aeanlhamoeba keratitis, 169 for chemical injuries, 358 for fungal keratitis, 166 for herpes simplex epithelial keratitis, 112 for recurrent corneal erosions, 84- 85 for thermal burns, 351 Decongestants, tear production affected by, 661 Decorin, 7, 9 in congenital stromal corneal dystrophy, 2691, 286 Deep anterior lamellar keratoplasty (DALK), 300, 413, 415-4161, 435-436 advantages of, 416t in children, 431 complications of intraoperative, 41St postoperative, 41St disadvantages of, 416/ indications for, 41St for keratoconus, 300 penet rating/selective keratoplasty compared with , 415-4 161 surgical technique for, 435-436 Defense mechanisms, host of external eye, 95-96, 99- 100 impaired, 100
Degenerations conjunctiva l,331 - 333 corneal,334- 345 defin ition of. 331 d >'strophies differentiated from. 3341 elastotic/e1astoid (elastosis), corneal, 334-335, 335/ See a/so Spheroidal degeneration scleral, 345-346, 346f Delayed hypersensitivity (type IV) reaction, 178f, 179/, 180 contact dermatitis/dermatoblepharitis as, 180, 183. 184- 185,184/ contact lens solutions and, 92 in graft reject ion, 408 topical medications/substances and, 183, 184- 185, 184f Del iver y (birth), difficult, corneal edema caused by, 265-266,266f Dellen, 90-91 Demodex, 142, 148 brevis, 97 . 142, 148 foIliell/orum, 97,142,148 as normal ocular flo ra, 97. 97/,142, 148 ocular infection caused by. 148 Demulcen ts, 58-60 Dendrites/dendritic keratitis, 21 t amebic infection and, 167 herpes Simplex virus causing, 107, 110, I II, I ll/ herpes zoster causing, 120 Dendri tic cells, 173, 174, 174j. 174t Dermalan sulfate. 7 in mucopolysaccharidoses, 305 Dermatan sulfate- proteoglycan, macular dystrophy and,283 Dermatitis atopic, 185 ke ratoconjunctivitis and, 190- 192, 191f contact, 180 herpetiform is. 205t zoster, 119-1 20 Dermatoblepharitis, lOll contact, 183-185 , 184/ herpes Simplex virus causing, 106, 106f, 110 va ricella-zoster virus causing, 117- 119 Dermoids, 245, 246/ epibulbar, 245-246, 245f Goldenhar syndrome and, 246 Dermolipomas, 246 Descemet membrane dystrophies, 268! Descemet stripping automated endothelial keratoplasty (DSAEK), 413, 415- 4161, 437-445 adva ntages of, 4161, 438 complications of intraoperative, 4151, 441, 44 If postoperative, 41 51, 442- 445, 442f, 443f, 444/ disadvantages of, 4161, 438 indications fo r. 4 151. 437 penetrating/selective keratoplasty compared with, 41 5-4 161 precut tissue for, 409, 438 surgical procedure for, 438- 441,440/ Descemetocele, management of, 403- 405 lamellar keratoplasty for, 434/
484 • Index Descemetorhexis, in Descemet stripping automated endothelial keratoplasty, 437 Descemet's membrane/layer, 7f, 9 age-related/ involutional changes in, 334 anatomy of, 7f, 9 detachment of, during intraocular surgery, 383, 383f intraocular surgery causing changes in, 383, 383/ pigmentation of, 348 - 349 retained, penetrating keratoplasty and, 421 rupture of birth trauma and, 265, 2661 in keratoconus, 298- 299 Descemet's membrane endothelial keratoplasty (DMEK), 445 Desquamating skin conditions, ocular surface involved in, 74 Dexamethasone for corneal graft rejection, 429 for vernal keratoconjunctivitis, 189 Diabetes mellitus, corneal changes in, 307- 308 neurotrophic keratopathy/ persistent corneal defects and,87 Diamidines, for Acal1tlwmoeba keratitis, 169 Diathermy for hyphema, 368 for recurrent corneal erosions, 84 Diethylcarbamazine, for loiasis, 170 Diffuse anterior scleritis, 28, 218, 2181, 218t Diffuse (simple) episderitis, 28, 216 Diffuse illumination, for slit-lamp biomicroscopy, 12 Dimorphic fungi , 138 Diopter, 37 Diphtheroids, 134 as normal ocular flora, 96, 97t, 134 Disciform keratitis, herpes simplex virus causing, 114, 114f persistent bullous keratopathy and, 117 Disodium ethylenediaminetetraacetic acid (EOTA), for band keratopathy, 343 Distichiasis, 89 OM. See Diabetes mellitus DMEK. See Descemet's membrane endothelial keratoplasty DNA, plasmid, 131 DNA viruses adenoviruses, 113 - 127 herpesviruses, 105- 123 papovaviruses, 128- 129 poxviruses, 127- 128 Donor cornea, 408 - 41 1 disease transmission and, 409-4 11, 4101 dislocation of, after Descemet stripping automated endothelial keratoplasty, 442, 443f endothelial failure of late non immune, 425- 426 primary, 422, 422f after Descemet stripping automated endothelial keratoplasty, 444- 445 preparation of for Descemet stripping automated endothelial keratoplasty,438 for penetrating keratoplasty, 41 7-418
rejection of, 407, 408, 427- 430, 4281, 4291, 436. See also Rejection selection/screening of, 409- 411, 410t storage of, 408- 409 Doxycycline for chlamydial conjunctivitis, 15 7 for meibomian gland dysfunction, 68 for recurrent corneal erosions, 84 for rosacea, 70 for seborrheic blepharitis, 72 Drugs dry eye caused by, 50, 65, 66t ocular cicatricial pemphigoid (pseudopemphigoid) caused by, 199, 361 contact dermatoblepharitis caused by, 183- 185, 184f corneal deposits and pigmentation caused by, 346- 349, 347t persistent corneal epithelial defects caused by, 86 toxici ty of conjunctivitis/keratoconjunctivitis and, 359- 361, 359/,36If ulcerative keratopathy and, 86 Dry· eye syndrome, 48- 55, 50f, 51! See also specific causative factor and Ocular surface, disorders of aqueous tear deficiency causing, 49 - 50, 501, 51, 51f, 52, 55- 65. See also Aqueous tear deficiency blephari tis and, 144t, 145 classification of, 51 - 52, 51! clinical presentation of, 55- 56, 56f, 57f, 58t evaporative tear dysfunction causing, 51, 51f, 52, 65- 75 glaucoma and, 61 in graft-vs-host disease, 203 imaging in evaluation of, 55 keratoprosthesis use and, 432 laboratory evaluation in, 57, 59f, 59t after LASIK, 50, 65 mechanisms of, 49- 51, 50f medications causing, 50, 65, 66t non - Sjogren syndrome, 50, 511, 52, 65 ocular infection and, 99 after photorefractive keratectomy, 65 refractive surgery and, 50, SOf, 65 rose bengal in diagnosis of, 17 sarcoidosis and, 73 severity of, 56, 58t Sjogren syndrome, 50, 51f, 52, 63- 65, 64t systemic diseases associated with, 59t tear-film evaluation in, 52- 55, 53f, 54f, 54t treatment of medical management, 57- 61, 60t surgical management, 61 - 63, 611, 62f DSA EK. See Descemet stripping automated endothelial keratoplasty Dye disappearance test, 17 Dysautonomia, familial (Riley-Day syndrome) congenital corneal anesthesia and, 264 neurotrophic keratopathy in , 87 Dyskeratosis, benign hereditary intraepithelial, 226t Dysmorphic sialidosis, 312
Index. 485 Dysplasia, of conjunctiva (conjunctival intraepithelial neopl asia), 2261, 228- 229, 229f, 230f squamous, 228 Dystroph ies corneal, 267-268, 268- 296. See also specific Iype and Corneal dystroph ies defin ition of, 267 degenerations di fferentiated from, 334t
Endophthalmitis after penetrati ng keratoplasty. 422 after perfo rating injury, 375 Endothelial cell density, specular photomicroscopy in evaluation of, 32, 32/ Endotheli al degenerations, 344- 345, 344/ Endothelial dystrophies, 2681, 29 1- 296 congenital hereditary, 260-263, 268t, 270t, 295-296, 29 5/
E coli. See Escherichia coli
EB. See Elementary body EBM D. See Epithelial/subepithelial d ystrophies, basement membrane EEY. See Epstein- Barr virus Eccrine sweat glands, of eyelid, 4 Echography. See Ultrasonography Ectasia/ectatic disorders, corneal, 296-303, 3021. See also specific type Ectodactyly-ectodermal dysplasial-clefting (EEC) syndrome, 75 Ectoderm, ocular structures derived from, 4 Ectodermal dysplasia, 74- 75 anhidrotic, 75 Ectopic lac rimal gland, 246 Eczema, of eyelid , 20t Edema corn eal. See Cornea, ed ema of epithelial, 201 central (Sattler veil), 9 1 intraocu lar surgery causing, 383 stromal, 29 EDS. See Ehlers- Danlos syndrome EDTA, for band keratopathy. 343 EEe (ectodactyly-ectodermal dysplasial-clefting) syndrome, 75 Eh lers-Danl os syndrome, 252, 320-325, 3221 blue sclera in, 252, 325 keratoglobus in, 302, 325 Eicosanoids, 177t "Eight-ball" hyphema, 365, 366f EK (end ot helial keratoplasty). See Keratoplasty, endothelial EKe. See Epidemic keratoconjun ctivitis Eiastases, in ocular infections, 98-99 Elastin, 9 Elastoid (e1 astotic) degeneration/elastosis, corneal, 334- 335, 335f See also Spheroidal degeneration ElectrolYSiS, for trichiasis, 89 Elementary body, Chlamydia, 137 Elevated intraocular pressure in chemical injury, management and, 358 in hyphema, 366, 367 surgery and, 368, 369t after penetrating keratoplasty, 421 Embryotoxon, posterior, 255, 256f, 26 1t in Axen feld- Rieger syndrom e, 256 Enantiomorphism, in keratoconus, 297 Encephalitozoon, 14 1 keratoconjunctivitis caused by, 170 Endoepit helial corneal dystrophy. See Fuchs endothelial corneal dystrophy Endoflagella, of spirochetes, 137 Endogenous ant igens, 407
CH ED I, 260, 2681, 270t, 295-296. 295f CH ED2. 260. 2681. 2701. 296. 296/ genetics 0[, 269(, 295, 296 Fuchs, 268/, 270t, 291-293, 292f gen etics of, 269t, 291 posterior polymorphous, 268t, 270(, 293-295, 294f genetics of, 269(, 293
Endothelial failure after Descemet stripping automated endothelial keratopla sty, primary, 444- 445 after penetrating keratoplasty late nonimm un e, 42 5- 426 primary, 422, 422/ Endothelial graft rejection, 429, 429f See also Rejection Endothelial keratoplasty. See Keratoplasty, endothelial Endothelial pump corneal edema and, 29 corneal hydration and , 8 Endothelial rings, corneal, traum ati c, 363 Endotheli it is (disciform kerati tis), herpes simplex virus causi ng, 11 4, I 1'if persistent bullous keratopathy and, ll7 Endotheli um, corneal, 7f, 8- 9 anatom y of, 7f, 8- 9 develo pment of, 4 dysfu11ction of, corneal edema and, 25 intraoc ular surgery causing changes in. 383, 383-385 pigmentation of, 349 drug- induced, 349 Endotoxi ns, microbial, 132 Enterobacter, 135 Enteroba cteriaceae, 135 Enterococcus, 133- 134 fa em /is, 133- 134 Enlerocytozooll, 14 1 Enterov iruscs, 129 conjullctiviti s caused by, 130 Enuclea tion, fo r sympathetic ophthalmia preventi on, 376 Envelope (vir us)/enveloped viruses, 104, 105 Environment/environ mental factors, in dry-eye syndrome, 51-52, 5 1/ Eosinophil chemotactic factor, 179t Eosinophils cytolog iC identification of, in immune-mediated keratoconjunctivitis, 1821 in external eye, 174t med iators released by. 179t Eotaxin, 1791 Ephelis, conjunctival, 233 Epibulbar tumors chorislomas, 245- 247, 246f, 247f dermoids, 245-246, 245/ Golden bar syndrome and. 246
486 • Index Epidemic keratoconjunctivitis, 124, 125, 125[' 126/ Epidermal necrolysis, toxic, 196, 196t Epidermis, eyelid, 4 Epidermolysis bullosa acquisita, lOSt Epilation, mechanical, for trichiasis, 89 Epinephrine, adrenochrome deposition caused by, 3371, 348, 348f Epiphora/ tearing, conjunctival inflammation causing, 20t
Episclera . disorders of. See also specific type and Episderitis immune~mediated, 216- 217, 2171 melanosis of, 235-236, 2351 Episcleritis, lit, 28, 216-217, 217/ in herpes zoster, 120 immune-mediated, 216- 217, 2171 nodular, 28, 216, 2171 in reactive arthritis/Reiter syndrome, 209 simple (diffuse), 28, 216 in Stevens -Johnson syndrome, 196 Epithelial cells. See also Epithelium keratinization of (keratinized/degenerated), 21 cytologic identification of, in immune-mediated keratoconjunctivitis, 182t in meibomian gland dysfunction, 65 in vitamin A deficiency, 77, 78, 781 Epithelial cysts, corneal, drug-induced, 348 Epithelial defects conjunctival, 20t corneal, 2It, 85- 87 ocular infection and, 99 after penetrating keratoplasty, 422, 4231 in toxic keratoconjunctivitis, 360 Epithelial degenerations, 334- 336, 3351 Epitheliallsubepithelial dystrophies, 268(, 270- 275 basement membrane (map-dot-fingerprint/Cog an microcystic/anterior basement membrane), 268(, 270- 272, 270t, 2711 genetics of, 269t, 270 recurrent corneal erosion and, 83, 271 , 272 Lisch, 268t, 270t, 273- 274, 2741 genetics of, 2691, 273 Meesmann (j uvenile hereditary epithelia!), 268t, 270t, 272-273, 2731 genetics of, 2691, 272 Epithelial edema, 20t central (Sattler vei!), 91 intraocular surgery causing, 383 Epithelial erosions herpetic keratitis and, 117 punctate of conjunctiva, 20t of cor~ea, 20t, 25, 26f, 27t vernal keratoconjunctivitis and, 187 Epithelial graft rejection , 428, 428f, 436. See also Rejection Epithelial inclusion cysts, 225- 226, 226/ Epithelial ingrowth, after Descemet stripping automated endothelial keratoplasty, 444, 4441 Epithelial keratitis/ keratopathy adenoviral, 124, 1261 dry eye and, 55, 56, 56/ herpes simplex virus causing, 110- 113, 111f, 112/
in herpes zoster ophthalmicus, 120 measles virus causing, 129 punctate, 20t, 25, 26f, 271 exposure causing, 80 herpes simplex virus causing, 110 microsporidial, 170 staphylococcal blepharitis/ blepharoconjunctivit is and, 145, 146f, 147 superficial Thygeson, 204- 207, 206! Epith elial melanosis, congenital, 233 Epithelial uicer, geographic, in herpes simplex keratitis, 110, 112f
Epitheliopathy in herpelic keratitis, 116- 117 m icrocystic,91 in toxic keratoconjunctivitis, 360 Epithelium . See also under Epithelial and Ocular surface conjunctival, 5 cysts of, 225 - 226, 2261 immunologic features of, 173, 174t tumors of, 226- 233, 226t wound healinglrepair and, 388 corneal. See Cornea, epithelium of development of, 4 in external eye defense, 96 immune and inflammatory cells in, 174t tumors of, 226-233, 226t benign, 226-228, 226t, 2271 malignant, 226t, 231 - 233, 232/ preinvasive, 226t, 228- 231, 229f, 230j, 231/ pigmented, 234t, 237- 238 Epstein-Barr virus ocular infection caused by, 122 - 123, 1231 Sjogren-like syndromes caused by, 63 Erosions conjunctival, 22t punctate epithelial, 20t corneal in herpetic keratitis, 11 7 punctate epithelial, 20t, 25, 26j, 27t vernal keratoconjunctivitis and, 187 recurrent, 83- 85, 851 eye pain in, 83 posttraumatic,372 eyelid, 20t Erythema multiforme, 196 major (Stevens-Johnson syndrome), 195- 198, 196/, 197f, 198f
mucous membrane grafting for, 198, 401 minor, 196 Erythroq1e sedimentation rate, in immune-mediated disease, 1821 Erythromycin for ch lamydial conjunctivitis, 157 in neonates, 154 for meibomian gland dysfunction, 68 for trachoma, 156 Escherichia coli (E coli), 135 as normal ocular flo ra, 96 ocular infection caused by, 135 Esthesiometry, 30-31 Etanercept, for cicatricial pemphigoid, 202
Index . 487 ETD. See Evaporative tear d ysfun ction Eukar)'otes/eukaryotic cell s, 131 Evaporative tear dysfunction , 5 1, 51f, 52 chalazion and, 72-73, 72/ desquamating skin conditions and, 74 ectodermal d ysplasia and, 74-75 ichth),osis and, 74 meibomian gland d ysfunction and, 65-69, 67f rosacea and, 69-7 1, 70f, 71/ sarcoidosis and, 73-74 seborrheic blepharitis and, 7 1-72 xeroderma pigmentosum and, 75 Evasion, as microbial virulence factor, 98 Examination, ophthalmic, 11 - 46. See also specific me/hod Ilsed and Refraction anterior segment photography in, 31-36. 32f, 33f, 34f,
35f, 36/ corneal pachometry in, 28-30, 29f, 30t corneal topography measurement in. 36-45 before corneal transplantation, 4 14 -417 in dry eye, 52 - 53, 53/ esthesiometry in, 30-31 infection prevention and, 45-46 in inna mmatory d isorders, 19-28,20-21 t, 22t, 27t in perforating injury, 373 -374, 3741 physical examination in, 11 - 12 slit-lamp biom icroscopy in, 12-16 stains used in, 17, 18f, 19/ vision testing, 11 Excimer laser, for phototherapeutic keratectomy (PT K). 402 -403 for recurrent corneal erosions, 85 Excisional biopsy, 390 Exen teration, for melanoma, 240 Exotox ins, microbial, 98 Exposure keratitis/keratopathy, 80 Exposure staining, 56, 56/ Extended-wear contact lenses, st romal neovascularization and, 92 External (outer) eye, 3. See also specific structure anatomy of, 4- 9, 5f, 7J, 8/ defense mechanisms of, 95-96 compromise of, 100 development of, 4 examination of, 11 - 46. See also Examination, ophthalmic function of, 3 infections of. See Infection (ocular ) photography in evaluation of, 3 1 External hordeolum (stye), 148 Exudati"e retinal detachment. See Retinal detachment Eye development of, 4 infection of. See In fection (ocular) normal flora of, 96- 97, 97t physical examination of, 11 - 12. See also Examination, ophthalmic preparation of for Descemet stripping aUlomated endothelial keratoplasty, 439-441, 440/ for penetrating keratoplasty. 418 Ere Bank Association of America (E BAA), 409 Eye banking, 408- 411 , 41 Ot
Eyelashes (cilia), 4, Sf accessory. See Distichiasis disorders of, 89 lice infestation of, 149 misdirection of. See Trichiasis in staphylococcal blepharitis, 1441, 145 Eyelid hygiene in blepharitis/meibomian gland dysfunction, 68, 72, 147 in staphylococcal eye infection, 147 Eyelid retractor/speculum for examination in chemical injury, 355, 357/ for examination in conjunctival foreign body, 370 Eyelid splints, as tarsorrhaphy alternative, 391 Eyelid taping for exposure keratopathy, 80 for noppy eyelid syndrome. 8 1 Eyelid weights, for exposu re keratopathy. 80 Eyelids absence of (ablepharon), 249 anatomy of, 4, 5/ in atopic dermatitis, 185 in contact dermatoblepharitis, 183 -185, 184/ development of, 4 disorders o f, 20t immune-mediated, 183-185, 184/ lice infestation, 149 examination of, 11 in external eye defense. 95 noppy, 53, 81, 81/ fusion of (anl1'loblepharon ), 249, 249f glands of, 4 in herpes simplex dermatoblephari tis, 106, lO6/. 107, 110 in herpes zoster ophthalmic us, 120 horizontal shortening/tightening of, for exposure keratopathy, 80 infection /inflammation of, 19- 21 , 20t, 143- 149, 144f, 144t, 146f See also Blepharitis fungal and parasitic, 148- 149 staphylococcal, 143- 148, 144J, 1441 , 146/ margin of infections of, 143 - 149, 144J, 144t, 146/ vascular and mesenchymal tumors of, 240-242, 241 t in molluscum contagiosull1, 128, 128/ normal flora of, 96-97, 97t skin of, 4 specimen collection from. 100, 10lt surgery/reconstruction of for cicatricial pemphigoid, 203 for Cf}'ptophthalmos/pseudocryptophthalmos, 250 for Stevens-Johnson syndrome, 198 tumors of sebaceous gland carcino ma, 233, 234/ vascula r and mesenchymal. 240-242, 24lt Fabry disease (angiokeratoma corporis diffusum universale), 310. 3 11 Facial hemiatrophy, progressive, 324t Factitious disorders. ocular surface , 89-90 Famciciovir for herpes simplex virus infect ions, 1091 for herpes zoster, 121
488 • Index Familial amyloidosis Finnish-type (amyloidosis V/geisolin-type lattice corneal dystrophy), 268t, 270t, 280, 2801, 3171,
319 genetics of, 269(, 280, 3I7t primary of cornea (subepithelial amyloidosisl gelatinous drop like dystrophy), 2681, 270t, 274-275, l7 Sf, 31 7t, 318, 318! genetics of, 269t, 274, 317t Familial amyloidotic polyneuropathy type IV (gelsolin type lattice corneal dystrophy), 268t, 270t, 280, 280f, 317t, 319 genetics of, 269t, 280, 317t Familial dysautonomia (Riley-Day syndrome) congenital corneal anesthesia and, 264 neurotrophic keratopathy in, 87 FAP-IV. See Familial amyloidotic polyneuropathy type IV Fasciitis, nodular, 242 Fatty acid supplements, for meibomian gland dysfunction, 68 FeD. See Fleck corneal dystrophy FD. See Familial dysautonomia FEeD/ FEeD 1. See Fuchs endothelial corneal dystrophy Fehr spotted dystrophy (macular corneal dystrophy), 268t, 270t, 278t, 283 - 284, 284/ genetics of, 2691, 283 Femtosecond laser for penetrating keratoplasty, 417, 418 for superficial anterior lamellar keratoplasty, 435 Ferry lines, 337t Fibrillin, in Marfan syndrome, 325 Fibrin,l77t Fibrin tissue adhesive, for corneal autograft fixation,
394 Fibronectin, 9 Fibrous histiocytoma, 242 Filamentary keratopathy, 56, 57f, 60- 61 bandage contact lenses for, 403 Filamentous fungi, 138, 1381, 139, 140, 238t as normal ocular flora, 97t ocular infection caused by, 139, 140 keratitis, 164 - 167, 165/ Filaments, corneal, 21t in dr y-eye states, 56, 57/ Filariae loa loa, 170- 171 onchocercal, 141 Fimbriae, bacterial, 132 Fingerprint lines, in epith elial basement membrane d ystrophy, 271 Finnish-type amyloidosis (gelsolin-type lattice corneal d ystrophy), 268t, 2701, 280, 280f, 317t, 319 genetics of, 269t, 280, 31 7t Fish eye disease, 310 Fitting (contact lens), trial, disinfection and, 46 FK506. See Tacrolimus Flagella, bacterial, 132 of spirochetes, 137 Flaps advancement, 400 bipedicle (bucket handle), 400
conjunctival, 398- 401,399/ for neurotrophic keratopalhy, 88-89 for wound closure after pterygium excision,
391 - 393, 392/ Gundersen, 399- 400, 399/ lamellar, for superficial anterior lamellar keratoplasty,
435 partial (bridge), 400 single-pedicle (racquet), 400 for wound closure after pterygium excision, 391 - 393 ,
392/ Fleck corneal d ystrophy, 2681, 270 1, 287,2871 genetics of, 2691, 287 Fleischer ring/line, in keratocon us, 298, 299[' 335 - 336, 3371 Floppy eyelid syndrome, 53, 8 1, 81/ Fluconazole, for yeast keratitis, 166 Fluorescein, 17, 18f, 19/ for applanation tonometry, 17 for aqueous deficiency diagnosis>56 for conjunctival foreign -body identification,
370 for dye disappearance test, 17 punctate staining patterns and, 17> 18! for tear breakup time testing, 17,52-53 Fluorescein angiography anterior segment, 33 before corneal transplan tation, 417 Fluorexon, 17 Fluoromethalone, for recurren t corneal erosions>84 Fluoroquinolones for bacterial keratitis, 162t, 163 for gonococcal conjunctivitis, 152 Fluorouracil for conjunctival intraepithelial neoplasia> 229, 2301 for corneal intraepithelial neoplasia, 231 Fly larvae, ocular infection caused by, 143 Follicles, conjunctival, 20t, 24, 24/ Follicular conjunctivitis, 22t, 24, 24/ in acute hemorrhagic conjunctivitis, 130 adenoviral, 124 Epstein-Barr virus causing, 122-1 23 in measles, 129 medication tox.icity causing, 3591, 360, 361f in mumps, 129- 130 RNA viruses causing, 129 varicella -zoster virus causing, 118 Folliculosis, benign lymphoid, 24, 24/ Foreign bodies, intraocular conjunctival, 370, 370/ corneal, 371- 372, 371/ iron, 337t, 371- 372, 371/ plant/vegetation, 362, 371 retained, endophthalmitis caused by, 375 Foreign-body sensation in corneal abrasion, 372 in dry eye, 55, 65 fluorescein in investigation of, 370 Forkhead genes/ forkhead transcription factor, AxenfeldRieger syndrome and, 256 Forme fruste, refractive surgery contraindicated in, topography in detection and, 43 - 44, 44/
Index. 489 Fornices, 4 reconstruction of for cicatricial pemphigoid, 203 conjunctival graft for, 395 for pseudocryptophthalmos, 250 FOXCI gene, in Peters anomaly, 258 Fran<;:ois, central cloudy dystrophy of, 268t, 270t, 289- 290,289/ genetics of, 269/, 289 hanyois~Neetens speckled corneal dyst rophy (Fleck corneal dystrophy), 268t, 270t, 287, 287f genetics of, 2691, 287 FRAS I gene, 250 Fraser syndrome, 249-250 Freckle, conj unctival, 233 Fredrickson classification, of hyperlipoproteinemias, 308, 3091 Free-living amebae, 140 Freezing, anterior segment injuries caused by, 35 1-352 Fuchs endothelial corneal dystrophy, 268t, 270t, 291-293,292/ genetics of, 269t, 291 Fuchs superficial marginal keratitis, 340 Fucosidosis, 312 Fumagillin, for microsporidial keratoconjunctivitis, 170 Fundus, xerophthalmic, 78 Fungi, 138-1 40, 138t eyelid infections caused by, 148-149 isolation techniques for identification of, 103 keratitis caused by, 164- 167, 165f plant sources of, 362 as normal ocular flora, 97t ocular infection caused by, 138-140 scleritis caused by, 171 stains and culture media for identification of, \03t Furrow degeneration, senile, 339 Fusarium, 139 keratitis caused by, 139, 165f, 166 oxysporum, 139 so/alii, 138f, 139, 165f GAGs. See Glycosaminoglycans a-Galactosidase A, in Fabry disease, 310, 311 J3-Galactosidase, deficiency of in gangliosidoses, 310 Gammopathy, benign monoclonal, corneal deposits in, 320 Gangliosidoses, 310 Gargoyle cells, in Illucopolysaccharidoses, 307 Gatifloxacin, for bacterial keratitis, 1621 , 163 Gaucher disease, corneal changes in, 311 GCD 1. See Granular corneal dystrophy, type 1 GCD2. See Granular corneal dyst rophy, type 2 GDLD. See Gelatinous droplike corneal dystrophy Gelatinase (MMP-2) in recurrent corneal erosion, 83 in Sjogren syndrome, 63 Gelatinous d roplike corneal dystrophy (primary familial amylo idosis), 2681, 2701, 274- 275, 275f, 3171, 318, 318/ genetics of, 2691, 274, 3171 Gelsolin gene mutation amyloidosis and, 3171 lattice corneal dystrophy and, 269/, 280, 3171
Gelsolin-type lattice corneal dystrophy, 2681 , 2701, 280, 280j, 317t, 319 genetics of, 269t, 280, 317t Generalized gangliosidosis (GM] gangliosidosis type 1), 310 Geographic corneal dystrophy. See Reis-Bi.icklers corneal dystrophy Geographic epithelialuicer, in herpes simplex keratitis, 110, 112/ Geographic map lines, in epithelial basement membrane dystrophy, 271, 271f Gestational pemphigoid , 205t Ghost dendrites, in herpes simplex keratitis, 110, 112f Giant papillary (contact lens- induced) conj llIlctivitis, 23J, 194- 195, 194/ Glands of Moll, 4, Sf Glands of Zeis, 4, Sf chalazion caused by obstruction of, 72 Glass foreign body, 371 Glaucoma congenital, 265 cornea plana and, 255 dry-eye disorders and, 61 iridocorneal endothelial (lCE) syndrome and, 345 megalocornea and, 254 microcornea and, 253 nanophthalmos and, 251, 252 penetrating keratoplasty and, 421 posterior polymorphous corneal dystrophy and, 295 scleritis and, 220 Globe blunt inj ury to, mydriasis/miosis caused by, 363 developmental anomalies of, 249- 253 in infant, 4 ru pture of, repair and, 375- 381. See also Corneosc1eral laceration, repair of Glucose-6-phosphate dehydrogenase deficiency, dapsone use in cicatricial pemphigoid and, 202 Glycoproteins scleral, 9 viral envelope, 104 Glycosaminoglycans in macular corneal dystrophy, 283 in mucopolysaccharidoses, 305, 307 GM ] gangliosidosis type I (generalized) , 310 GM 2 gangliosidosis type 1 (Tay-Sachs disease), 3 iO Goblet celis,S Gold compounds/salts, corneal pigmentation caused by, 3371,349 Gold eyelid weights, for exposure keratopathy, 80 Goldberg syndrome, 312 Goldenhar-Gorlin synd rome, 3231 Goldenhar syndrome, dermoids/dermolipomas in,
246 Gonococcus (Neisseria gonorrhoeaelgonorrhea), 134, 134J,149 conjunctivitis caused by, 134, 151 - 152, 15 1/ in neonates, 152, 153 penic i llin ~ resistant, 152, 153 Gout, 325-326 GPc. See Giant papi llary (contact lens- induced) conj u nctivitis Graft~vs-host disease, 1961,203-204, 204f
490 • Index Grafts conjunctival, , 94, 392f, 393-395 for chemical injuries, 358 ind ications for, 387(, 395 for wound closure after pterygium excision, 392f, 393,393 ~39 S
corneal. See also Donor cornea; Keratoplasty allografts, 413 aUiografts, 413, 43 1-432 disease recurrence in . 422, 423/ dislocation of after Descemet stripping automated endothelial ke ratoplasty, 442, 443f endothelial failure of late nonimmune, 425-426 primary, 422, 422/ after Descemet stripping automated endothelial keratoplasty. 444- 445 inflammatory nec rosis of, after lamellar keratoplasty,436-437 rejection of, 407, 408, 427-430, 428j, 429f, 436. See also Rejection fo r c}'elid repair, in burn patients, 351 HLAi transpiantation antigens and, 407 limbal, 94, 389, 395-398, 396-397/ for chemical injuries, 94, 358 indications for, 3871 mucous membrane, 389, 401-402 indications for, 3871, 401 -402 rejection of, 407, 408, 42 7-430, 428J, 429f, 436. See also Rejection HLAltranspiantatioll antigens and, 407 G ram-negative bacteria, 131, 132t cocci, 132/, 134, 1341 as normal ocular flora , 971 rods, 132/, 135- 136, 136/ Gram-positive bacteria, 131, 132, 132t cocci, 132- 134, 132/, 133/ filaments, 132/, 136-137 rods. 132t, 134- U S, 135/ Gram stain, 131 , 132t Granular corneal dystrophy, 268/, 2781. See also specific
type genetics of, 269/, 276, 281 type 1 (ciassiclGCDI ), 2681, 270t, 280-28\, 28 1/ type 2 (granular- lattice/GCD2), 268!, 269/, 270t, 278t, 282,282/ type 3 (Reis-Buckle rs), 268t. 269t, 2701, 275- 277, 276/ Granular-lattice corneal dystrophy, 268/, 270t, 278t, 282,282/ genetics of. 269!, 282 Granulomas chalazia, 72 - 73, 72/ conjunctival, 20r, 22/, 241-242, 241/ in Parinaud ocu loglandular syndrome, 157, 158 in sarcoidosis, 73-74 pyogenic, 241-242, 24 1/ in sarcoidosis, 73-74 Groenouw dystroph}' type I (granular corneal dystrophY. lype 1),268/.2701,280-28 1,281/ Groenouw dystrophy type II (macular corneal dYSirophy), 2681, 270!, 278t, 283-284. 2841 Growth factors, as inflammatory medi,Vors, 177t GSN gene, lattice cornea l dystrophy and, 269/, 280
Gundersen flap, 399-400, 399/ GV HD. See Graft-vs-host disease Haab striae, 265
HaemophiluslHaemopfrilus injluenzae, 136 biotype III (H aegyptius), conj unctivitis caused by. 150 conjuncti\itis caused by. 150 as normal ocular flora. 97r preseplal cellulitis caused by. 150 type b (Hib), 136 Hallermann-Streiff-Fran;;:ois syndrome, 3231 Hamartomas, of eyelid and conjunctiva, 2411 Hand washing, in infection control, 46 Hanna trephine, for penetrating keratoplasty, 418 Hassall- Henle bodies (peripheral corneal guttae), 334,
345 Hay fever conjunctivitis, 185-187 Head lice, ocular infection caused by, 149 Heat, anterior segment inj uries caused b}', 351 Heavy chain disease, corneal deposits in, 319-320 HEDS (Herpetic Eye Disease Study), 107, 108/, 109, 115-116 Heerfordt syndrome, 73 Helminths, 141-142 Helper T cells in anaphylact ic/atopic (type I) reactions, 179 in delayed hypersensitivity (type IV) reactions, 180 in external eye, 174/ Hemangiomas (hemangiomatosis) of conjunctiva, 240-241 of eyelid, 240-241 Hemiatrophy, progressive fadal, 324t Hemifacial microsomia, 323 / Hemoch romatosis, 328 Hemorrhages conjunctival, 76, 76(, 362-363 in hereditary hemorrhagic telangiectasia, 76 after Descemet stripping autom ated endothelial keratoplasty, 441/ salmon patch, syphilitic keratitis and, 208, 208/ subconjunctival, 76. 76t. 362-363 Hemorrhagic conjunctivitis, acute, 130 Hemorrhagic telangiectasia, hereditary (Rendu-OslcrWeber disease), 76 Henderson-Patterson bodies, 127 H EP. See Hepatoerythropoietic porphyria Heparan sulfate in microbial adherence, 98 in mucopolysaccharidoses, 305 Heparin, as inflammatory mediator, 179/ Hepatoerythropoietic porphyria (H EP). 326 Hepatolenticular degeneration (Wilson disease). 327-328,327/ Herbert pits, 154, ISS/ Hereditary benign intraepitheli al dyskeratosis, 2261 Hereditary hemorrhagic telangiectasia (Rendu-OslerWeber disease), 76 Hereditary sensory and autonomic neuropathy. type II [. See Familial dysautonomia Herpes simplex virus, 105-1 17 antiviral agents for, 109, 109/, 11 1-113 blepharoconjunctivitis caused by, 106, 106f, 110
Index. 491 iridocyclitis caused by, 114, 116- 117 keratitis caused by, 109, 110-11 6, 11 If; 1I2f, 114f, liS!
Acanthamoeba keratitis differentiated from, 168-1 69 disciform, 114, 1I'if persistent bullous keratopathy and, 117 epithelial, 110- 113, 1 1If, 1121 interstitial, 1\3, I I'if necrotizing, 115, 115f, 116 neurotrophic keratopathy/ulcers and, 87, 88, 117 stromal, 108t, 113-116, 114f, 1151 penetrating keratoplasty for, 117 ocular infection/in flammation caused by, 105-117 adenovirus infection differentiated from, 107 complications of, 116- 117 evasion and, 98 iridocorneal endothelial syndrome and, 344 pathogenesis of, 105-106 primary infection, 106, 106- 109, 106f, 107f, 108t, 109t recurrent infection, 109-117, IlIf, lI2f, 114f, 1151 treatment of, 108 t varicella-zoster virus infection differentiated from, lISt perinatal infection caused by, 106 type 1, 105 type 2, IDS Herpes zoster, lI8, 119-1 22. See also Varicella-zoster virus conjunctivitis and, 106, 1061 ophthalmic manifestations in, 119-122, 119f, 120f, 1211 varicella vaccine in prevention of, 121 Herpes zoster ophthalmicus, 119-122, 119f, 120f, 12 11 neurotrophic keratopathy in, 87,122 Herpesviruses/herpesviru s infection, 105-123. See also specific virus Herpetic Eye Disease Study (HEDS), 107, 108!, 109, 115- 116 Hexagonal cells, specular photomicroscopy in evaluation of percentage of, 32- 33 Hexosaminidase, deficiency of in gangliosidoses, 310 Hib. See Haemophilus/I-Jaemophilus inj7l1enzae, type b High -resolution ultrasonography, in corneal imaging, 29 Histamine, 177!, 179 t allergic conjunctivitis and, 185 Histiocytoma, fibrous , 242 Histocompatibility antigens, 407 History, ill penetrating/perforating injury, 373, 373t HIV (human immunodeficiency virus), 130 HIV infectionl AIDS, 130 conjunctival intraepithelial neoplasia in, 228 herpes simplex infection in, 109 Kaposi sarcoma in, 242 microsporidiosis in, 170 molluscum contagiosum in, 128, 1291 ocular in fection/ manifestations and, 100, 130 HLA. See Human leukocyte antigens HLA system. See Human leukoC}1e antigen (HLA) system HOlllogentisate I ,2 -dioxygenase, in alkap.tonuria, 315 Homologous antigens, 407
Honeycomb-shaped corneal dystrophy. See ThielBehnke corneal dystrophy Hordeolum, 148 external (stye), 148 internal, 14S Horizontal cyelid shortening/tightening, for exposure keratopathy,80 Horner-Trantas dots, 187, 1881 Host defenses impaired, 100 of outer eye, 95-96, 99-100 Houseplants, ocular injuries caused by, 362 HPV. See Hu man papillomaviruses Hudson-Stahli line, 336, 337t Human herpes virus 8, Kaposi sarcoma caused by, 129,
242 Human immunodeficiency virus (HIV), 130. See also HI V infection/ AIDS Human leukocyte antigen (HLA) system, 407 Human lcukocyte antigens (HLA), 407 in cicatricial pemphigoid, 199 in Sjogren syndrome, 63 transplantation and, 407 Human papillomaviruses, 128-129,226- 227 conjunctival intraepithelial neoplasia caused by, 228 ocular infection/ papillomas caused by, 128- 129, 226-227 Humoral immunity, in conjunctiva, ISO Hunter syndrome, 305, 306t, 307 Hurler-Scheie syndrome, 305 Hurler syndrome, 305, 306t congenitallinfantile corneal opacities and, 263 Hurricane (vortex) keratopathy (cornea verticillata), 31 0, 31 If, 346-348, 347t, 348f, 360 Hyaluronidase, streptococcal production of, 133 Hydrogen peroxide, as inflammatory mediator, 177t Hydrops, in keratoconus, 299 management of, 300 Hydroxyapatite, deposition of (calcific band keratopathy), 328, 342-344, 3431 in sarcoidosis, 73 Hydroxychloroquine, cornea verticillata caused by, 346 Hyfrecator, for punctal occlusion, 62 Hypercalcemia, corneal changes in, 32S, 342. See also Band keratopathy Hypercholesterolemia, in Schnyder corneal dystrophy, 285,309 Hyperemia, conjunctival, 20t, 75 Hyperlipoproteinemias, 30S-309, 309t Schnyder corneal dystrophy and, 309 Hyperopia cornea plana and, 255 microcornea and, 253 nanophthalmos and, 251, 252 Hyperosmolarity, tear, dry eye and, 49-50, 501 Hyperplasia lymphoid , 243, 2441 pseudoepitheliomatous, 226t Hypersensitivity reactions, 178- 1S0, 178f, 179t anaphylactic or atopic (type I), 178f, 179 - 180, 179t allergic conjunct ivitis and, 185 topical medications/substances and, IS3, 184, 1841 cytotoxic (type 11), 178f, 179t, ISO
492 • Index delayed
(~1"
IV). 178f, 1791. 180
contact dermatoblcpharitis as, 180, \83, 184-185, 184{ contact lens solutions and, 92 in graft rejection, 408 topical medications/substances and, 183, 184-.185, 1841 immune-complex (type Ill ), l iS/. 179t, 180 Hypertonic medications, for recurrent corneal erosions, 84 ' Hypertyrosinemia, 315 H)'Peruricemia, 325-326 Hyphae, 138, 138f
Hyphema after Descemet stripping automated endothelial keratoplasty,441/ microscopic, 365 spontaneous, 365 traumatic, 365-369, 365f, 366f. 367f, 369t medical management of, 367-368 rebleeding after, 365-367. 36/f sickle cell disease and, 369
surgery for, 368, 3691 H},poesthesia, corneal in diabetes mellitus, 308 in herpes simplex epithelial keratitis, 110 in neurotroph ic keratopathy, 87 H),polipoproteinemias, corneal changes in, 309-310 Hypophosphatasia, 323/ Hypoplasminogenemia, in ligneous conjunctivitis, 192 Hypovitaminosis A, 77-79, 77/. 78f Hystercsis, corneal, 9 HZO. See Herpes zoster ophthalmicus I-ccll (inclusion-cell) disease, 312 Ibuprofen, for scleritis, 222 [C3D classification of corneal dystrophies, 267-268,
268(, 2691,270t lCAI\I·I,177t in Sjogren syndrome, 63 ICE s)'ndrome. See lridocorneal endothelial (ICE) syndrome Ichthyosis, 74 [CSB (International Committee for Systemic Bacteriology), 131 (L·L·lduronidase, in lllucopolysaccharidoses, 305 IEK. See Intralase· enabled keratoplasty
Ig. See under Immunoglobulin 19A dermatosis, linear, 199, 205t IgA pemphigus, 205t IK (interstitial keratitis). See Keratitis, interstitial
IL. See 1Inder Ill/erlel/kill J11umination, for slit- lamp biomicroscope direct, 12-1 4, 13j, 14f indirect, 14-1 5, 15j, 16f Imbibition pressure, 8 Imidazoles, for AWlltlw/IIoeba keratitis, 169 Immediate hypersensitivity (type I) reaction, 17Sj, 179-180, 179/ allergic conjunctivitis and. ISS topical medications/substances and. 183, 184, 184f Immune-complex hypersensitivity (t)'P~ Ill) reaction, 17Sf, 179t, ISO
Immune (antigen-antibody) complexes, in type III hypersensitivity reaction, 178f, 179/, 180 Immune privilege, 407-408 corneal,174-175,407-40S Immune response (immunity) cellular, 178f, 179/, ISO humoral, 180 ocular, 173-1S2 cellular elements of. 173- 175, 174f, 174t of conjunctiva, 173, 174t, 180-IS \ of corneal sclera. 174-175, 174f, lSI disorders of clinical approach to, IS3-223 diagnostic approach to, 181 - IS2, IS21 infection and. iOO patterns of, 180- IS1 hypersensitivity reactions and, 178- \SO, 178f, 179t soluble mediators of, 175, 176f, 177t, 179t tearfiImand, 175-177, 177/ Immunocompromised host, ocular infection in, 100 herpes zoster, 120 Immunoglobulin A (lgA), secretory, 173 in tear film, in external eye defense, 95 Immunoglobulin A (lgA) dermatosis, linear, 199,2051 Immunoglobulin A (lgA) pemphigus, 205t Immunoglobulin E (lgE). in type [ hypersensitivityl anaphylactic reactions, 179. 183 Immunoglobulins disorders of syntheSiS of, 3 19-320 in external eye defense. 95 Immunologic competence, ocular infection and, 100 Immunologic tolerance, corneal transplantation and. 175,40S 1m m un otherapyIi m m u nosl.l pp ression fOt allergic conjunctivitis, 186 for atopic keratoconjunctivi tis, 191 for cicatricial pemphigoid, 202 for corneal graft rejection. 430 for graft-vs-host disease. 203 for peripheral ulcerative keratitis. 213 for scleritis, 223 (or Ste\'ens-Johnson syndrome, 198 for vernal keratoconjunctivitis, 189 Im preSSion cytology, 47-48 in Sjogren syndrome diagnosis, 57 in stem cell deficiency, 94 in superior limbic keratoconjunctivitis, 82 Inclusion · ceU (I -ceil) disease, 3 12 Inclusion cysts, epithelial, 225-226. 226/ Indomethacin, cornea verticillata caused by. 346 Infants conjunctivitis in, 152- 154 corneal transplantation in, 430-431,431/ cystinosis in, 313 herpes simplex infection in, 106 normal ocular Hora in, 96 ocular infections in, 152-154. See also specific type Infection (ocular). See also specific type, structure affected, ctlusatil'e agent and Inflammation bacterial/bacteriology. 131 -137, 132f cornea and scleral involvement and , 158-164 eyelid margin and conj unctival involvement and, 143- 148, 149-15S, 150/ basic concepts of, 95-103
Index. 493 C)1010gy in, 47-48 defense mechanisms and, 95-96, 99-100 diagnostic laboratory techniques in, 100-103, lOll, 102f, 103! fungal/mycology, 138-140, 138t cornea and scleral involvement and, 164- 167 eyelid margin and conjunctival involvement and, 148-149 in infants and children corneal anomalies and, 263-264 ophthalmia neonatorum, 152-154 inoculum and, 99 microbiology of, l aO, lOll normal flora and, 96-97, 97t parasitic/parasitology, 140-143 cornea and scleral involvement and, 167- 169 eyelid margin and conjunctival invoh-ement and, 148-149 pathogenesis of, 97- 100 prevention of, 45-46 prions causing, 143 public health ophthalmology and, 104 in Stevens- Johnson syndrome, 196. 197 systemic infections associated with, 169-170 viral/virology, 104- 130 virulence factors in, 98-99 Infection control, 45-46 Infectious crystalline keratopath)" 159, 160f after penetrating keratoplasty, 425, 425f InfeCliouskeratitis, 1011, 158-171. 160f, 1601, 1621, 168f
See also specific infectious agelll clinical presentation of, 159 contact lens wear and, 159, 165, 167, 168 intrauterine, 263-264 laboratory evaluation/causes of, 159-161, 1601 management of, 161 -164, 162t pathogenesis of, I S9 after penetrating keratoplasty. 425, 425f stains and culture in identification of, 103t Infectious mononucleosis, ocular invoh-ement in, 122-123.123/ Inflammation (ocular) in chemical injury, management and, 357 clinical evaluation of, 19-28,20-21 t, 22t, 27t conjunctival, 201, 21-24, 22f, 221, 23f, 24f corneal, 20-2 It, 24-25, 261, 27f, 271,28/ cytology in, 47-48 dry cre caused by. 48-49, 50 eyelid, 19-21, 20t scleral, 21t, 28 Inflammatory pseudoguuae, 25, 30 Inflammatory vascular tumors, 241-242, 24lJ, 241/ Infliximab, for scleritis, 222 Influenza virus, 129 Inoculum, 99 Insect hairs/stings, ocular injury/infection caused by, 361-362 Instantaneous radius of curvature (meridional! tangential power), 40, 41f Integrins.98 Interferons (IFNs) for conjunctival intraepithelial neoplasia, 229, 230/ for corneal intraepithelialneoplasia, 231
Interleukin -l, In, 177t in external eye defense, 96 In terleukin -la, in Sjogren syndrome, 63 Interleukin - \)3, in Sjogren syndrome, 63 Interleukin -4, atopy and, 179 Interleukin -6, in Sjogren syndrome, 63 Interleukin -8, in Sjogren syndromc, 63 Interleukins in external eye defense, 96 in Sjogren syndrome, 63 internal hordeolum, 148 International Committee for the Classification of Corneal Dystrophies, 267-268, 2681, 2691, 2701 International Committee for Systemic Bacteriology (ICSB).131 Interrupted sutures, for penetrating keratoplasty, 418-419. 419f, 420/ Interstitial keratitis_ See Keratitis, interstitial Intraepithelial dyskeratosis, benign hereditary, 2261 Intraepithelial neoplasia conjunctival (cti'\), 226r, 228-229, 229f, 230/ corneal, 2261, 229-231, 231f Intralase-enabled keratoplasty (IEK), precut tissue for, 409 Intraocular lenses (IOLs), corneal endothelial changes caused by, 385 Intraocular pressure in chemical injury, management and, 358 corneal thicknesslrigidity and. 8, 9, 30 in hyphema, 366, 367 surgery and, 368, 3691 Intrauterine ocular infection. corneal anomalies and, 263-264 keratectasia, 259 Invasion, as microbial virulence factor, 98- 99 Ionizing radiation, anterior segment injury caused by, 352-353 Iridectomy for bacterial keratitis, 164 with penetrating keratoplasty. 420 Iridocorneal endothelial (ICE) s}'ndrome, 344-345, 3tHf posterior polymorphous corneal dystrophy differentiated from, 293 Iridocyclitis, herpetic, 114, 116-117 Iridodi alysis, 364, 3Mf repair of, 381, 382/ lridogoniodysgenesis syndrome, 255-263. See also
specific disorder Iris atrophy of, 344, 344/ incarceration of, after penetrating keratoplasty, 421 repair of defects in. with penetrating keratoplasty, 420 traumatic damage to, repair of, 380-38 1, 381/ Iris nevus syndrome (Cogan-Reese syndrome), 345 Iriti s herpetic, 108t in reactive arthritis/Reiler syndrome, 209 traumalic, 363 Iron corneal deposits 0(. 335-336, 336f, 337r in keratoconus, 298, 299f, 335-336 fore ign bod)' of, 337t, 37 1-372, 37 1/ Iron lines. 336, 336J in pterygium, 332
494 • Inde x Irregular astigmatism corneal topography in detection/management of, 43, 43f, 44 retinoscopy in detection of, 45 irrigation for chemical injuries, 355 for conjunctival foreign body, 370 for hyphema, 368 for plant materials, 362 solutions for, endothelial changes caused by,
384- 385 Isolated stromal rejection, 429. See also Rejection Isolation techniques, in ocular microbiology, 103 iSQtrelinoin, cornea! pigmentation caused by, 349 Itraconazo]e, for fungal keratitis, 166 Ivermectin , for loiasis, 171 Junctional nevus, of conjunctiva, 236 Juvenile hereditary epithelial (Meesmann ) dystrophy, 2681, 270t, 272 - 273, 273f genetics of, 2691, 272 Juvenile xanthogranuloma, 242 Kaposi sarcoma, 242, 243! human herpes virus 8 causing, 129,242 Kaposi sarcoma- associated herpesvirus/human herpes virus 8, 129,242 Kayser-Fleischer ring, 327, 3271, 337t Keloids, corneal, 341 congenital, 264 KERA gene, in cornea plana, 254- 255 Keratan sulfate in cornea, 7 macular corneal dystrophy and, 283 mucopolysaccharidoses and, 305 mutation in gene for, in cornea plana, 254- 255 Keratectasia, 258 - 260, 262t Keratectomy, 402- 403 mechanical, 402 phototherapeutic (PTK), 402 - 403 for calcific band keratopathy, 344 for corneal/epithelial erosions, recurrent, 85 for epithelial basement membrane dystrophy, 272 superficial, 402 - 403 Keratic precipitates, 25 in sarcoidosis, 74 Keratin gene mutation, in Meesmann corneal dystrophy,
268, 269t, 272 Keratinization (keratinized/ degenerated epit helial cells}, 21 in immune-mediated keratoconjunctivitis,
182t in meibomian gland dysfunction, 65
in superior limbic keratoconjunct ivitis, 82 in vitamin A deficiency, 77, 78, 78! Keratinoid degeneration, 334- 335, 335f See also Spheroidal degeneration Keratitis, 20- 21t, 24 - 25, 26f, 27f, 27t, 28f, lOlt Acanthamoeba, 167- 169, 168! contact lens wear and, 167, 168 herpes simplex keratitis differentiated from, 168- 169 •
isolation techniques for diagnosis of, 103 stains and culture media for identification or, 1031 bacteria\, 158-1 64, 1601, 160(, 1621. See also Keratitis, i nfectious/mic robial clinical presentation of, 159 contact lens wear and, 159 intrauterine, 263- 264 laboratory evaluation/causes of, 159- 161, 1601 management of, 161 - 164, 162t pathogenesis of, 159 stains and culture media for identification of, 103t blepharitis and, 144t, 145- 146, 146! Candida causing, 165 in Cogan syndrome, 209, 210 contact lens wear and, 159, 165, 167, 168 dendritic herpes simplex vi rus causing, 107, 110, Ill, 11 If herpes zoster causing, 120 disciform, herpes simplex virus causing, 114, 114f persistent bullous keratopathy and, 11 7 epithelial adenoviral , 124, 126f herpes simplex virus causing, 110- 113, 1111, l I2f measles virus causing, 129 varicella-zoster virus causing, 117- 119 Epstein -Barr virus causing, 122- 123, 123f exposure, 80 Fuchs superficial marginal, 340 fungal, 164 - \67, 165! plant sources of, 362 gonococcal conjunctivitis and, 152 herpes simplex, 109, 110- 116, lllf, 1I2f, 114f, l I S! See also Herpes simplex virus, keratitis caused by AWl1tlwmoeba kerati tis differentiated from, 168- 169 neurotrophic keratopathy/ukers caused by, 87, 117 herpes zoster, 120 infectious/ microbial, IOlt, 158- 171, 160f, 160t, 162t,
168f See also specific infectious agent clinical presentation of, 159 contact lens wear and, 159, 165, 167, 168 intrauterine, 263- 264 laboratory evaluation/causes of, l59- 161, I60t management of, 161 - 164, 162t pathogenesis of, 159 after penetrating keratoplasty, 425, 425f stains and culture in identification of, 103t interstitial herpetic, 113, 114f in infectious disease, 207- 209, 20S! syphilitic, 207- 209, 208f intrauterine infection and, 264 intrauterine, 263- 264 keratectasia caused by, 259 measles virus causing, 129 Microsporida causing, 170 necrotizing, 25 herpes simplex causing, 115, 1151, 116 nonnecrotizing,2 7f in onchocerciasis, 141 peripheral, 27t differential diagnosis of, 21 1t scleritis and, 220
In dex . 495 in systemic immune-mediated diseases, 211-213, 21lt,21 2J
ulcerative, 211 - 213 , 211I, 2 12J punctate, 20t, 25, 26f, 27 t in reactive arthritis/ Reiter syndrome, 209 in rosacea, 70, 701 scleritis and, 220, 22 1, 22 1-222, 221/ staphylococcal, 145-146, 146/ stromal, 21 t, 25, 27f, 27t in Cogan synd rome, 209, 210 Epstein -Barr virus causing, 122-123, 123f herpes simplex virus causing, 108t, 113-116, 114f, liS!
penetrating keratoplasty for, 117 in herpes zoster ophthalmicus, 120 microsporidial, 170 necrotizing, 25 non necrotizing, 27f nonsuppurative, 21t, 25, 27f, 271 systemic infec tions and, 169-170 scleritis and, 221 suppurative, 211, 25, 27f, 271 syphilitic, 207, 208 syphilitic, 207-209, 20Sf intrauterine, 263 -2 64 Th)'geson superficial pu nctate, 204-207, 2061 toxic, 360 ulcerative, 211-213, 211 1, 212f, 339 differential diagnosis of, 211 t in rosacea, 70 in systemic immune- mediated diseases, 211-2 13, 2111, 2121 varicella-zoster virus causing, 117-119 in vitamin A defici ency, 78 yeast, 166 Keratocan, mutation in gene for, in cornea plana, 255 Keratoconjunctivitis adenoviral, 124, 125, 125I. 126/ atopic, 190-192, 191/ chlamydial,154 epidemic, 124, 125, 125I. 126f immune-mediated , ocular surface C),tology in, 182t microsporidial, 170 plants cansi ng, 362 sicca. See Aqueous tear deficienc),; Dry-eye syndrome superior limbic, 81-82, 82/ toxic contac t lens solutions causing, 92 medications causing, 359-361, 3591, 3611 vernal, 187-190, 188I. 189/ atopic keratoconjunctivitis differentiated from, 190.191! Keratoconus, 296- 300, 297I. 298f, 299f, 300f, 302t, 303! Fleischer ring in, 298, 299I. 335-336, 337t in floppy eyelid synd rome, 81 Marfan synd rome and , 325 posterior circumscribed, 258, 259f, 262t intrauterine keratitis and, 263-264 refractive surgery contrai ndicated in, 300 corneal topography and. 43-44, 44/ Keratocytes, 7
Keratoepithelin gene for, amyloidosis and, 3171 transforming growt.h factor ~- ind uced , in ReisBucklers corneal dystrophy, 276 Keratoglobus, 302- 303, 302t, 303/ Keratolimbal allograft, 398 Keratolysis (corneal melt ing) gonococcal infection and, 134 peripheral ulcerative kerat itis and, 21 1, 212, 213 Keratomalacia, in vitamin A deficiency, 78, 79 Keratometry, 38- 39 Keratopathy annular, traumatic, 363 band, calcific (calcium hyd roxyapatite deposition), 328,342- 344,343/ in sarcoidosis, 73 bullous bandage contact lenses fo r, 403 after cataract surger)" 384-385 d isciform keratitis and, 117 climatic droplet, 334-335, 335/ See also Spheroidal degeneration exposu re, 80 fi lamentary, 56, 5if, 60-6 1 bandage contact lenses for, 403 infectious crystalline, 159, 1601 after penetrating keratoplasty, 425, 425/ Labrador, 334 - 335, 335/ lipid, 342, 3421 in herpes zoster ophthalmic us, 120, 12 1/ measles, 129 medications causing, 359-36 1, 3591, 361/ neurotrophic, 87-89, 88/ diabetic neuropathy and, 87 esthesiometry in evaluation of, 30-3 1 herpetic eye disease and, 87, 88, 11 7,122 punctate epithelial, 20t, 25, 26I. 27t exposure causing, 80 microsporidial, liO staphylococcal btepharitis/blepharoconjunctivitis and, 145, 146f, 147 topical anesthetic abuse causing. 90 striate. intraocular su rgery cau sing, 383 toxic ulcerative, 86, 88 vortex (hurricane/cornea verticil!ata) , 3 J 0, 31 If, 346- 348, 347t, 348f, 360
Keratoplasty endothelial,413 in children, 413 Descemet stripping automated (DSAEK), 413, 415- 416t, 437-445 advantages of, 4161, 438 complications of intraoperative, 4151,44 1, 44 If postoperative, 4151, 442-44 5, 4421, 443f, 444f disadvantages of, 41 61. 438 donor cornea prepa ration in, 438 indications for, 41St, 437 penetrating/selective keratoplasty compared with, 415-416t precut tissue for, 409, 438 recipient eye preparation and, 439- 441, 440/ Descemet's membrane (DME K), 445
496 • Index Intralase-enabled (IEK), precut tissue for, 409 lamellar, 433-437 advantages of, 434- 4 35 anterior, 433-435, 4 34/ deep anterior (DALK ), 300, 413, 415-4161,
435-436 advantages of, 4i6t in children, 431 complications of intraoperative, 41St
postoperative, 415t disadvantages of, 4 161 indications for, 415t for keratoconus, 300 penetrating/ selective keratoplasty compared with , 415-4161 surgical technique for, 435-436 disadvantages of, 435 indications for, 413, 414t postoperative care and complications and,
436-437 rejection and, 436 superficial anterior (SA LK), 413, 415-416t, 435 advantages of, 4 16t complications of intraoperative, 4 1St postoperative, 41St disadvantages of, 416! indications for, 41St penetrating/selective keratoplasty compared with,415-4 16t surgical technique for, 435 surgical technique for, 435-436 penetrating (PK), 4 13, 415-416/ , 41 7-430 for Acanthamoeba keratitis, 169 advantages of, 416t astigmatism after, control of, 426-427, 427/ topography and, 44, 426, 427/ for bacterial keratitis, 164 for chemical injuries, 358 in children, 430-431,431 t for cicatricial pemphigoid, 203 complications of in children, 430-431 intraoperative, 4151, 421 postoperative, 415/ , 421-426 conjunctival flap removal and, 401 for corneal changes in mucopolysaccharidoses,
307 disadvantages of, 4161 disease recurrence in graft and, 422, 423/ donor cornea preparation in, 41 7-418 graft rejection and, 427-430, 428f, 429/ for herpetic eye disease complications, 117 indications for, 4 13, 4141, 41St for keratoconus, 300 for keratoglobus, 303 for neurotrophic keratopathy, 88 for pellucid marginal degeneration, 302 for peripheral ulcerative keratitis, 213 postoperative care and, 421-426 in children, 431-432 procedures combined with, 419~420
recipient eye preparation and, 418 refractive error after, control of, 426-427, 427/ in rosacea patients, 70 selective keratoplasty compared with, 415- 416t
in Stevens-Johnson syndrome, 198 surgical technique for, 417-419, 419! suture techniques for, 418-419, 4191, 420/ postoperative problems and, 423-425, 424/ removal in children and, 431, 431t tectonic for herpetic eye disease complications, 117 for peripheral ulcerative keratitis, 213 Keratoprosthesis, 413, 432-433, 433/ for chemical injuries, 358-359 for children, 431 for cicatricial pemphigoid, 203 for Stevens-Johnson syndrome, 198 Keratorefractive surgery (KRS) astigmatism and, corneal topography in detection/ management of, 44 corneal topography and, 43- 44, 44/ iron lines associated with, 336 Keratoscopy, 39, 39/ computerized, 40- 45, 401, 411, 421, 431, 44f photographic, 39 Keratosis, 201 Keratotomy astigmatic, for astigmatism/ refractive errors after penetrating keratoplasty, 427 radial, iron lines associated with, 336 Keratouveitis, varicella, 118, 121 Ketoconazole, for fungal keratitis, 166 Ketorolac, for recurrent corneal erosions, 84 Khodadoust line, 429, 429J KID (congenital keratitis -ichthyosis-deafness) syndrome, 74 Killer cells, 180 Kinins, 1771 Klebsiella , 135 KP. See Keratic precipitates KPro. 5ee Hoston keratoprosthesis KRT3/KRT12 mutations, in Meesmann corneal dystrophy, 268, 269t, 272 Krukenberg spindles, 337t, 345 Labial gland biopsy, in Sjogren syndrome, 57, 59J Labrador keratopathy, 334-335, 335J Lacerations conjunctival, 369-370 corneoscleral. See also Anterior segment, trauma to; Perforating injuries repair of, 375-381, 376J anesthesia for, 376 postoperative management and, 381-382 preoperative management and, 374-375 secondary repair measures and, 380-381, 38 If, 382f
steps in, 376-380, 377t, 378!, 379! Seidel test in identification of, 17, 19J iris, repair of, 380-381, 381f Lacrimal functional unit, 48, 491, 173
Index. 497 Lacrimal glands biopsy/histologic features of, in Sjogren syndrome. 57,63 dysfunction of non-Sjogren syndrome, 50, 5 11. 52. 65 in sarcoidosis, 73 ill Sjogren syndrome. SO. 51f, 63 tear composition assays in, 54- 55 ectopic. 246 Epstein-Barr virus infection and. 122- 123 . in external e}'e defense, 95 immune response/imm unologic fea ture... of, 1761 inflammatory damage to, dry eye and, 50 sarcoidosis involving. 73 Lactoferrin, in lear film , 54-55 in external eye defense. 95 Lagophthalmos causes of, so exposure keratopathy and, 80 Lamellae. corneal, 7-8 Lamellar fl ap, for superficia l anterior lamellar keratoplasty, 435 Lamellar surgery keratectomy, 402 keratoplasty. See Keratoplasty Lamellar tec tonic graft. for keratoglobus. 303 Lancefic1d groups, 133 Langerhans ceils, 173, 1741 in external eye defense. 96 Lantibiotics, staphylococc i producing, 133 Larva migrans ocular, 142 visceral, 142 Laser burns, corneal endothelial damage caused by, 385 Laser in situ keratomileusis (LASIK) dry eye after, 50, 65 keratit is after, atypical mycobacteria causi ng, 164 in keratoconus patients, 300 corneal topography and, 43-44, 44/ Laser scanning confoc"l microscope, 36. See also Confocal microscopy Laser therapy (laser surgcry) for ker"toconus, 300 ocular damage after (laser burns), 385 LASIK. See Laser in situ keratomileusis Latency (vi ral), herpesvirus infection and, 99, lOS, 109, 117-1 18,1 19 Lattice corneal dystrophy, 2681, 2781 classic (TG FBI-type/LC D1 ), 268/, 2701, 278 - 279, 279/ genetics of, 178, 2691 gelsolin-type (LCD2). 2681, 270t, 280, 280f, 3171, 3 t9 genctics of, 269t, 280, 317t Lattice lines, 279, 279f, 280, 280f Law of refraction (Snell's Jaw), 38 LCD. See Lattice corneal dystrophy LCD I. Sec Lattice corne"l dystrophy, classic (TGFBJ type) LCD2. Sec Lattice corneal dystrophy, gelsolin type LECD. Sce Lisch epithelifl] corneal dystrophy Lecithin -cholesterol acyltransfera se (LeAT) defkiency, 309-310 Leiom),osarcoma, conjunctival, 240 Leishmatria (leishmaniasis), 14 1
Leukocyte oxidants, as in flammatory mediators, 1771 Leukotrienes, 177t, 1791 LevofloxflCin, for bacterial keratitis. 163 Lewis antigens, transplant rejection and. 407 LFU, See Lacrimal funct ional unit Lice, ocular infection caused by, 142. 142f, 149 Ligneous conju nctivitis, 192-193, 192/ Limbal dermoids, 245- 246, 246f Limbal stem cells, 6, 92- 93 in corneal epithelium maintenance, 6. 92-93 deficiency of, 92-94, 931, 94f, 395-398. See also Limbal transplflntation toxic imults/toxic kerrttoconjunctivitis from medications and, 87, 360 Limbaltransplantation (limb"l autograft/allograft/stem cell transplantation), 94, 389, 395-398. 396-397/ for chemical injuries, 94, 358 indications for, 3871 Limba l vernal keratoconjunctivitis, 187, 188/ Limbus. 5, 37, 37f See also IIl1der UIII/wl marginal corneal infiltrrttes in blepharoconjunctivitis and,210 squamous cell carcinoma of, 23 1- 232, 232/ Linea r IgA dermatosis, 199, 205t Linear staining, 56 Lipid keratopathy, 342. 342/ in herpes zosterophthalmicus, 120, 121/ Lipid layer of tear film , in external eye defense, 95 Lipidoses. See Lipids, disorders of metabolism and storage of Lipids, disorders of metabolism and storage of (lipidoses), 308-313, 3091 corncaichanges in, 308-3 13,309t in Schnyder cornea l dystrophy, 284, 309 mucolipidoses and. 3 12 Lipopolysaccharide. bacterial, 132 Lisch epithelial corneal d}'strophy, 2681, 270r, 273-274, 274/ genetics of, 2691, 273 Lissaminc green, 17 in tear-film evaluation, 17,56 Lith iasis, conjunctival, 333 LK. See Keratoplasty, lamellar Lon loa (loiasis), 141 , 170- 171 Lodoxamide, for "llergic conjunctivitis, 186 Lofgren syndrome, 73 Louis-Bar syndrome (ataxia-telangiectasia), 77. 241 Lowe disease (oculocerebrorenal syndrome), congenital corneal kcloids in, 264 LSCM. See L"ser scanning confoc,, 11l1 icroscope Lubricants fo r chemical injuries, 358 for dry eye, 57, 601 fur peripheralul ceralive keratitis, 212 fur persistent corneal epithelial defects, 87 for recurrent corneal erosions, 84 fo r Stevens-Johnson syndrome, 196- 197 Lumican,7 mutation in gen e for, in cornea plana, 255 Lyme dise"se/Lyme borreliosis, 137 Lymphangiectasia. 76-77, 243 Lymphangiomas, 243 Lymphatic/lymphocytic tumors, conjunctival, 242- 244
498 • In dex Lymphatics, conjunctival, 173 Lymphocytes, cytologic identification of, in immunemediated keratoconjunctivitis, 1821 Lymphoid follicuiosis, benign, 24, 241 Lymphoid hyperplasia (reactive hyperplasia), of conjunctiva, 243, 244/ Lymphoid tissues, mucosa-associated (MALT), 173 of conjunctiva (conjunctiv3-associated/CALT), 3, 5, 180-181 Lymphomas, conjunctival, 244, 245/ Lysin, S, in external eye defense, 95 Lysosomal storage disorders, 305-307, 306t. See also Mucopolysaccharidoses Lysozyme. in tear film, 54-55 in external eye defense, 9S Lys)'l hydroxylase, defects in gene for, in Ehlers Danlos syndrome, 252, 325 !HI S1 gene, in amyloidosis, 317t M proteins overproduction of, corneal deposits and, 319 strepLOcoccal, 133 M -like proteins, streptococcal, 133 J'\llacroglobulinemia, \Valdenstrom, corneal deposits in,
320 Macrophage colony-stimulating factor, in cicatricial pemphigoid, 199 Macular corneal dystrophy, 2681, 2701, 278t, 283-284,
2841 genetics of, 2691, 283 Macular edema, cystoid, in sarcoidosis, 74 Macule, of eyelid, 201 Madarosis, in staphylococcal blepharitis, 1441, 145 Maggots (fly larvae), ocular infection caused by, 143 Major basic protein, 179! Major histocompatibility complex (M HC), 174, 407 Malassezia furfur as normal ocular flo ra, 97,971 ocular infection caused by, 148 Mandibulofacial dysostosis, 324! lvlanifest refraction, after penetrating keratoplasty, 426, 427f Mannosidosis, 312 Map-dot-fingerprint dystrophy. See Epitheliall subepithelial dystrophies, basement membrane Map lines, in epithelial basement membrane dystrophy, 271, 271f Marfan syndrome, 3231, 325 megalocornea and, 254, 325 Marginal corneal infiltrates, staphylococcal blepharitisl blepharoconjunctivitis and, 145, 146f, 147,210 Marginal degeneration pellucid, 301 - 302, 301f, 3021, 303f refractive surgery contraindicated in, 44 Terrien, 339-340, 340f Marginal keratitis, Fuchs superficial, 340 Maroteaux-Lamy syndrome, 3061 Mast-cell stabilizers for giant papillary conjunctivitis, 195 for ocular allergy, 186 for vernal keratoconjunctivitis, 18&
Mast cells cytologic identification of, in immune-mediated keratoconjunctivitis, 182t in external eye, 1741, 181 mediators released by, 179!, 181 Matrix metalloproteinases in ligneous conj unctivitis, 192 in ocular infection, 99 in Sjogren syndrome, 63 McCannel technique for iridodialysis repair, 381, 3821 for iris laceration repair, 380-38 1, 381f McCarey-Kaufman tissue transport medium, for donor corneas, 408-409 MCD. See Macular corneal dystrophy MCDCI. See Macular corneal dystrophy Mean curvature/ mean curvature map, 41, 42f Measles (rubeola) virus, 129 MECD. See Meesmann corneal (juvenile hereditary epithelial) dystrophy Mechanical blepharoptosis/ptosis, 21 Mediators, 175, 1761, 177t, 179t. See also specific type allergiC conjunctivitis and, 185 cytokines, 177, 177t in Sjogren syndrome, 63 Medrm..-yprogesterone for chemical injuries, 358 for neurotrophic keratopathy, 88 Meesmann corneal {juvenile hereditary epithelial} dystrophy, 268t, 270t, 272 -273, 2731 genetics of, 269t, 272 Megalocornea, 253-254, 2541, 26lt Marfan syndrome and, 254, 325 Meibomian glands, 4, Sf chalazion caused by obstruction of, 72 dysfunction of, 50, 501, 65-69, 67f, 143, 144! blepharitis in, 68,143, 144t dry eye and, 50, 501, 65-69, 671 in external eye defense, 95 immune responselimmunologic features of, 175, 176[ Melanin, cornea! pigmentation caused by, 337t, 345 Melanin-like pigment, corneal pigmentation caused by, 337t, 348, 348f u ~Melanocyte-stimulating hormone (u -MSH), Int Melanocytes, tumors arising from, 233, 234t. See also Pigmented lesions Melanocytosis ocular, 235-236, 2351, 238t oculodermal (nevus ofOta), 235-236, 238t Melanokeratosis, striate, 234 Melanomas conjunctiva!, 238 - 240, 238t, 239f ocular melanocytosis and, 239 Melanosis, 233, 238t benign, 234, 235f congenital epithelial, 233 ocular (racia!) , 238t primary acquired, 237-238, 237f, 238t melanoma arising from, 239 Membrane-type frizzled protein (MFRP) gene, in nanophtha!mos, 251
Index. 499 Membranes conjunctival, 20t, 22t in epidemic keratoconjunctivitis, 124, 125, 125f in ligneous conjunctivitis, 192, J 92f retrocorneal fibrous (posterior collagenous layer), 29 Mendelian Inheritance in Man (M IM) abbreviations/ numbers, for corneal dystrophies, 270t Meretoja syndrome (gelsolin -type lattice corneal dystrophy), 2681, 2701, 280, 280f, 317t, 319 . genetics of, 269/, 280, 3 17t Mesenchymal cells, in ocular development, 4 Mesenchymal tumors, eyelid and conjunctiva, 240- 242, 2411 Mesodermal dysgenesis, 255- 163. See also specific disorder Metabolic disorders. See also specific Iype corneal changes and, 305-329 Metaherpetic ulcer, 117 Metalloproteinases, matrix in ocular infection, 99 in Sjogren syndrome, 63 Metastatic eye disease, of conjunctiva, 245 Methotrexate fo r peripheral ulcerative keratitis, 213 for scleritis, 223 Methylprednisolone, for corneal graft rejection, 430 Metrogel. See Metronidazole Metronidazole, for rosacea, 70 MFRP (membrane-type frizzled protein) gene, in nanophthalmos,2S1 MGD. See Meibomian glands, dysfunction of MHC. See Major histocompatibility complex Microbial keratitis. See Keratitis, infectious/microbial Microbiology, 100, 101 I, 131 - 171. See also specific organism bacteriology, 131- 137, 132t cytologic identification of organisms and, 47- 48 diagnostic laboratory techniques in, 100- 103, lOIt, 102J, 103t mycology, 138- 140, 138t parasitology, 140- 143 prions, 143 virology, 104- 130 virulence factors and, 98 - 99 Micrococcus, as normal ocular flora, 971 Microcornea, 253, 2611 cornea plana and, 255 Microc)'stic dystrophy, Cogan. See Epithelial/ subepithelial dystrophies, basement membrane Microcystic epitheliopathy, 91 Microcysts in epithelial basement membrane dystrophy, 270, 271,271f in Meesmann corneal dystrophy, 272 Microfilariae loa loa, 170-171 onchocercal, 141 Micropannus. See Pannus Microphthalmia (microphthalmos), 250- 251, 250f, 253 anterior, 253 Micropuncture, anterior stromal, for recurrent corneal erosions, 84, 85f
Microscope confocal, 35- 36, 36/ slit-lamp. See Slit-lamp biomicroscopy/examination specular, 14,31 -33, 32f Microsomia, hemifacial, 3231 Microsporida (microsporidiosis), 141, 170 in HIV infection/AIDS, 170 keratitis/keratoconjunctivitis caused by, 170 Microtrauma, ocular infection and, 99 Migration inhibitory factor, in cicatricial pemphigoid, 199
Mikulicz syndrome, 73 MIM (Mendelian Inheritance in Man) abbreviations/ numbers, for corneal dystrophies, 2701 Mimecan, mutation in gene for, in cornea plana, 255 Mineral metabolism, disorders of, corneal changes in, 327- 328,327f Minocycline for meibomian gland dysfullction, 68 for rosacea, 70 Miosis/miotic agents dry eye and, 61 toxic keratoconjunctivitis and, 360 traumatic injury and, 363 Mitomycin/ mitomycin C for conjunctival intraepithelial neoplasia, 229, 230f for corneal intraepithelial neoplasia, 231 in phototherapeutic keratectomy, 403 in pterygium surgery, 394- 395 toxic keratoconjunctivitis caused by, 360 MLs. See Mucolipidoses ML I. See Dysmorphic sialidosis ML II. See Inclusion -cell (I -ceil) disease ML III. See Pseudo-Hurler polydystrophy ML I \~ 312 MMC. See Mitomycinfmitomycin C MMP. See Matrix metailoproteinases; Mucous membrane (ocular cicatricial) pemphigoid MMP-2 (gelatinase) in recurrent corneal erosion, 83 in Sjogren syndrome, 63 MMP-3, in Sjogren syndrome, 63 MMP-9 in ligneous conjunctivitis, 192 in recurrent corneal erosion, 83 in Sjogren syndrome, 63 MMP-13, in Sjogren syndrome, 63 Molds, 138, 138t Moll, glands of, 4, Sf Molluscum contagiosum , 127, 128f, 129f Monoclonal gammopathy, benign, corneal deposits in, 320 Monocytes, C}1ologic identification of, in immunemediated keratoconjunctivitis, 182t Mononucleosis, infectious, ocular involvement in, 122- 123,123f Mooren ulcer, 213- 216, 21Sf Moraxella blepharoconjunctivitis caused by, 145 iacunata, 145 as norma! ocular flora, 971 Morquio syndrome, 306t
500 • Index Mosaic degeneralion (anterior crocodile shagreen), 337 Moxifloxacin, for bacterial keratitis, 1621, 163 MP$s. Sec Mucopolysaccharidoses MPS I H. See Hurler syndrome MPS I HIS . See Hurler-Scheie syndrome MPS I S. See Schcic syndrome MP$ [I. See Hunter syndrome MPS Ill. See Sanfilippo syndrome MPS IV. See Morquio syndrome . MPS V. See Seheie syndrome MPS VI. See Maroteaux-Lamy syndrome a -M5H (u -melanocyte-stimulating hormone) , 1771 Mlleins, tear film, 3 in dry-eye syndrome, 49, SO! in external eye defense, 95 Mucoepidermoid carcinoma, 226t, 232 - 233 Mucolipidoses, 312
corneal changes in, 312 congenital/infantile opacities and, 263 Mlicopolysaccharidoses, 305 - 307, 306t
corneal changes io,305- 307, 3061 congen ital/infantile opacities and, 263 Mucor (mucormycosis), 140 lvlucosa-associated lymphoid tissue (MALT) , 173 of conj unctiva (conj unctiva-associated/CALT) , 3, 5, 180- 181 Mucous membrane gra fting (transplantation) , 389, 40 1- 402 indications for, 3871,401 - 402 Mucous membrane (ocular cicatricial) pemphigoid, 180, 1961 , 198- 203, 1991, 200f, 20 If, 202f, 205t drug-induced (pseudopemphigoid) , 199, 361 mucous membrane grafting for, 401 Mucus excess, conjunctival, 20t Mucus-fishing syndrome, 90 Multifocal cornea, retinoscopy in detection of, 45 Multiple endocrine neoplasia conjunctival neurogenic/smooth muscle tumors in,
240 corneal nerve enlargement in, 328 - 329, 3291 Multiple sulfatase defiCiency, 310 Mumps vi r us, 129- 130 Munson sign, in keratoconus, 298 , 298/ Muscle relaxants, tear production affected by, 66t Mutton -fat keratic precipitates, 25 in sarcoidosis, 74 Mycelium, 138 Mycobacterium (mycobacteria), 136- 137 che/onei, 137 /ortuiturn, 137 leprae, 136 non tuberculous (atypical) infection caused by, 164 ocular infectionlinflammation caused by, 136- 137, 164 stains and culture media for identification of, 103t tuberculosis, 136 Mycology, 138- 140, 1381 Mydriasis/mydriatics, traumatic injury and, 363 Myiasis, 143 Na +,K ' -ATPase corneal hydration and, 8 in Fuchs endothelial corneal dystrophy, 291
Nail-patella syndrome, 323t Nanophthalmos, 251 - 252, 253 Natamycin, for fungal keratitis, 166 Nd:YAG laser therapy, for epithelial basement membrane dystrophy, 272 Necrobiotic xanthogranuloma, 242 Necrotizing keratitis, 25 herpes simplex causing, 115, 1151, 116 Necrotizing scleritis, 21 t, 28, 218-220, 21tH, 2191, 2201, 222, 223 with inflammation, 218t, 219, 219/ without inflammation (scleromalacia perforans), 218t, 220, 220/ Needle sticks, prevention of, 46 Negative staining (fluorescein) , 17 Neisseria, 134, 134/ gonorrlweae (gonococcus), 134, 1341, 149 conjunctivitis caused by, 134, 15 1-152, 151/ in neonates, 152, 153 penicillin-resistant, 152, 153 meningitidis (meningococcus), 134, 149 Neonates conjunctivitis in, 152- 154 corneal transplantation in, 430-431, 43 It her pes simplex infection in, 106 normal ocular flora in, 96 Neoplasia, ocular surface, 225- 247. See also specific type or structure involved of epithelial origin, 226- 233, 226t of neuroectodermal origin, 233-240, 234t Ncovascularization cor neal contact lenses causing, 92 inflammation and, 25 after lamellar keratoplasty, 436 medications causing, 360 after pediatric corneal transplantation, 431 stem cdl defiCiency and, 93, 94 stroma!, contact lenses causing, 92 Nephropathic (infantile) cystinosis, 313 Neural crest cells, 4 ocular structures derived from, 4 Neuralgia, postherpetic, 121-122 Neurocristopathy, 255-263. See also specific type Neuroectoderm, 4 tumors arising in, 233-240, 234t Neurofibromas, conjunctival, 240 Neurogenic tumors, conjunctiva\, 240 Neuroglial choristoma, 247 Neuroma, conjunctival, 240 Neuropathy, diabetic, neurotrophic keratopathy/ persistent corneal defects and, 87 Neuropeptides,l77t for neurotrophic keratopathy, 88 Neurotransmitters, in cornea, 6 Neurotrophic keratopathy, 87- 89, 88/ diabetic neuropathy and, 87 esthesiometry in evaluation of, 30- 31 herpetic eye disease and, 87, 88, 117, 122 Neurotrophic ulcers, herpetic keratitis and, 87, 88, 117 Neurotrophins, for neurotrophic keratopathy, 88 Neutrophil chemotactic fac tor, 179t
Index . 501 Neutrophils in chemical injuries, 357. 358 cytologic identification of, in immune-mediated keratoconjunctivitis, 1821 in external eye, 174t Nevus blue, 235 conjunctival, 236-237, 236f, 238t flammeus (port-wine stain), 241 junctional, 236 ofOta (oculodermal melanocytosis), 235-236, 238t Nevus cells, tumors arising from, 233, 234t_ See also Pigmented lesions Newborn conjunctivitis in, 152- 154 corneal transplantation ill, 430-431. 43lt herpes simplex infection in, 106 normal ocular flora in, 96 Night blindness, in hypovitaminosis A, 78 Nocardia/ Nocardia asleroides (nocardiosis), 137 Nodular anterior sclerit is, 28. 218, 218t. 219/ Nodular episcleritis, 28, 216, 217/ Nodular fasciitis, 242 Noncontact corneal esthesiometry, 31 Noncontact specular microscopy/photomicroscopy, 32 Nonenveloped viruses, 105 Non-Hodgkin lymphomas. conjunctival, 2-14, 145/ Nonnecrotizing keratitis, 27/ Nonnecrotizing scleritis. 21 t, 28 Nonseptate filamento us fungi, 138r. 1-10 Non-Sjogren syndrome dry eye, 50. 51j. 52, 65 Nonsteroidal anti -inflammatory drugs (NSAJDs) for allcrgic conjunct ivitis, 187 for scleritis, 222 Noritatc. See Metronidazole Normal flora, ocular, 96-97, 971
Nosema, 141 stromal keratitis caused by, 170 NSSDE. See Non - Sjogren synd rome dry eye Nucleic acids, viral. J04 Nucleotides, corneal changes in disorders of metabolism of, 325-326 Nutritional deficiency, ocular surface disorders and, 77-79 Nyctalopia, in hypovitaminosis A, 78 Obesity, floppy eyelid syndrome and, 81 Ochronosis, 314t. 316, 337t OCP. See Ocular cicatricial (mucous membrane) pemphigoid OCT. See Optical coherence tomography Ocular adnexa, in external eye defense, 95 Ocular cicatricial (mucous membrane) pemphigoid, 180,1961,198-203, 1991, 200j. 20 If, 202[, 205t drug-induced (pseudopcmphigoid), 199,361 mucous membrane grafting for, 401 Ocular cytology. See Cytology Ocular graft-vs-bost disease, 1961, 203-204, 204f Ocular immunologylimmune response. See Immune response Ocular infection. See Infection Ocular inflammation. See Inflammation; Uveitis Ocular inju ry. See Perforating injuries; Trauma
Ocular larval migrans. 142 Ocular melanocytosis, 235-236, 235j. 2381 Ocular (racial) melanosis, 238t Ocu lar pain. See Pain Ocular-scoliotic-lype Ehlers-Danlos syndrome, 325 Ocular surface. See also Conjunctiva; Cornea; Epithelium dcfinition of, 387 development of, 4 disorders of aqueous tear defiCiency. 55-65 contact lens wear and, 91-92 diagnostic approach to, 47-94. 181-182, 1821. See
also specific disorder ocular cytology in, 47-48 tear-film evaluation and, 52-55, 53f, 54f, 541 dry-eye syndrome, 48-52. See also Dry-eye syndrome evaporative tear d),sfunction. 5 1, 51f, 52, 65-75 factitious, 89-90 immune-mediated, 183-223, 1961. See also specific
disorder clinical approach to, 183-223, 1961 diagnostic approach to, 18 1- 182, 1821 patterns of, 180-1S1 infectious. See Infection limbal stem cell deficiency and, 91-94, 931, 94J, 395-398 neoplastic, 225-247. See also Ocular surface, tumors of noninflammatory vascular conjunctival anomalies, 75-77 nutritional/physiologic disorders, 77-79 structural/exogenous, SO-92 hypersensitivity reactions of, 178- 180, 178f, 1791 immunologic features of, 173- 175, 174f, 1741 maintenance of. 388-389 surgery of, 387-405. See also specific procedure indications for, 3871 lumors of, 225-247 epithelial origin of, 226-233, 2261 neuroectodermal origin of, 233-240, 2341 \\'otllld healing/repair and, 387-388 response to, 388-389 Ocular Surface Disease Index (OSDI), 56 Ocular {intraocular} surgery anterior segment trauma caused by, 382-385, 3841 ocular surface, 387-405, 3871 Oculoauricular d ysplasia/ ocu loau ricu lovertebral sequence, 3231. See also Golden har syndrome Oculocerebrorenal syndrome (Lowe disease), congenital corneal keloids in, 264 Oculodentoosseous dysplasia, 323t Oculodermal melanocytosis (nevus of Ota), 235-236, 2381 Oculoglandular syndrome, Parinaud, 157- 158 OClilomandibulodyscephaly, 323t Oculomycosis, trauma and, 139 Ofloxacin for bacterial keratitis, 163 for gonococcal conjunctivitis. 152 Omega-3 fatty acid supplements, for mcibomian gland dysfunction, 68
502 • Index Onchocerca/Onchocerca volvulus (onchocerciasis), 141 Oncoq1oma, 233 Onychoosteodysplasia,3231 OOKP. See Osteo-odonto-keratoprosthesis Open -angle glaucoma cornea plana and, 255 microcornea and, 253 penetrating keratoplasty and, 421 posterior polymorphous corneal dystrophy and, 295 Ophthalmia neonatorum, 152- 154 chlamydial, 153-154 gonococcal, 153 nodosum,372 sympathetic, enucleation in prevention of, 376 Ophthalmic irriganls. See also Irrigation endothelial changes caused by, 384-385 Ophthalmometry. See Keratometry Ophlhalmomyiasis, 143 Opportunistic infections, 100 Optic cup, development of, 4 Optic vesicle, 4 Optical coherence tomography, 29, 34, 35/ before corneal transplantation, 417 Optical pachometry, 28 Optical zone, 37 Optisol GS, for donor cornea preservation, 409 Orbit, in external eye defense, 95 Organ culture storage techniques, for donor cornea, 409 Onhomyxoviruses, 129 OSDI (Ocular Surface Disease Index), 56 Osmolarity, tear film, 54 Osmotic force, transendothelial, 8 Osseous choristoma, 247 Osteodystrophy, Albright hereditary, 322t Osteogenesis imperfecta, 252, 3231 blue sclera in, 252 Osteo-odonto-keratoprosthesis,432 Outer eye. See External (outer) eye Overrefraction, acuity testing in corneal abnormalities and,11 Overwear syndromes (contact lens), metabolic epithelial damage in, 91
PACD. See Posterior amorphous corneal dystrophy Pachometry (pachometer), 28- 30, 291, 30t in Fuchs endothelial dystrophy, 293 infection control and, 46 in keratoconus, 299, 30qf Paecilomyces, 139 Pain corneal abrasion causing, 372 in recurrent corneal erosion , 83 in scleritis, 217- 218, 219 in traumatic hyphema, 367 Palisades ofVogt, 5 Palpebral conjunctiva, 4, 6. See also Conjunctiva Palpebral vernal keratoconjunctivitis, 187, 188/ PAM. See Primary acquired melanosis Panencephalitis, subacute sclerosing, 119
Pannus/ micropannus, 25, 28/ contact lens wear causing, 92 bandage con tact lenses and, 403 in trachoma/ chlamydial conjunctivitis, 155, 1561, 157 in vernal keratoconjunctivitis, 187 Papillae, conjunctival, 20t, 21-22, 22f, 22t, 23f in atopic keratoconjunctivitis, 190, 191f in floppy eyelid syndrome, 81, 8 1f in giant papUiary (contact lens- induced) conjunctivitis, 231, 193, 194, 194/ in palpebral vernal keratoconjunctivitis, 187, 188/ Papillary conjunctivitis, 22t, 23/ giant (contact lens- induced), 23f, 194-195, 194/ in reactive arthritis/Reiter syndrome, 209 Papillomas, 129 conjunctival, 128, 129,226-228, 226t, 227f Papovaviruses/papovavirus infection, 128- 129 Papule, of eyelid, 20t Paracentesis, anterior chamber/aqueolls, for hyphema,
368 Paracentral zone, 37, 37f Paramyxoviruses. 129 Paraneoplastic pemphigus, 205t Paraprotein, corneal deposition of, 319-320 Parasites, ocular infection caused by, 140-143 cornea and scleral involvement and, 167- 169 eyelid margin involvement and, 148- 149 Moorell ulcer and, 214, 215 Parasitology, 140- 143. See also Parasites Parinaud oculoglandular syndrome, 157- 158 Parkinson disease/ parkinsonism, medications for, tear production affected by, 661 Parry-Romberg syndrome, 3241 Partial (bridge) conjunctival flap, 400 Patching for corneal abrasion, 372 for perforating injury, 375 PAX6 gene mutation, in Peters anomaly, 258 POCO. See Pre-Descemet corneal dystrophy "Peculiar substance;' in Meesmann corneal dystrophy, 272 Pediatric corneal transplantation, 430- 431, 43lt Pediculus (pediculosisllice) humanus capitis, 149 humallus corporis, 149 ocular infection caused by, 142, 142f, 149 Pellucid marginal degeneration, 301 - 302, 30 If, 302t, 303! refractive surgery contraindicated in, 44 Pemphigoid bullolls, lOSt cicatricial (mucous membrane), 180, 196t, 198- 203, 1991. 200f, '0 If, 20'f, 2051 drug-induced (pseudopempbigoid), 199,361 mucous membrane grafting for, 401 gestational, 205t Pemphigus foliacetls,205t IgA,205t paraneopiastic,20St vulgaris, 200, 20St Penciclovir, for herpes simplex virus infections, 109t Penetrating injuries, definition of, 373
Index . 503 Penetrating keratoplasty. See Keratoplasty, penetrating Penicillamine, for Wilson disease, 327- 328 Penicillin -resistant N gonorrhoeae, 152,153 Peptidoglycan, in bacterial cell wall, 132 Perennial allergic conjunctivitis, 185- 187 Perforating injuries anterior segment, 373-382, 373t, 374(, 376f, 3771, 37Sf, 379f, 38 If, 382/ ancillary tests in, 3741 evaluation of, 373 -374, 373t, 374t examination in, 373-374, 374t history in, 373, 3731 management of, 374-382 nonsurgical, 375 postoperative, 381 -382 preoperative, 374- 375 surgical, 375- 381, 3771, 378f, 379f, 381f, 382f ocular signs of, 3741 definition of, 373 penetrating injury differentiated from, 373 Perineuritis, radial, Acanlhamoeba keratitis and, 167 Peripheral corneal guttae (Hassall -Henle bodies/warts), 334,345 Peripheral iridectomy for bacterial keratitis, 164 with penetrating keratoplasty, 420 Peripheral keratitis, 271 scleritis and, 220 ulcerative, 211 - 213, 2111, 212f, 339 differential diagnosis of, 21lt in systemic immune-mediated diseases, 211 - 213, 211t,212f Peripheral nervous system disorders, Sjogren syndrome and, 63 Peripheral ulcerative keratitis. See Peripheral keratitis, ulcerative Peripheral zone, 37, 37f Periphlebitis, in sarcoidosis, 74 Peritomy incision, fo r Gundersen flap, 399f, 400 Peroxidase, 179t Persistence, as microbial virulence factor, 99 Persistent corneal epithelial defects, 85-89, 88f oc ular infection and, 99 after penetrating keratoplasty, 422, 423J Peters anomaly, 256- 258, 257f, 261t PG. See Prostaglandins Phaco burn, 384 Phacoemulsification, corneal complications of, 384 Phakomatous choristoma, 247 Pharyngoconjunctival fever, 124 Phenol red- impregnated cotton thread test, of tear secretion, 54 Phenothiazines, corneal pigmentation caused by, 346, 348- 349 Phialophora, 139 Phlyctenules/phlyctenulosis, 20t, 145-146, 146f, 147 PHMB. See Polyhexamethylene biguanide PHN. See Postherpetic neuralgia Phosphatid yl in osi tol-3 -phosphate/ phospha tid ylinosi tol 5-kinase type III (PIP5K3), in Fleck corneal dystrophy, 269t, 287 Photographic keratoscope/photokeratGscopy, 39
Photomicroscop}" specular, 14, 31 -3 3, 32f Photorefractive keratectomy (PRK), dry eye and, 65 Phototherapeutic keratectomy (PTK), 402-403, 413 for calcific band keratopathy, 344 for corneal/epithelial erosions, recurrent, 85 for epithelial basement membrane dystrophy, 272 Phthiriasis palpebrum (Phth irus pubis infection), 142, 149
Phthirus pl/bis (crab/pubic louse), 142, 142f ocular infection (phthiriasis palpebrum) caused by, 142,1 49 Phytanic acid storage disease (Refsum syndrome), ichthyosis and, 74 Picornaviruses, 129 Pierre Robin malformation, 324t Pigment spot of sclera, 233 Pigmentations/pigment deposits. See also Pigmented lesions conjunctival,233- 240 corneal, 321 t drug-induced, 346- 349, 347t Pigmented lesions, 233- 240, 234t benign, 233- 237,234t malignant, 2341, 238- 240 preinvasive, 234t, 237- 238 Pili, bacterial, 132 Pilocarpine, for dry eye, 60 Pinguecula, 331-332 conjunctival graft for, 395 subconjunctival hemorrhage caused by, 76t P1P5K3 (phosphatidylinositol -3-phosphate/ phosphatidylinositol 5-kinase type !II), in Fleck corneal dystrophy, 269/, 287 PITX2 gene, in Peters anomaly, 258 PK (penetrating keratoplasty). See Keratoplasty, penetrating Placido-based topography/Placido disk, 39, 40, 40f in keratoconus, 43-44, 44J, 299, 300f Plants/vegetation , ocular injuries caused by, 362 corneal foreign bod}', 371 Plaques, senile scleral, 9, 345-346, 346f Plasma cells in external eye, 174r monoclonal proliferation of, corneal deposits and, 319- 320 Plasm ids, bacterial, 131, 132 Plasminogen, in ligneous conjunctivitis, 192, 193 Platelet -activating factors, 179t Platinum eyelid weights, for exposure keratopathy, 80 PleistoplJOra, 141 Pleomorphism, specular photom icroscopy in evaluation of,32 - 33 Pneumococcus. See Streptococcus, pneumoniae Plleumocysris carini; (Pneumocystis jiroveci) infections, 140
Pneumol ysin, 133 Poliosis, in staphylococcal blepharitis, 144/, 145 Polydystrophy, pseudo- Hurler, 312 Polyhexamethylene biguanide, fo r Acanthamoeba infection , 169 Polymegethism, specular photomicroscopy in evaluation of, 32
504 • Index Polymorphic amyloid degeneration, 338, 339/ Polymorphous dystrophy, posterior, 2681, 2701, 293-295,294/ genetics of, 2691, 293 Polyneuropathy, familial amyloidotic type IV (gclsolintype lattice corneal dystrophy), 2681, 2701, 280, 280f, 317t,319 genetics of, 269t, 280, 3171 Pork tapeworm (Taenia solium), 142 .porphyria/ porphyria cutanea tarda, 326 Port-wine stain (nevus flammeus), 241 Posaconazole, for fungal keratitis, 166 Positive staining (fluorescein), 17 Posterior amorphous corneal dystrophy, 2681, 270t, 288-289,288/ genetics of, 2691, 288 Posterior collagenous layer (retrocorneal fibrous membrane),29 Posterior embryotoxon, 255, 256f, 2611 in Axenfcld-Rieger syndrome, 256 Posterior polymorphous corneal dystrophy, 268t, 2701, 293-295,294/ genetics of, 2691, 293 Postherpetic neuralgia, 121-122 Postoperati ve care of ophthalmic surgery patient corneosderallaceration repair and, 381-382 Descemet stripping automated endothelial keratoplasty and, 415t, 442-445, 442f, 443f, 444/ lamellar keratoplasty and, 436-437 penetrating keratoplasty and, 421-426 in children, 430-431 Power (optical), refractive, of cornea, 37-38 keratometry in measurement of, 38-39 Power maps, 40-43, 4 If, 42/ keratorefractive surgery and, 44 Poxviruses/poxvirus infection, 127- 128 PPCD/PPCDI. See Posterior polymorphous corneal dystrophy PPMD. See Posterior polymorphous corneal dystrophy Prealbumin. See Transthyretin Pre-Descemet corneal dystrophy, 268t, 2701, 290, 290/ genetics of, 2691, 290 Prednisolone for corneal graft rejection, 429 for stromal keratitis, 115-116 Prednisone for hyphema, 368 for Stevens- Johnson syndrome, 197 Pregnancy gonococcal infection during, ophthalmia neonatorum and, 153 herpes simplex virus infection during, 106 pemphigoid during, 2051 rubella during, 130 Preoperative assessment/preparation for ocular surgery corneal transplantation and, 414-417 perforating injury repair and, 374-375 Preseptal cellulitis, Haemophilus causing, 150 Preservatives in contact lens solutions al lergic/sensitivity reactions and, n giant papillary conjunctivitis and, 195
in ocular medications allergic/adverse reactions to, 183 demulcents, 58- 59 persistent corneal defects caused by {toxic ulcerative keratopathy}, 86 toxic keratoconjunctivitis caused by, 359, 360 Preventive medicine, ophthalmology practices and, 45- 46 Primary acquired melanosis (PAM), 237-238, 237f, 238t melanoma arising from, 239 Primary endothelial failure, 422, 422J after Descemet stripping automated endothelial keratoplasty, 444-445 Prions/prion diseases, 143 PRK. See Photorefractive keratectomy PRNG. See Penicillin-resistant N gOllorrlweae Progressive facial hemiatrophy, 324t Prokaryotes/prokaryotic cells, 131. See also Bacteria Propamidine, for AcantlJal110eba keratitis, 169 Propionibacterium/ Propionibacterium acnes, 134- 135,
135/ as normal ocular flora, 97, 97t, 134 ocular infection caused by. 135 Proptosis, exposure keratopathy and, 80, 385 Prostaglandins, 1791 Proteases corneal, as inflammatory mediators, 177t microbial, in ocular infections, 99 Protein AF, 316 Protein AP, 316 Proteinaceous degeneration, 334-335, 335f See also Spheroidal degeneration Proteins, disorders of metabolism of, corneal changes in, 316- 319 Proteoglycans corneal,7 scleral,9 Proteus, 135 Protozoa/protozoal infection, ocular, 140- 141 Acanthamoeba keratitis, 167- 169, 168/ Proximal illumination, for slit-lamp biomicroscopy, 14 Pseudocryptophthalmos, 2-19, 250 Pseudoepitheliomatous hyperplasia, 226t Pseudoguttae, inflammatory, 25, 30 Pseudo -Hurler polydystrophy, 312 Pseudomembrane, 201, 221 in epidemic keratoconjunctivitis, 124 in ligneous conjunctivitis, 192, 192/ Pseudomonas aeruginosa , 135, 136/ ocular infectionlinflammation caused by, 135 keratitis, 159, 160/ Pseudopemphigoid, 199,361 Pseudophakic bullous edema/ keratopathy, after cataract surgery, 384- 385 Psychotropic drugs, tear production affected by, 661 Pterygium, 332, 332f, 391 conjunctival transplantation for, 392f, 393, 393- 395 excision of, 391 - 393, 392J bacterial scleritis after, 171, 171/ recurrent, after conjunctival autograft, 394- 395 subconjunctival hemorrhage caused by, 76t PTK. See Phototherapeutic keratectomy
Ind ex . 505 Ptosis (blepharoptosis), mechanical, 21 Pubic louse (Phlhirus pubis), 142, 142f ocular infection caused by, 142, 149 Public health ophthalmology, 104 PUK. See Peripheral keratitis, ulcerative Punctalocclusion for cicatricial pemphigoid, 203 for dry eye, 601, 6\-62, 61f, 62/ Punctal plugs for cicatricial pemphigoid, 203 for dry eye, 60t, 6\-62, 62f Punctate epithelial defects/erosions conjunctival, 20t corneal, 201, 25, 26f, 27t in vernal keratoconjunctivitis, 187 Punctate epithelial keratitis/ keratopathy, 201, 25, 26j, 271
exposure causing, 80 herpes simplex causing, 110 microsporidial, 170 staphylococcal blepharitis/blepharoconjunctivitis and, 145, 146f, 147 superficial Thygeson, 204 - 207, 206/ topical anesthetic abuse causing, 90 Punctate staining patterns (f1uorescein), 17, 18f Pupillar>' 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
510 • Index TEN . See Toxic epidermal necrolysis Terrien marginal degeneration, 339- 340, 340j Tetracyclines for chemical injuries, 358 for chlamydial conjunctivitis, 157 for meibomian gland dysfunction, 68 for persistent corneal defects/neurotrophic keratopathy, 86, 88 for recurrent corneal erosions, 84 for rosacea, 69-70 for trachoma, 156 TGF-ps. See Transforming growth factor ps TGFBl gene, corneal d ystrophies associated with, 268t, 269t epithelial basement membrane, 269t, 270 granular type 1,281 granular type 2, 2691, 282 lattice, 269t, 278 Reis-Biicklers, 269t, 276 stromal, 278- 282, 27St Thiel-Behnke, 269t, 277 Therapeutic contact lenses. See Bandage contact lenses Thermal cautery, for punctal occlusion, 61, 6 If, 62 Thermal injury (burns), anterior segment, 351 -352 Thiel-Behnke corneal dystrophy, 2681, 270t, 277- 278, 278f genetics of, 2691, 277 Thimerosal, allergic/ sensitivity/ toxic reactions and, 92,
360 Thygeson superficial punctate keratitis, 204 - 207, 206f ThyrOid eye disease, superior limbic keratoconjunctivitis and, 81-82, 82f Tibia bone tissue keratoprosthesis, 432 Ticks, Lyme disease transmitted by, 137 Tight junctions, in corneal epithelium, 6 Tissue adhesives cyanoacrylate, 403 - 404. See also Cyanoacrylate adhesives fibrin , for corneal autograft fixation, 394 TKPro. See Tibia bone tissue keratoprosthesis TNF. See Tumor necrosis factor Tobramycin, for bacterial keratitis, 162t Togaviruses, 129 Tolerance (immunologic), corneal transplantation and, 175,408 Tonometry (tonometer) corneal thickness affecting, 30 infection control and, 46 Topography, corneal, 36- 45. See also Cornea, topography of scanning-slit, 34, 34f Toxic conjunctivitis/keratoconjunctivitis contact lens solutions causing, 92 medications causing, 359- 361, 359t, 361f Toxic epidermal necrolysis, 196, 196r Toxic keratitis, 360. See a/50 Toxic conjunctivitis/ keratoconjunctivitis Toxic ulcerative keratopathy, 86, 88 Toxocara canis/cati (toxocariasis), 142 Toxoplasma gOlldii (toxoplasmosis), 141 Trachipleistophora, 141 Trachoma, 154- 156, 155f, 156f Tranexamic acid, for hyphema, 368
Transendothelial osmotic force, 8 Transforming growth factor ~ - induced gene. See TGFBI gene Transforming growth factor ~ - induced (TGFBI) keratoepithelin, in Reis-Biicklers corneal dystrophy, 276 Transforming gro\\1h fac tor ~s , 177t in Sjogren syndrome, 63 Transit amplification, in stem cell differentiation, 93 Transitional zone (peripheral zone), 37, 37f Transplant rejection. See Rejection Transplantation amniotic membrane, 389 for chemical injuries, 358 indications for, 387t conjunctival, 392f, 393 - 395 for chemical injuries, 358 indications for, 387t, 395 for wound closure after pterygium excision, 392f, 393,393- 395 corneal, 407- 411, 413- 445. See also Donor cornea; Keratoplasty autograft procedures for, 413, 431 - 432 basic concepts of, 407- 411 for chemical injuries, 358 clinical approach to, 413- 445 comparison of procedures for, 415- 4161 donor selection and, 408- 411 , 410t eye banking and, 408- 411 , 4 10t histocompatibility antigens and, 407 immune privilege and, 175,407- 408 immunobiology of, 407- 408 lamellar keratoplasty for, 413, 433- 437, 43'if pediatric, 430- 431 , 43lt penetrating keratoplasty for, 413, 415- 416t , 417- 430 preoperative evaluation/ preparation and, 414- 417 rabies virus transmission and, 130 rejection and, 407, 408, 42 7- 430, 428f, 429f, 436. See also Rejection histocompatibility antigens and, 407 immune privilege and, 174 - 175,407-408 immunobiology of, 407- 408 limbal, 94, 389, 395- 398, 396- 397f for chemical injuries, 94, 358 indications for, 387t mucous membrane, 389 indications for, 387t rejection and. See Rejection Transplantation antigens, 407 Transthyretin (prealbumin), amyloidosis and, 317t, 319 Trauma. See a/50 under Traumatic animal and plant substances causing, 361 - 362 anterior segment, 351 - 385 chemical injuries, 353- 359, 353t, 354f, 356t, 357/ concussive, 362- 369, 364f, 365f, 366f, 367f, 369t corneal blood staining and, 366- 367, 367f nonperforaling mechanical, 369- 372, 370f, 371f ocular infection and, 99 perforating. See Perforating injuries spheroidal degeneration and, 335 subconjunctival hemorrhage caused by, 76t, 362- 363 surgical, 382~385 , 384f
Index. 511 temperature and radiation causing, 351-353 toxic reactions to medications and, 359-361, 3591, 361/ Traumatic corneal endothelial rings, 363 Traumatic hyphema , 365-369, 365f, 366f. 367f, 3691 medical management of, 367-368 rebleeding after, 365-367, 367/ sickle cell disease and, 369 surgery for, 368, 369t Traumatic iritis, 363 Traumatic miosis, 363 Trau matic mydriasis. 363 Traumatic posterior annular keratopathy, 363 Treacher Collins syndrome, 324t Tree sap, ocular injuries caused by. 362 "I'reph in ation/treph i nes for deep anter ior lamellar keratoplasty, 436 for penetrating keratoplasty, 417, 418 for superficial anterior lamellar keratoplasty. 435 Treponema pailidllm, \37
Trial contact lens fitting, disinfection and, 46 Triamcinolone for chalazion, 73 fo r corneal graft rejection, 429 fo r vernal keratoconjunctivitis, 189 Triazoles, for Acamlwmoeba keratitis, 169 Trichiasis, 89 in staphylococcal blepharitis, 145 Tritluridine, for herpes simplex virLlS infections, 1091 epithelial keratitis, 112 st romal keratitis, 108t , 115 Tryptase,1 79t TSCM . See Tandem scanning confocal microscopy TTR, See Transthyretin Tumor-associated calcium signal transducer 2 (TACSTD2) gene, in gelatinous droplike corneal dystrophy, 2691, 274 Tumor necrosis factor- Cl, 177, 177t in cicatricial pemphigoid, 199 in Sjogren synd rome, 63 Tumor necrosi s factor inhibitors, for scleritis, 222 Tumors, ocular surface, 225- 247. See also specific Iype and structure or organ affected of epithelial origin, 226-233, 2261 of neuroectodermal origin, 233-240, 234t Tyrosine aminotransferase, defective, 315 Tyrosinemia, 314-315. 3 14t Tyrosinuria, 315 UbiA prenyltransferase domain-containing protein I (UBlADl ), in Schnyder corneal dystrophy, 269/, 284 Ulcerative keratitis peripheral, 211-213, 211 t, 212/, 339 differential diagnosis of, 211 1 in systemic immune-mediated di seases, 211- 213, 2 11 t,212/
in rosacea, 70 Ulcerative keratopathy, toxic, 86, 88 Ulcers conjunctival,22t corneaL See Cornealulcersi Kerat itis eyelid,201 ~ooren,2 1 3-216,2 1 5f
neurotrophic, herpetic keratitis and, 87, 88, 117
Ultrasonography/ult rasound (echography) anterior segment (u ltrasound biomicroscopy), 33, 33/ before corneal transplantation, 417 high-resolution, in corneal imaging, 29 fo r pachometry. 28 Ultrasound biomicroscopy, 33, 33/ before corn ea l transplantation, 4 17 Ultraviolet light (u lt raviolet radiation), eye disordersl injury associated with anterior segment inj ury, 352 conjunctival intraepithelialneopiasia , 228 pinguecula, 331-332 pterygium, 332 spheroi dal degeneration (Labrador keratopathy), 334-335,335/ Universal precautions, 45-46 Urinalysis, in immune-med iated disease, 1821 Urticating hairs, ocu lar inflam mation caused by, 362 Uveitis Lyme, 137 sarcoidosis and, 74 scleritis and, 220, 220-221 Uveoparotid fever (Heerfordt syndrome), 73 Vaccinialvaccin ia infection, 128 Vaccinia-immune globulin, 128 Valacyclovir for herpes simplex virus infection s, 1091 epithelial keratitis, 113 stromal keratitis, 115 for herpes zoster, 121 Vancomycin, for bacterial keratitis, 1621 Varicella (chickenpox), 117, 118 Varicella-zoster virus immunization against, 11 9, 121 ocular infection caused by, 117-122, 118t, 119f, 120f, 12If herpes simplex virus infection differentiated from, 1181 Vascular endothelial growth factor (VEGF), 177t Vasc ular tu fts, papillary conjunctivitis causing, 22, 22f, 23/ Vascular tumors, of eyelid and conjunctiva, 240-242, 2411 benign, 240-241 inflammatory, 24 1-242, 241/ malignant, 242, 243/ Vasoactive amines, 1771 Vasoconstrictors, for allergic conjunctivitis, 186 Vegetation/plants, ocular inj uries caused by, 362 corneal foreign body, 37 1 VEG F. See Vascu lar endothel ial growth factor Venomous insect stings, ocular injury!i nfection caused by, 361 -362 Vernal keratoconjunctivitis, 187- 190, 188f, 189/ atopic keratoconjunctivitis differentiated from, 190, 191/ Verrucae (warts), papillomavirus causing, 128, 129 Vesicle of eyelid, 20t optic, 4 Vidarabin e, for herpes simplex virus infections, 109t Videokeratography, in keratoconus, 299, 300/
512 • Index Videokeratoscopy, 39, 39/ in keratoconus, 298 tear breakup evaluated with, 53 Videophotography, 31 VIG. See Vaccinia-immune globulin Viral capsid, 104 Virology, 104- \30. See also Viruses Virulence (microbial), 98- 99 Viruses, 104. See also specific organism or type of
infectioll ocular infectionlinOammation caused by, 104- 130 adherence and. 98 invasion and, 99 isolation techniques for diagnosis of, 103 specimen collection for diagnosis of, 101 t Sjogren-like syndromes caused by, 63 Visceral larva migrans, 142 Viscoeiastics, for penetrating keratoplasty, 418 Visual acuity, testing, 11 after perforating injury, 374, 382 Vitamin A for cicatricial pemphigoid, 202 deficiency of, 77- 79, 77 t, 78! Corynebacterium xerosis and, 134 metabolism of, 771 Vitamin C (ascorbic acid) fo r chemical injuries, 79, 358 deficiency of (scurvy), 79 Vitreocorneal adherence, after cataract surgery, 384 Vittajorma/\filfajorI1UJ cornetle, 14 1, 170 VKC. See Vernal keratoconjunctivitis Vogt palisades of, 5 white limbal girdle of, 336 Vogt lines, in keratoconus, 298 von Hippcl internal corneal ulcer, intrauterine inflammation and, 263 - 264 Voriconazole, for fungal keratitis, 166 Vortex (hurricane) keratopathy (cornea verticillata), 310, 31 If, 346- 348, 347t, 3481, 360 Waardenburg- Jonkers corneal dystrophy_ See ThielBehnke corneal d )fstrophy \Vaite-Beetham lines, 30, 308 \Valdenstr6m macroglobulinemia, corneal deposits in, 320 Warts (verruca), papillomavirus causing, 128, 129
Wasp stings, ocular injury caused by, 361-362 Wavefront analysis, dr y eye and, 55 \'Verner syndrome, 324t \Vessely immune ring, 181 \Vhite limbal girdle, 336 \"lhite ring, Coats, 334, 335/ Wilson disease (hepatolenticular degeneration), 327- 328,327/ cataracts associated with, 327 Wound healing/ repair of conjunctiva, 388 of cornea, 387 - 388 ocuiar surface response to, 388- 389 promotion of in chemical injuries, 358 \Vound leaks, after penetrating keratoplasty, 421 X-linked disorders Fabry disease, 305, 310 Hunter syndrome, 305, 306t ichthyosis, 74 Lisch corneal dystrophy, 273 megalocornea, 253- 254, 254/ Xanthelasma, in dyslipoproteinemial hyperlipoproteinemia, 308, 3091 Xanthogranuloma juvenile, 242 necrobiotic, 242 Xanthomas, fibrous (fibrous histiocytoma), 242 Xeroderma pigmentosum, 75 Xerophthalmia, 77-78, 79 Xerophthalmic fundus, 78 Xerosis Corynebacterium xerosis and, 134 in vitamin A deficienc)" 77, 78,134 in vitamin C deficiency, 79 XP. See Xeroderma pigmentosum Yeasts, 138, 138t, 139, 139J keratitis caused by, 166 as normal ocular flora, 97t z-heightlz-maps,42 ZEBl gene, in posterior polymorphous corneal dystrophy, 269t Zeis, glands of, 4, 5/ chalazion caused by obstruction of, 72 Zoster. See Herpes zoster
