7 Cornea / External Disease
Anatomy / Physiology
Conjunctiva
Nonkeratinized stratified columnar epithelium with goblet cells (most numerous in fornices) underlying loose stromal tissue (substantia propria)
Plica semilunaris
narrow fold of medial bulbar conjunctiva near caruncle; rudimentary structure analogous to nictitating membrane in certain animals
Precorneal Tear Film
Layers
Cornea (Figure 7-1)
Average measurements
Epithelium
50 µm thick (5% of corneal thickness); hydrophobic (hydrophilic molecules penetrate poorly)
Basal lamina
scaffold for epithelium; adjacent to Bowman’s membrane; composed of type IV collagen secreted by basal epithelium (use PAS stain)
Bowman’s membrane
10 µm thick; type I collagen enmeshed in GAG matrix, rich in fibronectin, acellular; formed from secretion from both basal epithelial cells and stromal keratocytes
Stroma
480 µm thick centrally, 900 µm peripherally; 78% water by weight
Descemet’s membrane
3 (birth) to 12 µm (adults) thick; PAS-positive basement membrane
Figure 7-2 Hydrops demonstrating corneal edema (thickening) with breaks in Descemet’s membrane.
(From Yanoff M, Fine BS: Ocular Pathology, 5th edn, St Louis, Mosby, 2002.)
Endothelium
Example: diabetes (buildup of sorbitol in endothelial cells with hyperglycemia); contact lens (inhibits Na+/K+ pump and cells swell); earliest endothelial change (endothelial bleb response) occurs within minutes of insertion of a thick, soft or rigid contact lens (resolves rapidly after lens removal or slowly after 30 minutes of lens wear)
Stains
OF CORNEA: lagophthalmos / exposureConjunctival Disorders
Inflammation
Follicles
Gray-white round elevations with avascular center and vessels at periphery
Well-circumscribed focus of lymphoid hypertrophy (lymphocytes with a germinal center) due to reactive hyperplasia
Generally most prominent in inferior fornix (except in trachoma)
Papillae
Small to large elevations with central vascular tuft and pale avascular valleys
Epithelial proliferation, hypertrophy, and infoldings; hyperplasia of vascular stroma with chronic inflammatory cells
Nonspecific reaction to conjunctival inflammation (edema and leakage of fluid from vessels)
Subepithelial substantia propria of tarsal and limbal conjunctivae contains fibrous tissue septa that interconnect to form polygonal lobules with a central vascular bundle
Chemosis
Conjunctival edema; may be caused by allergy or infection, can occur after eyelid surgery or be idiopathic
Phlyctenule
Usually unilateral; more common in children
Etiology
type IV hypersensitivity reaction to Staphylococci, coccidioidomycosis, Candida, HSV, lymphogranuloma venereum (LGV), TB
Findings
round, elevated, focal, sterile infiltrate on bulbar conjunctiva, limbus, or cornea; overlying epithelium breaks down (stains with fluorescein); may have corneal vascularization
Degenerations
Amyloidosis
Yellow-salmon, subepithelial, interpalpebral plaque in primary localized disease
Systemic amyloidosis is not associated with conjunctival amyloid but is associated with amyloid of lid
Concretions (Lithiasis)
Small, round, yellow-white deposits in palpebral conjunctiva
May erode through conjunctiva and abrade ocular surface causing foreign body sensation
Conjunctivochalasis
Redundant, loose, nonedematous inferior bulbar conjunctiva interposed between globe and lower eyelid
Due to elastoid degeneration, possible mechanical factor from dry eye or blepharitis (lid rubbing, dry conjunctiva)
Pingueculum
Small nodule composed of abnormal subepithelial collagen; may calcify
Located at limbus, nasal more common than temporal; does not involve cornea
Caused by actinic (UV light) exposure
Pterygium
Interpalpebral, wing-shaped, fibrovascular tissue that invades cornea
Associated with actinic exposure
Findings
Stocker’s line (corneal iron line at head of pterygium); may induce astigmatism with flattening in meridian of pterygium; may decrease vision if crosses visual axis
Pathology
elastoid degeneration with destruction of Bowman’s membrane; may have epithelial dysplasia; in recurrences after excision may have fibrotic response not elastoid degeneration
Conjunctival Telangiectasia
Associated with Louis-Barr syndrome (ataxia telangiectasia), Osler-Weber-Rendu (hereditary telangiectasia), Sturge-Weber syndrome, diabetes, sickle cell disease, Fabry’s disease, increased orbital pressure (C-C fistula), blood-filled lymphatic tissue, irradiation
Allergy
Type I hypersensitivity reaction
airborne allergens (pollen, mold, dander) cross link IgE receptors on mast cells causing degranulation with release of histamine, eosinophil chemotactic factors, platelet-activating factor, major basic protein, and prostaglandin D2
Treatment
topical antihistamine (emedastine [Emadine], levocabastine [Livostin]), mast cell stabilizer (pemirolast [Alamast], nedocromil [Alocril], lodoxamide [Alomide], cromolyn sodium [Crolom]), antihistamine / mast cell stabilizer combination (azelastine [Optivar], olopatadine [Patanol, Pataday], ketotifen [Zaditor, Alaway], epinastine [Elestat], bepotastine [Bepreve], alcaftadine [Lastacaft]), NSAID (ketorolac [Acular]), steroid, artificial tears, cold compresses
Allergic Conjunctivitis
20% of the US population has allergies
90% of patients with systemic allergies will have ocular symptoms
Most commonly seasonal or perennial allergic conjunctivitis
Associated with allergic rhinitis
Giant Papillary Conjunctivitis
Etiology
allergic reaction to material coating a foreign body (e.g. contact lens [CL], exposed suture, ocular prosthesis); true giant papillae also occur in vernal and atopic keratoconjunctivitis
Atopic Keratoconjunctivitis (AKC)
Atopy
hereditary allergic hypersensitivity (10–20% of population)
Types I < IV hypersensitivity reactions
Onset usually between ages 30 and 50 years
Clinical diagnosis (atopic skin disease [eczema], hay fever, asthma)
Findings
atopic dermatitis of eyelids (may have blepharitis, madarosis [loss of lashes], punctal ectropion), papillary conjunctivitis (small or medium-sized papillae in inferior fornix); may develop symblepharon, corneal vascularization, and scarring
Associated with keratoconus (10%), subcapsular cataracts (Maltese cross pattern), bilateral HSV keratitis, pellucid marginal degeneration
Superior Limbic Keratoconjunctivitis (SLK)
Recurrent inflammation of superior bulbar and palpebral conjunctiva; unknown etiology
Associated with CL wear and thyroid dysfunction (50%)
Female preponderance (70%), onset usually between ages 30 and 55 years
Recurrent episodes; lasts 1–10 years, eventually resolves permanently
70% bilateral; symptoms worse than signs
Findings
conjunctival injection, thickening, redundancy of superior bulbar conjunctiva with fine punctate staining (rose bengal), velvety papillary hypertrophy of upper palpebral conjunctiva, micropannus, filamentary keratitis (50%), decreased Schirmer’s test (25%)
Conjunctivitis Associated with Systemic Diseases
Mucocutaneous disorders
Stevens-Johnson syndrome, ocular cicatricial pemphigoid (OCP), bullous pemphigoid, pemphigus, epidermolysis bullosa, dermatitis herpetiformis, arthropathies (Reiter’s syndrome, psoriatic arthritis), infections (Parinaud’s oculoglandular syndrome, Kawasaki’s disease), Wegener’s granulomatosis
Infectious Conjunctivitis
May be hyperacute, acute, or chronic
Usually viral in adults and bacterial in children
Findings
papillae, follicles, conjunctival injection, chemosis, discharge; may have preauricular lymphadenopathy, lid swelling, membranes, keratitis, corneal infiltrates, AC reaction
DDx of conjunctivitis with preauricular lymphadenopathy
EKC, HSV, Gonococcus, Chlamydia, Parinaud’s oculoglandular syndrome, Newcastle’s disease
DDx of acute follicular conjunctivitis
EKC, PCF, chlamydial, primary HSV, medicamentosa (antivirals, atropine, Propine, apraclonidine [Iopidine], brimonidine [Alphagan], neomycin), viral lid infections (verruca, molluscum), Newcastle’s disease, acute hemorrhagic (enteroviral) conjunctivitis
Viral
Adenovirus
Most common; double-stranded DNA; primary infection provides lifelong immunity; 51 stereotypes, 1/3 associated with ocular infection
Findings
initially diffuse epithelial keratitis with normal vision; later, focal epithelial keratitis, coalescence of fine spots that become subepithelial infiltrates
Epidemic keratoconjunctivitis (EKC)
adenovirus types 8, 19 and 37; bilateral in 75% to 90%
Newcastle’s Disease
Unilateral follicular conjunctivitis, pneumonitis, preauricular lymphadenopathy
Occurs in poultry handlers; self-limited, lasts 1 week
Bacterial
Hyperacute (<24 hours)
Copious purulent discharge, marked conjunctival injection and chemosis
Neisseria gonorrheae
preauricular lymphadenopathy, corneal infiltrates; can penetrate intact corneal epithelium; can perforate within 48 hours
Acute (hours to days)
Purulent discharge, not as severe as hyperacute
Streptococcus pneumoniae, Staphylococcus, Haemophilus influenzae, Pseudomonas
Chlamydial
Inclusion Conjunctivitis (TRIC – Trachoma Inclusion Conjunctivitis)
Chlamydia trachomatis serovars D to K
Chronic, follicular conjunctivitis
Associated with urethritis (5%)
Trachoma
Bilateral keratoconjunctivitis; leading cause of preventable blindness
Chlamydia trachomatis serovars A to C
Findings (progressive)
bilateral infection of upper tarsal and superior bulbar conjunctiva, papillary reaction, conjunctival follicles, repeated infections, conjunctival scarring (Arlt’s line), tarsal shortening, entropion, trichiasis, corneal abrasion, superior corneal pannus, corneal scarring, cicatrized limbal follicles (Herbert’s pits)
Classification
Pathology
epithelial cells contain initial bodies (basophilic intracytoplasmic inclusions of Halberstaedter and Prowazek); Leber’s cells (macrophages in conjunctival stroma with phagocytosed debris)
Other Conjunctivitis
Parinaud’s Oculoglandular Syndrome
Monocular granulomatous conjunctivitis, with necrosis and ulceration of follicles; fever, malaise, lymphadenopathy; may have rash
DDx
cat-scratch disease (Bartonella henselae), tularemia, sporotrichosis, TB, syphilis, LGV, Actinomyces, mononucleosis, Rickettsia, coccidioidomycosis
Reiter’s Syndrome
Triad of urethritis, uveitis, and arthritis; mucopurulent discharge, conjunctivitis in 30%; may have keratoderma blenorrhagicum
Staphylococcal Disease
Blepharitis, conjunctivitis, keratitis (SPK, marginal infiltrates), phlyctenule
Tumors
Hamartoma
growth arising from tissue normally found at that site (e.g. nevus, neurofibroma, neurilemmoma, schwannomma, glioma, hemangioma, hemangiopericytoma, lymphangioma, trichoepithelioma)
Cystic Tumors
Squamous Tumors
Squamous Papilloma
Benign proliferation of conjunctival epithelium, appears as sessile or pedunculated fleshy mass with prominent vascular tufts
Pedunculated
usually caused by HPV, occurs in children, often located near caruncle; frequently recurs after excision; can regress spontaneously
Pathology
vascular cores covered by acanthotic, nonkeratinized, stratified squamous epithelium (Figure 7-4)
Conjunctival Intraepithelial Neoplasia (CIN)
Replacement of conjunctival epithelium by atypical dysplastic squamous cells
Usually transluscent or gelatinous appearance; <10% exhibit leukoplakia (keratinization)
Carcinoma in situ
total replacement of epithelium by malignant cells; BM intact; no invasion into substantia propria; characterized by leukoplakia, thickened epithelium, and abnormal vascularization
Usually begins at limbus and spreads onto cornea
Associated with HPV subtype 16 and 18 (check HIV in young patient), and actinic exposure
Pathology
dysplastic epithelium spreads anterior to Bowman’s membrane, fine vascularity with hairpin configuration (similar to papilloma), anaplastic cells, dyspolarity (Figure 7-5)
Squamous Cell Carcinoma
Malignant cells have broken through epithelial basement membrane
Most common malignant epithelial tumor of conjunctiva; rarely metastasizes
Most common in Africa and Middle East
Appearance similar to carcinoma in situ
Mucoepidermoid Carcinoma
Rare, aggresive variant of squamous cell carcinoma with malignant goblet cells
Typically occurs in individuals >60 years old
Very aggressive, can invade globe through sclera
Suspect in cases of recurrent squamous cell carcinoma
Pathology
epidermoid and mucinous components; stains with mucicarmine, Alcian blue, and colloidal iron
Melanocytic Tumors
Racial Melanosis
Light brown, flat, perilimbal pigmentation; increased melanin in basal epithelium
Most common in pigmented individuals
Nevus
Congenital nests of benign nevus cells along basal epithelial and / or substantia propria
50% have epithelial inclusion cysts
Often enlarges or becomes more pigmented during puberty or pregnancy
Types (classified by location)
Primary Acquired Melanosis (PAM, Acquired Melanosis Oculi)
Unilateral, flat, diffuse, patchy, brown pigmentation; waxes and wanes
Proliferation of intraepithelial melanocytes; no cysts (Figure 7-8)
Figure 7-8 PAM with pigmentation throughout the epithelium.
(From Yanoff M, Fine BS: Ocular Pathology, 5th edn, St Louis, Mosby, 2002.)
Most frequently on bulbar conjunctiva or in fornices, but can occur on palpebral (tarsal) conjunctiva
Analogous to lentigo maligna of skin
Occurs in middle-aged to elderly whites
20–30% risk of malignant transformation, nodular thickening is indication for excisional biopsy
Secondary Acquired Conjunctival Melanosis
Addison’s disease, radiation, pregnancy, topical epinephrine
Malignant Melanoma
Rare, variably pigmented, elevated mass most commonly on bulbar conjunctiva
Arises from PAM (67%) or preexisting nevi (25%), or de novo
Pathology
intraepithelial pagetoid spread; need to bleach specimen to determine amount of atypia (Figure 7-9), stain with S-100 and HMB-45
Treatment
document with photos; complete excision (no touch technique) with clear margins, partial lamellar sclerectomy, and cryotherapy
Prognosis
20% mortality; 25% risk of metastases (regional lymph nodes and brain); more likely to invade sclera than SCC
If more than 2 mm thick, increased risk of metastasis and mortality
Involvement of caruncle, fornices, palpebral conjunctiva has worst prognosis
Better prognosis than cutaneous melanoma
Vascular Tumors
Pyogenic Granuloma
Exuberant proliferation of granulation tissue
Vascular mass with smooth convex surface occurring at site of previous surgery (usually strabismus or chalazion excision)
Kaposi’s Sarcoma
Lymphoid Tumors
(See Ch. 6, Orbit / Lids / Adnexa)
Smooth, flat, fleshy, salmon-colored mass; single or multiple
Occurs in substantia propria; overlying epithelium is smooth; can be bilateral
20% associated with systemic disease (but systemic lymphoma rarely presents in conjunctiva)
Spectrum of disease from benign to malignant; cannot distinguish clinically; requires immunohistochemical studies (fresh, unfixed tissue specimen)
Requires systemic workup, including CT scan, bone scan, SPEP, medical consultation
Other Tumors
Fibrous Histiocytoma
Yellow-white mass composed of fibroblasts and histiocytes
Extends from limbus to peripheral cornea
Benign Hereditary Intraepithelial Dyskeratosis (BHID) (AD)
Originally seen in triracial families in Halifax County, North Carolina (Haliwa Indians)
Usually presents in 1st decade of life
Findings
bilateral dyskeratotic lesions (plaques with gelatinous base and keratinized surface) involving bulbar conjunctiva near limbus; may have similar plaques on buccal mucosa or oropharynx
Pseudoepitheliomatous Hyperplasia
Benign proliferation of conjunctiva onto corneal epithelium
Usually occurs away from limbus (in contrast to squamous hyperplasia or carcinoma)
Pathology
thickened squamous epithelium; occasional mitotic figures; no atypia; no clear demarcation between normal and abnormal cells
Corneal Disorders
Trauma
Abrasion
Epithelial defect, most commonly traumatic (e.g. fingernail, plant branch)
Increased risk of infection, especially in contact lens wearer
Findings
epithelial defect stains with fluorescein, conjunctival injection, ciliary flush; may have mild AC reaction
Foreign Body (FB)
Often metal (usually associated with adjacent rust ring), glass, or organic material
Laceration
Partial- or full-thickness cut in cornea
Requires surgical repair and topical antibiotic and steroid
Complications include scarring and irregular astigmatism, which if affect vision, may be treated with rigid contact lens or keratoplasty
Recurrent Erosion
Associated with anterior basement membrane dystrophy (ABMD) in 50% or previous corneal abrasion; also occurs in other corneal dystrophies
Abnormal adhesion of epithelium to Bowman’s membrane allows spontaneous sloughing
Symptoms usually occur in morning upon awakening (epithelium swells 4% overnight, and mechanical force of lids rubbing across corneal surface when open eyes or blink can dislodge epithelium)
Duration of symptoms depends on size of erosion
Findings
epithelial defect (may be partially healed), conjunctival injection; may have mild AC reaction and signs of corneal dystrophy (i.e. ABMD with irregular epithelium, areas of negative stain)
Treatment
lubrication, hypertonic saline (Muro 128 5% ointment qhs × 3-12 months); if recurs, consider bandage contact lens, epithelial débridement, anterior stromal puncture / reinforcement, diamond burr (débride and polish Bowman’s membrane), laser (phototherapeutic keratectomy [PTK] with excimer laser, or micropuncture with Nd : YAG laser (1 mJ, aim just below epithelium)); also, consider treatment with matrix metalloproteinase-9 inhibitors (doxycycline 50 mg PO bid × 2 months and topical steroids tid × 2-3 weeks); débridement for subepithelial scarring
Burns
Alkali
denatures but does not precipitate proteins, also saponifies fat; therefore penetrates deeply
Radiation
thermal burn (similar to acid burn)
Grading systems
of limbus; good prognosis, some scarring
to 
of limbus; guarded prognosis
of limbus; poor prognosis, risk of perforationTreatment
Ocular Surface Disease
Causes tear film disturbance and dry eye
Due to deficiency in tear film component(s)
Aqueous Deficiency
Lacrimal gland dysfunction (aplasia, surgical removal), infiltration (sarcoidosis, thyroid disease, lymphoma, amyloidosis, TB), inflammation (mumps, Sjögren’s syndrome), denervation (Riley-Day [familial dysautonomia], Shy-Drager [adult dysautonomia, idiopathic autonomic dysfunction], Möbius’ syndrome), drugs that decrease lacrimal secretion (antihistamines, diuretics, anticholinergics, psychotropics)
Keratoconjunctivitis Sicca
Adult women (95%), often associated with Sjögren’s syndrome
Symptoms
burning, dryness, foreign body sensation, tearing; worse later in day, with prolonged use of eye, and in dry or windy environments
Findings
decreased tear meniscus height (normal = 0.5 mm), decreased tear breakup time (<10 seconds), increased mucus, filaments in severe cases, interpalpebral corneal and conjunctival staining with rose bengal / lissamine green or fluorescein, Schirmer’s test (<10 mm/5 min), increased tear osmolarity (>311 mOsm), Phenol red thread test (<9 mm/15 seconds)
Treatment
lubrication with artificial tears and ointments, punctal occlusion, humidifier, moisture chamber goggles; consider acetylcysteine (Mucomyst) or bandage contact lens for filaments; topical cyclosporine (Restasis)
Mucin Deficiency
Goblet cell dysfunction due to conjunctival scarring and keratinization (vitamin A deficiency, OCP, Stevens-Johnson syndrome, alkali burns, trachoma, GVH disease); impression cytology measures number of goblet cells
Xerophthalmia
Epithelial keratinization due to vitamin A deficiency
Vitamin A required for conjunctival goblet cell mucin production, corneal stromal metabolism, retinal photoreceptor metabolism, normal iron metabolism, normal growth, resistance to measles
Incidence 5 million new cases / year; affects 20-40 million children worldwide
Usually in developing countries (50% in India); in developed countries, due to lipid malabsorption (short bowel syndrome, chronic liver dysfunction, cystic fibrosis) and poor diet (chronic alcoholism)
Findings
night blindness (nyctalopia), conjunctival xerosis (leathery appearance) and Bitot’s spots (gray foamy plaques), corneal xerosis with keratomalacia, ulceration, and scarring, xerophthalmic fundus (fine white mottling)
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