Gross anatomy. The conjunctiva is a thin, transparent mucous membrane lining the inner surface of the eyelid (palpebral conjunctiva) and covering the anterior sclera (bulbar conjunctiva). The palpebral portion is designated as marginal, tarsal, and orbital and merges with the conjunctiva of the superior and inferior fornices in loose folds. The bulbar conjunctiva is adherent to the underlying Tenon capsule and therefore to sclera, with the tightest adhesion occurring in a narrow band at the corneoscleral limbus. A delicate vertical crescent, the semilunar fold (plica semilunaris), separates the bulbar conjunctiva from the lacrimal caruncle at the medial canthus. The conjunctiva tends to be a mobile tissue and is capable of great distention with edema fluid, as is often seen with trauma or inflammation.

Microscopically, the conjunctiva is composed of (a) an anterior stratified columnar epithelium that is continuous with the corneal epithelium, and (b) a lamina propria composed of adenoid and fibrous layers. The epithelium is from two to seven layers thick and contains numerous unicellular mucous glands (goblet cells) that secrete the inner mucoid layer of the tear film. Although the healthy epithelium is never keratinized, it may become keratinized in certain disease states. The lamina propria is composed of connective tissue housing blood vessels, nerves, and glands. The accessory lacrimal glands of Krause are located deep in the substantia propria in the superior and inferior fornices. The accessory lacrimal glands of Wolfring are situated near the upper margin of the superior tarsal plate. The adenoid layer of the lamina propria, which develops particularly after 3 months of age, contains lymphocytes enmeshed in a fine reticular network without the presence of true lymphoid follicles. The fibrous layer of the lamina propria surrounds the smooth palpebral muscle of Müller.

The blood supply of the palpebral conjunctiva originates from peripheral (bulbar and fornix) and marginal arterial arcades of the eyelid. Within 4 mm of the limbus, the vascular supply is derived from the anterior conjunctival branches of the anterior ciliary arteries (superficial plexus), which anastomose with the posterior conjunctival vessels from the peripheral arcade. Conjunctival vessels move with the conjunctiva and constrict with instillation of 1:1,000 epinephrine—a point of differentiation from the deeper episcleral and ciliary vessels.

Innervation of the bulbar conjunctiva is via the sensory and sympathetic nerves from the ciliary nerves. The remaining palpebral and fornix conjunctiva is innervated by the ophthalmic and maxillary divisions of the trigeminal nerve (cranial nerve V).

Lymphatic drainage of the conjunctiva parallels that of the lid, with lateral drainage to the preauricular nodes and medial drainage to the submandibular nodes.

Gross anatomy. The cornea represents the anterior 1.3 cm² of the globe and is the main refracting surface of the eye. Although the cornea is continuous with the sclera at the limbus, the anterior corneal curvature (radius equal to 7.8 mm) is greater than that of the sclera, with the central 4-mm optical zone almost
spherical and the periphery gradually flattening toward the scleral curve. The horizontal diameter of the anterior surface of the cornea (11.6 mm) is longer than the vertical diameter (10.6 mm), so that the anterior aspect of the cornea forms a horizontal ovoid. Viewed from the posterior surface, the cornea is circular (with a diameter of 11.6 mm). A corneal diameter greater than 12.5 mm is termed megalocornea; a corneal diameter less than 11 mm is termed microcornea. The height of the cornea from the basal plane of the visible limbus to the apex is 2.7 mm. The central thickness of the cornea is 0.52 mm, which increases to 0.7 mm in the far periphery.

Microscopically, the cornea consists of five strata: the epithelium and its basement membrane, Bowman layer, stroma, Descemet membrane, and endothelium.

The blood supply of the cornea arises predominantly from the conjunctival, episcleral, and scleral vessels that arborize about the corneoscleral limbus. The cornea itself is avascular.

The innervation of the cornea is that of a rich sensory supply mostly via the ophthalmic division of the trigeminal nerve. This innervation is via the long ciliary nerves that branch in the outer choroid near the ora serrata region. These
nerves pass via the sclera into the middle third of the cornea as 70 to 80 large nerve trunks that lose their myelin sheaths approximately 2 to 3 mm from the limbus but can be visualized as fine filaments beyond. There is significant dichotomous and trichotomous branching, and the subsequent passage of nerve fibers through the Bowman layer ends freely between the epithelial cells.

The physiology of the cornea and conjunctiva is best introduced in a discussion of the precorneal tear film. This film, which is 6 to 10 μm thick, is composed of three layers: (a) superficial lipid layer, (b) middle aqueous layer, and (c) inner mucous layer. The normal tear volume in the conjunctival sac is about 3 to 7 μL and can increase to the conjunctival sac capacity of 25 μL before overflow occurs. Tear flow rate is approximately 1 μL per minute and comes from the secretion of the main and accessory lacrimal glands. After their release in the superotemporal region, the tears are distributed by the blinking action of the lids, with the tear meniscus forming superior and inferior marginal tear strips before draining into the lacrimal puncta located near the medial canthus. With a pH of 7.6 and an osmolarity comparable to sodium chloride 0.9%, there is a low glucose concentration and an electrolyte distribution similar to plasma, with the exception of a slightly greater potassium content. Oxygen dissolves readily in the tear film, and the dissolved protein content of the tear film includes immunoglobulins and lysozyme. These characteristics allow the tear film to provide a smooth surface for refraction, to mechanically wash and protect the cornea and conjunctiva, to provide oxygen exchange for the epithelium, to lubricate the surface during a blink, and to provide bacteriostasis. Tear film homeostasis requires an intact “lacrimal function unit,” which is a feedback loop involving cranial nerves V (sensory) and VII (motor), the lacrimal apparatus, and integrative structures within the central nervous system. Perturbation of any of these components can interfere with the proper composition and function of the tear film.

Corneal function. The primary physiologic function of the cornea is to maintain an optically smooth surface and a transparent medium while protecting the intraocular contents of the eye. This duty is fulfilled by the effective interaction of the epithelium, stroma, and endothelium. The epithelium, endothelium, and Descemet membrane are transparent because of the uniformity of their refractive indices. The transparency of the stroma is conferred by the special physical arrangement of the component fibrils. Although the refractive index of collagen fibrils differs from that of the interfibrillar substance, the small diameter of the fibril (300 Å) and the small distance between them (300 Å) provide a separation and regularity that causes little scattering of light despite the optical inhomogeneity. The relative state of deturgescence is provided by the barrier functions of the epithelium and endothelium, as well as by the dehydrating function of the endothelium. Disturbance of this equilibrium, such as occurs in corneal edema, will increase light scattering and the opacity of the stroma.

Etiologically, corneal perforation can result from any corneal ulceration, either infectious (bacterial, fungal, or viral), inflammatory (rheumatoid arthritis or collagen disease), posttraumatic (burn), or trophic defects of degenerations, neurotrophic ulcer, or postherpetic ulcer. Use of topical nonsteroidal anti-inflammatory drugs (NSAIDs) such as diclofenac in at-risk patients may trigger or worsen thinning and perforation.

Treatment. Occasionally, these perforations will seal with a small knuckle of iris and rarely can be self-sealing, but they usually result in partial or complete loss of the anterior chamber. Thus, in most cases, they represent an urgent situation to be treated. Small, noninfectious perforations can often be splinted by use of a therapeutic soft contact bandage lens (Permalens, Kontur). Such treatment will sometimes allow healing of the perforation but often is a stabilizing or interim treatment that requires further definitive therapy. Medical adhesive is of great use in helping to seal small perforations. Cyanoacrylate tissue adhesive (Dermabond Ethicon; not U.S. Food and Drug Administration [FDA] approved for ocular use) can successfully seal a perforation without excess ocular toxicity. It is essential that epithelium and necrotic stroma be débrided to allow firm adhesion of the cyanoacrylate glue to surrounding healthy basement membrane. A thin application of this glue will often remain intact for several months and is tolerated by the patient if covered with a continuously worn soft contact lens (Plano T). Healing of the corneal defect will often occur beneath the glue. Even if spontaneous healing of the leak is not expected, the glue will provide adequate time to obtain corneal donor material if keratoplasty becomes necessary. It is essential to observe the patient closely to ensure that the anterior chamber has reformed and that there is no associated superinfection. Topical antibiotic coverage is advisable after gluing and with the use of a soft contact lens. When contact lens or adhesive therapy is inadequate, surgical patch grafting will usually be successful. For moderate-size perforations, a small lamellar button may be sutured into the débrided defect. In the event of large central perforations, it may be preferable to perform penetrating keratoplasty.

Acute blepharitis often overlaps with meibomian gland dysfunction. Staphylococcus aureus is the most common cause of infection, but other species may be at fault. It is characterized by tender lid edema; erythema; lash loss; hard, anterior lid location of fibrinous crusts and scales; and occasional lid ulceration, tear instability, corneal punctate keratitis, infiltrates, vascularization, and phylctenulosis.

Acute and chronic bacterial conjunctivitis. Conjunctivitis is an inflammation of the conjunctiva characterized by vascular dilation, cellular infiltration,
and exudation. The differential features of bacterial conjunctivitis versus those caused by virus, allergy, or toxic factors are listed in Table 5.1.

The acute stage of conjunctivitis is classically recognized by vascular engorgement and mucopurulent discharge, with the associated symptoms of irritation, foreign body sensation, and sticking together of the lids. Occasionally, a severe reaction with purulent conjunctivitis and corneal involvement can occur. The chronic conjunctival infection is more innocuous in its onset, runs a protracted course, and is often associated with involvement of the lids or lacrimal system by low-grade inflammatory reaction. A wide variety of bacterial organisms can infect the conjunctiva. Although the bacterial etiology is often clinically apparent, the identity of the causative organism may not be obvious. Certain clinical features determined by the pathogenicity of the infectious agent, however, may provide an accurate clinical diagnosis.

Conjunctival cultures should be taken prior to the use of topical anesthetics, because these agents and their preservatives will reduce the recovery of certain bacteria. Cultures are taken by moistening a sterile alginate or dacron (not cotton) swab with sterile saline and wiping the lid margin or conjunctival cul-de-sac. The culture medium is then inoculated directly with the swab tip. Inoculation of solid media can be made in the shape of the letter R for the right lid and L for the left lid margin. On the same plate, a conjunctival culture may be inoculated at a different site using a zigzag pattern. In this way, the site of culture may be distinguished by the pattern of growth on the plate. After inoculating solid media, the tip of the applicator may be broken off and dropped into a tube of liquid culture medium (e.g., thioglycollate broth).

For bacterial isolation and identification, the most widely used and generally available media are blood agar and chocolate agar. Meat broth has a significantly higher growth rate for most common organisms but must be secondarily plated for identification. Chocolate agar is well suited for growth of any organism that can be isolated on blood agar and has the added advantage of isolating Haemophilus, the fastidious Neisseria organisms, and fungi. Thayer-Martin medium is a chocolate agar medium containing vancomycin, colistimethate, and nystatin and is of use in culture and isolation of gonococcus. Thioglycolate medium is a commonly used medium in cultivating aerobic and anaerobic organisms from ocular infection. Liquid Sabouraud medium may be useful in isolating fungal organisms when solid agar medium has failed. Table 5.3 summarizes the culture media of use in specific ocular infectious states. Cultures for B. henselae (catscratch disease) are difficult. Diagnosis is usually based on polymerase chain reaction (PCR) testing on local tissue biopsy and serology.

Scrapings for microscopic examination are made after cultures have been taken. Local anesthetic is instilled. A platinum spatula is flamed and allowed to cool to room temperature. The spatula can then be used to gently scrape the involved conjunctival surface, and the material obtained can be spread in a thin layer on a precleaned glass slide. If possible, two or three such slides are made and stained for microscopic examination (Table 5.4). Because scrapings

are only about 70% reliable and may be traumatic to the patient, cultures take priority, and in appropriate situations, scrapings are omitted.

Stains most useful for identifying organisms and inflammatory cell type are the Gram or acridine orange. The Hansel stain is also a useful technique for rapid identification of any eosinophilic response. The Giemsa and Wright stains are most useful in revealing the condition and character of epithelial cells and inflammatory cells. The Giemsa stain is most effective in showing the presence or absence of viral cytoplasmic or intranuclear inclusion bodies and outlining the morphology of bacteria. The Gram stain is useful in revealing whether an organism is Gram positive or negative. It also provides some information about the morphology of the organism. For mycobacteria acid fast, lectin, and Gram stain, for fungi and acanthamoeba calcofluor white, and acridine orange are most useful. These organisms very rarely colonize the lids or conjunctiva.

The cytologic features of each type of conjunctivitis are helpful in diagnosis. As a rule, a polymorphonuclear leukocyte response occurs with bacterial conjunctivitis (with the exception of diplobacillus). Acute Stevens-Johnson syndrome may produce a polymorphonuclear response, as will the early stages of a viral infection. A mixed outpouring of polymorphonuclear leukocytes and lymphocytes is commonly noted with adult and neonatal inclusion conjunctivitis. Such a mixed response, with the added presence of plasma cells and macrophages (Leber cells), is almost diagnostic of trachoma. Chemical conjunctivitis can also produce a polymorphonuclear response. A predominantly lymphocytic response is most commonly seen in viral infections but can also be seen in drug-induced toxic follicular conjunctivitis. Numerous eosinophils are indicative of vernal conjunctivitis or allergic conjunctivitis. The appearance of eosinophils and polymorphonuclear leukocytes in conjunction with a hyperacute conjunctivitis may be indicative of early erythema multiforme, particularly if associated with systemic symptoms. Basophils, rarely seen in conjunctival scrapings, are equivalent in interpretation to eosinophilic reaction. Epithelial cells may demonstrate cytoplasmic inclusions that, if basophilic, suggest inclusion conjunctivitis and, if eosinophilic, suggest pox virus. Pink intranuclear inclusions on Giemsa stain are diagnostic of herpesvirus infection (either simplex or zoster). Multinucleate giant cells are suggestive of a viral disorder.

When organisms are identified, Gram-positive cocci in pairs or chains may indicate S. pyogenes. The Gram-negative diplococci, appearing within polymorphonuclear leukocytes and having the “coffee bean” shape, indicate Neisseria
sp. Large Gram-negative diplobacilli characterize Moraxella sp. H. influenzae is a pleomorphic organism variably appearing as Gram-negative coccobacillus or slender rods. Gram-negative rods may also be noted but are difficult to differentiate as to species. Candida may appear hyphate on scrapings but are round organisms on culture.

Hyperacute bacterial conjunctivitis (acute purulent conjunctivitis) is a more serious situation and demands more vigorous therapy. After the patient is
examined and the necessary cultures and scrapings are obtained, it is important to institute treatment prior to obtaining the culture results.

Chronic conjunctivitis and blepharitis (see Sections III.B, earlier, and VII.I, as well as Chapter 3 for anterior and posterior blepharitis review) are especially common in patients with acne rosacea. It is rarely cultured, and then only if there is no response to standard treatment, and is then retreated in accordance with the sensitivities obtained after the pathogen is cultured.

Corneal marginal infiltrates and ulcerations that occur with chronic staphylococcal blepharoconjunctivitis respond to mild topical steroids with antibiotic cover, usually within 4 or 5 days. See IV.B.2.

Hordeolum, a tender, sometimes fluctuant lid margin nodule, is commonly seen with chronic blepharitis and may be multiple. Internal hordeola are inflammatory or infectious nodules in the meibomian glands, and external hordeola are the same but in the glands of Zeiss or lash follicles. Many will resolve within 2 weeks with warm compresses, lid hygiene, manual expression, and topical bacitracin tid or trimethoprim-polymyxin drops (Polytrim) qid. A nonresolving internal hordeolum becomes a chalazion, a chronic granulomatous nodule. Treatment is intralesional injection of 0.1 mL of triamcinolone 25 mg/mL to 40 mg/mL, or incision and drainage (vertical cut along the tarsal conjunctiva). As depigmentation may occur with dark-skinned patients, incision is probably the better choice for them. The steroid injection may be repeated if necessary. Meibomian gland carcinoma should be considered in the event of recurrence or nonresponse to therapy.

Morphology. The lesions include punctate epithelial erosions that are focal defects in the corneal epithelium, best visualized by rose bengal and fluorescein
staining and slitlamp biomicroscopy. Punctate epithelial keratitis is characterized by focal inflammatory infiltration of the epithelium, resulting in minute opaque epithelial lesions observed in focal illumination or with the slitlamp. Although they may occur without staining, they often do stain with rose bengal or fluorescein because of associated punctate epithelial erosion. Punctate subepithelial infiltrates are nonstaining focal areas that occur as semiopaque spots in the superficial stroma.

Identification of the morphology and distribution of the lesions is greatly enhanced by the use of clinical vital stains, most notably rose bengal, lisamine green and fluorescein. Rose bengal and lissamine green stain dead or degenerating cells or cells without their normal mucin surface and are available as sterile paper strips (wet with saline, not proparacaine). Prior instillation of proparacaine 0.5% will relieve the smarting sensation produced by rose bengal, but tetracaine and cocaine should be avoided because they will often produce an artifactual rose bengal staining pattern. Rose bengal and lissamine green are also excellent stains for mucus and filaments. Fluorescein in combination with an anaesthetic solution (Fluress) or from a Fluri-strip wet with saline will stain epithelial defects or bared basement membrane and is also used when highlighting corneal filaments.

The distribution of the epithelial and subepithelial lesion is of diagnostic value. Figure 5.1 summarizes the six clinical patterns and their respective etiologies. Diffuse and nonspecific punctate epithelial erosions may occur with early bacterial or viral infections of many types. Breakdown of microcystic areas of epithelial edema can also produce this pattern, and such areas of edema will also demonstrate areas of negative staining in the fluorescein film corresponding to intact epithelial microcysts. Any toxic reaction to topical medications, chemicals, or aerosol sprays can produce this pattern. Mechanical trauma from a foreign body or eye rubbing must also be considered. The epithelial erosions secondary to molluscum contagiosum of the lids will occur in areas contiguous to the lesion. Inferior punctate epithelial erosions frequently result from staphylococcal blepharitis or blepharoconjunctivitis and are often accompanied by epithelial keratitis and subepithelial infiltrates. Trichiasis or incomplete lid closure (exposure keratopathy) can produce this distribution of erosion, and the pattern is also occasionally seen in dry eye patients. The interpalpebral distribution is typical of keratitis sicca, ultraviolet radiation exposure, chronic exposure, or incomplete blinking. Conjunctival staining usually will accompany the corneal lesion. Episodic recurrent erosions frequently will occur in the inferior area or interpalpebral area. The superior distribution of epithelial erosion is typical of superolimbic keratoconjunctivitis but can also be seen in vernal conjunctivitis and with trachoma. Corneal epithelial filaments (filamentary keratitis) consisting of coiled epithelial remnants and adherent mucous strands may be associated with any of these patterns, but most typically appear with superolimbic keratoconjunctivitis or keratoconjunctivitis sicca. Central lesions, with or without some peripheral punctate, suggest contact lens malfit or overwear, and linear lesions suggest a foreign body on the lid rubbing the cornea.

The etiology of punctate epithelial erosion is often local desiccation. Instability of the tear film results in focal dry spots and epithelial breakdown. Epithelial membrane damage from detergent chemicals, liquid solvents, quaternary amines, and a variety of drugs also results in erosions. Superficial viral and chlamydial infections can produce focal erosions, as can the epithelial hypoxia of contact lens overwear. Punctate epithelial keratitis with minute focal opacities is typical of viral keratitis, especially that associated with epidemic keratoconjunctivitis of adenovirus, but may also be seen with staphylococcal and chlamydial infections. The infiltrates also occur with vaccinia, Reiter syndrome, and acne rosacea. The coarse, granular infiltrates of punctate epithelial keratitis are quite characteristic of Thygeson superficial punctate keratitis.

Nonstaining punctate subepithelial infiltrates in the superficial stroma are sometimes seen after such entities as adenoviral, herpes simplex, herpes zoster,
Epstein-Barr viral, vaccinial, chlamydial, Reiter, Lyme disease, and rosacea keratitis. Staphylococcal infection must be considered when this pattern appears in a marginal infiltrate distribution. Inferior peripheral limbal infiltrates can accompany acute H. influenzae conjunctivitis.

Central ulcer. Predominant causes of central bacterial keratitis are Staphylococcus (e.g., S. aureus and S. epidermidis), Streptococcus (e.g., S. pneumococcus and groups A–G Streptococcus), other Gram-positive organisms (e.g., Bacillus and Propionibacterium sp), the Gram-negative organisms Haemophilus, Pseudomonas, and Moraxella, and other Enterobacteriaceae (e.g., Proteus, Serratia,
E. coli, and Klebsiella). Mycobacterium chelonae keratitis may follow laser-assisted in situ keratomileusis (LASIK) surgery. Gram-negative diplococci are an uncommon cause of corneal ulceration except in inadequately treated cases of hyperacute gonococcal conjunctivitis. Infection of the cornea usually tends to occur after injury to the epithelium or in compromised hosts, except for Neisseria and Corynebacterium, which may invade intact epithelium. Stromal infiltration in an area of an epithelial defect with surrounding edema and folds associated with endothelial fibrin plaques or anterior chamber reaction is usually indicative of microbial infection. Staphylococcal ulcers are often more localized, whereas pneumococcus may produce a shaggy undermined edge of an ulcer that is associated with a hypopyon. A destructive keratitis with rapid necrosis and adherent mucopurulent discharge is highly suggestive of Pseudomonas, Streptococcus, or anaerobic infection. Other uncommon causes are Nocardia and non–spore-forming anaerobes. Infectious crystalline keratopathy is an indolent, noninflammatory branching crystalline growth commonly associated with Streptococcus viridans, but also reported with Peptostreptococcus sp, S. epidermidis, H. influenzae, and two fungal species. There is also often a history of local ocular trauma, contact lens use, steroid use, and/or chronic antibiotic administration. Response to antibiotic therapy is very slow and may fail. Surgical intervention with neodymium:yttrium, aluminum, garnet (Nd:YAG) laser disruption (e.g., 3.2 mJ × 30) creates diffuse haze of the protective glycocalyx matrix within the intrastromal crystals, making the bacteria drug-susceptible. This should be considered before more extensive surgical steps are taken.

Marginal ulcers. The corneal limbus contains many antigen-presenting cells that mobilize T-lymphocytes to produce immune peripheral corneal infiltrates with or without ulceration. These usually sterile superficial white infiltrates are a hypersensitivity reaction seen most commonly with staphylococcal blepharoconjunctivitis but may also be seen with contact lens wear, trauma, and endopthalmitis. They are located 1 mm inside the limbus leaving a clear zone to the limbus. The ulceration must be distinguished from the Mooren ulcer and the peripheral ulceration seen with collagen vascular diseases such as rheumatoid arthritis. Moraxella sp has also been described as producing ulcers that extend to the limbus, especially inferiorly. Treatment is topical antibiotic with or without mild steroid for 7 to 10 days.

Laboratory tests similar to those for hyperacute conjunctivitis (see Section III.C) apply also to bacterial corneal disease.

Treatment of central bacterial ulcers is based on clinical impression and results, if any, of the scraping. Coverage should be broad, intensive, and
amenable to change when final culture and sensitivity reports are available. Contact lens wearers with central corneal ulcers should particularly be covered for Pseudomonas (q1h fortified tobramycin, netilmicin, and/or a quinolone [moxifloxacin, levofloxacin] for broader-spectrum cover). Antibiotic treatment of infectious corneal ulcers must be aggressive using fortified solutions (made up by compounding pharmacists), and patients should be kept under close observation to prevent serious scarring or frank perforation. Initial antibiotic therapy may be guided by the results of the Gram stain of the corneal scraping, but broad-spectrum therapy should be used (see Tables 5.5, 5.6, and 5.7 and Appendix B for detailed lists of drug indications, dosage, and routes of administration).

Collagen shields (Surgilens, Bausch & Lomb) are contact lenses initially developed to enhance corneal epithelial healing after surgery, trauma, or dystrophic erosions and filaments, but are also used as effective high-dose drug delivery systems (the lenses are not FDA approved as drug delivery systems). The lenses come in two sizes and dissolve spontaneously over 24 to 72 hours. Soaking the lenses in antibiotics, such as tobramycin 40 mg solution for 10 minutes, results in a 30-fold increase in antibiotic penetration into the aqueous compared to subconjunctival injection or a regular therapeutic soft contact lens (TSCL) and q1h drops. The high level of drug may be maintained with q4h drops using the collagen shields.

Special pediatric considerations. Subconjunctival therapy is usually not feasible unless the child is under general anesthesia at the time of a corneal culture and scraping. Should systemic medication be considered necessary, it is best done with the consultation of a pediatrician or internist. See Appendix B for dosages and organism indications.

Signs of clinical improvement

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