Chapter 5. Conjunctiva & Tears

Conjunctivitis

Inflammation of the conjunctiva (conjunctivitis) is the most common eye disease worldwide. It varies in severity from a mild hyperemia with tearing to a severe conjunctivitis with copious purulent discharge. The cause is usually exogenous, but rarely may be endogenous.

Conjunctivitis Due to Infectious Agents

The types of conjunctivitis and their most common causes are summarized in Tables 5–1 and 5–2. Conjunctival inflammation that occurs in the setting of uveitis, or scleral or episcleral inflammation is discussed in Chapter 7.

Because of its location, the conjunctiva is exposed to many microorganisms and other environmental factors. Several mechanisms protect the surface of the eye. In the tear film, the aqueous component dilutes infectious material, mucus traps debris, and a pumping action of the lids constantly flushes the tears to the tear duct. In addition, the tears contain antimicrobial substances, including lysozyme and antibodies (IgG and IgA).

Common pathogens that can cause conjunctivitis include Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, Neisseria meningitidis, most human adenovirus strains, herpes simplex virus type 1 and type 2, and two picornaviruses. Two sexually transmitted agents that cause conjunctivitis are Chlamydia trachomatis and Neisseria gonorrhoeae.

Cytology of Conjunctivitis

Damage to the conjunctival epithelium by a noxious agent may be followed by epithelial edema, cellular death and exfoliation, epithelial hypertrophy, or granuloma formation. There may also be edema of the conjunctival stroma (chemosis) and hypertrophy of the lymphoid layer of the stroma (follicle formation). Inflammatory cells, including neutrophils, eosinophils, basophils, lymphocytes, and plasma cells, may be seen and often indicate the nature of the damaging agent. These cells migrate from the conjunctival stroma through the epithelium to the surface. They then combine with fibrin and mucus from the goblet cells to form conjunctival exudate, which is responsible for the “mattering” on the lid margins (especially in the morning).

The inflammatory cells appear in the exudate or in scrapings taken with a sterile platinum spatula from the anesthetized conjunctival surface. The material is stained with Gram's stain (to identify the bacterial organisms) and with Giemsa's stain (to identify the cell types and morphology). A predominance of polymorphonuclear leukocytes is characteristic of bacterial conjunctivitis. Generally, a predominance of mononuclear cells—especially lymphocytes—is characteristic of viral conjunctivitis. If a pseudomembrane or true membrane is present (eg, epidemic keratoconjunctivitis or herpes simplex virus conjunctivitis), neutrophils usually predominate because of coexistent necrosis. In chlamydial conjunctivitis, neutrophils and lymphocytes are generally present in equal numbers.

In allergic conjunctivitis, eosinophils and basophils are frequently present in conjunctival biopsies, but they are less common on conjunctival smears; eosinophils or eosinophilic granules are commonly found in vernal keratoconjunctivitis. High levels of proteins secreted by eosinophils (eg, eosinophil cationic protein) can be found in the tears of patients with vernal, atopic, or allergic conjunctivitis. Eosinophils and basophils are found in allergic conjunctivitis, and scattered eosinophilic granules and eosinophils are found in vernal keratoconjunctivitis. In all types of conjunctivitis, there are plasma cells in the conjunctival stroma. Unlike other inflammatory cells, they do not migrate through the epithelium, and are therefore not present in smears of exudate or of scrapings from the conjunctival surface unless the epithelium has become necrotic (eg, trachoma). In trachoma, the rupturing of a follicle allows the plasma cells to reach the epithelial surface. As the mature follicles of trachoma rupture easily, the finding of large, pale-staining lymphoblastic (germinal-center) cells in scrapings strongly suggests trachoma.

Symptoms of Conjunctivitis

The important symptoms of conjunctivitis include foreign body sensation, scratching or burning sensation, sensation of fullness around the eyes, itching, and photophobia.

Foreign body sensation and scratching or burning sensation are often associated with the swelling and papillary hypertrophy that normally accompany conjunctival hyperemia. Pain rather than discomfort commonly indicates corneal involvement.

Signs of Conjunctivitis (Table 5–2)

The important signs of conjunctivitis include hyperemia, tearing, exudation, pseudoptosis, papillary hypertrophy, chemosis, follicles, pseudomembranes and membranes, granulomas, and preauricular adenopathy.

Hyperemia is the most conspicuous clinical sign of acute conjunctivitis. The redness is most marked in the fornix and diminishes toward the limbus by virtue of the dilation of the posterior conjunctival vessels. (A perilimbal dilation or ciliary flush suggests inflammation of the cornea or deeper structures.) A brilliant red suggests bacterial conjunctivitis, whereas a milky appearance suggests allergic conjunctivitis. Hyperemia without cellular infiltration suggests irritation from physical causes, such as wind, sun, smoke, etc, but it may occur occasionally with diseases associated with vascular instability (eg, acne rosacea).

Tearing (epiphora) is often prominent in conjunctivitis, the tears resulting from the foreign body sensation, the burning or scratching sensation, or the itching. Mild transudation also arises from the hyperemic vessels and adds to the tearing. An abnormally scant secretion of tears and an increase in mucous filaments suggest dry eye syndrome.

Exudation is a feature of all types of acute conjunctivitis. The exudate is flaky and amorphous in bacterial conjunctivitis and stringy in allergic conjunctivitis. “Mattering” of the eyelids occurs upon awakening in almost all types of conjunctivitis, and if the exudate is copious and the lids are firmly stuck together, the conjunctivitis is probably bacterial or chlamydial.

Pseudoptosis is a drooping of the upper lid secondary to infiltration and inflammation of Müller's muscle. The condition is seen in several types of severe conjunctivitis, for example trachoma and epidemic keratoconjunctivitis.

Papillary hypertrophy is a nonspecific conjunctival reaction that occurs because the conjunctiva is bound down to the underlying tarsus or limbus by fine fibrils. When the tuft of vessels that forms the substance of the papilla (along with cellular elements and exudates) reaches the basement membrane of the epithelium, it branches over the papilla like the spokes in the frame of an umbrella. An inflammatory exudate accumulates between the fibrils, heaping the conjunctiva into mounds. In necrotizing disease (eg, trachoma), the exudate may be replaced by granulation tissue or connective tissue.

When the papillae are small, the conjunctiva usually has a smooth, velvety appearance. A red papillary conjunctiva suggests bacterial or chlamydial disease (eg, a velvety red palpebral conjunctiva is characteristic of acute trachoma). With marked infiltration of the conjunctiva, giant papillae form. Also called “cobblestone papillae” in vernal keratoconjunctivitis because of their crowded appearance, giant papillae are flat-topped, polygonal, and milky-red in color. On the upper tarsus, they suggest vernal keratoconjunctivitis and giant papillary conjunctivitis with contact lens sensitivities; on the lower tarsus, they suggest atopic keratoconjunctivitis. Giant papillae may also occur at the limbus, especially in the area that is normally exposed when the eyes are open (between 2 and 4 o'clock and between 8 and 10 o'clock). Here they appear as gelatinous mounds that may encroach on the cornea. Limbal papillae are characteristic of vernal keratoconjunctivitis but rarely occur in atopic keratoconjunctivitis.

Chemosis of the conjunctiva strongly suggests acute allergic conjunctivitis but may also occur in acute gonococcal or meningococcal conjunctivitis and especially in adenoviral conjunctivitis. Chemosis of the bulbar conjunctiva is seen in patients with trichinosis. Occasionally, chemosis may appear before there is any gross cellular infiltration or exudation.

Follicles are seen in most cases of viral conjunctivitis, in all cases of chlamydial conjunctivitis except neonatal inclusion conjunctivitis, in some cases of parasitic conjunctivitis, and in some cases of toxic conjunctivitis induced by topical medications such as idoxuridine, brimonidine, apraclonidine, and dipivefrin, or by preservatives in eye drops or contact lens solutions. Follicles in the inferior fornix and at the tarsal margins have limited diagnostic value, but when they are located on the tarsi (especially the upper tarsus), chlamydial, viral, or toxic conjunctivitis (following topical medication) should be suspected.

The follicle consists of a focal lymphoid hyperplasia within the lymphoid layer of the conjunctiva and usually contains a germinal center. Clinically, it can be recognized as a rounded, avascular white or gray structure. On slitlamp examination, small vessels can be seen arising at the border of the follicle and encircling it.

Pseudomembranes and membranes are the result of an exudative process and differ only in degree. A pseudomembrane is a coagulum on the surface of the epithelium, and when it is removed, the epithelium remains intact. In contrast, a true membrane is a coagulum involving the entire epithelium, and if it is removed, a raw, bleeding surface remains. Both pseudomembranes and membranes may accompany epidemic keratoconjunctivitis, primary herpes simplex virus conjunctivitis, streptococcal conjunctivitis, diphtheria, mucous membrane pemphigoid, Stevens–Johnson syndrome, toxic epidermal necrolysis, and erythema multiforme. They may also be an aftermath of chemical exposure, especially alkali burns.

Ligneous conjunctivitis is a peculiar form of recurring membranous conjunctivitis. It is bilateral, seen mainly in children, and predominantly in females. It may be associated with other systemic findings, including nasopharyngitis and vulvovaginitis.

Granulomas of the conjunctiva always affect the stroma and most commonly are chalazia. Other endogenous causes include sarcoidosis, syphilis, cat-scratch disease, and, rarely, coccidioidomycosis. Parinaud's oculoglandular syndrome includes conjunctival granulomas and a prominent preauricular lymph node, and this group of diseases may require biopsy examination to establish the diagnosis.

Phlyctenules represent a delayed hypersensitivity reaction to microbial antigen, for example staphylococcal or mycobacterial antigens. Phlyctenules of the conjunctiva initially consist of a perivasculitis with lymphocytic cuffing of a vessel. When they progress to ulceration of the conjunctiva, the ulcer bed has many polymorphonuclear leukocytes.

Preauricular lymphadenopathy is an important sign of conjunctivitis. A grossly visible preauricular node is seen in Parinaud's oculoglandular syndrome and, rarely, in epidemic keratoconjunctivitis. A large or small preauricular node, sometimes slightly tender, occurs in primary herpes simplex conjunctivitis, epidemic keratoconjunctivitis, inclusion conjunctivitis, and trachoma. Small but nontender preauricular lymph nodes tend to occur in pharyngoconjunctival fever and acute hemorrhagic conjunctivitis. Occasionally, preauricular lymphadenopathy may be observed in children with infections of the meibomian glands.

Bacterial Conjunctivitis

Two forms of bacterial conjunctivitis are recognized: acute (including hyperacute and subacute) and chronic. Acute bacterial conjunctivitis is usually benign and self-limited, lasting no more than 14 days. Treatment with one of the many available antibacterial agents usually cures the condition within a few days. In contrast, hyper-acute (purulent) conjunctivitis caused by N gonorrhoeae or N meningitidis may lead to serious ocular complications if not treated promptly. Chronic conjunctivitis is usually secondary to eyelid disease or nasolacrimal duct obstruction.

Clinical Findings

Symptoms and Signs

The organisms that account for most cases of bacterial conjunctivitis are listed in Table 5–1. Generally it manifests as bilateral irritation and injection, purulent exudate with sticky lids on waking, and occasionally lid edema. The infection usually starts in one eye and may be spread to the eye by direct contact from the hands. It may be spread from one person to another by fomites.

Hyperacute (purulent) bacterial conjunctivitis (caused by N gonorrhoeae, Neisseria kochii, and N meningitidis) is marked by a profuse purulent exudate (Figure 5–1). Meningococcal conjunctivitis may occasionally be seen in children. Any severe, profusely exudative conjunctivitis demands immediate laboratory investigation and immediate treatment. If there is any delay, there may be severe corneal damage or loss of the eye, or the conjunctiva could become the portal of entry for either N gonorrhoeae or N meningitidis, leading to septicemia or meningitis.

Acute mucopurulent (catarrhal) conjunctivitis often occurs in epidemic form and is called “pinkeye” by most laymen. It is characterized by an acute onset of conjunctival hyperemia and a moderate amount of mucopurulent discharge. The most common causes are S pneumoniae in temperate climates and Haemophilus aegyptius in warm climates. Less common causes are staphylococci and other streptococci. The conjunctivitis caused by S pneumoniae and H aegyptius may be accompanied by subconjunctival hemorrhages. H aegyptius conjunctivitis in Brazil has been followed by a fatal purpuric fever produced by a plasmid-associated toxin of the bacteria.

Subacute conjunctivitis is caused most often by H influenzae and occasionally by Escherichia coli and proteus species. H influenzae infection is characterized by a thin, watery, or flocculent exudate.

Chronic bacterial conjunctivitis occurs in patients with nasolacrimal duct obstruction and chronic dacryocystitis, which are usually unilateral. It may also be associated with chronic bacterial blepharitis or meibomian gland dysfunction. Patients with floppy lid syndrome or ectropion may develop secondary bacterial conjunctivitis.

Rarely, bacterial conjunctivitis may be caused by Corynebacterium diphtheriae and Streptococcus pyogenes. Pseudomembranes or membranes caused by these organisms may form on the palpebral conjunctiva. The rare cases of chronic conjunctivitis produced by Moraxella catarrhalis, the coliform bacilli, proteus, etc, are as a rule indistinguishable clinically.

Laboratory Findings

In most cases of bacterial conjunctivitis, the organisms can be identified by the microscopic examination of conjunctival scrapings stained with Gram's stain or Giemsa's stain; this reveals numerous polymorphonuclear neutrophils. Conjunctival scrapings for microscopic examination and culture are recommended for all cases and are mandatory if the disease is purulent, membranous, or pseudomembranous. Antibiotic sensitivity studies are also desirable, but empirical antibiotic therapy should be started. When the results of antibiotic sensitivity tests become available, specific antibiotic therapy can then be instituted.

Complications & Sequelae

Chronic marginal blepharitis often accompanies staphylococcal conjunctivitis except in very young patients who are not subject to blepharitis. Conjunctival scarring may follow both pseudomembranous and membranous conjunctivitis, and in rare cases corneal ulceration and perforation supervene.

Marginal corneal ulceration may follow infection with N gonorrhoeae, N kochii, N meningitidis, H aegyptius, S aureus, and M catarrhalis; if the toxic products of N gonorrhoeae diffuse through the cornea into the anterior chamber, they may cause toxic iritis.

Treatment

Specific therapy of bacterial conjunctivitis depends on identification of the microbiologic agent. While waiting for laboratory reports, the physician can start topical therapy with a broad-spectrum antibacterial agent (eg, polymyxin-trimethoprim). In any purulent conjunctivitis in which the Gram stain shows gram-negative diplococci suggestive of neisseria, both systemic and topical therapy should be started immediately. If there is no corneal involvement, a single intramuscular dose of ceftriaxone, 1 g, is usually adequate systemic therapy. If there is corneal involvement, a 5-day course of parenteral ceftriaxone, 1–2 g daily, is required.

In purulent and mucopurulent conjunctivitis, the conjunctival sac should be irrigated with saline solution as necessary to remove the conjunctival secretions. To prevent spread of the disease, the patient and family should be instructed to give special attention to personal hygiene.

Course & Prognosis

Acute bacterial conjunctivitis is almost always self-limited. Untreated, it may last 10–14 days; if properly treated, 1–3 days. The exceptions are staphylococcal conjunctivitis (which may progress to blepharoconjunctivitis and enter a chronic phase) and gonococcal conjunctivitis (which, when untreated, can lead to corneal perforation and endophthalmitis). Since the conjunctiva may be the portal of entry for the meningococcus to the bloodstream and meninges, septicemia and meningitis may be the end results of meningococcal conjunctivitis.

Chronic bacterial conjunctivitis may not be self-limited and may become a troublesome therapeutic problem.

Chlamydial Conjunctivitis

Trachoma

Although worldwide the number of individuals with profound vision loss from trachoma has dropped from 6 million to 1.3 million, trachoma remains one of the leading causes of preventable blindness. It was first recognized as a cause of trichiasis (misdirected lashes) as early as the 27th century BC. It is usually endemic in regions with poor hygiene, overcrowding, poverty, lack of clean water and poor sanitation. Blinding trachoma occurs in many parts of Africa, in some parts of Asia, among Australian aborigines, and in northern Brazil. Communities with milder nonblinding trachoma occur in the same regions and in some areas of Latin America and the Pacific Islands.

Trachoma usually presents bilaterally and often spreads by direct contact or fomites, most often from other family members, who should also be examined for the disease. Insect vectors, especially flies, may play a role in transmission. The acute forms of the disease are more infectious than the cicatricial forms, and the larger the inoculum, the more severe the disease. Spread is often associated with epidemics of bacterial conjunctivitis and with the dry seasons in tropical and semitropical countries.

Clinical Findings

Symptoms and Signs

Trachoma begins as a chronic follicular conjunctivitis of childhood that progresses to conjunctival scarring (Figure 5–2). In severe cases, trichiasis occurs in early adult life as a result of severe conjunctival scarring. The constant abrasion of inturned lashes and a defective tear film lead to corneal scarring, usually after the age of 30 years (Figure 5–3).

The incubation period of trachoma averages 7 days but varies from 5–14 days. In an infant or child, the onset is usually insidious, and the disease may resolve with minimal or no complications. In adults, the onset is often subacute or acute, and complications may develop early. At onset, trachoma often resembles other bacterial conjunctivitis. The signs and symptoms usually consist of tearing, photophobia, pain, exudation, edema of the eyelids, chemosis of the bulbar conjunctiva, hyperemia, papillary hypertrophy, tarsal and limbal follicles, superior keratitis, pannus formation, and a small, tender preauricular node.

In established trachoma, there may also be superior epithelial keratitis, subepithelial keratitis, pannus, or superior limbal follicles, and ultimately the pathognomonic cicatricial remains of these follicles, known as Herbert's pits—small depressions covered by epithelium at the limbocorneal junction. The associated pannus is a fibrovascular membrane arising from the limbus, with vascular loops extending onto the cornea. All of the signs of trachoma are more severe in the upper than in the lower conjunctiva and cornea.

To establish the presence of endemic trachoma in a family or community, a substantial number of children must have at least two of the following signs:

1. Five or more follicles on the flat palpebral conjunctiva lining the upper eye lid.

2. Typical conjunctival scarring of the upper palpebral conjunctiva.

3. Limbal follicles or their sequelae (Herbert's pits).

4. An even extension of blood vessels on to the cornea, most marked at the upper limbus.

While occasional individuals will meet these criteria, it is the wide distribution of these signs in individual families and in a community that identify the presence of trachoma.

For control purposes, the World Health Organization has developed a simplified method to describe the disease (Table 5–3).

The presence of TF and TI indicates active infectious trachoma and a need for treatment. TS is evidence of damage from the disease. TT is potentially blinding and is an indication for corrective lid surgery. CO is the final blinding lesion of trachoma.

Laboratory Findings

Chlamydial inclusion bodies may be found in Giemsa-stained conjunctival scrapings, but they are not always present. Inclusions appear in the Giemsa-stained preparations as particulate, dark purple, or blue cytoplasmic masses that cap the nucleus of the epithelial cell. Fluorescent antibody stains and enzyme immunoassay tests are available commercially and are widely used in clinical laboratories. These and other new tests, including polymerase chain reaction (PCR), have superseded Giemsa staining of conjunctival smears and isolation of chlamydial agent in cell culture.

The agent of trachoma resembles the agent of inclusion conjunctivitis morphologically, but the two can be differentiated serologically by microimmunofluorescence. Trachoma is usually caused by C trachomatis serovars A, B, Ba, or C.

Differential Diagnosis

Epidemiologic and clinical factors to be considered in differentiating trachoma from other forms of follicular conjunctivitis can be summarized as follows:

1. No history of exposure to endemic trachoma speaks against the diagnosis.

2. Viral follicular conjunctivitis (due to infection with adenovirus, herpes simplex virus, picornavirus, and coxsackievirus) usually has an acute onset and is clearly resolving by 2–3 weeks.

3. Infection with genitally transmitted chlamydial strains usually has an acute onset in sexually active individuals.

4. Chronic follicular conjunctivitis with exogenous substances (molluscum nodules of the lids, topical eye medications) resolve slowly when the nodules are removed or the drug is withdrawn.

5. Parinaud's oculoglandular syndrome is manifested by massively enlarged preauricular or cervical lymph nodes, although the conjunctival lesion may be follicular.

6. Young children often have some follicles (like hypertrophied tonsils), a condition known as folliculosis.

7. The atopic conditions vernal conjunctivitis and atopic keratoconjunctivitis are associated with giant papillae that are elevated and often polygonal, with a milky-red appearance. Eosinophils are present in smears.

8. Look for a history of contact lens intolerance in patients with conjunctival scarring and pannus; giant papillae in some contact lens wearers can be confused with trachoma follicles.

Complications & Sequelae

Conjunctival scarring occur as a frequent complication of trachoma and can destroy the accessory lacrimal glands and obliterate the ductules of the lacrimal gland. These effects may drastically reduce the aqueous component of the precorneal tear film, and the film's mucous components may be reduced by loss of goblet cells. The scars may also cause distortion of the upper lid with inward deviation of individual lashes (trichiasis) or of the whole lid margin (entropion), so that the lashes constantly abrade the cornea. This often leads to corneal ulceration, bacterial corneal infections, and corneal scarring.

Ptosis, nasolacrimal duct obstruction, and dacryocystitis are other common complications of trachoma.

Treatment

Striking clinical improvement can usually be achieved with tetracycline, 1–1.5 g/d orally in four divided doses for 3–4 weeks; doxycycline, 100 mg orally twice daily for 3 weeks; or erythromycin, 1 g/d orally in four divided doses for 3–4 weeks. Several courses are sometimes necessary for actual cure. Systemic tetracyclines should not be given to a child under 7 years of age or to a pregnant woman. Tetracycline binds to calcium in the developing teeth and in growing bone and may lead to congenital yellowish discoloration of the permanent teeth and skeletal (eg, clavicular) abnormalities. Recent studies in developing countries have demonstrated that azithromycin is an effective treatment for trachoma given orally as a 1-g dose in children. Because of minimal side effects and ease of administration, this macrolide antibiotic has become the drug of choice for mass treatment campaigns.

Topical ointments or drops, including preparations of sulfonamides, tetracyclines, erythromycin, and rifampin, used four times daily for 6 weeks, are equally effective.

From the time therapy is begun, its maximum effect is usually not achieved for 10–12 weeks. The persistence of follicles on the upper tarsus for some weeks after a course of therapy should therefore not be construed as evidence of therapeutic failure.

Surgical correction of trichiasis is essential to prevent scarring from late trachoma in developing countries. Such surgery is increasingly done by nonspecialist physicians or specially trained auxiliary personnel.

Course & Prognosis

Characteristically, trachoma is a chronic disease of long duration. Under good hygienic conditions (specifically, face-washing of young children), the disease resolves or becomes milder so that severe sequelae are avoided.

Inclusion Conjunctivitis

Inclusion conjunctivitis is often bilateral and usually occurs in sexually active young people. The chlamydial agent infects the urethra of the male and the cervix of the female. Transmission to the eyes of adults is usually by oral-genital sexual practices or hand to eye transmission. About 1 in 300 persons with genital chlamydial infection develops the eye disease. Indirect transmission has been reported to occur in inadequately chlorinated swimming pools. In newborns, the agent is transmitted during birth by direct contamination of the conjunctiva with cervical secretions. Credé prophylaxis (1% silver nitrate) gives only partial protection against inclusion conjunctivitis.

Clinical Findings

Symptoms and Signs

Inclusion conjunctivitis may have an acute or a subacute onset. The patient frequently complains of redness, pseudo-ptosis, and discharge, especially in the mornings. Newborns have papillary conjunctivitis and a moderate amount of exudate, and in hyper-acute cases, pseudomembranes occasionally form and can lead to scarring. Since the newborn has no adenoid tissue in the stroma of the conjunctiva, there is no follicle formation; but if the conjunctivitis persists for 2–3 months follicles appear, similar to the conjunctival picture in older children and adults. In the newborn, chlamydial infection may cause pharyngitis, otitis media, and interstitial pneumonitis.

In adults, the conjunctiva of both tarsi—especially the lower tarsus—have papillae and follicles (Figure 5–4). Since pseudomembranes do not usually form in the adult, scarring does not usually occur. Superficial keratitis may be noted superiorly and, less often, a small superior micropannus (<1–2 mm). Subepithelial opacities, usually marginal, often develop. Otitis media may occur as a result of infection of the auditory tube.

Laboratory Findings

Because of the sexually transmitted nature of adult inclusion conjunctivitis and the need for systemic treatment of the patient and the patient's sexual partners, rapid diagnostic tests such as the direct fluorescent antibody test and enzyme-linked immunosorbent assay (ELISA) and PCR have replaced Giemsa staining in routine clinical practice. In the case of chlamydial ophthalmia neonatorum, rapid diagnosis is also imperative to prevent systemic complications such as chlamydial pneumonitis. Inclusion conjunctivitis is usually caused by C trachomatis serovars D–K with occasional isolations of serotype B. Serologic determinations are not useful in the diagnosis of ocular infections, but measurement of IgM antibody levels is extremely valuable in the diagnosis of chlamydial pneumonitis in infants.

Differential Diagnosis

Inclusion conjunctivitis can be clinically differentiated from trachoma on the following grounds:

1. Active, follicular trachoma occurs commonly in young children or others living in or exposed to a community with endemic trachoma; inclusion conjunctivitis occurs in sexually active adolescents or adults.

2. Conjunctival scarring is very rare in adult inclusion conjunctivitis.

3. Herbert's pits serve as a hallmark of previous trachoma infection.

Treatment

In Infants

Oral erythromycin suspension, 50 mg/kg/d in four divided doses for at least 14 days may be used to treat infants. Systemic treatment is necessary because chlamydial infection also involves the respiratory and gastrointestinal tracts. Topical antibiotics (tetracyclines, erythromycin, sulfonamides) are not useful in newborns treated with oral erythromycin. Both parents also should be treated with oral tetracycline or erythromycin.

In Adults

In adults, cure of chalmydial disease can be achieved with doxycycline, 100 mg orally twice daily for 7 days; erythromycin, 2 g/d for 7 days, or possibly azithromycin 1 g in a single dose. (Systemic tetracyclines should not be given to a pregnant woman or a child under 7 years of age, since they cause epiphysial problems in the fetus or staining of the young child's teeth.) The patient's sexual partners should be examined and treated.

When one of the standard therapeutic regimens is followed, recurrences are rare. If untreated, inclusion conjunctivitis runs a course of 3–9 months or longer with an average duration of 5 months.

Conjunctivitis Caused by Other Chlamydial Agents

Lymphogranuloma venereum conjunctivitis is a rare sexually transmitted disease, manifesting as dramatic granulomatous conjunctival reaction with greatly enlarged preauricular nodes (Parinaud's syndrome). It is caused by C trachomatis serovars L1, L2, or L3.

Chlamydia psittaci only rarely causes conjunctivitis in humans. Strains from parrots (psittacosis) and cats (feline pneumonitis) have caused follicular conjunctivitis in humans. The prototype strains of C pneumoniae were isolated from the conjunctiva but have not been identified as a cause of ocular disease.

Viral Conjunctivitis

Viral conjunctivitis, a common affliction, can be caused by a wide variety of viruses. Severity ranges from severe, disabling disease to mild, rapidly self-limited infection.

Acute Viral Follicular Conjunctivitis

Pharyngoconjunctival Fever

Pharyngoconjunctival fever is characterized by fever of 38.3–40°C, sore throat, and a follicular conjunctivitis in one or both eyes. The follicles are often very prominent on both the conjunctiva (Figure 5–5) and the pharyngeal mucosa. The disease can be either bilateral or unilateral. Injection and tearing often occur, and there may be transient superficial epithelial keratitis and occasionally some subepithelial opacities. Preauricular lymphadenopathy (nontender) is characteristic. The syndrome may be incomplete, consisting of only one or two of the cardinal signs (fever, pharyngitis, and conjunctivitis).

Pharyngoconjunctival fever is most frequently caused by adenovirus type 3 and occasionally by types 4 and 7. The virus can be grown on HeLa cells and identified by neutralization tests. As the disease progresses, it can also be diagnosed serologically by a rising titer of neutralizing antibody to the virus. Clinical diagnosis is a simple matter, however, and clearly more practical.

Conjunctival scrapings contain predominantly mononuclear cells, and no bacteria grow in cultures. The condition is more common in children than in adults and can be transmitted in poorly chlorinated swimming pools. The conjunctivitis is self-limited, and as such, only supportive treatment is indicated, with the episode resolving in approximately 10 days.

Epidemic Keratoconjunctivitis

The onset of epidemic keratoconjunctivitis is often unilateral, with both eyes subsequently being affected but the first eye usually being more severely affected. Initial symptoms include conjunctival injection, moderate pain, and tearing. Usually by 5–14 days, photophobia, epithelial keratitis, and round subepithelial opacities have also developed (Figure 5–6). Corneal sensation is normal. A tender preauricular node is characteristic. Edema of the eyelids, chemosis, and conjunctival hyperemia mark the acute phase, with follicles and subconjunctival hemorrhages often appearing within 48 hours. Pseudomembranes (Figure 5–7) (and occasionally true membranes) may occur and may be followed by flat scars or symblepharon formation.

The conjunctivitis usually resolves by 3–4 weeks at most. The subepithelial opacities are concentrated in the central cornea, usually sparing the periphery, and may persist for months but generally heal without scars.

Epidemic keratoconjunctivitis is caused by adenovirus types 8, 19, 29, and 37 (subgroup D of the human adenoviruses). They can be isolated in cell culture and identified by neutralization tests. Scrapings from the conjunctiva show a primarily mononuclear inflammatory reaction (Figure 5–8); when pseudomembranes occur, neutrophils may also be prominent.

Epidemic keratoconjunctivitis in adults is confined to the external eye, but in children there may be systemic symptoms of viral infection as fever, sore throat, otitis media, and diarrhea. Nosocomial transmission during eye examinations takes place all too often by way of the physician's examination, use of improperly sterilized ophthalmic instruments, or use of contaminated solutions. Eye solutions, particularly topical anesthetics, can be contaminated when a dropper tip aspirates infected material from the conjunctiva or cilia. The virus can persist in the solution, which becomes a source of spread.

The danger of contaminated solution bottles can be avoided by the use of individual sterile droppers or unit-dose packages of eye drops. Regular hand washing between examinations and careful cleaning and sterilization of instruments that touch the eyes—especially tonometers—are also mandatory. Applanation tonometers should be cleaned by wiping with alcohol or hypochlorite, then rinsing with sterile water and carefully drying.

There is no specific therapy at present, but cold compresses and artificial tears will relieve some symptoms. Corticosteroids utilized during acute conjunctivitis may prolong late corneal involvement and should be avoided whenever possible. Antibacterial agents should be administered if bacterial superinfection occurs.

Herpes Simplex Virus Conjunctivitis

Herpes simplex virus (HSV) conjunctivitis, usually a disease of young children, is an uncommon entity characterized by unilateral injection, irritation, mucoid discharge, pain, and mild photophobia. It occurs during primary infection with HSV or during recurrent episodes of ocular herpes (Figure 5–9). It is often associated with herpes simplex keratitis, in which the cornea shows discrete epithelial lesions that usually coalesce to form single or multiple branching epithelial (dendritic) ulcers (Figure 5–10). The conjunctivitis is follicular or, less often, pseudomembranous. (Patients receiving topical antivirals may develop follicular conjunctivitis that can be differentiated because the herpetic follicular conjunctivitis has an acute onset.) Herpetic vesicles may sometimes appear on the eyelids and lid margins, associated with severe edema of the eyelids. Typically, there is a small tender preauricular node.

No bacteria are found in scrapings or recovered in cultures. If the conjunctivitis is follicular, the predominant inflammatory reaction is mononuclear, but if it is pseudomembranous, the predominant reaction is polymorphonuclear, owing to the chemotaxis of necrosis. Intranuclear inclusions (because of the margination of the chromatin) can be seen in conjunctival and corneal cells if Bouin fixation and the Papanicolaou stain are used but not in Giemsa-stained smears. The finding of multinucleated giant epithelial cells has diagnostic value.

The virus can be readily isolated by gently rubbing a dry Dacron or calcium alginate swab over the conjunctiva and transferring the infected cells to a susceptible tissue culture.

HSV conjunctivitis may persist for 2–3 weeks, and if it is pseudomembranous, it may leave fine linear or flat scars. Complications consist of corneal involvement (including dendrites) and vesicles on the skin. Although type 1 herpesvirus causes the overwhelming majority of ocular cases, type 2 is the usual cause of herpetic conjunctivitis in newborns and a rare cause in adults. In the newborn, there may be generalized disease with encephalitis, chorioretinitis, hepatitis, etc. Any HSV infection in the newborn must be treated with systemic antiviral therapy (acyclovir) and monitored in a hospital setting.

If the conjunctivitis occurs in a child over 1 year of age or in an adult, it is usually self-limited and may not require therapy. Topical or systemic antivirals should be given, however, to prevent corneal involvement. For corneal ulcers, corneal debridement may be performed by gently wiping the ulcer with a dry cotton swab, applying antiviral drops, and patching the eye for 24 hours. Topical antivirals alone should be applied for 7–10 days (eg, trifluridine every 2 hours while awake). Herpetic keratitis may also be treated with 3% acyclovir ointment (not available in the United States) five times daily for 10 days, or with oral acyclovir, 400 mg five times daily for 7 days. Corticosteroid use is contraindicated since it may aggravate herpetic infections causing a prolonged and usually more severe course.

Newcastle Disease Conjunctivitis

Newcastle disease conjunctivitis is a rare disorder characterized by burning, itching, pain, redness, tearing, and (rarely) blurring of vision. It often occurs in small epidemics among poultry workers handling infected birds or among veterinarians or laboratory helpers working with live vaccines or virus.

The conjunctivitis resembles that caused by other viral agents, with chemosis, a small preauricular node, and follicles on the upper and lower tarsus. No treatment is available or necessary for this self-limited disease.

Acute Hemorrhagic Conjunctivitis

All of the continents and most of the islands of the world have had major epidemics of acute hemorrhagic conjunctivitis. It was first recognized in Ghana in 1969. It is caused by enterovirus type 70 and occasionally by coxsackievirus A24.

Characteristically, the disease has a short incubation period (8–48 hours) and course (5–7 days). The usual signs and symptoms are pain, photophobia, foreign-body sensation, copious tearing, redness, lid edema, and subconjunctival hemorrhages (Figure 5–11). Chemosis sometimes also occurs. The subconjunctival hemorrhages are usually diffuse but may be punctate at onset, beginning in the upper bulbar conjunctiva and spreading to the lower. Most patients have preauricular lymphadenopathy, conjunctival follicles, and epithelial keratitis. Anterior uveitis has been reported; fever, malaise, and generalized myalgia have been observed in 25% of cases; and motor paralysis of the lower extremities has occurred in rare cases in India and Japan.

The virus is transmitted by close person-to-person contact and by such fomites as common linens, contaminated optical instruments, and water. Recovery occurs within 5–7 days, and there is no known treatment. In the United States, at times closure of schools has been needed to stop epidemics.

Chronic Viral Conjunctivitis

Molluscum Contagiosum Blepharoconjunctivitis

A molluscum nodule on the lid margins or the skin of the lids or brow may produce unilateral chronic follicular conjunctivitis, superior keratitis, and superior pannus that resembles trachoma. The inflammatory reaction is predominantly mononuclear (unlike the reaction in trachoma), and the round, waxy, pearly-white, noninflammatory lesion with an umbilicated center is typical of molluscum contagiosum (Figure 5–12). Biopsy shows eosinophilic cytoplasmic inclusions that fill the entire cytoplasm of the enlarged cell, pushing its nucleus to one side.

Excision or simple incision of the nodule, thus allowing peripheral blood to permeate it, or cryotherapy cures the conjunctivitis. On very rare occasions, molluscum nodules have occurred on the conjunctiva. In these cases, excision of the nodule has also relieved the conjunctivitis. Multiple lid or facial lesions of molluscum contagiosum occur in patients with AIDS.

Varicella-Zoster Blepharoconjunctivitis

Hyperemia and an infiltrative conjunctivitis—associated with the typical vesicular eruption along the dermatomal distribution of the ophthalmic branch of the trigeminal nerve (Figure 5–13) —are characteristic of ophthalmic (herpes) zoster (shingles), due to reactivation of varicella-zoster virus infection. The conjunctivitis is usually papillary, but follicles, pseudomembranes, and transitory vesicles that later ulcerate have all been noted. A tender preauricular lymph node occurs early in the disease. Scarring of the lid, entropion, and the misdirection of individual lashes are sequelae.

The lid lesions of varicella, which are like the skin lesions (pox) elsewhere, may appear on both the lid margins and the lids and often leave scars. A mild exudative conjunctivitis often occurs, but discrete conjunctival lesions (except at the limbus) are very rare. Limbal lesions resemble phlyctenules and may go through all the stages of vesicle, papule, and ulcer. The adjacent cornea becomes infiltrated and may vascularize.

In both zoster and varicella, scrapings from lid vesicles contain giant cells and a predominance of polymorphonuclear leukocytes; scrapings from the conjunctiva in varicella and from conjunctival vesicles in zoster may contain giant cells and monocytes. The virus can be recovered in tissue cultures of human embryo cells.

In the immunocompetent, oral antiviral therapy (acyclovir 800 mg orally five times daily, famciclovir, 500 mg three times daily, or valacyclovir, 1 g three times daily, all for 7 days), if started within 72 hours after appearance of the rash, reduces the incidence of ocular complications but not necessarily of postherpetic neuralgia. The value of supplementary therapy with oral prednisone, initially 60 mg per day reducing over 3 weeks, is uncertain. In the immunocompromised, oral antiviral therapy should be continued for up to 2 weeks and may need to be given intravenously if there is evidence of progression of disease. Oral prednisone is contraindicated.

Measles Keratoconjunctivitis

The characteristic enanthem of measles frequently precedes the skin eruption. At this early stage, the conjunctiva may have a peculiar glassy appearance, followed within a few days by swelling of the semilunar fold (Meyer's sign). Several days before the skin eruption, an exudative conjunctivitis with a mucopurulent discharge develops. At the time of the skin eruption, Koplik's spots appear on the conjunctiva and occasionally on the caruncle. At some time (early in children, late in adults), epithelial keratitis supervenes.

In the immunocompetent patient, measles keratoconjunctivitis has few or no sequelae, but in malnourished or otherwise immunocompromised patients, the ocular disease is frequently associated with a secondary HSV or bacterial infection due to S pneumoniae, H influenzae, and other organisms. These agents may lead to purulent conjunctivitis with associated corneal ulceration and severe visual loss. Herpes infection can cause severe corneal ulceration with corneal perforation and loss of vision in poorly nourished children in developing countries.

Conjunctival scrapings show a mononuclear cell reaction unless there are pseudomembranes or secondary infection. Giemsa-stained preparations contain giant cells. Since there is no specific therapy, only supportive measures are indicated unless a secondary infection is present.

Rickettsial Conjunctivitis

All rickettsiae recognized as pathogenic for humans may attack the conjunctiva, and the conjunctiva may be their portal of entry.

Q fever is associated with severe conjunctival hyperemia. Treatment with systemic tetracycline or chloramphenicol is curative.

Marseilles fever (boutonneuse fever) is often associated with ulcerative or granulomatous conjunctivitis and a grossly visible preauricular lymph node.

Endemic (murine) typhus, scrub typhus, Rocky Mountain spotted fever, and epidemic typhus have associated, variable, and usually mild conjunctival signs.

Fungal Conjunctivitis

Candidal Conjunctivitis

Conjunctivitis caused by Candida species (usually Candida albicans) is a rare infection that usually appears as a white plaque. This may occur in diabetics or immunocompromised patients as an ulcerative or granulomatous conjunctivitis.

Scrapings show a polymorphonuclear cell inflammatory reaction. The organism grows readily on blood agar or Sabouraud's medium and can be readily identified as a budding yeast or, rarely, as pseudohyphae.

The infection responds to amphotericin B (3–8 mg/mL) in aqueous (not saline) solution or to applications of nystatin dermatologic cream (100,000 U/g) four to six times daily. The ointment must be applied carefully to ensure that it reaches the conjunctival sac and does not just build up on the lid margins.

Other Fungal Conjunctivitides

Sporothrix schenckii may rarely involve the conjunctiva or the eyelids. It is a granulomatous disease associated with a visible preauricular node. Microscopic examination of a biopsy of the granuloma reveals gram-positive, cigar-shaped conidia (spores).

Rhinosporidium seeberi may rarely affect the conjunctiva, lacrimal sac, lids, canaliculi, and sclera. The typical lesion is a polypoid granuloma that bleeds after minimal trauma. Histologic examination shows a granuloma with enclosed large spherules containing myriad endospores. Treatment is by simple excision and cauterization of the base.

Coccidioides immitis may rarely cause a granulomatous conjunctivitis associated with a grossly visible preauricular node (Parinaud's oculoglandular syndrome). This is not a primary disease but a manifestation of metastatic infection from a primary pulmonary infection (San Joaquin Valley fever). Disseminated disease suggests a poor prognosis.

Parasitic Conjunctivitis

Thelazia Californiensis Infection

The natural habitat of this roundworm is the eye of the dog, but it can also infect the eyes of cats, sheep, black bears, horses, and deer. Accidental infection of the human conjunctival sac has occurred. The disease can be treated effectively by removing the worms from the conjunctival sac with forceps or a cotton-tipped applicator.

Loa Loa Infection

L loa is the eye worm of Africa. It lives in the connective tissue of humans and monkeys, and the monkey may be its reservoir. The parasite is transmitted by the bite of the horse or mango fly. The mature worm may then migrate to the lid, the conjunctiva, or the orbit.

Infection with L loa is accompanied by a 60–80% eosinophilia, but diagnosis is made by identifying the worm on removal or by finding microfilariae in blood examined at midday.

Diethylcarbamazine is currently the drug of choice.

Ascaris Lumbricoides Infection (Butcher's Conjunctivitis)

Ascaris may cause a rare type of violent conjunctivitis. When butchers or persons performing postmortem examinations cut tissue containing ascaris, the tissue juice of some of the organisms may accidentally splash in the eye. A violent and painful toxic conjunctivitis ensues, marked by extreme chemosis and lid edema. Treatment consists of rapid and thorough irrigation of the conjunctival sac.

Trichinella Spiralis Infection

T spiralis does not cause a true conjunctivitis, but in the course of its general dissemination, there may be a doughy edema of the upper and lower eyelids, and over 50% of patients have chemosis—a pale, lemon-yellow swelling most marked over the lateral and medial rectus muscles and fading toward the limbus. The chemosis may last a week or more, and there is often pain on movement of the eyes.

Schistosoma Haematobium Infection

Schistosomiasis (bilharziasis) is endemic in Egypt, especially in the region irrigated by the Nile. Granulomatous conjunctival lesions appearing as small, soft, smooth, pinkish-yellow tumors occur, especially in males. The symptoms are minimal. Diagnosis depends on microscopic examination of biopsy material, which shows a granuloma-containing lymphocytes, plasma cells, giant cells, and eosinophils surrounding bilharzial ova in various stages of disintegration.

Treatment consists of excision of the conjunctival granuloma and systemic therapy with antimonials such as niridazole.

Taenia Solium Infection

T Solium rarely causes conjunctivitis but more often invades the retina, choroid, or vitreous to produce ocular cysticercosis. As a rule, the affected conjunctiva shows a subconjunctival cyst in the form of a localized hemispherical swelling, usually at the inner angle of the lower fornix, which is adherent to the underlying sclera and painful on pressure. The conjunctiva and lid may be inflamed and edematous.

Diagnosis is based on a positive complement fixation or precipitin test or on demonstration of the organism in the gastrointestinal tract. Eosinophilia is a constant feature.

The best treatment is to excise the lesion. The intestinal condition can be treated by niclosamide.

Pthirus Pubis Infection (Pubic Louse Infection)

P. pubis may infest the cilia and margins of the eyelids. Because of its size, the pubic louse seems to require widely spaced hair. For this reason it has a predilection for the widely spaced cilia as well as for pubic hair. The parasites apparently release an irritating substance (probably feces) that produces a toxic follicular conjunctivitis in children and an irritating papillary conjunctivitis in adults. The lid margin is usually red, and the patient may complain of intense itching.

Finding the adult organism or the ova-shaped nits cemented to the eyelashes is diagnostic.

Lindane (Kwell) 1% or RID (pyrethrins), applied to the pubic area and lash margins after removal of the nits, is usually curative. Application of lindane or RID to the lid margins must be undertaken with great care to avoid contact with the eye. Any ointment applied to the lid margin tends to smother the adult organisms. The patient's family and close contacts should be examined and treated. All clothes and fomites should be carefully washed.

Ophthalmomyiasis

Myiasis is infection with larvae of flies. Many different species of flies may produce myiasis. The ocular tissues may be injured by mechanical transmission of disease-producing organisms and by the parasitic activities of the larvae in the ocular tissues. The larvae are able to invade either necrotic or healthy tissue. Many individuals become infected by accidental ingestion of the eggs or larvae or by contamination of external wounds or skin. Infants and young children, alcoholics, and debilitated unattended patients are common targets for infection with myiasis-producing flies.

These larvae may affect the ocular surface, the intraocular tissues, or the deeper orbital tissues.

Ocular surface involvement may be caused by Musca domestica, the housefly, Fannia, the latrine fly, and Oestrus ovis, the sheep botfly. These flies deposit their eggs at the lower lid margin or inner canthus, and the larvae may remain on the surface of the eye, causing irritation, pain, and conjunctival hyperemia.

Treatment of ocular surface myiasis is by mechanical removal of the larvae after topical anesthesia.

Immunologic (Allergic) Conjunctivitis

Immediate Humoral Hypersensitivity Reactions

Hay Fever Conjunctivitis

A mild, nonspecific conjunctival inflammation is commonly associated with hay fever (allergic rhinitis). In most cases, there is a history of allergy to pollens, grasses, animal danders, etc. The patient complains of itching, tearing, and redness of the eyes and often states that the eyes seem to be “sinking into the surrounding tissue.” There is mild injection of the palpebral and bulbar conjunctiva, and during acute attacks often a severe chemosis, which no doubt accounts for the “sinking” description (Figure 5–14). There may be a small amount of ropy discharge, especially if the patient has been rubbing the eyes. Eosinophils are difficult to find in conjunctival scrapings. A papillary conjunctivitis may occur if the allergen persists.

Treatment consists of the instillation of topical anti-histamine-vasoconstrictor preparations. Cold compresses are helpful to relieve itching, and antihistamines by mouth are of some value. The immediate response to treatment is satisfactory, but recurrences are common unless the antigen is eliminated. Fortunately, the frequency of the attacks and the severity of the symptoms tend to moderate as the patient ages.

Vernal Keratoconjunctivitis

Vernal keratoconjunctivitis, also known as “spring catarrh,” “seasonal conjunctivitis” or “warm weather conjunctivitis,” is an uncommon bilateral allergic disease that usually begins in the prepubertal years and lasts for 5–10 years. It occurs much more often in boys than in girls. The specific allergen or allergens are difficult to identify, but patients with vernal keratoconjunctivitis usually show other manifestations of allergy known to be related to grass pollen sensitivity. The disease is less common in temperate than in warm climates and is almost nonexistent in cold climates. It is almost always more severe during the spring, summer, and fall than in the winter. It is most commonly seen in sub-Saharan Africa and the Middle East.

The patient usually complains of extreme itching and a ropy discharge. There is often a family history of allergy (hay fever, eczema, etc), and sometimes there is a history of allergy in the young patient as well. The conjunctiva has a milky appearance with many fine papillae in the lower palpebral conjunctiva. The upper palpebral conjunctiva often has giant papillae that give a cobblestone appearance (Figure 5–15). Each giant papilla is polygonal, has a flat top, and contains tufts of capillaries.

A stringy conjunctival discharge and a fine, fibrinous pseudomembrane (Maxwell-Lyons sign) may be noted, especially on the upper tarsus on exposure to heat. In some cases, especially in persons of black African ancestry, the most prominent lesions are located at the limbus, where gelatinous swellings (papillae) are noted (Figure 5–16). A pseudogerontoxon (arcus-like haze) is often noted in the cornea adjacent to the limbal papillae. Trantas' dots are whitish dots seen at the limbus in some patients with vernal keratoconjunctivitis during the active phase of the disease. Many eosinophils and free eosinophilic granules are found in Giemsa-stained smears of the conjunctival exudate and in Trantas' dots.

Micropannus is often seen in both palpebral and limbal vernal keratoconjunctivitis, but gross pannus is unusual. Conjunctival scarring usually does not occur unless the patient has been treated with cryotherapy, surgical removal of the papillae, irradiation, or other damaging procedure. Superficial corneal (“shield”) ulcers (oval and located superiorly) may form and may be followed by mild corneal scarring. A characteristic diffuse epithelial keratitis frequently occurs. None of the corneal lesions respond well to standard treatment.

The disease may also be associated with keratoconus.

Treatment

Since vernal keratoconjunctivitis is a self-limited disease, it must be recognized that the medication used to treat the symptoms may provide short-term benefit but long-term harm. Topical and systemic steroids, which relieve the itching, affect the corneal disease only minimally, and their side effects (glaucoma, cataract, and other complications) can be severely damaging. Newer mast cell stabilizer-antihistamine combinations are useful prophylactic and therapeutic agents in moderate to severe cases. Vasoconstrictors, cold compresses, and ice packs are helpful, and sleeping (and, if possible, working) in cool, air-conditioned rooms can keep the patient reasonably comfortable. Probably the best remedy of all is to relocate to a cool, moist climate. Patients able to do so benefit from a marked reduction in symptoms, if not a complete cure.

The acute symptoms of an extremely photophobic patient who is unable to function can often be relieved by a short course of topical or systemic steroids followed by vasoconstrictors, cold packs, and regular use of histamine-blocking eye drops. Topical nonsteroidal anti-inflammatory agents, such as ketorolac, mast cell stabilizers, such as lodoxamide, and topical antihistamines (see Chapter 22) may provide significant symptomatic relief but may slow the reepithelialization of a shield ulcer. As has already been indicated, the prolonged use of steroids should be avoided. Recent clinical studies have shown that topical 2% cyclosporine eye drops are effective in severe unresponsive cases. Supratarsal injection of depot corticosteroids with or without surgical excision of giant papillae has been demonstrated to be effective for vernal shield ulcers.

Desensitization to grass pollens and other antigens has not been rewarding. Staphylococcal blepharitis and conjunctivitis are frequent complications and should be treated. Recurrences are the rule, particularly in the spring and summer; but after a number of recurrences, the papillae disappear completely, leaving no scars.

Atopic Keratoconjunctivitis

Patients with atopic dermatitis (eczema) often also have atopic keratoconjunctivitis. The symptoms and signs are a burning sensation, mucoid discharge, redness, and photophobia. The lid margins are erythematous, and the conjunctiva has a milky appearance. There are fine papillae (Figure 5–17), but giant papillae are less developed than in vernal keratoconjunctivitis and occur more frequently on the lower rather than upper palpebral conjunctiva. Severe corneal signs appear late in the disease after repeated exacerbations of the conjunctivitis. Superficial peripheral keratitis develops and is followed by vascularization. In severe cases, the entire cornea becomes hazy and vascularized, and visual acuity is reduced.

There is usually a history of allergy (hay fever, asthma, or eczema) affecting the patient or the patient's family. Most patients have had atopic dermatitis since infancy. Scarring of the flexure creases of the antecubital folds and of the wrists and knees is common. Like the dermatitis with which it is associated, atopic keratoconjunctivitis has a protracted course and is subject to exacerbations and remissions. As in vernal keratoconjunctivitis, it tends to become less active when the patient reaches the fifth decade.

Scrapings of the conjunctiva show eosinophils, though not nearly as many as are seen in vernal keratoconjunctivitis. Scarring of both the conjunctiva and cornea is often seen, and an atopic cataract, a posterior subcapsular plaque, or an anterior shield-like cataract may develop. Keratoconus, retinal detachment, and herpes simplex keratitis are all more likely than usual in patients with atopic keratoconjunctivitis, and there are many cases of secondary bacterial blepharitis and conjunctivitis, usually staphylococcal.

The management of atopic keratoconjunctivitis is often discouraging. Any secondary infection must be treated. Environmental control should be considered. Chronic topical therapy with mast cell stabilizers, antihistamines, and nonsteroidal anti-inflammatory agents (see Chapter 22) is the mainstay in treatment. Oral antihistamines are also beneficial. A short course of topical steroids may also relieve symptoms. In severe cases, plasmapheresis or systemic immunosuppression may be an adjunct to therapy. In advanced cases with severe corneal complications, corneal transplantation may be needed to improve the visual acuity.

Giant Papillary Conjunctivitis

Giant papillary conjunctivitis with signs and symptoms resembling those of vernal conjunctivitis may develop in patients wearing plastic artificial eyes or contact lenses (Figure 5–18). It is probably a basophil-rich delayed hypersensitivity disorder (Jones-Mote hypersensitivity), perhaps with an IgE humoral component. Use of glass instead of plastic for prostheses and spectacle lenses instead of contact lenses is curative. If the goal is to maintain contact lens wear, additional therapy will be required. Careful contact lens care, including preservative-free agents, is essential. Hydrogen peroxide disinfection and enzymatic cleaning of contact lenses may also help. Alternatively, changing to a weekly disposable or daily disposable contact lens system may be beneficial. If these treatments are unsuccessful, use of contact lenses should be discontinued.

Delayed Hypersensitivity Reactions

Phlyctenulosis

Phlyctenular keratoconjunctivitis is a Type IV delayed hypersensitivity response to microbial proteins, including the proteins of the tubercle bacillus, Staphylococcus species, C albicans, Coccidioides immitis, H aegyptius, and C trachomatis serovars L1, L2, and L3. Until recently, by far the most frequent cause of phlyctenulosis in the United States was delayed hypersensitivity to the protein of the human tubercle bacillus. This is still the most common cause in regions where tuberculosis is still prevalent. In the United States, however, most cases are now associated with delayed hypersensitivity to S. aureus.

The conjunctival phlyctenule begins as a small lesion (usually 1–3 mm in diameter) that is hard, red, elevated, and surrounded by a zone of hyperemia. At the limbus it is often triangular in shape, with its apex toward the cornea (Figure 5–19). In this location it develops a grayish-white center that soon ulcerates and then subsides within 10–12 days. The patient's first phlyctenule and most of the recurrences develop at the limbus, but there may also be corneal, bulbar, and, very rarely, even tarsal phlyctenules.

Unlike the conjunctival phlyctenule, which leaves no scar, the corneal phlyctenule develops as an amorphous gray infiltrate and always leaves a scar. Consistent with this difference is the fact that scars form on the corneal side of the limbal lesion and not on the conjunctival side. The result is a triangular scar with its base at the limbus—a valuable sign of old phlyctenulosis when the limbus has been involved.

Conjunctival phlyctenules usually produce only irritation and tearing, but corneal and limbal phlyctenules are usually accompanied by intense photophobia. Phlyctenulosis is often triggered by active blepharitis, acute bacterial conjunctivitis, and dietary deficiencies (Figure 5–20). Phlyctenular scarring, which may be minimal or extensive, is often followed by Salzmann's nodular degeneration.

Histologically, the phlyctenule is a focal subepithelial and perivascular infiltration of small round cells, followed by a preponderance of polymorphonuclear cells when the overlying epithelium necrotizes and sloughs—a sequence of events characteristic of the delayed tuberculin-type hypersensitivity reaction.

Phlyctenulosis induced by tuberculoprotein and the proteins of other systemic infections responds dramatically to topical corticosteroids. A major reduction of symptoms occurs within 24 hours and disappearance of the lesion in another 24 hours. Phlyctenulosis produced by staphylococcal proteins responds somewhat more slowly. Topical antibiotics should be added for active staphylococcal blepharoconjunctivitis. Treatment should be aimed at the underlying disease, and steroids, when effective, should be used only to control acute symptoms and persistent corneal scarring. Severe corneal scarring may require corneal transplantation.

Mild Conjunctivitis Secondary to Contact Blepharitis

Contact blepharitis caused by atropine, neomycin, broad-spectrum antibiotics, and other topically applied medications, or the preservatives in them, is often followed by a mild infiltrative conjunctivitis that produces hyperemia, mild papillary hypertrophy, a mild mucoid discharge, and some irritation (Figure 5–21). Examination of Giemsa-stained scrapings often discloses only a few degenerated epithelial cells, a few polymorphonuclear and mononuclear cells, and no eosinophils.

Treatment should be directed toward finding the offending agent and eliminating it. The contact blepharitis may clear rapidly with topical corticosteroids, but their use should be limited. Long-term use of steroids on the lids may lead to steroid glaucoma and to skin atrophy with disfiguring telangiectasis.

Conjunctivitis Due to Autoimmune Disease

Sjögren's Syndrome

Sjögren's syndrome is an autoimmune disease characterized by dry eye syndrome (keratoconjunctivitis sicca) and dry mouth (xerostomia). When associated with a generalized autoimmune disease, usually rheumatoid arthritis, it is known as secondary rather than primary Sjögren's syndrome. The syndrome is overwhelmingly more common in women at or beyond the menopause than in other groups, although men and younger women may also be affected. The lacrimal gland is infiltrated with lymphocytes and occasionally with plasma cells, leading to atrophy and destruction of the glandular structures.

Dry eye syndrome is characterized by bulbar conjunctival hyperemia (especially in the palpebral aperture) and symptoms of irritation that are out of proportion to the mild inflammatory sign, pain increasing by the afternoon and evening but being absent or only slight in the morning. It often begins as a mild conjunctivitis with a mucoid discharge. Blotchy epithelial lesions appear on the cornea, more prominently in its lower half (Figure 5–22), and filaments may be seen. Rose bengal or lissamine green staining of the cornea and conjunctiva in the palpebral aperture is a helpful diagnostic test. The tear film is diminished and often contains shreds of mucus. Results of the Schirmer test are abnormal.

The diagnosis is confirmed by demonstrating lymphocytic and plasma cell infiltration of the accessory salivary glands in a labial biopsy obtained by means of a simple surgical procedure (Figure 5–23).

Treatment should be directed toward preserving and improving the quality of the tear film with artificial tears, with obliteration of the puncta, and with side shields, moisture chambers, and Buller shields. Recent clinical studies have demonstrated the efficacy of preservative-free, low-dose corticosteroid preparations and topical cyclosporine in the treatment of Sjögren's syndrome. As a rule, the simpler measures should be tried first.

(Dry eye syndrome [keratoconjunctivitis sicca] is also discussed in the subsequent section on Tears.)

Mucous Membrane (Ocular Cicatricial) Pemphigoid

Mucous membrane pemphigoid usually begins as a nonspecific chronic conjunctivitis that is resistant to therapy. The conjunctiva may be affected alone or, as indicated by its name, in combination with the mouth, nose, esophagus, vulva, and skin. The conjunctivitis leads to progressive scarring, obliteration of the fornices (especially the lower fornix), symblepharon formation (Figure 5–24), and entropion with trichiasis. The patient complains of pain, irritation, and blurring of vision. The cornea is affected only secondarily as a result of trichiasis and lack of the precorneal tear film. The disease is often more severe in women than in men and typically occurs in middle life, very rarely before age 45. In women, it may progress to blindness in a year or less; in men, progress is slower, and spontaneous remission sometimes occurs.

Conjunctival biopsies may contain eosinophils, and the basement membrane will stain positively with certain immunofluorescent stains (IgG, IgM, IgA complement). Active inflammatory disease may respond to dapsone or conventional immunosuppressant therapy but newer agents, such as tumor necrosis factor (TNF) antagonist, increasingly are being used. The secondary consequences, such as tear deficiency, trichiais, and ocular toxicity need to be recognized and treated appropriately. Generally, the course is long and the prognosis poor, with blindness due to complete symblepharon and corneal desiccation.

Chemical or Irritative Conjunctivitis

Iatrogenic Conjunctivitis from Topically Applied Drugs

A toxic follicular conjunctivitis or an infiltrative, nonspecific conjunctivitis, followed by scarring, is often produced by the prolonged administration of topical medications such as idoxuridine, brimonidine, apraclonidine, and dipivefrin, or by preservatives in eye drops. Silver nitrate instilled into the conjunctival sac at birth (Credë prophylaxis) is a frequent cause of mild chemical conjunctivitis. If tear production is reduced by continual irritation, the conjunctiva can be further damaged by the lack of dilution of the noxious agent as it is instilled into the conjunctival sac.

Conjunctival scrapings often contain keratinized epithelial cells, a few polymorphonuclear neutrophils, and an occasional oddly shaped cell. Treatment consists of stopping the offending agent and using bland drops or none at all. Often the conjunctival reaction persists for weeks or months after its cause has been eliminated.

Occupational Conjunctivitis from Chemicals & Irritants

Acids, alkalies, smoke, wind, and almost any irritating substance that enters the conjunctival sac may cause conjunctivitis. Some common irritants are fertilizers, soaps, deodorants, hair sprays, tobacco, makeup preparations (mascara, etc), and various acids and alkalies. In certain areas, smog has become the most common cause of mild chemical conjunctivitis. The specific irritant in smog has not been positively identified, and treatment is nonspecific. There are no permanent ocular effects, but affected eyes are frequently chronically red and irritated.

In acid burns, the acids denature the tissue proteins and the effect is immediate. Alkalies do not denature the proteins, but tend to penetrate the tissues deeply and rapidly and to linger in the conjunctival tissue. Once in contact with the ocular surface, alkalies saponify fatty acids and continue to inflict damage for hours or days, depending on the molar concentration of the alkali and the amount introduced. Adhesions between the bulbar and palpebral conjunctiva (symblepharon) and corneal scarring are more likely to occur if the offending agent is an alkali. In either event, pain, injection, photophobia, and blepharospasm are the principal symptoms of caustic burns. A careful history will usually the identify the precipitating event.

Immediate and profuse irrigation of the conjunctival sac with water or saline solution is of great importance, and any solid material should be removed mechanically. Do not use chemical antidotes. Further treatment may involve intensive topical steroids, ascorbate and citrate eyedrops, cycloplegics, antiglaucoma treatment as necessary, cold compresses, and systemic analgesics (see Chapter 19). Bacterial conjunctivitis may be treated with appropriate antibacterial agents. Corneal scarring may require corneal transplantation, and symblepharon may require reconstruction of the conjunctiva. Severe conjunctival and corneal burns have a poor prognosis even with surgery, but if proper treatment is started immediately, scarring may be minimized and the prognosis improved.

Caterpillar Hair Conjunctivitis (Ophthalmia Nodosum)

On rare occasions, caterpillar hairs are introduced into the conjunctival sac, where they produce one or many granulomas (ophthalmia nodosum). Under magnification, each granuloma is seen to contain a small foreign body.

Treatment by removal of each hair individually is effective. If a hair is retained, invasion of the sclera and uveal tract may occur.

Conjunctivitis of Unknown Cause

Folliculosis

Folliculosis is a widespread benign, bilateral noninflammatory conjunctival condition characterized by follicular hypertrophy. It is more common in children than in adults, and the symptoms are minimal. The follicles are more numerous in the lower than in the upper cul-de-sac and palpebral conjunctiva. There is no associated inflammation or papillary hypertrophy, and complications do not occur.

There is no treatment for folliculosis, which disappears spontaneously after a course of 2–3 years. The cause is unknown, but folliculosis may be only a manifestation of a generalized adenoidal hypertrophy.

Chronic Follicular Conjunctivitis (Axenfeld's Conjunctivitis)

Chronic follicular conjunctivitis is a bilateral transmissible disease of children characterized by numerous follicles in the upper and lower palpebral conjunctiva. There are minimal conjunctival exudates and minimal inflammation but no complications. Treatment is ineffective, but the disease is self-limited within 2 years.

Ocular Rosacea

Ocular rosacea is a common complication of acne rosacea and probably occurs more often in light-skinned people, especially those of northern European ancestry. It is usually a blepharoconjunctivitis, but in severe cases, corneal ulceration and scarring may also occur. The patient generally complains of mild injection and irritation but discomfort increases if there is acute corneal involvement.

There is dilation of the blood vessels of the eyelid margin (Figure 5–25) and frequently an accompanying staphylococcal blepharitis. The conjunctiva is hyperemic, especially in the exposed interpalpebral region. Less often, there may be a nodular conjunctivitis with small gray nodules on the bulbar conjunctiva, especially near the limbus, which may ulcerate superficially. The lesions can be differentiated from phlyctenules by the fact that even after they subside, large dilated vessels persist. Microscopic examination of the nodules shows lymphocytes and epithelial cells.

The peripheral cornea may ulcerate, characteristically with a narrow base at the limbus and a wider infiltrate centrally; vascularize, the resulting pannus often being wedge or spade-shaped and situated predominantly inferiorly; and scar (Figure 5–26).

Treatment of ocular rosacea consists of the elimination of hot, spicy foods and of alcoholic beverages, which are responsible for dilation of the facial vessels (Figure 5–27). Any secondary staphylococcal infection, which may also result in conjunctival concretions (Figure 5–28), should be treated. A course of oral tetracycline, standard doxycycline, or sustained release doxycycline may be used, with a maintenance dose often being needed to control more severe disease.

Ocular rosacea is a chronic, recurrent disease and may respond poorly to treatment. If the cornea is not affected, the visual prognosis is good; but corneal lesions tend to recur and progress, and the vision grows steadily worse over a period of years.

Psoriasis

Psoriasis vulgaris usually affects the areas of the skin not exposed to the sun, but in about 10% of cases, lesions appear on the skin of the eyelids, and the plaques may extend to the conjunctiva, where they cause irritation, a foreign body sensation, and tearing. Psoriasis also causes nonspecific chronic conjunctivitis with considerable mucoid discharge. Rarely, the cornea may show marginal ulceration or a deep, vascularized opacity.

The conjunctival and corneal lesions wax and wane with the skin lesions and are not affected by specific treatment. In rare cases, conjunctival scarring (symblepharon, trichiasis), corneal scarring, and occlusion of the nasolacrimal duct have occurred.

Stevens–Johnson Syndrome, Toxic Epidermal Necrolysis, and Erythema Multiforme

Stevens–Johnson syndrome and toxic epidermal necrolysis, the more extensive variant of the same disease, as well as erythema multiforme, cause skin and mucous membrane lesions, the latter possibly leading to cicatrizing conjunctivitis with the potential for severe corneal dryness and scarring (see Chapter 16). The skin lesion is an erythematous, urticarial bullous eruption that appears suddenly and is often distributed symmetrically. Bilateral conjunctivitis, often membranous, is a common manifestation. The patient complains of pain, irritation, discharge, and photophobia. The cornea becomes affected secondarily, and vascularization and scarring may seriously reduce vision.

Cultures are negative for bacteria and conjunctival scrapings show a preponderance of polymorphonuclear cells. Systemic steroids are thought to shorten the course of the systemic disease but have little or no effect on the eye lesions. Careful cleansing of the conjunctiva to remove the accumulated secretion is helpful, however, and tear replacement may be indicated. If trichiasis and entropion supervene, they should be corrected. Topical steroids probably have no beneficial effect, and their protracted use can cause corneal melting and perforation.

The acute episode usually lasts about 6 weeks, but the conjunctival scarring, loss of tears, and complications from entropion and trichiasis may result in prolonged morbidity and progressive corneal cicatrization.

Dermatitis Herpetiformis

Dermatitis herpetiformis is a rare skin disorder characterized by symmetrically grouped erythematous papulovesicular, vesicular, or bullous lesions. The disease has a predilection for the posterior axillary fold, the sacral region, the buttocks, and the forearms. Itching is often severe. Rarely, a pseudomembranous conjunctivitis occurs and may result in cicatrization resembling that seen in mucous membrane pemphigoid. The skin eruption and conjunctivitis usually respond readily to systemic sulfones or sulfapyridine.

Epidermolysis Bullosa

This is a rare hereditary disease characterized by vesicles, bullae, and epidermal cysts. The lesions occur chiefly on the extensor surfaces of the joints and other areas exposed to trauma. The severe dystrophic type that leads to scarring may also produce conjunctival scars similar to those seen in dermatitis herpetiformis and mucous membrane pemphigoid. No known treatment is satisfactory.

Superior Limbic Keratoconjunctivitis

Superior limbic keratoconjunctivitis is usually bilateral and limited to the upper tarsus and upper limbus. The principal complaints are irritation and hyperemia. The signs are papillary hypertrophy of the upper tarsus, redness of the superior bulbar conjunctiva, thickening and keratinization of the superior limbus, epithelial keratitis, recurrent superior filaments, and superior micropannus. Rose bengal staining is a helpful diagnostic test (Figure 5–29). The keratinized epithelial cells and mucous debris pick up the stain. Scrapings from the upper limbus show keratinizing epithelial cells.

In about 50% of cases, the condition has been associated with abnormal function of the thyroid gland. Applying 0.5% or 1% silver nitrate to the upper palpebral conjunctiva and allowing the tarsus to drop back onto the upper limbus usually result in shedding of the keratinizing cells and relief of symptoms for 4–6 weeks. This treatment can be repeated. There are no complications, and the disease usually runs a course of 2–4 years.

In severe cases, one may consider 5-mm resection of the perilimbal superior conjunctiva.

Ligneous Conjunctivitis

This is a rare bilateral, chronic or recurrent, pseudomembranous or membranous conjunctivitis that arises early in life, predominantly in young girls, and often persists for many years. Granulomas are often associated with it, and the lids may feel very hard. Recent studies have shown an underlying type 1 plasminogen deficiency in patients suffering from ligneous conjunctivitis. Cyclosporine has been an effective treatment. Future therapies will focus on topical delivery of plasminogen.

Reiter's Syndrome

A triad of disease manifestations—nonspecific urethritis, arthritis, and conjunctivitis—constitutes Reiter's syndrome. Iritis can also occur, but tends to be a late complication. The syndrome occurs much more often in men than in women and has been found in association with HLA-B27 antigen. The conjunctivitis is papillary in type and usually bilateral. Conjunctival scrapings contain polymorphonuclear cells. No bacteria grow in cultures. The arthritis usually affects the large weight-bearing joints. There is no satisfactory treatment, although nonsteroidal anti-inflammatory agents may be effective. Corticosteroids usually help in resolution of iridocyclitis if present.

Mucocutaneous Lymph Node Syndrome (Kawasaki Disease)

This disease of unknown cause was first described in Japan in 1967. Conjunctivitis is one of its six diagnostic features, of which the others are (1) fever that fails to respond to antibiotics; (2) changes in the lips and oral cavity; (3) such changes in the extremities as erythema of the palms and soles, indurative edema, and membranous desquamation of the fingertips; (4) polymorphous exanthem of the trunk; and (5) acute nonpurulent swelling of the cervical lymph nodes.

The disease occurs almost exclusively in prepubertal children and carries a 1–2% mortality rate from cardiac failure. The conjunctivitis has not been severe, and no corneal lesions have been reported.

Recent findings suggest a possible infectious cause of Kawasaki disease.

Treatment is supportive only.

Conjunctivitis Associated with Systemic Disease

Conjunctivitis in Thyroid Disease

In orbital Graves' disease, the conjunctiva may be red and chemotic and the patient may complain of copious tearing. As the disease progresses, the chemosis increases, and in advanced cases the chemotic conjunctiva may extrude between the lids (Figure 5–30).

Treatment is directed toward control of the thyroid disease, and every effort must be made to protect the conjunctiva and cornea by bland ointment, surgical lid adhesions (tarsorrhaphy) if necessary, or even orbital decompression if the lids do not close enough to cover the cornea and conjunctiva.

Gouty Conjunctivitis

Patients with gout often complain of a “hot eye” during attacks. On examination, a mild conjunctivitis is found that is less severe than suggested by the symptoms. Gout may also be associated with episcleritis or scleritis, iridocyclitis, keratitis, vitreous opacities, and retinopathy. Treatment is aimed at controlling the gouty attack with colchicine and allopurinol.

Carcinoid Conjunctivitis

In carcinoid, the conjunctiva is sometimes congested and cyanotic as a result of the secretion of serotonin by the chromaffin cells of the gastrointestinal tract. The patient may complain of a “hot eye” during such attacks.

Conjunctivitis Secondary to Dacryocystitis or Canaliculitis

Conjunctivitis Secondary to Dacryocystitis

Both pneumococcal conjunctivitis (often unilateral and unresponsive to treatment) and beta-hemolytic streptococcal conjunctivitis (often hyperacute and purulent) may be secondary to chronic dacryocystitis (see Chapter 4). The nature and source of the conjunctivitis in both instances are often missed until the lacrimal system is investigated.

Conjunctivitis Secondary to Canaliculitis

Canaliculitis due to canalicular infection with A israelii or Candida species (or, very rarely, Aspergillus species) may cause unilateral mucopurulent conjunctivitis, often chronic (see Chapter 4). The source of the condition is often missed unless the characteristic hyperemic, pouting punctum is noted. Expression of the canaliculus (upper or lower, whichever is involved) is curative provided the entire concretion is removed.

Conjunctival scrapings show a predominance of polymorphonuclear cells. Cultures (unless anaerobic) are usually negative. Candida grows readily on ordinary culture media, but almost all of the infections are caused by A israelii, which requires an anaerobic medium.

II. Degenerative Diseases of the Conjunctiva

Pinguecula

Pingueculae are extremely common in adults. They appear as yellow nodules on both sides of the cornea (more commonly on the nasal side) in the area of the palpebral aperture. The nodules, consisting of hyaline and yellow elastic tissue, rarely increase in size, but inflammation is common. In general, no treatment is required, but in certain cases of pingueculitis, weak topical steroids (eg, prednisolone 0.12%) or topical nonsteroidal anti-inflammatory agents may be given (Figure 5–31).

Pterygium

A pterygium is a fleshy, triangular encroachment of a pinguecula onto the cornea, usually on the nasal side bilaterally (Figure 5–32). It is thought to be an irritative phenomenon due to ultraviolet light, drying, and windy environments, since it is common in persons who spend much of their lives out of doors in sunny, dusty, or sandy, windblown surroundings. The pathologic findings in the conjunctiva are the same as those of pinguecula. In the cornea, there is replacement of Bowman's layer by hyaline and elastic tissue.

If the pterygium is enlarging and encroaches on the pupillary area, it should be removed surgically along with a small portion of superficial clear cornea beyond the area of encroachment. Conjunctival autografts combined with surgical excision have been shown to reduce the risk of recurrent disease.

Climatic Droplet Keratopathy (Bietti's Band-Shaped Nodular Dystrophy, Labrador Keratopathy, Spheroidal Degeneration)

Climatic droplet keratopathy is an uncommon degenerative disorder of the cornea characterized by aggregates of yellowish-golden spherules that accumulate in the subepithelial layers. The cause is unknown, but certain factors such as exposure to ultraviolet light, aridity, and microtrauma are recognized predisposing factors. The deposits may result in elevation of the epithelium in a band-shaped configuration. The condition is more common in geographic regions with high levels of direct and reflected sunlight.

III. Miscellaneous Disorders of the Conjunctiva

Lymphangiectasis

Lymphangiectasis is characterized by localized small, clear, tortuous dilations in the conjunctiva. They are merely dilated lymph vessels, and no treatment is indicated unless they are irritating or cosmetically objectionable. They can then be cauterized or excised (Figure 5–33).

Congenital Conjunctival Lymphedema

This is a rare entity, unilateral or bilateral, and characterized by pinkish, fleshy edema of the bulbar conjunctiva. Usually observed as an isolated entity at birth, the condition is thought to be due to a congenital defect in the lymphatic drainage of the conjunctiva. It has been observed in chronic hereditary lymphedema of the lower extremities (Milroy's disease) and is thought to be an ocular manifestation of this disease rather than an associated anomaly.

Cystinosis

Cystinosis is a rare congenital disorder of amino acid metabolism characterized by widespread intracellular deposition of cystine crystals in various body tissues, including the conjunctiva and cornea. Three types are recognized: childhood, adolescent, and adult. Life expectancy is reduced in the first two types.

Subconjunctival Hemorrhage

This common disorder may occur spontaneously, usually in only one eye, in any age group. Its sudden onset and bright-red appearance usually alarm the patient. The hemorrhage is caused by rupture of a small conjunctival vessel, sometimes preceded by a bout of severe coughing or sneezing (Figure 5–34).

The best treatment is reassurance. The hemorrhage usually absorbs in 2–3 weeks.

In rare instances, if the hemorrhages are bilateral or recurrent; the possibility of blood dyscrasias should then be ruled out.

Ophthalmia Neonatorum

Ophthalmia neonatorum in its broad sense refers to any infection of the newborn conjunctiva. In its narrow and commonly used sense, however, it refers to a conjunctival infection, chiefly gonococcal, that follows contamination of the baby's eyes during its passage through the mother's cervix and vagina or during the postpartum period. Because gonococcal conjunctivitis can rapidly cause blindness, the cause of all cases of ophthalmia neonatorum should be verified by examination of smears of exudate, epithelial scrapings, cultures, and rapid tests for gonococci.

Gonococcal neonatal conjunctivitis causes corneal ulceration and blindness if not treated immediately. Chlamydial neonatal conjunctivitis (inclusion blennorrhea) is less destructive but can last months if untreated and may be followed by pneumonia. Other causes include infections with staphylococci, pneumococci, haemophilus, and herpes simplex virus and silver nitrate prophylaxis.

The time of onset is important but not entirely reliable in clinical diagnosis since the two principal types, gonorrheal ophthalmia and inclusion blennorrhea, have widely differing incubation periods: gonococcal disease 2–3 days and chlamydial disease 5–12 days. The third important birth-canal infection (HSV-2 keratoconjunctivitis) has a 2- to 3-day incubation period and is potentially quite serious because of the possibility of systemic dissemination.

Treatment for neonatal gonococcal conjunctivitis is with ceftriaxone, 125 mg as a single intramuscular dose; a second choice is kanamycin, 75 mg intramuscularly. To treat chlamydial conjunctivitis in newborns, erythromycin oral suspension is effective at a dosage of 50 mg/kg/d in four divided doses for 2 weeks. In both gonococcal and chlamydial conjunctivitis, the parents need to be treated. Herpes simplex keratoconjunctivitis is treated with acyclovir, 30 mg/kg/d in three divided doses for 14 days. Neonatal disease from HSV requires hospitalization because of the potential neurologic or systemic manifestations. Other types of neonatal conjunctivitis are treated with erythromycin, gentamicin, or tobramycin ophthalmic ointment four times daily.

Credé 1% silver nitrate prophylaxis is effective for the prevention of gonorrheal ophthalmia but not inclusion blennorrhea or herpetic infection. The slight chemical conjunctivitis induced by silver nitrate is minor and of short duration. Accidents with concentrated solutions can be avoided by using wax ampules specially prepared for Credé prophylaxis. Tetracycline and erythromycin ointment are effective substitutes.

Oculoglandular Disease (Parinaud's Oculoglandular Syndrome)

This is a group of conjunctival diseases, usually unilateral, characterized by low-grade fever, grossly visible preauricular adenopathy, and one or more conjunctival granulomas (Figure 5–35). The most common cause is cat-scratch disease, but there are many other causes, including M tuberculosis, Treponema pallidum, Francisella tularensis, Pasteurella (Yersinia) pseudo-tuberculosis, C trachomatis serovars L1, L2, and L3, and Coccidioides immitis.

Conjunctival Cat-Scratch Disease

This protracted but benign granulomatous conjunctivitis is found most commonly in children who have been in intimate contact with cats. The child often runs a low-grade fever and develops a reasonably enlarged preauricular node and one or more conjunctival granulomas. These may show focal necrosis and may sometimes ulcerate. The regional adenopathy does not suppurate. The clinical diagnosis is supported by serology.

The disease appears to be caused by a slender pleomorphic gram-negative bacillus (Bartonella [formerly Rochalimaea] henselae), which grows in the walls of blood vessels. With special stains, this organism can be seen in biopsies of conjunctival tissue. The organism closely resembles Leptotrichia buccalis, and the disease was previously known as leptotrichosis conjunctivae (Parinaud's conjunctivitis). The organism is commonly found in the mouth in humans and always in the mouth in cats. The eye may be contaminated by saliva on the child's fingers or by cat saliva on the child's pillow. Afipia felis has been incriminated also and may still play a role.

The disease is self-limited (without corneal or other complications) and resolves in 2–3 months. The conjunctival nodule can be excised; in the case of a solitary granuloma, this may be curative. Systemic tetracyclines may shorten the course but should not be given to children under 7 years of age.

Conjunctivitis Secondary to Neoplasms (Masquerade Syndrome)

When examined superficially, a neoplasm of the conjunctiva or lid margin is often misdiagnosed as a chronic infectious conjunctivitis or keratoconjunctivitis. Since the underlying lesion is often not recognized, the condition has been referred to as masquerade syndrome. The masquerading neoplasms on record are conjunctival capillary carcinoma, conjunctival carcinoma in situ, infectious papilloma of the conjunctiva, sebaceous gland carcinoma, and verrucae. Verrucae and molluscum tumors of the lid margin may desquamate toxic tumor material that produces a chronic conjunctivitis, keratoconjunctivitis, or (rarely) keratitis alone.

This section presents an overview of the most common and most important neoplasms, hamartomas, and choristomas of the conjunctiva. Readers are referred to other sections of this chapter for information about inflammatory and degenerative lesions of the conjunctiva (eg, pingueculum and pterygium) that can simulate conjunctival neoplasms.

Benign Tumors of Conjunctiva

Benign neoplasms are acquired tumors of cells that are atypical but not sufficient to be classified as malignant. They may enlarge slowly, but have little or no invasive potential and no metastatic capability. Hamartomas are congenital tumors composed of normal or near-normal cells and tissues for the anatomic site but in excessive amounts. Choristomas are congenital tumors consisting of normal cells and tissue elements but not occurring normally at the anatomic site.

Melanocytic Nevus of Conjunctiva

Melanocytic nevus of the conjunctiva (conjunctival nevus) is a benign acquired, rarely congenital, neoplasm arising from melanocytes that are present normally in limited numbers within the basal layers of the conjunctival stratified squamous epithelium. It is probably the most commonly encountered conjunctival neoplasm, but its exact incidence has never been calculated. It affects men and women equally. It is almost always a unilateral unifocal lesion. It is usually first noted by the child's parents during the first decade of life, but occasionally it does not become apparent until the teenage years or even later. It manifests as a dark brown to tan lesion, most characteristically located adjacent the limbus in the interpalpebral fissure (Figure 5–36). Less frequently, it involves the semilunar fold or caruncle. Slitlamp biomicroscopy frequently reveals intralesional cysts and fine blood vessels. The lesion can grow to over 5 mm in diameter and over 1 mm in thickness, especially if it contains multiple microcysts. Treatment consists of surgical excision of the entire lesion.

Conjunctival Choristomas

Limbal dermoid is the commonest conjunctival choristoma, characteristically located inferotemporally in one or both eyes. It consists of a variety of cells and tissues of mesenchymal (mesodermal) origin, including fat cells, fibroblasts, and hair follicles, and manifests as a slightly elevated dome- shaped white mass straddling the limbus, thus involving the cornea as well as the conjunctiva (Figure 5–37). On slitlamp biomicroscopy, fine hair shafts are frequently evident on the surface. Unilateral unifocal lesions frequently occur as isolated abnormalities. Bilateral limbal dermoids are usually a sign of Goldenhaar syndrome. Small lesions can usually be left alone. Larger ones that extend to or near the visual axis, or cause pronounced irregular astigmatism, are usually treated by penetrating or lamellar keratoplasty.

Conjunctival dermolipoma is composed principally of fat cells and other dermal elements, the most common of which are hair follicles. It typically occurs in the forniceal conjunctiva superotemporally, manifesting as a pale pink to golden subepithelial mass that is soft and non-tender. It is frequently not recognized until teenage to adult years and in most cases can be left alone. Surgical excision may be performed to remove or reduce the size of the lesion.

Benign Lymphoid Hyperplasia of Conjunctiva

Benign lymphoid hyperplasia of the conjunctiva is composed of mildly atypical lymphocytic cells within the conjunctival substantia propria. Usually it does not develop until middle age. It affects both men and women, and it can be unifocal, multifocal, or diffuse in one or both eyes. The individual lesion appears as an ill-defined pink mass within the bulbar or forniceal conjunctiva, which cannot be distinguished clinically from a malignant lymphoid tumor (see later in the chapter). Incisional or excisional biopsy thus may be indicated to exclude lymphoma.

Conjunctival Hemangioma

Conjunctival hemangioma is a hamartoma of the conjunctival blood vessels. It is present at birth but may not become apparent until it enlarges. It is virtually always unilateral and manifests as a prominent collection of large caliber blood vessels thickening the conjunctiva (Figure 5–38). On slitlamp biomicroscopy, some of the deeper blood vessels may be seen to extend into the sclera. Unlike capillary hemangiomas of the eyelids and orbit, conjunctival hemangiomas rarely regress spontaneously. The principal indication for treatment is unsightly appearance, but no treatment has been shown to be both safe and effective. Surgical excision can be complicated by difficult to control bleeding and incomplete removal that fails to improve or worsens the appearance. Double freeze-thaw cryotherapy is sometimes effective in inducing at least partial regression.

Conjunctival Lymphangioma

Conjunctival lymphangioma is a hamartoma composed of conjunctival lymphatic channels lined by endothelial cells. Although congenital, it frequently does not manifest until older childhood. It often enlarges abruptly during episodes of upper respiratory infection and may even fill with blood. Like conjunctival hemangioma, it is notoriously difficult if not impossible to eradicate by surgical excision.

Conjunctival Tumors Intermediate between Benign and Malignant

The tumors described are categorized as neoplasms of borderline malignancy because clinically they cannot be categorized reliably as either benign or malignant. If a biopsy is performed, pathologic studies may reveal benign cells, malignant cells, or cells deemed to be borderline even by cytologic criteria. Tumors that cannot be classified unequivocally as either completely benign or definitely malignant are frequently referred to as pre-malignant or precancerous lesions.

Conjunctival Primary Acquired Melanosis

Primary acquired melanosis (PAM) of the conjunctiva represents hyperplasia of conjunctival melanocytes. It is almost exclusively a unilateral unifocal lesion. It affects men and women with equal frequency. It rarely develops before middle age and most commonly manifests in older individuals. It can arise from the limbal, bulbar, forniceal or even palpebral conjunctiva. Clinically, it appears as a flat to minimally elevated dark brown patch of conjunctiva in an area that was normal in appearance previously (Figure 5–39). If it involves the limbal conjunctiva, it may extend into the corneal epithelium. The lesion usually enlarges slowly over several years. Prominent patches of PAM occasionally give rise to conjunctival melanomas (see later in the chapter), so they should be regarded as pre-malignant lesions. Suspicious lesions should be excised or biopsied for histopathologic study. The crucial pathologic features are the degree of atypia of the melanocytic cells and the extent of their replacement of the conjunctival epithelial cells. High-risk PAM that cannot be excised completely may benefit from topical drug therapy using mitomycin C, 5-fluorouracil, or interferon alpha 2b.

Dysplasia of Conjunctival Stratified Squamous Epithelium

Dysplasia of the conjunctival stratified squamous epithelium is a disordered growth and maturation of the epithelium that can be a precursor to squamous cell carcinoma (see later in the chapter). The disease is almost always unilateral, unifocal, and involving the limbus in the interpalpebral fissure, ie sun exposed area, and virtually always occurs in older middle aged or elderly individuals. Typically it appears as an irregular off-white thickening of the limbal conjunctiva. Accumulation of keratin sometimes results in focal leukoplakia (white patch of hyperkeratotic epithelium). Because it is not possible to distinguish the lesion clinically from squamous cell carcinoma, surgical excision is usually recommended.

Conjunctival and/or Corneal Intraepithelial Neoplasia

Conjunctival and/or corneal intraepithelial neoplasia (CIN) is a pre-malignant to in situ malignant disorder affecting the conjunctival and/or corneal stratified squamous epithelium. It occurs in middle-aged to older adults and is most evident in the corneal epithelium. On slitlamp biomicroscopy, CIN appears as a translucent area of mild corneal epithelial thickening without vascularization or hyperkeratosis (Figure 5–40). It may be limited to the peripheral cornea or extend across the visual axis. It is frequently associated with one or more foci of conjunctival squamous cell carcinoma (see later in the chapter). It can be managed by surgical removal of the visibly abnormal epithelial cells and/or topical therapy with mitomycin-C, 5-fluorouracil, or interferon-alpha 2b.

Atypical Lymphoid Hyperplasia of Conjunctiva

Atypical lymphoid hyperplasia of the conjunctiva is composed of moderately atypical lymphocytic cells within the conjunctival substantia propria. It is generally regarded as part of the spectrum of conjunctival lymphocytic infiltrates, intermediate between benign lymphoid hyperplasia (see earlier in the chapter) and malignant lymphoma (see later in the chapter). It usually does not develop until middle age. It affects both men and women, and can be unifocal, multifocal, or diffuse in one or both eyes, manifesting as a pink mass within the bulbar or forniceal conjunctiva. It cannot be distinguished clinically from benign lymphoid hyperplasia or malignant lymphoma of the conjunctiva. If the lesion is prominent, incisional or excisional biopsy is indicated to exclude lymphoma. Some patients with lesions classified pathologically as atypical lymphoid hyperplasia eventually develop extra-ophthalmic foci of systemic lymphoma, so patients with this type of conjunctival lesion are usually treated with relatively low dose external beam radiation therapy to the affected eye(s) and monitored periodically over the ensuing years for signs of systemic lymphoma.

Malignant Conjunctival Tumors

Malignant conjunctival tumors consist of morphologically abnormal cells and tissues. Invasive features are generally evident clinically and pathologically, and regional and distant metastases are potential sequelae.

Conjunctival Squamous Cell Carcinoma and Its Variants

Squamous cell carcinoma of the conjunctiva is composed of very atypical neoplastic cells arising from the stratified squamous epithelium. It tends to occur in middle-aged to elderly persons, except in xeroderma pigmentosum when it tends to develop early in life. It is almost exclusively unilateral and unifocal, occurring more commonly in men than women. It usually develops at the limbus in the interpalpebral fissure.

Clinically, squamous cell carcinoma of the conjunctival manifests in most cases as (1) a focal leukoplakic lesion (Figure 5–41), (2) a gelatinous conjunctival mass (Figure 5–42), or (3) a papillary tumor (Figure 5–43). If neglected or particularly aggressive, conjunctival squamous cell carcinoma can invade the sclera and extend intraocularly, or invade the orbit. Excision of the lesion is generally regarded to be the treatment of choice. Double freeze-thaw cryotherapy to the conjunctiva and sclera immediately surrounding the excised tissue, and even supplemental excision of lamellar sclera and peripheral cornea underlying the site of the tumor, are frequently employed to reduce the chance of local recurrence. If clinical examination, or pathologic study of the excised specimen, suggests residual conjunctival or corneal intraepithelial neoplasia, topical therapy with mitomycin-C, 5-fluorouracil, or interferon-alpha 2b is probably indicated. If intraocular extension is evident, plaque radiotherapy to the intraocular tumor or attempted en bloc resection of the tumor and adjacent conjunctiva, cornea, and sclera, with insertion of donor cornea and/or sclera may be attempted to salvage the eye. If the intraocular involvement is too extensive or cannot be eradicated by these methods, the eye is usually enucleated. If the orbit is involved, exenteration is usually recommended.

Mucoepidermoid carcinoma of the conjunctiva is a particularly aggressive variant of conjunctival squamous cell carcinoma. The tumor tends to be ill-defined and lumpy and frequently exhibits a yellowish color (Figure 5–44). It tends to be highly invasive and frequently extends into the orbit by the time it is diagnosed. In most cases, exenteration is required.

Conjunctival Melanoma

Conjunctival melanoma arises from the intraepithelial melanocytes of the conjunctiva. It is almost exclusively unilateral, but may be multifocal if it arises from pre-existing primary acquired melanosis (see earlier in the chapter). It usually affects middle- aged or older individuals. It affects both men and women with equal frequency. It is much more common in Caucasians.

Conjunctival melanoms can arise from any region of the conjunctiva (limbal, bulbar, forniceal, palpebral, or caruncular), but is most common near the limbus in the interpalpebral area. It typically manifests as a dark brown nodular mass, which tends to be densely vascularized by conjunctival blood vessels (Figure 5–45). It frequently attains a thickness of 1 to 3 mm before it is recognized. It has the capability of invading the conjunctival stromal, extending into the conjunctival lymphatics, and metastasizing to regional lymph nodes in the head and neck and then to distant organs. Unfavorable prognostic factors for metastasis and metastatic death include larger tumor size, involvement of the fornix or caruncle, and local recurrence following surgical excision. Treatment usually consists of wide surgical excision followed by conjunctival closure using sliding or transpostion flaps or a mucous membrane graft. Supplemental cryotherapy to the adjacent conjunctiva or topical therapy with mitomycin-C, 5-fluorouracil, or interferon-alpha 2b is frequently performed to reduce the likelihood of local recurrence. Ruthenium plaque radiation therapy has also been employed in a few centers, with success rates similar to those after excision plus supplemental treatments. Regional lymph node dissection at the time of initial treatment is being performed in some centers, but the benefits of this treatment have not yet been identified. There is no evidence that exenteration of the orbit improves the survival prognosis of patients with orbital invasion by conjunctival melanoma. Thus exenteration is usually limited to patients with massive orbital involvement without evidence of distant metastasis. A substantial proportion of patients with larger conjunctival melanomas involving the fornix or caruncle at the time of initial treatment will eventually die from metastatic disease despite aggressive local therapy.

Conjunctival Lymphoma

Malignant lymphoma of the conjunctiva is composed of an abnormal proliferation of atypical lymphocytic cells within the conjunctival stroma. It usually occurs in middle aged and older persons. It affects both men and women, and it can be unifocal, multifocal or diffuse in one or both eyes. The individual lesion manifests as a pink mass within the bulbar or forniceal conjunctiva (Figure 5–46), which cannot be distinguished clinically from benign or atypical lymphoid hyperplasia of the conjunctiva (see earlier in the chapter). If the lesion is prominent clinically, incisional or excisional biopsy is indicated to establish the diagnosis. Approximately 20% of patients with lesions classified pathologically as malignant lymphoma eventually develop extra-ophthalmic foci of systemic lymphoma, so patients are usually treated with fractionated external beam radiation therapy to the affected eye(s) and monitored periodically over the ensuing years for signs of systemic lymphoma.

Conjunctival Kaposi Sarcoma

Kaposi sarcoma of the conjunctiva is composed of pleomorphic, malignant cells that become densely vascularized. Most commonly it develops in individuals with AIDS, and in middle-aged or older men. It is usually unilateral and unifocal but can be bilateral and multifocal. Typical Kaposi sarcoma of the conjunctiva manifests as a nodular red mass that is frequently hemorrhagic. Focal treatment can be performed by excision, cryotherapy, or even radiation therapy, but whole body therapy is generally indicated because lesions eventually develop in many sites in individuals with AIDS.

Tears form a thin layer approximately 7–10 μm thick that covers the corneal and conjunctival epithelium. The functions of this ultrathin layer are (1) to make the cornea a smooth optical surface by abolishing minute surface epithelial irregularities; (2) to wet and protect the delicate surface of the corneal and conjunctival epithelium; (3) to inhibit the growth of microorganisms by mechanical flushing and antimicrobial action; and (4) to provide the cornea with necessary nutrient substances.

Layers of the Tear Film

The tear film is composed of three primary layers (Figure 5–47).

1. The superficial lipid layer is a monomolecular film derived from meibomian glands. It is thought to retard evaporation and form a watertight seal when the lids are closed.

2. The middle aqueous layer is elaborated by the major and minor lacrimal glands and contains water-soluble substances (salts and proteins).

3. The deep mucinous layer is composed of glycoprotein and overlies the corneal and conjunctival epithelial cells. The epithelial cell membranes are composed mainly of lipoproteins and are therefore relatively hydrophobic. Mucin is partly adsorbed onto the corneal epithelial cell membranes and is anchored by the microvilli of the surface epithelial cells. This provides a new hydrophilic surface for the aqueous tears to spread over, which is wetted by a lowering of surface tension.

Composition of Tears

The normal tear volume is estimated to be 7 ± 2 μL in each eye. Albumin accounts for 60% of the total protein in tear fluid. Immunoglobulins IgA, IgG, and IgE as well as lysozymes make up the remaining 40% of total protein. IgA predominates and differs from serum IgA in that it is not only transudated from serum but is produced by plasma cells located in the lacrimal gland. In certain allergic conditions such as vernal conjunctivitis, the IgE concentration of tear fluid increases. Tear lysozymes form 21–25% of the total protein and—acting synergistically with gamma globulins and other nonlysozyme antibacterial factors—represent an important defense mechanism against infection. Other tear enzymes may also play a role in diagnosis of certain clinical entities, for example hexoseaminidase assay for diagnosis of Tay–Sachs disease.

K+, Na+, and Cl– also occur in higher concentrations in tears than in plasma. Tears contain a small amount of glucose (5 mg/dL) and urea (0.04 mg/dL), and changes in blood concentration parallel changes in tear glucose and urea levels. The average pH of tears is 7.35, although a wide normal variation exists (5.20–8.35). Under normal conditions, tear fluid is isotonic. Tear film osmolarity ranges from 295 to 309 mosm/L.

Dry Eye Syndrome (Keratoconjunctivitis Sicca)

Dryness of the eye may result from any disease associated with deficiency of the tear film components (aqueous, mucin, or lipid), lid surface abnormalities, or epithelial abnormalities. Hence there are many causes of dry eye syndrome (keratoconjunctivitis sicca) (Table 5–4). Primary Sjögren's syndrome, an immune-mediated disorder of the lacrimal and salivary glands, characteristically manifesting as dry mouth as well as dry eyes, is an important specific disease entity that predominantly presents in women in the 5th to 7th decades of life. When associated with rheumatoid arthritis or other autoimmune diseases, it is known as secondary Sjögren's syndrome.

Etiology

Many of the causes of dry eye syndrome affect more than one component of the tear film or lead to ocular surface alterations that secondarily cause tear film instability. Histopathologic features include the appearance of dry spots on the corneal and conjunctival epithelium, formation of filaments, loss of conjunctival goblet cells, abnormal enlargement of nongoblet epithelial cells, increased cellular stratification, and increased keratinization.

Clinical Findings

Patients with dry eyes complain most frequently of a scratchy or sandy (foreign body) sensation. Other common symptoms are itching, excessive mucus secretion, inability to produce tears, a burning sensation, photosensitivity, redness, pain, and difficulty in moving the lids. On gross examination the eyes may appear normal, but on careful slit lamp examination, subtle indications of the presence of chronic dryness and irritation are found. The most characteristic feature is interruption or absence of the tear meniscus at the lower lid margin. Tenacious yellowish mucus strands are sometimes seen in the lower conjunctival fornix. The bulbar conjunctiva loses its normal luster and may be thickened, edematous, and hyperemic.

The corneal epithelium shows varying degrees of fine punctate stippling in the interpalpebral fissure. The damaged corneal and conjunctival epithelial cells stain with 1% rose bengal, and defects in the corneal epithelium stain with fluorescein (Figures 5–22 and 5–48). In the late stages of keratoconjunctivitis sicca, filaments may be seen—one end of each filament attached to the corneal epithelium and the other end moving freely (Figure 5–49).

In Sjögren's syndrome conjunctival scrapings may show increased numbers of goblet cells. Lacrimal gland enlargement occurs uncommonly in patients with Sjögren's syndrome. The principal diagnostic investigations in Sjögren's syndrome are detection of antibodies against Ro (SSA) and La (SSB) or histopathologic features in salivary gland biopsy.

Accurate diagnosis and grading of dry eye syndrome can be achieved using various diagnostic tests (Table 5–4).

Schirmer Test

Schirmer strips (Whatman filter paper No. 41) are inserted into the lower conjunctival cul-de-sac at the junction of the mid and temporal thirds of the lower lid (Figure 5-50). The moistened exposed portion is measured 5 minutes after insertion. When performed without anesthesia, the test measures the function of the main lacrimal gland, whose secretory activity is stimulated by the irritating nature of the filter paper. Less than 10 mm of wetting without anesthesia is considered abnormal.

Schirmer tests can be performed after topical anesthesia (0.5% tetracaine) to measure the function of the accessory lacrimal glands, but the test is considered unreliable. Less than 5 mm in 5 minutes is abnormal.

The Schirmer test is a screening test for assessment of tear production. False-positive and false-negative results occur. Low readings are sporadically found in normal eyes, and normal tests may occur in dry eyes—especially those secondary to mucin deficiency.

Tear Film Break-Up Time

Measurement of the tear film break-up time may sometimes be useful to estimate the mucin content of tear fluid. Deficiency in mucin may not affect the Schirmer test, which quantifies tear production, but may lead to instability of the tear film, resulting in its rapid break-up. “Dry spots” (Figure 5–51) are formed in the tear film, followed by exposure of the corneal or conjunctival epithelium. This process ultimately damages the epithelial cells, which can then be stained with rose bengal. Damaged epithelial cells may be shed from the cornea, leaving areas susceptible to punctate staining when the corneal surface is flooded with fluorescein.

The tear film break-up time is measured by applying a slightly moistened fluorescein strip to the bulbar conjunctiva and asking the patient to blink. The tear film is then scanned with the aid of the cobalt filter on the slitlamp while the patient refrains from blinking. The time that elapses before the first dry spot appears in the corneal fluorescein layer is the tear film break-up time. Normally it is over 15 seconds, but it will be reduced appreciably by the use of local anesthetics, by manipulating the eye, or by holding the lids open. Tear film break-up time is reduced in eyes with aqueous tear deficiency and is always shorter than normal in eyes with mucin deficiency.

Ocular Ferning Test

A simple and inexpensive qualitative test for the study of conjunctival mucus is performed by drying conjunctival scrapings on a clean glass slide. Microscopic arborization (ferning) is observed in normal eyes. In patients with cicatrizing conjunctivitis (mucous membrane pemphigoid, Stevens–Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, diffuse conjunctival cicatrization), ferning of the mucus is reduced or absent.

Impression Cytology

Impression cytology is a method by which goblet cell densities on the conjunctival surface can be counted. In normal persons, the goblet cell population is highest in the infranasal quadrant. Loss of goblet cells has been documented in trachoma, mucous membrane pemphigoid, Stevens–Johnson syndrome, and avitaminosis A.

Fluorescein Staining

Touching the conjunctiva with a dry strip of fluorescein is a good indicator of wetness, and the tear meniscus can be seen easily. Fluorescein will stain the eroded and denuded areas as well as microscopic defects of the corneal epithelium (Figures 5–22 and 5–48).

Rose Bengal and Lissamine Green Staining

Rose bengal (Figure 5–29) and lissamine green are equally sensitive for staining the conjunctiva. Both dyes will stain all desiccated nonvital epithelial cells of the conjunctiva and to a lesser extent the cornea. Unlike rose bengal, lissamine green does not cause significant irritation.

Tear Lysozyme Assay

Reduction in tear lysozyme concentration usually occurs early in the course of Sjögren's syndrome and is helpful in diagnosis. Tears can be collected on Schirmer strips and assayed, usually by spectrophotometric methods.

Tear Osmolality

Hyperosmolality of tears has been documented in dry eye syndrome and in contact lens wearers, and is thought to be a consequence of decreased corneal sensitivity. Reports claim that hyperosmolality is the most specific test for dry eye syndrome. Hyperosmolality may be found even when Schirmer test and staining with rose bengal and lissamine green are normal.

Lactoferrin

Tear lactoferrin is low in patients with hyposecretion of the lacrimal gland. Testing kits are commercially available.

Complications

Early in the course of dry eye syndrome, vision is slightly impaired. As the condition worsens, discomfort can become disabling. In advanced cases, corneal ulceration, corneal thinning, and perforation may develop. Secondary bacterial infection occasionally occurs, and corneal scarring and vascularization may result in marked reduction in vision. Early treatment may prevent these complications.

Treatment

The patient should understand that dry eye syndrome is a chronic condition and complete relief is unlikely except in mild cases when the corneal and conjunctival epithelial changes are reversible. Artificial tears, particularly preservative-free tears in more advanced cases, are the mainstay of treatment. Ointment is useful for prolonged lubrication, especially when sleeping. Additional relief can be achieved by using humidifiers, moisture-chamber spectacles, or swim goggles.

The primary function of these measures is fluid replacement. Restoration of mucin is a more formidable task. In recent years, high-molecular-weight water-soluble polymers have been added to artificial tears in an attempt to improve and prolong surface wetting. Other mucomimetic agents include sodium hyaluronate and autologous serum. If the mucus is tenacious, as in SjÖgren's syndrome, mucolytic agents (eg, acetylcysteine 10%) are helpful.

Patients with excessive tear lipids may require specific instructions for removal of lipid strands from the eyelid margin. Antibiotics topically or systemically may be necessary. Dietary supplementation with omega-3 fatty acids or flax seed oil has been advocated to modulate favorably meibomian gland secretion. Topical vitamin A may be useful in reversing ocular surface metaplasia.

Recent clinical studies have demonstrated the efficacy of preservative-free, low-dose corticosteroid preparations in the treatment of Sjögren's syndrome. Presumably due to its effects on ocular surface and lacrimal gland inflammation, cyclosporine 0.05% ophthalmic emulsion (Restasis) twice a day has been shown to be beneficial in moderate and severe dry eye syndrome with few adverse effects even in individuals treated for up to 4 years. Oral hydroxychloroquine is reported to improve tear production in Sjögren's syndrome.

All chemical preservatives in artificial tears induce a certain amount of corneal toxicity. Benzalkonium chloride is the most damaging of the commonly used preparations. Patients who require frequent drops fare better with non-preserved solutions. Preservatives can also cause idiosyncratic reactions. This is most common with thimerosal.

Patients with dry eyes from any cause are more likely to have concurrent infections. Chronic blepharitis is common and should be treated with appropriate lid hygiene and topical antibiotics as needed. If there is acne rosacea treatment with systemic doxycycline may be helpful.

Surgical treatment for dry eyes includes insertion of temporary (collagen) or extended (silicone) punctal plugs to retain lacrimal secretions. Permanent closure of the puncta and canaliculi can be achieved by thermal, electrocautery, or laser treatment. Injection of botulinum toxin into the medial lower eyelid is reported to improve discomfort by reducing tear drainage.

Conjunctiva

Conjunctival Tumors

Tears