Part 5 – CORNEA AND EXTERNAL DISEASE
Chapter 55 – Disorders of the Conjunctiva and Limbus
JONATHAN B. RUBENSTEIN
SHARON L. JICK
Choristomas are common congenital lesions that possess little growth potential. They contain both dermal and epithelial elements that are not normally found in the conjunctiva. Three types of conjunctival choristomas are found—the solid limbal dermoid, the more diffuse dermolipoma, and the complex choristoma.
Solid limbal dermoids are compact, pale yellow growths that typically occur unilaterally at the inferotemporal limbus ( Fig. 55-1 ). Most limbal dermoids are superficial and only minimally involve the cornea and sclera. However, some tumors can penetrate deeply into the cornea, sclera, and conjunctiva. Surgical excision usually involves shaving the lesion off the cornea and sclera; however, complete excision of the dermoid may require reconstruction with lamellar or penetrating keratoplasty. Histological examination reveals a thick, collagenous lesion that may contain hair, sweat glands, fat, sebaceous glands, or teeth ( Fig. 55-2 ). Eyelid colobomas may occur in association with limbal dermoids, which suggests the postulate that both anomalies may result from incomplete fusion of the lids with displacement of skin elements into the dermoid tumor.
Dermolipomas are less dense than solid dermoids and contain more adipose tissue. These are true choristomas, because fatty tissue is usually not found anterior to the orbital septum. They are typically found on the superior temporal bulbar conjunctiva. These masses can extend from the limbus anteriorly to the posterior aspect of the globe and orbit between the superior and lateral rectus. Care must be taken during surgical removal not to damage the extraocular muscles, levator, or lacrimal
Figure 55-1 Limbal dermoid in a 5-year-old child. This is typically located at the inferotemporal limbus.
gland. Usually, surgery is restricted to partial resection of the anterior portion of the tumor.
Bilateral limbal dermoids or dermolipomas are found in children who have Goldenhar’s syndrome (oculoauriculovertebral dysplasia).  Unilateral colobomas of the upper lid may also be seen, along with iris colobomas and aniridia. Other systemic features of this first branchial arch syndrome include preauricular skin tags, blind-ended preauricular fistulas, hypoplasia of the facial bones, and other vertebral anomalies.
Complex choristomas consist of variable combinations of ectopic tissues such as cartilage, adipose tissue, smooth muscle, and acinar glands. Clinically, these lesions resemble dermoids and lipodermoids. When acinar elements compose the majority of the tumor, complex choristomas may assume a fleshier, vascularized appearance with raised translucent nodules. These raised nodules have been referred to as ectopic lacrimal glands. Although mild growth may occur, especially during puberty, malignant transformation is rare. As these tumors also tend to invade deeply into the globe, excision is usually avoided.
Epibulbar Osseous Choristomas
Osseous choristomas are solitary nodules that resemble dermoids. However, they can be differentiated from dermoids clinically because of their location 5–10?mm posterior to the limbus and their more discrete borders. They are composed of mature, compact bone along with other typical choristomatous elements such as pilosebaceous units and hair follicles. Usually, excision is performed for cosmetic reasons only. 
Figure 55-2 Corneal dermoid. Histological section shows epidermis, dermis, epidermal appendages, and adipose tissue.
Figure 55-3 Epithelial inclusion cyst. This cyst occurred at the site of a conjunctival incision that accompanied muscle surgery.
Epithelial inclusion cysts can be found in both the bulbar and palpebral conjunctiva. They are filled with clear fluid and lined with nonkeratinized, stratified squamous epithelium ( Fig. 55-3 ). They remain symptom free and present only a cosmetic concern. Treatment, if desired, consists of simple excision; however, these cysts can recur.
Amyloid, an avascular, noncollagenous protein, may be deposited in the conjunctiva, cornea, adnexal tissues, vitreous, retina, choroid, ciliary body, and orbit. Ocular involvement is most common in primary systemic or localized amyloidosis but may also occur as secondary localized amyloidosis associated with trichiasis, trachoma, chronic keratitis, keratoconus, and stromal corneal dystrophies. Conjunctival amyloidosis is usually asymptomatic. It presents as a discrete, nontender, nonulcerative, waxy, yellow-white, firm subconjunctival mass. It is most often found in the inferior fornix but can also occur anywhere on the bulbar conjunctiva or at the limbus ( Fig. 55-4 ). 
Usually, the diagnosis is suspected on clinical grounds; however, definite diagnosis is made on the basis of biopsy. The histochemical reactions include birefringence and dichroism with Congo red, metachromasia with crystal violet, and fluorescence with thioflavin-T.
Treatment may involve work-up for systemic amyloidosis, but local excision of conjunctival masses is not usually necessary.
Bacterial conjunctivitis, which is uncommon, is characterized by a rapid onset of unilateral conjunctival hyperemia, lid edema, and mucopurulent discharge. The second eye typically becomes involved 1–2 days later.
The pathogenesis of bacterial conjunctivitis usually involves a disruption of the host defense mechanisms. Examples are abnormalities of the ocular surface secondary to eyelid abnormalities, surface trauma, tear film abnormalities, or a preceding infection such as herpes simplex. Systemic immunosuppression may also increase the incidence of bacterial conjunctivitis.  
Bacterial conjunctivitis can be classified into three clinical types—acute, hyperacute, and chronic ( Table 55-1 ). The most common conjunctival pathogens include Staphylococcus, Streptococcus pneumoniae, Haemophilus species, Moraxella, Corynebacterium diphtheriae, Neisseria species, and enteric gram-negative rods.
Figure 55-4 Conjunctival amyloidosis. Associated with primary systemic amyloidosis.
TABLE 55-1 — PATHOGENS THAT CAUSE BACTERIAL CONJUNCTIVITIS
Conjunctival membranes and pseudomembranes are among the findings associated with bacterial conjunctivitis and may be produced in association with Neisseria gonorrhoeae, ß-hemolytic streptococci, and C. diphtheriae, among others. Pseudomembranes are a combination of inflammatory cells and an exudate that contains mucus and proteins ( Fig. 55-5 ). They are loosely adherent to the underlying conjunctival epithelium and can be peeled away with no bleeding or damage to the epithelium. True membranes occur with more intense inflammation. The conjunctival epithelium becomes necrotic, and firmer adhesions are formed between the necrotic cells and the overlying coagulum. When the membrane is peeled, the epithelium tears to leave a raw, bleeding surface.
ACUTE BACTERIAL CONJUNCTIVITIS.
Acute bacterial conjunctivitis usually begins unilaterally with hyperemia, irritation, tearing, mucopurulent discharge, and mattering of the lids ( Fig. 55-6 ). Punctate epithelial keratitis can also occur. The most common pathogens include Staphylococcus aureus, Str. pneumoniae, and H. influenzae.  The most common cause worldwide is Str. aureus. The characteristic disease that results ranges from acute mucopurulent conjunctivitis to chronic, smoldering disease. Other common ocular manifestations include blepharitis, keratitis, marginal ulcers, and phlyctenulosis. The pathogens Str. pneumoniae and H. influenzae occur more commonly in young children and may occur in institutional epidemics. Often H. influenzae is associated with systemic infection, including upper respiratory infection and fever. Systemic antibiotics should be used if such findings are present.
The treatment of acute bacterial conjunctivitis consists of topical antibiotic drops or ointments. Although these infections are normally self-limited, lasting 7–10 days, antibiotic therapy usually speeds the resolution and lessens the severity of the disease. The choice of antibiotic is based upon results of cultures, if available. However, if the treatment is based upon clinical characteristics alone, a broad-spectrum antibiotic with good gram-positive coverage such as a third- or fourth-generation fluoroquinolone, 10% sodium sulfacetamide, or trimethoprim-polymyxin may be used for 7–10 days.
Figure 55-5 Pseudomembrane. A combination of inflammatory cells, mucus, and protein exudate covers the superior tarsal conjunctiva.
Figure 55-6 Acute bacterial conjunctivitis. This patient was culture positive for pneumococcus.
HYPERACUTE BACTERIAL CONJUNCTIVITIS.
The most common cause of hyperacute bacterial conjunctivitis is N. gonorrhoeae. This oculogenital disease is seen primarily in neonates and sexually active young adults. A careful history helps to identify contacts that may be in need of antibiotic treatment. Signs include profuse, thick, yellow-green purulent discharge, painful hyperemia, chemosis of the conjunctiva, and tender preauricular nodes. Untreated cases may lead to peripheral corneal ulceration and eventual perforation with possible endophthalmitis. A similar, but somewhat milder, form of conjunctival and corneal disease is caused by N. meningitidis.
The treatment of hyperacute bacterial conjunctivitis is directed at the specific pathogen. Conjunctival scraping for Gram stain and culture on blood and chocolate agar are strongly suggested. If gram-negative diplococci are seen, suspect gonococcus. Gonococcal conjunctivitis is treated with both topical and systemic antibiotics. An effective regimen includes 1?g of intramuscular ceftriaxone followed by a 2- to 3-week course of oral tetracycline or erythromycin. Topical medications may include penicillin (333,000?U/ml) or bacitracin or erythromycin ointment every 2 hours. As large amounts of tenacious discharge occur, frequent irrigation of the ocular surface is helpful. Patients need to be seen daily in case of corneal involvement.
CHRONIC BACTERIAL CONJUNCTIVITIS.
Chronic bacterial conjunctivitis, which is defined by a duration of longer than 3 weeks, may result from a number of organisms. The most common
Figure 55-7 Staphylococcal marginal keratitis. Note the inferior marginal corneal ulcers and the blepharoconjunctivitis.
of these are S. aureus and Mo. lacunata; other causative organisms include the enteric bacteria Proteus mirabilis, Escherichia coli, Klebsiella pneumoniae, and Serratia marcescens and Branhamella catarrhalis from the upper respiratory tract. The most common causative agent in chronic bacterial blepharoconjunctivitis is S. aureus, which colonizes the eyelid margin, from which it causes direct infection of the conjunctiva or conjunctival inflammation through its elaboration of exotoxins. Chronic angular blepharoconjunctivitis of the inner and outer canthal angles most commonly results from Mo. lacunata. A chronic follicular conjunctivitis may accompany both chronic angular blepharoconjunctivitis and chronic staphylococcal conjunctivitis.
The clinical signs of chronic staphylococcal conjunctivitis include diffuse conjunctival hyperemia with either papillae or follicles, minimal mucopurulent discharge, and conjunctival thickening. Eyelid involvement may comprise redness, telangiectasis, lash loss, collarettes, recurrent hordeolae, and ulcerations at the base of the cilia. Chronic staphylococcal blepharoconjunctivitis may lead to marginal corneal ulcers ( Fig. 55-7 ), which usually occur along the inferior limbus and probably result from an immune-mediated reaction to staphylococcal toxins. Maceration and crusting of the lateral canthal angle are seen in chronic angular blepharitis caused by Moraxella species. Corneal findings include an inferior punctate epithelial keratitis.
The treatment of chronic bacterial conjunctivitis combines proper antimicrobial therapy and good lid hygiene, which includes hot compresses and eyelid scrubs. Scrubs may be performed using a commercial product or a dilute, gentle shampoo applied with a washcloth, followed by complete rinsing with lukewarm water. Erythromycin and bacitracin ointments are effective adjunct topical antibiotics. When severe inflammation exists, antibiotic and corticosteroid combination drops or ointments can be rubbed into the lid margins after the eye scrubs. Oral therapy with tetracycline 250?mg four times a day or doxycycline 100?mg twice a day may be needed for more severe infections.
Viral conjunctivitis is extremely common and is one of the most frequent reasons for visits to an emergency room or doctor’s office. The diagnosis can usually be made clinically, so viral culture and laboratory investigation are rarely undertaken. Viral conjunctivitis usually has an acute onset, unilateral at first, with involvement of the second eye within 1 week. It is manifested by a watery discharge and conjunctival hyperemia and is usually accompanied by preauricular lymphadenopathy on the affected side. Most cases of
viral conjunctivitis resolve spontaneously, without sequelae, within days to weeks. Many different viruses cause conjunctivitis, and each produces a slightly different disease.
Adenoviruses produce two of the most common viral conjunctivitides, pharyngoconjunctival fever and epidemic keratoconjunctivitis. Of the 41 adenovirus serotypes, 19 can cause conjunctivitis. These infections are spread via respiratory droplets or direct contact from fingers to the lids and conjunctival surface. The incubation period is usually 5–12 days, and the clinical illness is present for 5–15 days. After recovery, immunocompetent hosts are protected from further infection by the specific serotype that caused the infection.
Pharyngoconjunctival fever is the most common ocular adenoviral infection and is produced by adenovirus serotypes 3, 4, and 7. It is a condition characterized by a combination of pharyngitis, fever, and conjunctivitis ( Fig. 55-8 ). The conjunctivitis is predominantly follicular with a scant watery discharge, hyperemia, and mild chemosis. The cornea may be involved with a fine punctate epitheliopathy, and preauricular lymph nodes are enlarged in about 90% of cases. As the disease resolves spontaneously within 2 weeks, treatment is usually supportive with cold compresses, artificial tears, and vasoconstrictor eyedrops.
Another common form of viral conjunctivitis is epidemic keratoconjunctivitis (EKC), usually produced by adenovirus serotypes 8, 19, and 37.
Figure 55-8 Acute bilateral viral conjunctivitis. This 22-year-old man has pharyngoconjunctival fever, and the conjunctivitis was preceded by a viral upper respiratory tract infection.
Figure 55-9 Epidemic keratoconjunctivitis. Early pseudomembrane formation may be seen in the inferior fornix.
It is a more severe type of conjunctivitis than pharyngoconjunctival fever and lasts for 7–21 days. EKC produces a mixed papillary and follicular response of the conjunctival stroma with a watery discharge, hyperemia, chemosis, and ipsilateral preauricular lymphadenopathy ( Fig. 55-9 ).  Subconjunctival hemorrhages and conjunctival membrane formation are common ( Figs. 55-9 and 55-10 ).  Membranes occur in approximately one third of cases and are more common with severe infections. Histologically, these conjunctival membranes consist of fibrin and leukocytes with occasional fibroblast infiltration. Both true membranes and pseudomembranes may occur in EKC, and conjunctival scarring and symblepharon formation may follow their resolution.
Corneal involvement in EKC is variable. Most patients have a diffuse, fine, superficial keratitis within the first week of the disease. Focal, elevated, punctate epithelial lesions that stain with fluorescein develop by day 6 to 13 ( Fig. 55-11 ), producing a foreign body sensation. By day 14, subepithelial opacities develop under the focal epithelial lesions in 20–50% of cases ( Fig. 55-12 ). Often, these opacities are visually disabling and may persist for months to years, but eventually they resolve with no scarring or vascularization. 
Treatment of EKC consists of amelioration of symptoms and minimization of transmission of this highly contagious disease. Patients may be infectious for up to 14 days after onset,   and outbreaks are especially common in ophthalmology offices and clinics. Transmission usually occurs from eye to fingers to eye,
Figure 55-10 Pseudomembrane in epidemic keratoconjunctivitis. An early pseudomembrane is forming in the inferior fornix.
Figure 55-11 Epidemic keratoconjunctivitis subepithelial infiltrates. These infiltrates develop 2 weeks after the onset of the disease and persist for months to years.
but tonometers, contact lenses, and eyedrops are other routes of transmission. Preventive measures include frequent hand washing, relative isolation of infected individuals in an office setting, and disinfection of ophthalmic instruments.  During the stage of acute conjunctivitis, treatment is usually supportive and includes cold compresses and decongestant eyedrops. An antihistamine drop may be considered in cases of severe itching. When patients have decreased visual acuity or disabling photophobia from subepithelial opacities, topical corticosteroid therapy may be beneficial. High-dose topical corticosteroids, such as 1% prednisolone acetate three to four times a day, eliminate the subepithelial infitrates. Cidofovir, an antiviral agent, has been investigated in the treatment of EKC.  Although the application of cidofovir drops may prevent the formation of corneal opacities, use has been limited by local toxicity, and a commercial product is not yet available.
ACUTE HEMORRHAGIC CONJUNCTIVITIS.
Acute hemorrhagic conjunctivitis, also known as Apollo disease, was first described in Ghana during the time of the lunar landing mission of 1969.  Two picornaviruses, enterovirus 70 and coxsackievirus A24, are the usual causative agents.  The signs of the disease include rapid onset of severe, painful papillary conjunctivitis with chemosis, tearing, and the development of tiny subconjunctival hemorrhages. The hemorrhages are petechial at first and then coalesce. The cornea may be involved with a fine punctate keratopathy but rarely with subepithelial opacities. The conjunctivitis resolves within 4–6 days, but the hemorrhages clear more slowly. The disease tends to occur in epidemics, especially in developing countries, with more than 50% of the local population affected in some cases.
HERPES SIMPLEX CONJUNCTIVITIS.
Primary herpes simplex conjunctivitis usually occurs in children under 5 years of age. Most cases go undiscovered and undocumented because of their nonspecific nature. Typical signs include ocular irritation, watery discharge, follicular conjunctivitis, and preauricular lymphadenopathy. Epidermal vesicular eruptions of the eyelids and lid margins may accompany the conjunctivitis ( Fig. 55-13 ), and the cornea may be involved. Corneal involvement may include a coarse, punctate epithelial keratitis, marginal infiltrates, or a dendritic ulcer (see Chapter 62 ). Although herpetic blepharoconjunctivitis is associated mainly with the primary disease, it may occur as a manifestation of recurrent disease with or without
Figure 55-12 Time course of the clinical features of epidemic keratoconjunctivitis.
typical herpetic keratitis. Most ocular herpetic infections result from herpes simplex virus type 1. Infections that result from the type 2 serotype may be seen in newborns or adults who have a history of orogenital contact. 
The conjunctivitis usually resolves spontaneously without treatment, although some physicians administer topical antiviral drops to patients with corneal involvement or to patients with lid vesicles with the goal of preventing corneal involvement. Care should be taken to avoid the cavalier use of corticosteroids in the treatment of patients who have acute follicular conjunctivitis, as some of these patients may have herpetic disease and corticosteroids may enhance the severity of herpetic epithelial keratitis.
Other causes of viral conjunctivitis include the rubella, rubeola, varicella-zoster, Epstein-Barr, and Newcastle disease viruses. Rubella virus produces a nondescript, catarrhal conjunctivitis associated with the systemic disease, and a follicular reaction may occur. Rubeola produces a catarrhal, papillary conjunctivitis with tearing, pain, and photophobia. Pale, discrete, avascular spots, which resemble Koplik’s spots seen in the mouth, may appear on the conjunctiva. Varicella-zoster virus produces pustules and phlyctenule-like lesions on the conjunctiva, and a follicular conjunctivitis may occur with the recurrent skin disease. The follicular conjunctivitis associated with the Epstein-Barr virus occurs in association with infectious mononucleosis. Newcastle disease viral conjunctivitis occurs in poultry workers and veterinarians in whom direct conjunctival inoculation of the virus has occurred while infected birds are handled. The disease is self-limited, lasts 7–10 days, and leaves no ocular sequelae.
Chronic Follicular Conjunctivitis
A follicular conjunctivitis that lasts for more than 16 days is considered to be a chronic follicular conjunctivitis ( Box 55-1 ). Chlamydia trachomatis is the most common cause of chronic follicular conjunctivitis; the organism causes three clinical syndromes—trachoma, adult inclusion conjunctivitis, and neonatal conjunctivitis.
Trachoma results from C. trachomatis serotypes A–C, is endemic in many parts of the world, and is especially prevalent in areas of close human contact and poor hygiene. Blinding trachoma still occurs in parts of Africa, the Middle East, India, and Southeast Asia. Trachoma begins as a follicular
Figure 55-13 Primary herpes simplex blepharoconjunctivitis. Note the bilateral vesicular eruptions in this child who has a primary herpes simplex infection.
Causes of Chronic Follicular Conjunctivitis
• adult inclusion conjunctivitis
Drug-induced or toxic
Axenfeld’s chronic follicular conjunctivitis
Merrill–Thygeson type follicular conjunctivitis
Parinaud’s oculoglandular syndrome
Folliculosis of childhood
TABLE 55-2 — MACCALLAN CLASSIFICATION OF TRACHOMA
Early lymphoid hyperplasia with immature follicle formation on the superior tarsal conjunctiva, diffuse punctate keratitis, and early pannus
Mature follicles on the superior tarsus
Florid inflammation with increases in pretarsal and limbal follicular and papillary hypertrophy and increasing pannus
Resolution of papillary hypertrophy, continued tarsal follicles, and early conjunctival cicatrization
No active inflammation; replacement of papillae and follicles with scar and resolution of pannus
Stages of the disease based upon conjunctival findings.
conjunctivitis of the upper palpebral conjunctiva with associated limbal follicles. Other early findings include conjunctival papillary hypertrophy, a mucopurulent discharge, a superiorly based superficial corneal pannus, and a fine epithelial keratitis. Eventually, the inflammation leads to scarring and cicatrization of the cornea, conjunctiva, and eyelids. In 1908, MacCallan divided the disease into four stages based on the conjunctival findings ( Table 55-2 ). The World Health Organization has also developed a grading system for trachoma, structured around the presence or absence of follicular conjunctivitis, diffuse inflammation, tarsal scarring, trichiasis, and corneal opacification.
The complications of trachoma that cause blindness occur as a result of corneal ulceration and scarring secondary to severe conjunctival scarring and eyelid deformities. Proliferation of connective tissue in the conjunctiva results in cicatrization. Arlt’s line (a horizontal line that results from conjunctival scarring at the junction of the anterior one third and posterior two thirds of the conjunctiva) is a characteristic finding on the superior pretarsal conjunctiva. Herbert’s pits are a unique sequel of trachoma ; these sharply delineated depressions occur after cicatrization of the limbal follicles, and the resultant clear space is filled with epithelium. A diffuse haze of the superior cornea can result after regression of the superior pannus.
Eyelid deformities such as trichiasis, distichiasis, entropion, and ectropion may all occur. Resulting corneal complications include scarring, vascularization, ulceration, and perforation. The resultant poor ocular surface leads to decreased visual acuity and possible blindness.
Treatment of trachoma usually consists of a 3- to 4-week course of oral tetracycline (tetracycline 1?g/day or doxycycline 100?mg/day) or oral erythromycin. The clinical response may be slow and take 9–18 weeks. Therefore, topical tetracycline or erythromycin ointment is used twice a day for 5 days each month for 6 months. Repeated topical therapy is especially useful where the disease is endemic and repeated exposure is likely. Widespread use of systemic antibiotics in endemic areas has been tried in an attempt to eradicate the disease. Oral azithromycin has shown promise in this regard. 
Figure 55-14 Adult inclusion conjunctivitis. This 50-year-old man had prominent follicular conjunctivitis with a large and tender preauricular lymph node.
Figure 55-15 Giemsa stain of a conjunctival scraping. The epithelial cells show basophilic cytoplasmic inclusions typical of a chlamydial infection.
ADULT INCLUSION CONJUNCTIVITIS.
Adult inclusion conjunctivitis results from C. trachomatis serotypes D–K, which cause a chronic follicular conjunctivitis that can occur in adults or in the neonate. It presents as a unilateral red eye with mucopurulent discharge, marked hyperemia, papillary hypertrophy, and a predominant follicular conjunctivitis ( Fig. 55-14 ). A tender, enlarged preauricular lymph node is common. Women often have a concomitant vaginal discharge secondary to a chronic cervicitis, and men may have symptomatic or nonsymptomatic urethritis. The conjunctivitis is often chronic, lasting many months. Keratitis may develop during the second week after onset. Corneal involvement includes a superficial punctate keratitis, small marginal or central infiltrates, EKC-like subepithelial infiltrates, limbal swelling, and a superior limbal pannus. The untreated disease has a chronic, remittent course, and keratitis and possible iritis occur more commonly in the later stages of the disease.
Diagnosis is based upon the clinical appearance plus laboratory tests. Basophilic intracytoplasmic epithelial inclusions are seen with Giemsa staining of conjunctival scrapings ( Fig. 55-15 ). Immunofluorescent staining of the conjunctival scrapings is also useful. Serum immunoglobulin G (IgG) titers to chlamydia may be obtained.
The adult disease is transmitted venereally or from hand-to-eye contact. The epidemiology of the disease revolves around sexual contact. The modes of transmission include orogenital activities and hand-to-eye spread of infective genital secretions. The incubation period is 4–12 days. It is estimated that 1 in 300 patients who have genital chlamydial disease develops adult inclusion conjunctivitis. It is important to treat all sexual partners
TABLE 55-3 — CAUSES OF NEONATAL CONJUNCTIVITIS
Time of Onset (Postpartum)
Chemical (silver nitrate)
Bacteria (Staphylococcus, Streptococcus, Haemophilus)
Virus (herpes simplex virus types 1 and 2)
The cause of the conjunctivitis is established by the clinical picture, time course, and laboratory confirmation.
simultaneously to prevent reinfection. It also is prudent to examine all sexual partners for other venereal diseases, such as gonorrhea and syphilis. Treatment consists of systemic antibiotics, as topical antibiotics are relatively ineffective in the treatment of the eye disease. Recommended treatment, which is given for 3 weeks, includes either oral tetracycline 500?mg four times a day, oral doxycycline 100?mg twice a day, or oral erythromycin stearate 500?mg four times a day. Tetracycline should be avoided in children younger than 7 years of age and in pregnant or lactating women.
NEONATAL CONJUNCTIVITIS (OPHTHALMIA NEONATORUM).
Conjunctivitis of the newborn is defined as any conjunctivitis that occurs within the first 4 weeks of life ( Table 55-3 ). It may be caused by a bacterial, viral, or chlamydial infection or by a toxic response to topically applied chemicals. Because the infectious agent may produce a severe localized infection of the eye plus a potentially serious systemic infection, precise identification of the cause is essential.
A number of factors contribute to neonatal conjunctivitis, including the following:
• Organisms harbored in the mother’s birth canal,
• Maternal infections during pregnancy,
• Exposure of the infant to infectious organisms,
• Inadequacy of ocular prophylaxis immediately after birth,
• Susceptibility of the infant’s eye to infection, and
• Ocular trauma during delivery
All infants are exposed to infectious agents in the birth canal; the duration of the exposure is an important factor in the development of disease.
Chemical conjunctivitis classically results from the instillation of silver nitrate drops used for infection prophylaxis. Credé introduced this practice in 1881 to protect against gonococcal infection. The chemical conjunctivitis begins a few hours after delivery and lasts for 24–36 hours. Approximately 90% of infants who receive silver nitrate develop mild, transient conjunctival injection with tearing. The severity of these symptoms has been lessened since the development of single-use 1% buffered silver nitrate ampules. Before this, silver nitrate was kept in large, multiuse bottles, which often resulted in more concentrated doses of the chemical being obtained when an aliquot was drawn from the bottom of the bottle. Although effective against N. gonorrhoeae, silver nitrate has a relatively limited spectrum of activity against bacteria and is ineffective against chlamydial or viral infections. Silver nitrate may injure epithelial cells and thus render them more susceptible to invasion by other infectious agents. Although this method is still used in the majority of countries as the primary means of infection prophylaxis, many hospitals are changing to the use of erythromycin or tetracycline ointments.
The most frequent cause of neonatal conjunctivitis in the United States is C. trachomatis. The Centers for Disease Control and Prevention estimates that 3 million new cases of chlamydial infection occur annually. Chlamydial infections occur in 4–10% of pregnant women in the United States. Infants whose mothers have untreated
Figure 55-16 A 10-day-old infant who has unilateral conjunctivitis. The mother had an untreated chlamydial infection of the birth canal.
chlamydial infections have a 30–40% chance of developing conjunctivitis and a 10–20% chance of developing pneumonia. Symptoms typically develop 5–14 days after delivery and may be unilateral or bilateral. Initially, infants have a watery discharge that may progressively turn mucopurulent. Signs include lid edema, a papillary conjunctival response, and pseudomembrane formation ( Fig. 55-16 ). Usually, the infection is mild and self-limited; however, severe cases may occur and result in conjunctival scarring and a peripheral corneal pannus with corneal scarring. If either erythromycin or tetracycline ointment is applied within 1 hour of delivery, the chance of developing chlamydial conjunctivitis is essentially eliminated. 
Laboratory data are very helpful in the diagnosis of chlamydia. Originally, the two most common techniques for the identification of inclusion bodies involved the use of a Giemsa stain of a conjunctival scraping and a McCoy cell culture. Unfortunately, the Giemsa test is only 50–90% sensitive, and a well-trained technician must read the slides. The cell culture is expensive, and it takes 2–3 days to obtain results. Fortunately, other laboratory tests are now available for the diagnosis of chlamydia. An enzyme-linked immunoassay test is nearly 90% sensitive, over 95% specific, and provides results within several hours. A direct immunofluorescent monoclonal antibody stain of conjunctival smears is probably the most useful serological test as it has over 95% sensitivity and 77–90% specificity for chlamydia, depending on the prevalence of the disease. It may show infections missed by the other assays and can be read immediately. DNA detection techniques including polymerase chain reaction and ligase chain reaction are also available and are approximately 90% sensitive and 100% specific.
The objectives of the treatment of infants who have chlamydial conjunctivitis include the resolution of infectious conjunctivitis and the eradication of respiratory colonization. Topical therapy alone is not sufficient to treat chlamydial conjunctivitis. The recommended treatment is oral erythromycin syrup 50?mg/kg/day in four divided doses for 14 days (see Table 55-4 ). If a complete response does not occur, a second course of the same therapy may be given. The mother and sexual partners are treated with either oral tetracycline 500?mg four times a day or oral erythromycin 500?mg four times a day for 7 days (pregnant or breast-feeding women are given erythromycin). Prevention still remains the best treatment as good prenatal care and treatment of chlamydial, gonococcal, or herpetic infections during pregnancy significantly lower the incidence of neonatal conjunctivitis. Proper eye cleaning using sterile cotton followed by the instillation of an antibiotic ointment immediately after birth provides the necessary prophylaxis to prevent neonatal ocular infection.
TABLE 55-4 — GUIDELINES FOR TREATMENT OF NEONATAL CONJUNCTIVITIS
Oral erythromycin 50?mg/kg/day in four divided doses for 14 days
Erythromycin 0.5% ointment four times a day
Penicillin G drops 10,000–20,000 units every hour and intravenous penicillin G drops 100,000 units/kg/day in four divided doses for 7 days
Intravenous or intramuscular ceftriaxone 25–50?mg/kg/day once a day for 7 days
Gentamicin or tobramycin ointments
Trifluorothymidine drops every 2 hours for 7 days
Neonatal conjunctivitis caused by N. gonorrhoeae, a gram-negative diplococcus that can penetrate an intact epithelium, has decreased significantly since the advent of prophylaxis. The clinical picture of gonococcal conjunctivitis consists of the development of a hyperacute conjunctivitis 24–48 hours after birth characterized by marked eyelid edema, profound chemosis, and excessive purulent discharge. The discharge is often so copious that it reaccumulates immediately after the eye has been wiped clean. Conjunctival membrane formation may occur. Because the organism may penetrate an intact epithelium, corneal ulceration with possible perforation can also occur if the conjunctivitis is not treated adequately.
Diagnosis is made by identification of gram-negative intracellular diplococci on smears from the conjunctiva. The organism is best cultured on chocolate agar or Thayer-Martin agar incubated at 37°C in 10% carbon dioxide, and sensitivities are obtained after culture. Prompt diagnosis by examination of an immediate Gram stain is essential to timely and effective therapy.
Local treatment consists of aqueous penicillin G 10,000–20,000 units. Drops are given every hour with a loading dose of one drop every 5 minutes for 30 minutes. Systemic therapy should also be instituted with either intravenous aqueous penicillin G 100,000 units/kg/day in four divided doses or penicillin G benzathine 50,000 units/kg/day for 7 days. Intravenous or intramuscular ceftriaxone 25–50?mg/kg once a day for 7 days is also effective if there is suspicion of a penicillinase-producing strain (see Table 55-4 ).
OTHER BACTERIAL INFECTIONS.
Many different organisms can cause bacterial neonatal conjunctivitis. Bacteria are probably transmitted through the air to the infant shortly after birth, and there may be an association with obstruction of the nasolacrimal duct. Usually, these infections are caused by gram-positive bacteria such as S. aureus, Str. pneumoniae, Str. viridans, and S. epidermidis. Gram-negative organisms that have been implicated include Haemophilus species, E. coli, Proteus species, K. pneumoniae, Enterobacter species, and Ser. marcescens.  A rare cause, Pseudomonas sp., deserves particular mention in that infection with this organism can result in corneal ulceration and perforation.
Typically, these infections arise 2–5 days after birth but may occur at any time within the postpartum period. Signs include lid edema, chemosis, and conjunctival injection with discharge. The work-up includes conjunctival scrapings for Gram stain and cultures, the results of which direct the choice of therapy. For gram-positive organisms, erythromycin 0.5% ointment four times a day is administered. Gentamicin, tobramycin, or fluoroquinolone drops or ointment four times a day can be used for gram-negative organisms (see Table 55-4 ).
Viral conjunctivitis of the newborn is rare but can be associated with significant morbidity and mortality.
Figure 55-17 Acute atopic conjunctivitis. A man with itching, mucoid discharge, chemosis, and a papillary conjunctival reaction.
Both herpes simplex virus type 1 and herpes simplex type 2 can be associated with conjunctivitis, but type 2 infection is more common. Type 1 may be transmitted by a kiss from an adult who has an active “cold sore,” and type 2 is more commonly transmitted through the birth canal. Onset is usually within the first 2 weeks of life and may be associated with vesicular skin lesions of the lid or lid margin (see Fig. 55-13 ). The conjunctivitis may be followed by herpetic keratitis or keratouveitis. The keratitis consists of microdendrites or small geographical ulcers. Vitritis, retinitis, retinal detachment, optic neuritis, and cataract have all been reported in association with neonatal ocular herpes. The diagnosis may be confirmed by the presence of eosinophilic intranuclear inclusions on smears, positive viral cultures, or positive monoclonal antibody immunoassays.
Treatment consists of trifluorothymidine 1% drops every 2 hours for 7 days or acyclovir ointment five times a day (see Table 55-4 ). Herpes simplex type 2 may be more resistant to treatment. In cases of systemic disease associated with pneumonitis, septicemia, and meningitis, systemic acyclovir should be used. Good prenatal care and frequent culture and treatment of mothers who have known herpes genital infections decrease the incidence of herpetic neonatal conjunctivitis.
Guidelines for Work-up
Prompt examination, work-up, and therapy are essential for proper resolution of neonatal conjunctivitis. A detailed maternal history is obtained with attention to a background of venereal disease or exposure during pregnancy. The results of any vaginal or cervical cultures are checked. A history of the labor, including duration and any premature rupture of membranes, is noted.
A conjunctival scraping with a spatula or moistened Ca2+ alginate swab is obtained. Gram and Giemsa stains are performed. Cultures are sent to the laboratory on blood agar, chocolate agar, and Thayer-Martin agar plates. Viral and chlamydial cultures are requested. The laboratory is informed about the organisms that are suspected and the importance of a rapid and accurate diagnosis.
Results of the laboratory tests are checked early and often. Treatment is based on the results of conjunctival scrapings and cultures, not on the clinical findings of severity of disease and time of onset, because these are nonspecific and may be misleading.
ACUTE ATOPIC CONJUNCTIVITIS.
Acute atopic conjunctivitis is an immediate type (type 1) allergic response mediated by IgE. This response is stimulated by airborne allergens such as dust,
TABLE 55-5 — MEDICATIONS USED IN THE TREATMENT OF ALLERGIC CONJUNCTIVITIS
H1 receptor agonists
Levocabastine, emedastine difumarate
Use for isolated, acute allergic attacks. Use alone or in combination with mast cell stabilizers and nonsteroidal anti-inflammatory drug (NSAID) medication
Mast cell stabilizers
Cromolyn sodium, lodoxamide, pemirolast, nedocromil sodium
Most useful for chronic allergies. May take 1–2 weeks to be effective. Pemirolast and nedocromil have antihistamine effects as well. Nedocromil also reduces eosinophil and neutrophil chemotaxis
Antihistamines with mast cell–stabilizing activity
Olopatadine, ketotifen fumarate, azelastine
These medications combine the immediate effect of selective antihistamines with the long-term effects of mast cell stabilization. They have convenient twice- a-day-dosing. Ketotifen and azelastine have anti-inflammatory properties as well.
Can reduce itching but stings when applied
Available over the counter; instruction must be given to patients to avoid chronic use and rebound redness.
Loteprednol, fluorometholone, rimexolone
May be useful in serious cases or until control is achieved with other agents. Side effects limit chronic use.
Fexofenadine, loratadine, cetirizine
Useful when systemic allergic symptoms are present but may cause dry eyes.
molds, pollens, spores, and animal dander. Symptoms consist of the sudden onset of itching, burning, hyperemia, and conjunctival edema, followed by the development of a glassy chemosis and a watery or mucoid discharge ( Fig. 55-17 ). The reaction may be limited to the eye, or it may be part of a generalized allergic reaction with nasal and respiratory symptoms. Often, a family history of atopy is present, and cytological examination of conjunctival scrapings shows eosinophils. Unfortunately, avoidance of the offending antigens is usually impossible. Many new medications have become available for the treatment of allergic conjunctivitis (see Table 55-5 ). Histamine (H1 receptor specific) agonists such as levocabastine and emedastine difumarate are used for intermittent, acute allergic reactions from a limited exposure to the antigen. Mast cell stabilizers such as cromolyn sodium, lodoxamide, pemirolast, and nedocromil sodium are used for chronic allergies. Combination medications that act as both mast cell stabilizers and H1 -specific antihistamines such as olopatadine, ketotifen fumarate, and azelastine are effective for acute and chronic antigen exposure. Some of these medications have additional inhibitory effects on late phase leukocyte recruitment. Vasoconstrictors with nonspecific antihistamines can still be used symptomatically with mild allergic reactions. Topical steroids and nonsteroidal anti-inflammatory agents can be used to reduce the acute inflammatory response until the mast cell stabilizers and antihistamines take effect. Therapy should be tailored to the individual’s clinical picture, keeping in mind that some medications may not be effective for up to 2 weeks. Evaluation by an allergist is often useful in severe cases.
CHRONIC ATOPIC CONJUNCTIVITIS.
Chronic atopic conjunctivitis is characterized by the same symptoms as in the acute condition, but there is a longer duration of the signs of inflammation. The conjunctiva exhibits a pale edema with papillary hypertrophy and a mild, mucopurulent discharge. Giant cobblestone papillae may occur ( Fig. 55-18 ). Conjunctival scrapings reveal numerous eosinophils. As this chronic condition also occurs in atopic individuals who have a compromised immune system, secondary infections must also be ruled out in these patients.
Contact allergy of the eyelids and conjunctiva represents the most common form of allergic reaction seen by the ophthalmologist. It represents a delayed, cell-mediated (type IV) hypersensitivity reaction. Previous sensitization can have occurred as little as 5 days or as long as years previously. The most common stimuli for this reaction are eyedrops, cosmetics, clothing, jewelry, plastics, animal or vegetable products, and industrial chemicals. The ocular drugs commonly associated with this reaction include neomycin, gentamicin, idoxuridine, atropine, thimerosal, and
Figure 55-18 Chronic atopic conjunctivitis. Mild conjunctival injection with numerous giant cobblestone papillae.
penicillin. Other preservatives may stimulate allergy as well. The allergic reaction usually begins with severe itching and a papillary conjunctivitis that is worse on the inferior palpebral conjunctiva. A mucoid or mucopurulent discharge is seen. The adjacent skin of the lower lids and lateral canthi become involved in a typical eczematous dermatitis ( Fig. 55-19 ). Chronic use of the allergen can lead to keratinization of the lid with eventual punctal edema and stenosis. The cornea may show punctate epithelial keratitis and erosions. Conjunctival scrapings show monocytes, polymorphonuclear neutrophil leukocytes, mucus, and eosinophils. Treatment consists of eliminating the antigenic stimulus and quieting the eye with topical corticosteroids.
Microbiallergic conjunctivitis is a type IV hypersensitivity response to the toxic protein breakdown products of bacterial disintegration. In the eyes, the most common cause of this reaction is chronic staphylococcal blepharoconjunctivitis. This common infection results in the formation of breakdown products of the bacteria, which cause an allergic response in the conjunctiva and cornea. Usually, there is no history of allergy. Culture of the conjunctiva is negative for staphylococci. Marginal infiltrates of the cornea can be associated with this condition ( Fig. 55-20 ).
Phlyctenular keratoconjunctivitis is another manifestation of microbiallergic conjunctivitis. In the past, this condition was commonly associated with tuberculosis. Today, it is most frequently seen with chronic staphylococcal blepharoconjunctivitis.
Figure 55-19 Allergic dermatoconjunctivitis. Contact allergy of the eyelids after exposure to neomycin eyedrops. The skin shows a typical eczematous dermatitis.
Figure 55-20 Microbiallergic keratoconjunctivitis associated with staphylococci. A staphylococcal marginal infiltrate is seen in the superior cornea.
Other possible sources include Candida albicans, Coccidioides immitis, Chlamydia, parasites, and lymphogranuloma venereum. Phlyctenular disease presents as slightly raised, small, pinkish white or yellow nodules surrounded by dilated vessels. After a few days, the superficial part of the raised nodule becomes gray and soft; then the center of the lesion ulcerates, sloughs, and clears without scarring. Phlyctenules may occur both on the conjunctiva near the limbus and on the peripheral cornea. Classically, there is no clear zone between the limbus and the lesion. Involvement is usually bilateral and seasonal (occurring more in spring and summer), and the condition occurs most frequently in children and young adults.
Treatment of these microbiallergic conjunctivitides requires an attempt to identify the inciting organism and eradicate it. In chronic staphylococcal disease, elimination of the inciting bacteria can be difficult. Twice-daily lid scrubs (mechanical débridement of the lid margins with dilute baby shampoo or commercially prepared lid scrub pads) can usually achieve symptomatic improvement. Topical antibiotic or antibiotic-corticosteroid combination ointments or drops rubbed into the lid margins may also reduce the number of bacterial colonies. Corticosteroids are reserved for chronic recalcitrant blepharoconjunctivitis and are beneficial early in the treatment of phlyctenular disease. Tuberculosis should be ruled out in children or young adults as well as any adult who has had a recently converted purified protein derivative skin test. Systemic antibiotics, such as oral tetracycline
Figure 55-21 Vernal conjunctivitis. Cobblestone papillae cover the superior tarsal conjunctiva.
Figure 55-22 Vernal catarrh. Clinical appearance of the less commonly seen limbal reaction. (Courtesy of Dr. IM Raber.)
250?mg four times a day or oral doxycycline 100?mg twice a day, can help in cases of nontuberculous phlyctenular disease or persistent staphylococcal blepharoconjunctivitis.
Vernal conjunctivitis is a bilateral, recurrent inflammation of the conjunctiva that tends to occur in children. Its onset is most common in the spring and summer (hence the name vernal, which refers to spring), and the inflammation often goes into remission during the cooler months. The highest incidence of the disease is in the warm, temperate Middle East–Mediterranean region and Mexico. The condition occurs mainly in children and young adults in the age range 5–20 years, with peak incidence between 11 and 13 years. Boys are affected twice as frequently as girls, but the male-to-female ratio evens out when the disease affects adults. A family history of atopy is common. The disease is self-limited in children, with an average duration of 4–10 years. In adults, a more severe form of the disease may recur indefinitely. The prominent symptom is itching. Other complaints include photophobia, burning, tearing, mild ptosis, and a thick, ropy, yellow, mucoid discharge.
The three forms of the vernal conjunctivitis are palpebral, limbal, and mixed. The palpebral form is marked by cobblestone papillae on the superior tarsal conjunctiva ( Fig. 55-21 ) while the lower lid is minimally affected. The initial change is papillary hypertrophy, after which the connective tissue of the substantia propria undergoes hyperplasia and proliferation to form giant papillae. Then the pressure of the cornea flattens the tops of the giant
Figure 55-23 Vernal catarrh. Histological examination of a conjunctival smear shows the presence of many eosinophils. (Courtesy of Dr. IM Raber.)
papillae to produce a pattern that resembles cobblestones. Tiny twigs of vessels are found in the centers of the papillae, which helps to differentiate these from large follicles such as may be seen in trachoma. When wiped with a cotton-tipped applicator, a milky veil that overlies the cobblestones pulls off in a stringy fashion. The limbal form is marked by a broad, thickened, gelatinous opacification of the superior limbus that can override the cornea ( Fig. 55-22 ). Again, tiny, twig-like vessels arise in the centers of these rounded lumps, whereas in limbal follicles the vessels appear around the sides of the elevations only. Histologically, the tissue is infiltrated with lymphocytes, plasma cells, macrophages, basophils, and many eosinophils ( Fig. 55-23 ). A characteristic manifestation of limbal vernal conjunctivitis is the presence of Horner-Trantas dots, which are white, chalk-like dots composed of eosinophils and epithelial debris.
The cornea can be involved in up to 50% of cases. Corneal manifestations include a superficial pannus and a punctate epithelial keratitis. Small, gray patches of necrotizing epithelium may involve the upper one third to two thirds of the cornea—in severe cases, the cornea appears to be dusted with flour. The affected area stains with fluorescein. A vernal ulcer is a horizontally oval, shallow, nonvascularized, indolent ulcer of the superior cornea (see Fig. 55-23 ). The edges are composed of shaggy, gray, dead epithelial cells, and there is infiltration of the underlying superficial stroma. After the ulcer heals, a mild corneal opacity may persist at the level of Bowman’s layer.
The chronic nature of the disease must be considered when the treatment is decided. Topical corticosteroids certainly provide the patient with significant relief from symptoms. However, the chronic use of corticosteroids carries the risks of glaucoma, cataract, and, possibly, infectious keratitis. It may be difficult to persuade the patient to limit the use of corticosteroids because they provide such potent symptomatic relief. Cromolyn sodium 4% works well as long-term treatment. This drug works by preventing mast cell degranulation. A good strategy by which to control the acute exacerbation of symptoms is to start with frequent topical corticosteroids combined with topical cromolyn. The corticosteroids are then tapered off over a 2- to 3-week period as the therapeutic effects of the cromolyn take hold. Severe cases respond well to topical cyclosporin 2%. Cold compresses provide some relief as well. Finally, a move to a colder climate decreases the likelihood of disease recurrence.
Giant Papillary Conjunctivitis
Giant papillary conjunctivitis (GPC) is a syndrome of inflammation of the upper palpebral conjunctiva associated with contact
Figure 55-24 Giant papillary conjunctivitis. Giant papillae cover this patient’s superior tarsal conjunctiva after chronic exposure to soft contact lenses.
lens wear, ocular prostheses, and protruding ocular sutures.  Primarily, this is a syndrome linked to contact lens wear and is seen 10 times more frequently in soft lens wearers than in rigid lens wearers. The average time for the development of symptoms is 8 months for soft lens wearers and 8 years for hard lens wearers. Estimates of the prevalence vary from 1–5% of soft lens users to 1% of rigid lens users.
The symptoms of GPC appear before the signs of superior tarsal involvement. Patients complain of mild itching after removal of the contact lenses and increased mucus on the lenses and in the nasal canthus upon awaking. They also complain of increased lens awareness, blurring of vision after hours of lens wear, excessive lens movement, and eventual contact lens intolerance. Signs of GPC initially include a generalized thickening and hyperemia of the superior pretarsal conjunctiva. The normally small papillae become elevated. The conjunctiva becomes more translucent and eventually becomes opaque secondary to cellular infiltration. Macropapillae (0.3–1.0?mm) and giant papillae (1.0–2.0?mm) then form ( Fig. 55-24 ). Trantas dots and gelatinous nodules may develop at the limbus.  Inspection of the contact lenses almost always reveals whitish deposits.
The histology of GPC shows irregular thickening of the conjunctival epithelium over the papillae, with epithelial downgrowth into the stroma. The epithelium and stroma show infiltration of lymphocytes, plasma cells, polymorphonuclear neutrophil leukocytes, eosinophils, basophils, and macrophages along with fibroblast proliferation. The number of eosinophils and basophils is considerably lower than that seen in vernal conjunctivitis.
The cause of GPC is probably multifactorial. Patients are likely to have environmental antigens adhere to the mucus and proteins that normally coat the surface of all contact lenses. These antigens, which persist as deposits on the contact lenses, are forced into repeated contact with the superior tarsal conjunctiva with blinking. Mechanical trauma is also an important factor in the pathogenesis of GPC that develops in patients who have ocular prostheses and exposed suture ends. This repeated exposure to antigen combined with the trauma to the upper tarsal conjunctiva from contact lens wear may result in stimulation of a type IV basophil hypersensitivity of the conjunctiva, which resembles cutaneous basophil hypersensitivity. A type I IgE-mediated immediate hypersensitivity reaction occurs as well. Conditions that favor the development of GPC in lens wearers include increased lens deposits, increased wearing time, extended number of years the lenses have been worn, larger diameter lenses, and soft lenses.
Treatment of the condition initially requires discontinuation of lens wear until the inflammation subsides. Lens wear may resume
Figure 55-25 Molluscum contagiosum lesion on the lower eyelid. This patient had an accompanying chronic follicular conjunctivitis secondary to the toxic effect of viral proteins from this lesion.
Ocular Medications That Cause Toxic Follicular Conjunctivitis
Preservatives (thimerosal, benzalkonium chloride)
when the eye quiets down, but good care is essential. Patients must be instructed to clean their contacts thoroughly each night, and an attempt should be made to remove preservatives from the lens care system. Hydrogen peroxide disinfection is used. Patients should also clean their lenses enzymatically at least once a week and as often as each night with a papain enzymatic cleaner. Initially, a new lens of the same design may be used, but if this is not tolerated, a different lens design should be substituted. A silicone-containing lens such as the CSI lens or frequent replacement soft lenses may be successful. If soft lenses do not work, a rigid gas-permeable lens often does. When used in the early stages of GPC, cromolyn sodium 4% can be effective in the resolution of symptoms such as mucus production and itching. A short course of topical corticosteroids can lessen the symptoms in severe cases.
Toxic Follicular Conjunctivitis
Toxic follicular conjunctivitis follows chronic exposure of the conjunctiva to a variety of foreign substances, including molluscum contagiosum of the lid margin, infection of the lashes by Phthirus pubis, use of eye cosmetics, and prolonged use of various eye medications. Molluscum contagiosum infections are caused by a poxvirus and are common in the setting of human immunodeficiency virus infection. They are characterized by elevated, round, pearly white, waxy, noninflammatory lesions with umbilicated centers ( Fig. 55-25 ). When these lesions occur on or near the eyelid margin, the viral proteins spill into the conjunctiva to cause a chronic follicular conjunctivitis.  The virus itself does not grow in the conjunctiva; rather the conjunctivitis is a toxic reaction to its proteins. Removal of the lesion or curettage until it bleeds internally eliminates this condition.
Most commonly, toxic follicular conjunctivitis occurs in association with eye medications, such as neomycin, gentamicin, idoxuridine, and other topical antivirals, as well as many glaucoma medications including brimonidine, pilocarpine, and
Figure 55-26 Ligneous conjunctivitis. Woody induration of the superior and inferior tarsal conjunctiva.
other miotics ( Box 55-2 ). These drugs incite a type IV delayed hypersensitivity reaction with periocular erythema and a follicular conjunctivitis. The process is sometimes called “pseudotrachoma,” with follicles on the superior tarsus, papillary hypertrophy, conjunctival scarring, keratitis, and pannus. Herbert’s pits do not occur, however. A marked follicular response can also accompany the use of eye cosmetics such as mascara and eyeliner. A common finding is dark granules from the cosmetic incorporated in the follicles. If symptomatic, patients usually respond well to discontinuation of the cosmetic and substitution of smaller amounts of hypoallergenic preparations.
Ligneous conjunctivitis is a rare chronic conjunctivitis that has an acute onset. It is characterized by a woody induration of the tarsal conjunctiva associated with a membrane or pseudomembranes ( Fig. 55-26 ). Plasminogen deficiency, both homozygous and heterozygous, has been identified as a cause of ligneous conjunctivitis.  The condition is often associated with an acute infection or trauma of the upper respiratory tract, urinary tract, middle ear, sinuses, cervix, or vagina. Therefore, fever and other constitutional symptoms may accompany the conjunctivitis. Chronic, recurrent inflammation of the upper pretarsal conjunctiva becomes compacted and granulated to produce the woody membrane. The cornea may become involved secondarily with scarring and vascularization.
The pathophysiology of this disease involves increased vascular permeability of the conjunctival blood vessels. Widened spaces between endothelial cells are found. The membrane produced is composed of fibrin, albumin, IgG, new blood vessels, plasma cells, and activated T and B lymphocytes.
Many different therapies have been tried. Surgical excision of the membranes is technically difficult and usually results in a recurrence. Cryotherapy has been reported to have mixed results but overall is probably not helpful. Chymotrypsin, hyaluronidase, various antibiotics, topical corticosteroids alone, antiviral agents, cautery, and beta and X-ray irradiation all have been tried with little success. The most promising treatment to date is a combination of cyclosporin 2% and topical corticosteroids. It is thought that cyclosporin interferes with T-cell recruitment and activation because it decreases the production of or response to interleukin-2. Treatment with intravenous plasminogen has been shown to be beneficial in case studies.
Cicatricial pemphigoid is a rare disorder characterized by recurrent blisters or bullae of the skin and mucous membranes that
Figure 55-27 Cicatricial pemphigoid. Marked subepithelial fibrosis has resulted in shrinkage of the inferior conjunctival fornix, with overlying keratinization of the conjunctiva.
Figure 55-28 Symblepharon formation. Lower and upper lids to the cornea in cicatricial pemphigoid.
result in scar formation. It is a disease of older people (mean age of 70 years) and affects women more frequently than men. Oral and ocular involvements are common. In ophthalmic studies, 15–50% of patients show oral involvement and 100% show ocular involvement.  Skin may be involved in up to 25% of cases, with either a recurrent vesiculobullous, nonscarring eruption of the inguinal area or extremities or a localized erythematous plaque with overlying bullae and vesicles on the face near the involved mucous membranes; this can result in smooth atrophic scars. Mucous membrane involvement may include the conjunctiva, nose, mouth, pharynx, larynx, esophagus, anus, vagina, or urethra.
The course of ocular involvement is usually slow but unremittingly progressive. Often, asymmetrical bilateral involvement is seen. The initial symptoms are chronic conjunctival irritation, burning, and tearing, sometimes with a mucopurulent discharge. Secondary bacterial conjunctivitis is common, especially with coagulase-positive staphylococci. Conjunctival inflammation progresses to subepithelial fibrosis, which is the hallmark of the disease. Symblepharon, fibrotic bands, and blunting of the fornices occur next and most frequently involve the inferior fornix ( Fig. 55-27 ). Eventual obliteration of the fornices, ankyloblepharon, and a keratinized ocular surface epithelium occur at the end stage ( Fig. 55-28 ). Cicatricial pemphigoid is associated with dry eye because fibrosis beneath the conjunctival epithelium can cause occlusion of the ducts of the lacrimal and accessory lacrimal glands and result in an aqueous deficiency. Progressive conjunctival scarring results in loss of goblet cells and a mucin deficiency. Chronic associated staphylococcal blepharitis may produce meibomian gland dysfunction and a resultant lipid tear film abnormality. Therefore, all the components of the tear film are altered along with the decrease in the volume of tears. Entropion, trichiasis, and lagophthalmos occur. As a result of the severe dry eye and the mechanical irritation from the disturbed eyelid architecture, the cornea may develop recurring epithelial erosions, keratinization, neovascularization, ulcer formation, possible perforation, and secondary bacterial infection. In one study, 21% with treated ocular cicatricial pemphigoid progressed to legal blindness.
The pathogenesis of the disease is thought to involve an autoimmune attack of immunoglobulins (mostly IgG) on the basement membrane of the conjunctiva, which suggests a type II reaction.  The target autoantigen has been identified as the ß4 subunit of the a6ß4 integrin dimer. Both the classical and alternative complement pathways are stimulated, which results in an inflammatory response. Conjunctival biopsies demonstrate immunoglobulins and complement bound to the basement membrane. In the acute stages, subepithelial bullae with a separation between basal cells and the basement membrane occur. An infiltration of lymphocytes (mostly helper T cells), plasma cells, occasional eosinophils, and few neutrophils is seen. Later stages show pronounced fibrosis with hyperproliferation of conjunctival fibroblasts.
The differential diagnosis involves all other conditions that produce conjunctival scarring including radiation, thermal, or severe chemical burns. Sjögren’s syndrome, severe atopic keratoconjunctivitis, scleroderma, and sarcoidosis also produce conjunctival scarring and symblepharon. Postsurgical scarring and conjunctival carcinoma must also be considered. In addition, infections such as trachoma, adenoviral EKC, primary herpes simplex, diphtheria, and ß-hemolytic streptococcus result in conjunctival scarring. Medications such as systemic practolol, topical epinephrine (adrenaline), idoxuridine, echothiophate iodide, pilocarpine, timolol, demecarium, and dipivefrin may cause a drug-induced ocular cicatricial pemphigoid. This condition can be self-limited or progressive and essentially cannot be differentiated from true cicatricial pemphigoid. Erythema multiforme major may produce a clinical picture similar to that of cicatricial pemphigoid. Other bullous diseases, such as bullous pemphigoid and pemphigus, usually do not cause conjunctival scarring. The former is primarily a skin disease and the latter causes intraepithelial bullae.
Treatment can be difficult. Nonpreserved artificial tears are the mainstay of treatment of the dry eye. Although artificial tears can increase comfort and temporarily improve the ocular surface, they do not halt the progression of the disease. Punctal occlusion can be performed if the puncta do not scar closed. A therapeutic soft contact lens with frequent artificial tears can be tried in some patients who suffer continual corneal damage from trichiasis or lid abnormalities. Caution is needed, however, because of the increased risk of infection. The chronic staphylococcus blepharitis may be controlled with regular lid scrubs followed by an antibiotic ointment, such as bacitracin or erythromycin, rubbed into the lid margins. Oral tetracycline or doxycycline also helps to control the posterior aspect of blepharitis. Trichiasis can be treated with electrolysis for sporadic lashes or cryotherapy to eradicate large areas of trichiatic lashes. With advanced scarring, oculoplastic procedures to restore normal lid position and architecture can be tried but may activate the inflammatory process. Mucous membrane grafts can be used to replace scarred conjunctiva. However, the usual sources for mucous membranes (contralateral eye, oral mucosa) may be damaged by the disease. Amniotic membrane grafts can be used as a replacement for conjunctival basement membrane.
Long-term systemic immunosuppressive therapy can control the disease,   an approach that works best in the earlier stages.
Many different modalities are available. Dapsone is a good choice for patients who have only mild to moderate inflammation. Methotrexate, azathioprine, or cyclophosphamide may be the best choice for highly active cases; adjunctive oral prednisone (1?mg/kg/day) may be beneficial. Patients often need to have systemic immunosuppression for at least 12 months, and use of more than one medication is often necessary. Preliminary studies indicate that disease that is refractory to conventional treatment may respond to intravenous immunoglobulin or subconjunctival mitomycin C.  Corneal transplant surgery, even with preoperative stem cell transplants, is associated with a very poor prognosis. Some surgeons have found success with a keratoprosthesis.
Caution must be exercised when any surgical procedure is carried out on an eye that has cicatricial pemphigoid.  Cataract, glaucoma, or oculoplastic surgery may activate the conjunctival inflammatory process unless the patient’s disease is controlled adequately by systemic immunosuppressive therapy. If cataract surgery is needed, a clear corneal temporal incision, without conjunctival manipulation, is preferred.
Erythema Multiforme Major (Stevens-Johnson Syndrome)
Erythema multiforme, unlike cicatricial pemphigoid, is an acute, generally self-limited, nonprogressive inflammatory disorder of the skin and mucous membranes; it is classified into minor and major forms. The minor form primarily involves the skin and lasts 2–3 weeks in its acute phase. Erythema multiforme major, also known as Stevens-Johnson syndrome, is the more serious variant, characterized by skin lesions and erosive involvement of mucous membranes that lasts up to 6 weeks.  There are signs of systemic toxicity, which include malaise, fever, headache, and fluid imbalance. Toxic epidermal necrolysis is a severe variant of erythema multiforme major that is characterized by massive denudation of the epidermis. Erythema multiforme major classically occurs in previously healthy young people, men more than women, in their first three decades of life. There may be a genetic predisposition for the development of Stevens-Johnson syndrome with ocular involvement, as seen in the association of human leukocyte antigens HLA-Bw44 and HLA-B12. The disease can be fatal in 2–25% of patients, with death often secondary to sepsis. Twenty percent of those who have erythema multiforme suffer a recurrence over their lifetime.
The exact cause of erythema multiforme is unknown, although the disease seems to be precipitated by numerous antigens including bacteria (e.g., Mycoplasma pneumoniae), viruses, fungi, and drugs. Herpes simplex virus and Mycoplasma have a particularly strong association. Drugs implicated in the development of erythema multiforme include the sulfonamides, penicillin, barbiturates, salicylates, mercurial agents, arsenic, phenylbutazone, and phenytoin. Also, erythema multiforme has been reported following the use of topical ophthalmic scopolamine (hyoscine), tropicamide, and proparacaine. In addition, the onset of the disease has been related to neoplasms, radiation therapy, collagen vascular diseases, and vaccinations.
Erythema multiforme often begins with the symptoms of malaise, fever, and headache as well as symptoms of an upper respiratory tract infection. Next, skin lesions develop symmetrically on the extremities, but the trunk is often spared ( Fig. 55-29 ). Crops of skin lesions can reoccur every 2 weeks or so over a period of 6 weeks. The primary cutaneous lesion is a round, erythematous macule that develops into a papule and then a vesicle or bulla. Eventually, large bullae can rupture, which results in epidermal necrosis. The characteristic skin finding is a target lesion characterized by a red center surrounded by a pale zone and then an outer red ring. If extensive skin necrosis occurs, the condition is labeled toxic epidermal necrolysis ( Fig. 55-30 ). The extent of mucous membrane involvement usually parallels the extent of skin involvement. Any mucous membrane may be involved, but the mouth and eyes are affected most frequently and most
Figure 55-29 Acute phase of Stevens-Johnson syndrome. This child has the typical target-shaped macular skin lesions. A, The head, with an associated blepharoconjunctivitis. B, The trunk.
Figure 55-30 Severe skin and conjunctival necrosis. The patient has toxic epidermal necrolysis.
severely. In one study, 100% of patients had stomatitis and 63% had conjunctivitis.
The acute phase of ocular involvement lasts 2–3 weeks. The lids become swollen, ulcerated, and crusted. Patients develop an acute bilateral mucopurulent conjunctivitis, and those affected more severely develop chemosis, vesicles and bullae, pseudomembranes or membranes, and eventual ulceration. A
Figure 55-31 Stevens-Johnson syndrome. Residual conjunctival scarring is evident over the superior tarsal plate. Symblepharon formation and fibrous bands are present at the canthal angles.
more purulent conjunctivitis may develop as a result of bacterial secondary infection.  The major ocular problems occur from the cicatricial stage, after the acute toxic episode subsides. Conjunctival scarring and symblepharon may occur despite all supportive measures ( Fig. 55-31 ). Destruction of the conjunctival goblet cells, lacrimal gland, and accessory lacrimal gland tissue results in a severe dry eye, just as in cicatricial pemphigoid. Entropion, trichiasis, and lagophthalmos combined with the dry eye can produce severe corneal problems such as ulceration, vascularization, opacification, and eventual perforation. Although the acute phase of erythema multiforme may leave extensive conjunctival scarring in its wake, progressive scarring does not occur when the acute disease has subsided, unlike the situation in cicatricial pemphigoid. Fortunately, recurrences of erythema multiforme rarely involve the conjunctiva.
The histological changes in erythema multiforme suggest an underlying vasculitis or perivasculitis. Mononuclear cells, eosinophils, and polymorphonuclear neutrophil leukocytes accumulate around the vessels or within the vessel wall and induce fibrinoid necrosis of the wall. Subepithelial bullae are seen in the acute phase, and pseudomembranes and true membranes are found. Conjunctival goblet cell densities are reduced. Circulating immune complexes have been demonstrated in the sera of these patients. Also, immunoglobulins and complement are deposited at the dermal-epidermal junction.
Treatment often varies with the severity of the condition. Patients who have a more severe initial presentation suffer the worst late ocular complications. In the acute phase, local treatment involves lubrication of the ocular surface. Frequent lysis of developing symblepharon may have no effect on the eventual structure. Unfortunately, local treatment of the acute condition seems to have little influence on the severity of the eventual cicatricial complications. However, systemic corticosteroids (prednisone 60–80?mg/day for 3–4 weeks) may help control the acute disease.  Secondary bacterial conjunctivitis should be suspected and treated if present, although care must be taken not to use an antibiotic that could stimulate another toxic reaction. The cicatricial stage is treated with frequent nonpreserved artificial tears and/or ointments. If not already scarred, the puncta may be closed to help the dry eye. Surgery to correct lid keratinization, entropion, and trichiasis should be considered. Unlike that in cicatricial pemphigoid, eyelid or conjunctival surgery does not stimulate further scarring. Conjunctival or buccal mucous membrane grafts may be considered in order to restore the ocular surface. Amniotic membrane grafts may also be used to repair areas of conjunctival destruction. Stem cell transplantation through the use of living-related or cadaveric conjunctival and limbal allografts holds promise for the treatment of corneal surface
TABLE 55-6 — CLINICAL FORMS OF EPIDERMOLYSIS BULLOSA
Bilateral small cysts at epithelial basal cell layer
Severe conjunctival scarring—resembles pemphigoid
Little conjunctival involvement—can have scarring
Primarily corneal—with clouding, recurrent erosions, ulcers, and opacification
disease, and trials incorporating cultivated corneal epithelial stem cells using denuded amniotic membrane as a carrier have had encouraging results.
Epidermolysis bullosa comprises a group of skin and mucous membrane diseases that are characterized by the tendency to form blisters after minor trauma.  Symptoms occur shortly after birth or in early childhood and have a tendency to recur throughout the patient’s life. Men and women are affected equally, and both hereditary and acquired autoimmune forms exist. The hereditary forms of epidermolysis bullosa may be classified as simple (autosomal dominant), junctional (autosomal recessive), and dystrophic (autosomal dominant or recessive) ( Table 55-6 ).
Ocular problems have been described with all three types of epidermolysis bullosa; however, they are most common with the dystrophic form, which is also the most common form of the disease. Such patients may have marked conjunctival scarring, which includes symblepharon formation. A granular epithelial clouding of the cornea can occur, as can ulcers and opacification secondary to conjunctival scarring similar to that seen in cicatricial pemphigoid or erythema multiforme. Patients who have the junctional form, a rare type, have more primary corneal problems, such as recurrent erosions, and little conjunctival involvement. The acquired, autoimmune form may have both primary corneal subepithelial vesicles and secondary corneal involvement associated with conjunctival scarring and symblepharon.
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