104 CORNEA AND CONJUNCTIVA

PROMINENT CORNEAL NERVES (Mnemonic: LMNR2A): leprosy, MEN IIb (pheochromocytoma, medullary thyroid CA, conjunctival and mucosal neuromas), NF, Refsum’s disease, Riley-Day syndrome, and Acanthamoeba

More visible nerves: keratoconus, ichthyosis, Fuchs’ corneal dystrophy, corneal edema, congenital glaucoma

PUNCTATE EPITHELIAL EROSIONS (PEE) Dry eye, atopic KC, and topical toxicity

PUNCTATE EPITHELIAL KERATITIS (PEK) HSV, adenovirus, and Thygeson’s superficial punctate keratitis

RING CORNEAL INFILTRATE Acanthamoeba, HSV, Pseudomonas, topical anesthetic abuse, and Moraxella

STROMAL SCARRING HSV (by far the most common), HZV, and syphilis

SUBCONJUNCTIVAL HEMORRHAGE, BLOODY TEARS Trauma, conjunctivitis, Valsalva’s maneuver, febrile illness, vascular fragility, clotting disorder, and thrombocytopenia

SYMBLEPHARON (Mnemonic: ACID STORE): Atopic KC, chemical burns (especially alkali), inflammation of any type, drugs, SJS, trauma, OCP, radiation, EKC

VASCULAR CAUSES OF A RED EYE Lymphangioma, orbital varices, and hemangioma

VERTICILLATE, WHORL-LIKE CORNEAL EPITHELIAL OPACITY (Mnemonic: FIT CAP): Fabry’s disease, indomethacin or Naprosyn, tamoxifen, chloroquine, amiodarone (vortex keratopathy; may also cause anterior ischemic optic neuropathy or striate melanokeratosis), and phenothiazines. Whorl appearance is due to the pattern of epithelium migration from the limbus.

WHITE, LEUKOPLAKIC LESIONS OF CONJUNCTIVA Associated with SCC, CIN, Bitot’s spots, benign hereditary intraepithelial dyskeratosis (BHID), papilloma, amyloid, pinguecula, and amelanotic nevus or melanoma

Exam and Imaging

SCHIRMER’S TESTING Schirmer’s I—nonanesthetic; Schirmer’s II— anesthetic plus irritate the nasal mucosa

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SPECULAR MICROSCOPY Mean endothelial cell count 2400/mm2, coefficient of variation <0.3 (smaller indicates more uniform cells), pleomorphism <50% (cells that are not the normal hexagonal shape)

Polymegatheism caused by: CLW (causes release of arachidonic acid via the cP450 system, which is changed into hydroxyeicosatetraenoic acid [HETE], which in turn changes the cell cytoskeleton and increases endothelial cell size), inflammation, diabetes, and LASIK.

TOPOGRAPHY

Placido’s ring topography (conventional): usually gives axial topography, which is the average of all points compared with the center of the corneal radius of curvature, and thus smooths over localized defects

Tangential topography: compares one point to adjacent point and thus shows local defects more accurately.

Scanning slit topography (i.e., Orbscan): looks at light scatter from the cornea like a slit lamp. Based on the elevation of the corneal surface, not the radius of curvature. Determines the ‘‘best fit sphere’’ for the entire cornea, then maps if any areas are elevated above this ideal sphere (warm color) or are below the best fit (cool color). Standard four-frame printout shows: upper left—anterior surface elevation; upper right—endothelial surface elevation; bottom right—thickness (anterior minus posterior surface height); bottom left—standard keratometric topography. Posterior float >50 mm is suggestive of keratoconus if associated with corneal thinning.

Congenital and Genetic Disease

ANIRIDIA Central corneal vascularization and clouding after age 2 from limbal stem cell deficiency. Poor visual prognosis with limbal transplants or penetrating keratoplasty (PK). See Chapter 9.

CORNEA PLANA Small, thin, flat corneas (similar radius of curvature as sclera: keratometry measurements are <42, usually 20–30 D), diameter about 9 mm; cornea looks like dense arcus. Associated with, hyperopia, early cataract, and angle-closure glaucoma (ACG). Patients usually of Finnish descent. An autosomal recessive abnormality of chromosome 12q21 causes defective keratan sulfate (part of the ground substance of normal stroma). May also be autosomal dominant with other anomalies.

KERATOECTASIA Intrauterine infection and perforation with bulging opaque cornea (like anterior staphyloma) protruding through palpebral fissure at birth. Usually vitamin deficient.

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106 CORNEA AND CONJUNCTIVA

LIGNEOUS CONJUNCTIVITIS Pseudomembranous conjunctivitis in children from heritable defect in plasminogen gene; patients have deep fibrin ‘‘woody’’ infiltrate of conjunctiva and lids. May have similar exudative membranes in trachea, vagina, and elsewhere.

MEGALOCORNEA Bilateral, nonprogressive corneal enlargement >12 mm diameter at birth (normal 10 mm) or >13 mm after age 2. X-linked recessive, 90% male. Associated with cataract and ectopia lentis; 20% have open-angle glaucoma (exclude congenital glaucoma). May also be isolated or rarely associated with craniosynostosis, dwarfism, facial hemiatrophy, and Down, Marfan, or Alport’s syndromes.

MICROCORNEA <10 mm corneal diameter from fetal developmental arrest in the fifth month. Autosomal dominant; hyperopic with a flat cornea. Associated with ACG, cataract, coloboma, and PHPV.

MICROPHTHALMOS Small, disorganized eye, 1:2000 incidence; axial length <20 mm in adult (usually 17 mm in newborn). Seen with trisomies, especially chromosome 13; also associated with cataract, coloboma, PHPV, basal cell nevus syndrome, and odontogenic jaw cysts.

NANOPHTHALMOS Small ‘‘functional’’ or ‘‘normal’’ eye, axial length <20.5 mm. Associated with hyperopia, uveal effusions, and possible serous retinal detachment and ACG (usually at age 40–60). Disorder of abnormally arranged scleral collagen that becomes thickened and obstructs venous outflow. Avoid intraocular surgery. Needs laser peripheral iridotomy (LPI), maybe vortex vein decompression.

SCLEROCORNEA Noninflammatory, nonprogressive scleralization of cornea with an ill-defined limbus and corneal vessels and loss of transparency; 80% of patients also have cornea plana. Ninety percent bilateral; no sex predilection; 50% sporadic.

ANTERIOR SEGMENT DYSGENESIS

Axenfeld-Rieger: bilateral neurocrestopathy, autosomal dominant from chromosome 4q25 and 13q14 RIEG gene mutation with abnormal solurshin protein leading to mesenchymal changes (anterior iris structure is missing). Sixty percent of patients have glaucoma (8% congenital, 50% by second decade). Spectrum of clinical presentation:

Axenfeld’s anomaly: bilateral anterior displaced Schwalbe’s ring (posterior embryotoxon), iridocorneal adhesions; 50% of patients have juvenile glaucoma.

Axenfeld’s syndrome: above anomaly plus skeletal anomalies (hypertelorism, facial asymmetry)

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Rieger’s anomaly: above Axenfeld’s syndrome plus anterior stromal iris atrophy, corectopia, ectropion uvea, peripheral anterior synechiae (PAS); glaucoma in >50% of cases.

Rieger’s syndrome: above Rieger’s anomaly plus skeletal anomalies such as malar hypoplasia, prominence of lower lip, hypodontia, hypospadias, heart defects; umbilicus button does not resorb. Associated with oculocutaneous albinism.

Peters’ anomaly: corneal leukoma (central corneal opacity, peripherally clear) with posterior corneal defect with thinning or absence of endothelium and Descemet’s membrane. May have adhesions between lens and cornea, anterior polar or cortical cataract, microspherophakia, and anterior lens displacement. Fifty percent of patients have trabeculodysgenesis glaucoma. Cornea may be perforated at birth with loss of lens. Usually sporadic but also autosomal recessive; PAX 6 gene defect from failure of neural crest cell migration that normally separates the surface ectoderm of the cornea and the developing lens. Eighty percent are bilateral; may be associated with many other ocular defects, malformations, and fetal alcohol syndrome. Called Peters’-plus anomaly if cardiac, skeletal, or clefting abnormalities are present. Treat with PK usually at age 2–3 weeks.

Circumscribed posterior keratoconus: unilateral, nonprogressive, nonfamilial localized posterior cornea crater-like defect. F >M. Descemet’s membrane and endothelium intact. Normal vision.

Internal ulcer of von Hippel: posterior keratoconus with cloudy cornea following intrauterine inflammation

Posterior amorphous corneal dysgenesis: bilateral, limbus-to-limbus opacity; autosomal dominant

Posterior embryotoxon: thickened and anteriorly displaced Schwalbe’s ring. Autosomal dominant; present in 8 to 30% of normals; may be part of Axenfeld’s anomaly.

ANTERIOR CORNEAL DYSTROPHIES

Epithelial basement membrane, map-dot-fingerprint, Cogan’s microcystic dystrophy: disorder of the basement membrane and loss of epithelial cell polarity. Characterized by geographic plaques of thickened BM (maps), intraepithelial debris and pseudocysts (dots), ‘‘mare’s hairs’’ reduplications of BM (fingerprints), and recurrent corneal erosions (in 10% of patients, but is the cause of 50% of all recurrent corneal erosions). Autosomal dominant with incomplete penetrance; 6 to 18% prevalence, typically females age >50. Treat acute RCE, then try 5% NaCl ointment and lubricants, or BSCL 4–6 weeks, epithelial scraping, stromal puncture (cure 90%, may scar in visual axis; better for traumatic RCE), or PTK; avoid LASIK.

Meesman or juvenile epithelial dystrophy: rare disorder that presents at young age with central, mainly interpalpebral, tiny bubble-like

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108 CORNEA AND CONJUNCTIVA

intraepithelial vesicles and fine microcysts containing ‘‘peculiar substance.’’ These coalesce with age, and cysts begin to rupture usually about age 40 to 50, causing severe RCE. Autosomal dominant, with 60% penetrance from defect of keratin 3 gene (chromosome 12q13) and keratin 12 (chromosome 17q12). These gene mutations cause defective cytokeratins that are part of the intracellular cytoskeleton. Treat RCE; BSCL often helpful.

Reis-Buckler’s dystrophy: autosomal dominant, strong penetrance, defect of the keratoepithelian gene (big-h3 gene) found on chromosome 5q31 (like granular and lattice dystrophies). Bowman’s layer is replaced with superficial geographic or honeycomb gray-white granular material centrally. Multilaminar eosinophilic deposits beneath the epithelium stain red with Masson-trichrome, like granular dystrophy. Onset is age 10 to 20, with frequent recurrent corneal erosions. Treat with PTK; recurrence after PK common.

Type 1: rod-shaped bodies; same gene as granular dystrophy; has decreased corneal sensation.

Type 2 (Thiel-Behnke): most frequent type, has curly fibers, chromosome 10q24 gene defect. Presents in early childhood with recurrent corneal erosions; normal corneal sensation.

STROMAL CORNEAL DYSTROPHIES (Table 3–2)

Central cloudy dystrophy of Franc¸ois: autosomal dominant, nonprogressive; faint deep central shagreen, with normal VA.

Congenital hereditary stromal dystrophy (CHSD): very rare, autosomal dominant, bilateral, nonprogressive feathery central corneal clouding, periphery normally clear. Normal Descemet’s membrane and endothelium but abnormally aligned collagen. No corneal edema and normal thickness (unlike CHED), no photophobia or tearing.

Fleck or pre-Descemet’s dystrophy: rare, nonprogressive, faint disorder of excessive GAG and lipids in cornea. VA preserved, diagnosis of exclusion.

Gelatinous-droplike dystrophy: autosomal recessive primary familial amyloidosis, defect of chromosome 1p; found mainly in Japan.

TABLE 3–2

Major Stromal Dystrophies and Histologic Stains

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Granular dystrophy: autosomal dominant disorder of transforming growth factor-beta-induction gene (big-h3); also known as keratoepithelin gene found on chromosome 5q31 (like Reis-Buckler’s and lattice dystrophies). Second most common dystrophy and the most benign stromal dystrophy. Characterized by anterior stromal, discrete, crumblike or granular focal opacities with intervening clear spaces. Pathology shows hyaline material that stains with Masson-trichrome (mnemonic: Cells are red, collagen blue, Masson-trichome is the stain for you). Cornea has an irregular BM, and Bowman’s layer is thin or absent. Uncommonly have recurrent corneal erosions. Onset is early in life, although symptoms occur much later. Granular dystrophy is disciform in teens and not to limbus. Treat with PTK or PK late; often recurs after transplant.

Groenouw’s type I: most benign and most frequent type.

Groenouw’s type II: second decade onset; fewer and larger opacities with clear spaces; VA good.

Groenouw’s type III: onset in infancy with erosions (like ReisBuckler’s).

Avellino: combined granular (appears first) and lattice (latter) dystrophies with subepithelial deposits in older patients. Same gene but different location; autosomal dominant with high penetrance. Treat with BSCL or PTK; may recur after PK.

Lattice dystrophy: autosomal dominant disorder of chromosome 5q31 gene. Most common stromal dystrophy, with onset in first decade. Characterized by refractile lines of amyloid deposition; best seen

with retroillumination, and stains with Congo red. Severe, frequent recurrent corneal erosions. Graft recurrences most common of all the dystrophies. PTK may reduce erosions, improve VA, and delay PK.

Type I (Biber-Haab-Dimmer): localized to cornea, deposition of nonimmunoglobulin amyloid-associated (AA) protein, classic; symptoms appear by end of first decade; autosomal dominant, keratoepithelin gene.

Type II (Meretoja): unilateral ocular involvement with systemic amyloidosis; symptoms appear around age 30; usually seen in persons of Finnish ancestry; autosomal dominant, chromosome 9q34, gelsolin gene. Patients often have masklike facies, blepharochalasis, pendulous ears, dry, lax skin, and nerve palsies.

Type III: midstromal, amyloid pentagonal (AP) component; chromosome 1p31, autosomal recessive; symptoms appear around age 30.

Type IIIA: autosomal recessive, keratoepithelin gene; symptoms appear around age 50.

Macular dystrophy: autosomal recessive, chromosome 16q22 defect synthesizing keratan sulfate (can consider it a localized MPS disorder).

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The unsulfated keratan (GAG) accumulates within the endoplasmic reticulum and deposits beneath the epithelium, within stromal cells and the endothelium. Clear cornea at birth but cloudy by age 3 to 9, with focal gray-white superficial opacities that progress to full thickness and periphery with late guttae and erosions. Stains with colloidal iron or alcian blue. This is the least common but most severe dystrophy, with no clear spaces and total cornea involved. Most patients require PK by age 30 to 40; frequently recurs after transplant.

Schnyder’s central crystalline dystrophy: autosomal dominant disorder with fine needle-shaped cholesterol crystals in anterior stroma with dense arcus. Crystals are not indicative of a certain lipid level, but rule out hyperlipidemia. Often symptomatic with good VA.

POSTERIOR CORNEAL DYSTROPHIES

Congenital heriditary endothelial dystrophy (CHED): bilateral ‘‘ground glass’’ corneal opacification to limbus with epithelial and stromal edema (may be 4 normal thickness; adult cornea can only swell to about 1.4 ). No glaucoma, guttae, or associated ocular or systemic disease.

Type 1: autosomal dominant, progressive; presents around age 1 to 2 (no nystagmus) with corneal clouding, pain, photophobia, and tearing.

Type 2: autosomal recessive; more common than type 1; stationary; presents at birth with clouding, sensory nystagmus, and amblyopia. Defect on chromosome 20q11-cen, like PPMD.

Fuchs’ endothelial dystrophy: autosomal dominant, variable penetrance; F >M 2:1, usually postmenopausal. Affected females have 2.5 more guttae and 5.7 increased incidence of edema than males. Fuchs (1910) described a triad of stromal edema, subepithelial scar, and bullae and thought the condition was epithelial dystrophy.

Caused by accelerated apoptosis (programmed cell death) of endothelial cells (normally decrease 0.5% per year; thus, usually have enough for 150 to 200 years). Remaining endothelial cells spread out to cover the posterior cornea and demonstrate polymegathism and pleomorphism.

Early guttae (thickening and excrescences of Descemet’s membrane) with pigment dusting, followed by microcystic edema with decreased vision in the morning that improves during the day as

H2O evaporation increases tears’ hypertonicity. Later may develop bullous edema, recurrent corneal erosions, pannus, pain from ruptured bullae, with secondary infection and beaten metal appearance to endothelium. Up to 20% of patients have glaucoma (may be ACG with increased incidence of hyperopia).

Treat with hyperosmotic solutions and ointments; use hair dryer in the morning to dry cornea, and consider lowering IOP. Treat

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