Ординатура / Офтальмология / Английские материалы / Clinical Ocular Pharmacology 5th edition_Bartlett, Jaanus_2008

infectious agents. The manifestations of the condition vary and are nonspecific to the etiologic agent. Unilateral follicular conjunctivitis and conjunctival granulomas and ulcerations associated with prominent regional lymphadenopathy are the primary clinical characteristics of the condition. The conjunctivitis and adenopathy usually resolve in 4 to 5 weeks.The specific clinical entity most commonly associated with Parinaud’s oculoglandular syndrome is cat-scratch disease, which now is believed to be caused by Bartonella henselae, a Rickettsia-like organism. Box 25-4 lists the other agents responsible for Parinaud’s oculoglandular syndrome.

Ophthalmia Neonatorum

Ophthalmia neonatorum, or conjunctivitis of the neonate (within 30 days of birth), warrants special consideration because of its relatively common occurrence; up to 12% of newborns demonstrate this condition. Because of the potentially devastating effects of neonatal infections resulting from N. gonorrhoeae, Pseudomonas, Chlamydia, and HSV, laboratory investigation is essential in establishing the cause. Infants usually acquire infection from an infected birth canal. Premature membrane rupture and prolonged delivery can also cause increased exposure to maternal pathogens and an increased risk of neonatal infection.

Neisseria gonorrhoeae Ophthalmia Neonatorum. Gonococcal neonatal conjunctivitis is characterized by the neonate’s development of hyperacute conjunctivitis between 2 and 5 days postpartum. Most cases of neonatal gonococcal conjunctivitis are bilateral; periorbital edema, chemosis, and purulent exudate are prominent (Figure 25-18).

Because of the ability of N. gonorrhoeae to penetrate intact epithelium, prompt and accurate diagnosis is imperative to prevent corneal ulceration and perforation. N. gonorrhoeae can also be associated with systemic infection. Specific dermatologic manifestations are possible, and careful neurologic monitoring for evidence of central nervous system involvement is imperative.

Box 25-4 Causes of Parinaud’s Oculoglandular

Syndrome

Common

Cat-scratch disease

Tularemia

Sporotrichosis

Occasional

Tuberculosis

Syphilis

Coccidioidomycosis

Rare

Pasteurella septica

Yersinia pseudotuberculosis

Chancroid

Lymphogranuloma venereum

Listerellosis

Actinomycosis

Blastomycosis

Mumps

Figure 25-18 Neonatal conjunctivitis secondary to Neisseria gonorrhoeae. Note the copious purulent exudates and pronounced chemosis. (Courtesy William Wallace, O.D.)

Presumptive diagnosis is based on the finding of gramnegative diplococci on Gram staining of conjunctival exudate (Figure 25-19). Conjunctival cultures should be obtained and incubated on Thayer-Martin or chocolate agar at 37°C under 2% to 10% CO2. Antibiotic sensitivities are essential for all isolates due to the increasing incidence of penicillin-resistant strains of N. gonorrhoeae.

Topical antibiotic agents alone are inadequate and unnecessary when systemic treatment is administered. A single dose of ceftriaxone, 25 to 50 mg/kg intravenously or intramuscularly, not to exceed 125 mg, is the regimen currently recommended by the CDC. Simultaneous infection with C. trachomatis should be considered when a patient does not improve after treatment. Both mother and infant should be tested for chlamydial infection at the same time that gonorrhea testing is conducted.

Chlamydia trachomatis Ophthalmia Neonatorum. The leading infectious cause of ophthalmia neonatorum is C. trachomatis. This infection has been estimated to occur in 2% to 6% of all newborns. Its high incidence is attributable to the fact that up to 13% of women shed Chlamydia from the urogenital tract during the third trimester of pregnancy. The high incidence of infection may also be related to the ineffectiveness of silver nitrate in preventing chlamydial infection.

Chlamydial ophthalmia neonatorum is characterized by the onset of a mild to moderate unilateral or bilateral mucopurulent conjunctivitis 5 to 14 days postpartum (Figure 25-20). Eyelid edema, chemosis, and conjunctival membrane or pseudomembrane formation may also accompany this condition. Corneal findings occasionally include punctate opacities and micropannus formation. Ophthalmia neonatorum secondary to C. trachomatis was once considered a benign and self-limited condition. However, systemic chlamydial infection, especially pneumonitis, is now well recognized in patients with chlamydial conjunctivitis. More than 50% of infants who develop chlamydial pneumonitis may also have ophthalmia neonatorum.

Diagnosis of chlamydial ophthalmia neonatorum is established by conjunctival smears that reveal typical basophilic intracytoplasmic inclusions with Giemsa stain and by traditional specimen culture (Figure 25-21). Direct immunofluorescent, immunoenzyme antibody, or NAAT testing can also be helpful in confirming the diagnosis.

Optimal treatment of chlamydial ophthalmia neonatorum has not been determined. The CDC recommends erythromycin base or ethylsuccinate syrup 50 mg/kg/day orally divided into four doses daily for 14 days. Topical antibiotic therapy alone is inadequate and unnecessary when systemic treatment is administered. Another important aspect of treatment is concurrent therapy for the mother and her sexual partners.

Figure 25-19 Gram-stained smear from neonate with hyperacute conjunctivitis showing intracellular Neisseria gonorrhoeae (arrows). (Courtesy William Wallace, O.D.)

Figure 25-20 Neonatal inclusion conjunctivitis with prominent mucopurulent exudates. (Courtesy William Wallace, O.D.)

462 CHAPTER 25 Diseases of the Conjunctiva

Figure 25-21 Intracytoplasmic inclusions (arrow) associated with neonatal inclusion conjunctivitis. (Courtesy William Wallace, O.D.)

Other Bacterial Etiologies in Ophthalmia Neonatorum. Many cases of ophthalmia neonatorum result from nongonococcal bacterial infections. S. aureus, Haemophilus species, Streptococcus viridans, E. coli, and P. aeruginosa have been implicated as causative agents in ophthalmia neonatorum. These pathogens are most likely acquired as the newborn travels through the birth canal. All these bacteria are part of the normal bacterial flora of the female genital tract. Infection may arise from other sources as well, because 20% to 79% of the conjunctivae of infants delivered by cesarean section show bacterial growth.

Clinical manifestations of bacterial ophthalmia neonatorum are nonspecific and similar to those caused by other pathogens discussed previously. Infants experience the acute onset of hyperemia, chemosis, eyelid edema, and purulent or mucopurulent exudate 5 to 21 days postpartum. Practitioners should take care to rule out nasolacrimal duct obstruction, a finding that is relatively common in newborns and that can be associated with a secondary bacterial infection.

Because the etiology of ophthalmia neonatorum cannot be distinguished on the basis of clinical examination alone, laboratory investigations (smears and cultures) are mandatory. Differentiation of bacterial infections, particularly Pseudomonas, is important, because pseudomonal infections in premature infants can lead to septicemia and death if not aggressively and appropriately treated.

Initial treatment of bacterial ophthalmia neonatorum should be directed by the results of conjunctival smears. Broad-spectrum antibiotics with low toxicity should be used. Topical erythromycin or tetracycline ointment can be used four to six times daily for gram-positive organisms, and gentamicin or tobramycin solution four to six times daily can be started if gram-negative organisms are isolated. Trimethoprim-polymyxin B (Polytrim) has

broad-spectrum activity against a range of both gram-posi- tive and gram-negative organisms,including Pseudomonas species.

Herpes Simplex Virus Ophthalmia Neonatorum. HSV infection is an uncommon but important cause of neonatal infection and is associated with conjunctivitis in 5% to 10% of cases. The clinical manifestations are nonspecific and include conjunctival hyperemia, chemosis, periorbital edema, and mucous discharge. Corneal involvement is not uncommon and can include dendritic, geographic, or stromal keratitis. Herpetic ophthalmia neonatorum represents a primary herpetic infection. Central nervous system involvement, encephalitis, retinitis, optic neuritis, uveitis, choroiditis, and a fatal viremia can be serious sequelae of primary herpetic infections.

Diagnosis often is difficult, but laboratory testing can aid in establishing a diagnosis.An absence of bacteria in conjunctival smears should alert the clinician to the possibility of viral infection. Papanicolaou stain may reveal intranuclear inclusions and multinucleated giant cells can be seen on Giemsa staining. A maternal history of HSV infection and the characteristic corneal findings can also help to establish the diagnosis.Viral cultures can be obtained, particularly in cases that are refractory to antibiotic treatment.

The prognosis for an infant with neonatal HSV infection is guarded. Treatment of the conjunctivitis should include topical 1% trifluridine every 2 hours until the infection begins to resolve and then tapered according to the clinical response. Systemic therapy with intravenous acyclovir is indicated in the presence of viremia and disseminated disease.

Chemical Ophthalmia Neonatorum. Chemical conjunctivitis is the most common cause of ophthalmia neonatorum, occurring in up to 90% of infants to whom silver nitrate was administered. Mild transient conjunctival hyperemia and watery discharge occurring 1 to 2 days postpartum characterize chemical conjunctivitis.The conjunctivitis is self-limited over a course of 1 to 2 days. Most cases are the direct result of toxic reaction to silver nitrate used as prophylaxis for ophthalmia neonatorum. Silver nitrate can damage the corneal and conjunctival epithelium, disrupting the protective epithelial barrier and making the infant more susceptible to secondary bacterial infections. If the history confirms the use of silver nitrate, no treatment is necessary. If the condition does not improve after several days, other etiologic mechanisms must be considered (Table 25-6).

Prevention. The best method for preventing neonatal conjunctivitis is the diagnosis and treatment of infections in pregnant women through appropriate prenatal care. In 1881 Credé first described the advantage of silver nitrate prophylaxis for the prevention of gonococcal infection. Since that time the incidence of infection from

N. gonorrhoeae has decreased from approximately 10% to less than 0.66%. Silver nitrate prophylaxis, however, is not without limitations.This agent is toxic to the epithelium, because it acts by sloughing epithelial cells. Therefore it frequently causes chemical conjunctivitis. In addition, silver nitrate prophylaxis is not completely effective, failing to act against chlamydiae, a major cause of ophthalmia neonatorum. Various alternatives to silver nitrate prophylaxis have been advocated, and currently the CDC recommends a single application of 0.5% erythromycin or 1% tetracycline ointment immediately after birth for the prophylaxis of gonococcal conjunctivitis. The efficacy of these agents in preventing chlamydial conjunctivitis is unclear. In general, though, both erythromycin and tetracycline ointment are effective and less toxic alternatives to silver nitrate. Despite its shortcomings, silver nitrate continues to provide effective prophylaxis for gonococcal ophthalmia neonatorum and is commonly used.

OCULODERMATOLOGIC DISORDERS THAT AFFECT THE CONJUNCTIVA

Dermatologic disease and its related ocular complications are commonly encountered entities in general ophthalmic practice. The conjunctiva frequently is affected with ocular involvement. Although numerous dermatologic conditions can affect the eye, this section focuses on the three conditions that are most often encountered: acne rosacea, psoriasis, and atopic dermatitis.

Rosacea

Etiology

The etiology of rosacea, which is a comparatively common dermatologic condition, remains obscure. The disorder typically presents between the third and fifth decades and is more frequently seen in women than in men. However, men are typically more severely affected. Specific trigger factors have been associated with rosacea, including trauma. An ethnic predisposition has been noted. Use of alcohol was once considered a factor, but this is no longer believed to be true.

Rosacea has characteristic clinical findings. These include an acneiform papular-pustular eruption associated with erythema and hypertrophic sebaceous glands. Typically, these changes appear on the cheeks, nose, and forehead, known as the “facial flush” areas. The frontal area of the chest may also be involved. Infestation and possible inflammation caused by the hair follicle mites

Demodex folliculorum and Demodex brevis have been linked to rosacea. Rosacea has no known relationship to previous juvenile acne.

Diagnosis

Rosacea manifests with a wide spectrum of clinical presentations ranging from extremely subtle facial erythema to severely disfiguring facial scarring. When mild, rosacea may go unnoticed by the patient and unrecognized by many physicians. Stressful or emotional situations or even laughter often cause facial flushing, with patients’ faces turning “beet red.” Some patients go to extremes to mask the condition, such as using green-tinted makeup to balance their ruddy complexion. As the dermatologic disease progresses, recurrent episodes of livid inflammatory papules and pustules grow more frequent. Scarring causes coarseness of the skin and may eventually produce rhinophyma, a bulbous disfigurement of the nose that is pathognomonic of rosacea (Figure 25-22).

In some patients the eye alone is involved; in others, ocular involvement precedes the dermatologic manifestations. Still other patients manifest dermatologic disease in isolation. Up to 58% of patients with rosacea show ocular involvement. Children may also have ocular rosacea, although this may often go unrecognized. The ocular manifestations of rosacea mirror the dermatologic signs, with involvement of the meibomian glands and sebaceous glands of the eyelashes. This most commonly produces meibomianitis, blepharitis, or both, with resultant tear film instability and evaporative dry eye. Keratoconjunctivitis sicca (KCS) is more common in patients with rosacea. Abnormal lipid production and overcolonization of the eyelids by staphylococci lead to the development of chalazion, hordeolum, and conjunctivitis caused by staphylococcal exotoxin and tear film instability.

464 CHAPTER 25 Diseases of the Conjunctiva

Figure 25-22 Ocular rosacea with conjunctivitis, maculopustular involvement of skin, and rhinophyma. (Courtesy William Wallace, O.D.)

Patients with ocular rosacea often complain of foreign body sensation, irritation, burning, and, most notably, injection, especially toward the end of the day. Corneal involvement occurs later and may be severe and sight threatening. SPK, progressive inflammation, and infiltration starting at the limbus with neovascularization may be seen (Figure 25-23). In severe disease the cornea may actually thin, ulcerate, and ultimately perforate. Because of the chronic nature of this disease, recurrent episodes are common, which should lead the practitioner to consider rosacea as a possible etiology of a noninfectious recurrent or persistent red eye.

Figure 25-23 Corneal neovascularization in a patient with rosacea.

Management

The treatment of rosacea has remained relatively constant over the recent past, with newer variations in management favoring longer acting synthetic tetracyclines such as doxycycline. Tetracycline class drugs act multifactorially by decreasing bacterial flora and the expression of matrix metalloproteinases, altering meibum secretion, inhibiting the production of bacterial lipases, and providing an immunomodulatory effect.

Standard dosage for tetracycline is 250 mg four times daily for approximately 4 to 6 weeks. Results of the therapy then are assessed, and the medication is tapered over a more extended period. Doxycycline is as effective as tetracycline when used in a dosage of 100 mg twice daily by mouth over a 3- to 6-week period. As with tetracycline, this dose, if effective, may be tapered to as low as 50 mg/day for approximately 1 month and then to 50 mg every other day for several weeks, as long as effectiveness is sustained. When doxycycline is not effective, the recommended therapy is tetracycline, 250 mg four times daily. Erythromycin may be substituted when treating children with dosing based on the child’s age and weight.

In most instances patients demonstrate significant improvement of clinical symptomatology and physical signs in the first 2 to 3 weeks. Many patients, however, require chronic therapy and demonstrate exacerbations of the disease during its course. Metronidazole (MetroGel) is a topical gel developed to treat the skin of the facial area in patients with chronic disease and thus reduce the reliance on oral antimicrobial agents. It is applied twice daily. Although not yet an approved use, metronidazole gel applied to the eyelids was found to be an effective treatment of ocular rosacea.

Although topical antibiotics are used frequently in the management of ocular rosacea, no firm evidence demonstrates their efficacy as a sole therapeutic agent. Topical steroids, however, are effective for treating the inflammatory aspects and frequently are used four times daily in conjunction with antibiotics in combination products such as TobraDex (tobramycin-dexamethasone), Pred-G (gentamicin-prednisone), or Maxitrol (neomycinpolymyxin B-dexamethasone). Because of potential steroid-induced side effects, chronic use of these agents should be avoided.

In addition to management with medications, therapy for ocular rosacea must include eyelid hygiene and warm compresses to manage concurrent blepharitis and meibomianitis. Eyelid scrubs using commercial products or diluted baby shampoo applied with a washcloth or cotton-tipped applicator help to manage blepharitis by removing debris and debulking bacteria. In addition, moist heated compresses should be applied to the eyes several times daily initially and then tapered over several weeks. The compresses should be followed by a brisk massage of the eyelids; the heat melts the saturated oils and the massage clears the glands. Ideally, this treatment should be maintained indefinitely once daily or at least

every other day. It is important to explain to patients the chronic nature of rosacea. The need for continual care must be reinforced to manage this condition successfully. In severe cases of rosacea the primary concern of the ophthalmic practitioner is to prevent corneal involvement and the subsequent scarring and vascularization that occur secondary to inflammation.

Psoriasis Vulgaris

Etiology

Psoriasis vulgaris is a relatively chronic skin disease, of unknown etiology, that affects 1% to 4% of the population. Typically, the disease presents with circumscribed, erythematous, plaque-like elevations having a coarse, dry, silvery texture. As with other oculodermatologic conditions, it is typically more common in women, whites, and individuals younger than 40 years. Most patients present with focal outbreaks of the disease, usually on extensor surfaces such as the knee and elbow. It is also sometimes seen on the scalp. Most have a local or limited form of psoriasis, with approximately one in seven progressing to a more severe generalized disease process. The overall incidence of ocular involvement in patients with generalized psoriatic disease may be approximately 1 in 10; however, more recent studies suggest that this number may be as high as 2 of every 3 patients. The degree of clinical symptomatology is highly variable.

Diagnosis

Ocular involvement commonly is manifest as typical epidermal plaque formations on the conjunctiva or eyelids (Figure 25-24). Chronic blepharoconjunctivitis has also been reported to be a common finding among these patients. Early conjunctival changes in patients with

Figure 25-24 Psoriatic blepharoconjunctivitis.

psoriasis have been noted using impression cytology. Keratitis occurs in some individuals but is primarily limbal and is believed to be related to the localized activity in the conjunctiva and eyelid margin area. Sterile corneal abscesses may occur. There is also an increased frequency of uveitis, which differs from typical HLA-B27–associated forms. However, uveitis is not a significant component of this disease. Secondary involvement of the eyelids in the form of ectropion, entropion, and trichiasis usually relates to the eyelid lesions themselves and does not represent a primary component of the disease.

Psoriasis can occur in association with chronic juvenile arthritis as well as Reiter’s syndrome. Some investigators have demonstrated a significant increase in prevalence in patients with human immunodeficiency virus infection.The pathogenesis of this relationship is unclear, but an immune recognition event may occur related to the HLA-B27 antigen. A large, retrospective, populationbased study found that psoriatic arthritis is mild, uncommon, and not associated with a significant increase in mortality.

Management

The pharmacotherapeutic management of psoriasis has met with variable success.Therapy focuses primarily on altering the abnormal physiology of the epidermis. Tazarotene (Tazorac), a retinoid gel, has been used in combination with topical steroids and ultraviolet (UV) radiation with good success. Tazarotene is a vitamin A analogue believed to help normalize the rate at which epithelial cells differentiate or divide. Other topical agents include corticosteroids, calcipotriene, a vitamin D3 analogue (Dovonex), and coal tar products. Topical anthralin,a wood tar derivative (Anthra-Derm),successfully clears psoriatic lesions, but it can cause inflammation and staining of the unaffected surrounding skin. Alterations in anthralin’s structure minimize this complication.

Many individuals require systemic therapy to show significant improvement in the more severe psoriatic disease states. Currently, methotrexate is approved for systemic use in severe psoriasis. The standard dosage is 2.5 mg two to four times daily, three times weekly. Other agents such as hydroxyurea, aminopterin, thioguanine, and retinoid etretinate have also been shown to be effective. Cyclosporine may be useful in the treatment of severe recalcitrant disease but has been demonstrated to have significant side effects. Topical tacrolimus, a potent macrolide lactone anti-inflammatory and immunosuppressant, has proven effective in treating psoriasis, but recent warnings about an increased risk of certain cancers may temper its use.A new class of immunomodulators used for treating psoriasis has emerged. Etanercept (Enbrel) is a tumor necrosis factor antagonist approved in the United States, Canada, and Europe for treating adult patients with chronic moderate to severe plaque psoriasis.

466 CHAPTER 25 Diseases of the Conjunctiva

Photochemotherapy in the form of psoralen ultraviolet A irradiation (PUVA) is one of the most effective treatment modalities. PUVA involves the use of an oral agent (psoralen), which sensitizes the epidermis to UV light. The patient is treated intensively over a 2- to 3-week period and subsequently is placed on maintenance UV therapy for an extended time. Studies show that in the acute period this therapy is 90% successful in disease remediation and that in long-term therapy more than 60% of patients have remained in remission at 1 year. Risks associated with PUVA therapy include nonmelanoma skin cancers similar to those changes noted with any chronic solar exposure. Although case reports have suggested cataract formation as a complication of PUVA therapy, large-scale investigation has proven this association to be unfounded.

Atopic Dermatitis

Etiology

Atopic dermatitis is a unique form of hypersensitivity that presents with eczematous skin eruptions. Primarily, it is a disease typically initiating in childhood or early adolescence, although it can develop in adults. Immunologic factors have been implicated in the onset of this entity. Other etiologic factors suggest genetically mediated defects in metabolism or the biochemical response to exogenous substances. A decrease in cellular immunity and an abnormality in the IgE antibody response system have also been identified. The triggers for atopic keratoconjunctivitis appear to be similar to those of atopic dermatitis. Food allergies, such as eggs, peanuts, milk, soy, wheat, or fish, and airborne allergens, particularly dust mites and dander, should be considered and investigated.

Diagnosis

Atopic dermatitis is primarily characterized by a patchy excoriation of the skin with lability to heat and pressure stimulus.All aspects of the body surface may be involved. Ocular involvement may include erythema, scaling of the eyelids, and secondary staphylococcal blepharitis. Eyelid eczema (65.7%), atopic keratoconjunctivitis, and SPK (67.5%) appear to be the dominant ocular diseases in these patients. The conjunctiva frequently presents with chemosis and hyperemia as well as a papillary response (Figure 25-25). As the disease progresses, shrinkage of the fornices and subsequent scarring may occur. Corneal involvement can range from SPK to cicatrization and vascularization (Figure 25-26). The association between keratoconus and atopy has been well established, although eye rubbing may be the proximate factor in the genesis of keratoconus.

A significant hereditary component to the ocular disease has been noted among patients with either a personal or a family history of atopic dermatitis. Abnormalities in IgE production, leukocyte cyclic adenosine monophosphate response,and abnormal methacholine

Figure 25-25 Papillary response of upper tarsal conjunctiva in a patient with atopic keratoconjunctivitis.

inhalation testing have all been noted in association with the disease. Cataract formation and retinal detachments have also been linked to atopic dermatitis.Atopic keratoconjunctivitis is a specific severe ocular disorder associated with atopic dermatitis; it is described in detail in Chapter 27.

Management

Therapy for the patient with atopic dermatitis can be divided into three distinct categories: topical therapy for the skin, systemic therapy, and ocular therapy.Therapy for the skin includes the use of fluorinated corticosteroids such as triamcinolone or betamethasone or hydrocortisone

Figure 25-26 Corneal neovascularization in a patient with atopic keratoconjunctivitis. (Courtesy William Wallace, O.D.)

applied by an occlusive dressing or other method to potentiate the drug’s effect. In less severe cases the use of topical emollients, lubricants, oils, lotions, and creams can successfully keep the skin moist. As in other severe dermatologic disorders, coal tar derivatives can be used in cases in which steroids are ineffective. Systemic management is oriented primarily toward the use of oral corticosteroids. In the acute phase, high-dose prednisone is the most effective agent, but patients can be managed chronically on low-dose therapy of 5 to 10 mg/day for prolonged periods. In patients with severe pruritus, oral antihistamines can minimize itching and provide symptomatic relief.

Therapy for the eye-related complications of atopic dermatitis focuses on reducing inflammation. Specific management of this ocular disease is discussed in Chapter 27.

Surgical intervention in atopic dermatitis has been associated with a relatively high rate of complication. In particular, the incidence of retinal detachment is relatively high.The etiology is not clear, but one study noted breaks in the pars plicata of the ciliary body in four eyes of three patients with atopic dermatitis.

MUCOUS MEMBRANE DISORDERS OF THE CONJUNCTIVA

Mucous membrane disorders that involve the conjunctiva include cicatricial pemphigoid, erythema multiforme, and, less commonly, pemphigus vulgaris. Cicatricial pemphigoid and pemphigus vulgaris appear to be primarily type II hypersensitivity reactions, whereas erythema multiforme appears to be primarily a type III immune complex–mediated hypersensitivity reaction. Mucous membrane diseases are an immune-mediated reaction to antigens in the mucosal tissue’s basement membrane. Although our understanding of the etiology of these disorders has grown in the recent past,complete understanding remains elusive.

Ocular Cicatricial Pemphigoid

Etiology

Ocular cicatricial pemphigoid (OCP) is a bilateral cicatricial disease of the conjunctiva that initially presents as a diffuse inflammation with subepithelial vesicles, edema, and hyperemia. OCP is part of a spectrum of disorders termed mucous membrane pemphigoid, that affects other parts of the body, including the skin and mucous membranes lining the mouth, nose, trachea, esophagus, vagina, and rectum. The initial phase may be mild and is often mistaken for chronic nonspecific conjunctivitis. As the condition progresses, subepithelial fibrosis, loss of goblet cells, and conjunctival and eyelid keratinization clarify the nature of the disease. In advanced cases symblepharon formation, fornix foreshortening, trichiasis, and entropion occur.

Although the disorder is relatively rare, occurring in 1 in 30,000 people, the incidence of significant visual loss is as high as 25% to 33%. Repair of the damage caused by advanced disease is difficult, making early detection and treatment crucial for visual preservation. OCP affects females more than males and occurs in all races. It is typically diagnosed in a person’s sixth or seventh decade but is likely to originate earlier in many patients who present with subtle disease.Two distinct forms have been identified: idiopathic and a drug-induced pseudo-OCP.

Despite evidence that OCP affecting the eye alone is a clinically distinct disorder, involvement of the skin and other mucosal surfaces occurs in a significant percentage of cases with ocular findings. Dermatologic manifestations occur in 21% of patients and lesions of the oral mucosa in 50%. Unlike bullous pemphigoid, which rarely affects the eye, cicatricial pemphigoid invariably produces scarring and morbidity.

Diagnosis

The most common initial sign of OCP is a conjunctivitis associated with subepithelial fibrosis, which may be subtle and easily missed. OCP should be considered in any case of chronic conjunctivitis. Chronic inflammation accompanying fibrotic changes produces progressive shrinkage of the ocular tissue with subsequent symblepharon formation (Figure 25-27). In the more advanced stages of the disease, cicatrization begins to occur. The chronic contraction of conjunctival tissue can lead to shortening of the fornices, entropion, and subsequent trichiasis. In more advanced presentations the cornea may demonstrate persistent epithelial defects, limbal inflammation with stem cell destruction, and stromal thinning and ulceration. Keratinization of the conjunctiva and cornea can lead to profound vision loss (Figure 25-28). The resultant ocular surface disruption can lead to severe dry eye. A frequent finding is cicatricial closure of the puncta and lacrimal ducts. Cicatrization takes place in much the same way as the conjunctival adhesions and

Figure 25-27 Conjunctival shrinkage and symblepharon formation (arrows) in ocular cicatricial pemphigoid.

468 CHAPTER 25 Diseases of the Conjunctiva

Figure 25-28 Keratinization of conjunctiva and cornea in ocular cicatricial pemphigoid.

can produce marked epiphora or contribute to dry eye, depending on the degree of conjunctival scarring.

The differential diagnosis of OCP varies depending on the stage of the disease. It includes conditions that produce cicatricial changes of the ocular surface, such as chemical trauma, radiation injury, and other mucous membrane disorders. Conjunctival biopsy can aid in the diagnosis. Immunofluorescence study of the tissue demonstrates deposition of immunoreactants at the epithelial basement membrane zone in OCP.

Management

Although the predominant clinical findings in OCP are ocular, topical therapy alone generally proves insufficient. Historically, the most significant success follows the use of oral corticosteroids. Unfortunately, steroids act simply as a mechanism to suppress the response and are not curative. In most instances patients are placed initially on high-dose steroids, show significant remission of symptoms, and can be tapered to a maintenance dosage level. The initial dose generally is 40 to 60 mg prednisone daily. Maintenance therapy can be as little as 5 mg every other day.Approximately 25% of patients cannot continue longterm steroid therapy due to complications, and these patients eventually progress to severe visual impairment or blindness. Only one-third of patients on chronic immunosuppressive therapy can achieve long periods of remission off medication.

Dapsone is effective in treating the acute inflammatory stage of OCP. As with steroids, dapsone does not significantly affect the cicatricial component of the disease, but it does control the inflammatory aspect. In recent studies an initial dose of 100 mg/day was well tolerated with no toxicity. The use of 150 mg/day brought on significant side effects. Once an initial response was obtained (usually in 1 to 4 weeks), a maintenance dose of 50 to 100 mg on alternate days was used. Many patients experienced significant periods of remission, but in all instances therapy had to be reinstituted on a regular basis. Sulfapyridine has been suggested as an alternative to dapsone.

In patients with more advanced disease, who show rapid progression, or when either steroids or dapsone fails, immunosuppressive agents such as cyclophosphamide and azathioprine may produce sustained remission. The standard dose for cyclophosphamide is 1 to 2 mg/kg daily combined with an equal amount of prednisone.After a 1-month to 6-week initial treatment period, the effectiveness of therapy is assessed, and cyclophosphamide dosage may increase if the disease is still present or progressive. In most instances steroids can be reduced at this point because of the obvious complications with long-term use. Cyclophosphamide combined with highdose pulsed steroids has been found to be a successful therapeutic combination. This may reduce some of the risks inherent in long-term steroid use. Cyclophosphamide therapy routinely continues for a period of 12 months or longer. In the treatment of acute severe OCP, cyclophosphamide was successful in 96% of the patients when administered for 10 months or longer. Azathioprine was successful in 85% of the patients over the same period.

Recent therapeutic approaches have been directed to the immunologic aspects of OCP. Intravenous immunoglobulin immunomodulatory therapy has proven a safe and effective therapy for otherwise treatment-resistant OCP. Subconjunctival mitomycin C was recently described as a promising treatment of OCP. Currently, use of tacrolimus and etanercept has been reported to be successful in managing mucous membrane pemphigoid and OCP.

Adjunctive ocular therapy is directed toward management of the dry eye associated with OCP. Dry eye results from damage to the ocular surface and conjunctival goblet cells. Chronic lubricant therapy is beneficial. Ideally, nonpreserved agents should be used. Ointments or gels are effective in providing lubrication either overnight or, in the more advanced forms of the disease, during the daytime hours. The patient’s symptoms determine dosage frequencies. Use of adjunctive therapy such as eyelid hygiene and the treatment of secondary infections should be implemented on an individual basis. However, the chronic use of antibiotics is contraindicated because of potential overgrowth of resistant organisms and antibiotic toxicity.

The goal of therapy is the maintenance of corneal integrity and patient comfort. Procedures such as eyelash epilation, eyelid scrubs, and antibiosis can help in the early phases of the disease process. As the disease progresses, surgical procedures may be of benefit. These include procedures for the correction of entropion and trichiasis as well as oculoplastic surgery for the resolution of symblepharon and conjunctival shrinkage. Buccal mucosal grafting shows promise in the rehabilitation of this disease, and investigators have evaluated nasal mucosal grafts as adjunctive therapy.Amniotic membrane transplantation to reconstruct the ocular surface has been successful. Limbal stem cell transplantation and, more recently, transplantation of autologous limbal epithelial cells cultured on amniotic membrane have

been used effectively to reconstruct the corneal surface. Surgical intervention should generally be withheld until the disease progresses unchecked by methods that are more conservative and, ideally, should be performed with the disease under medical control. Surgery itself can induce further inflammation. Unfortunately, penetrating keratoplasty and other corneal procedures are not particularly successful in treating OCP.

Stevens-Johnson Syndrome, Erythema Multiforme Major, and Toxic Epidermal Necrolysis

Etiology

SJS was for many years considered a severe variant of erythema multiforme major (EMM); however, over the past decade some experts have reclassified SJS as a less severe variant of toxic epidermal necrolysis (TEN) rather than a form of EMM. However, this perspective is not universally accepted. SJS occurs acutely in all ages, with 20% in children and a peak incidence in adults between the second and fourth decades of life. SJS is a potentially fatal disorder with a mortality of approximately 5%. TEN has a mortality rate of approximately 30%. About 50% of cases of these disorders are idiopathic. Identifiable causal factors include microbial infection, particularly with Mycoplasma pneumoniae and HSV, and medications, including sulfonamides, tetracycline, penicillin, nonsteroidal anti-inflammatory drugs (NSAIDs), psychotropic agents, antiepileptics, and immunizing vaccines. Recent research suggests that HSV infection is a principal factor in the genesis of EMM, whereas medications are a more likely precipitant of SJS and TEN.

Erythema multiforme minor is comparatively benign. SJS or EMM involves the ocular tissues and produces the classic signs of a catarrhal pseudomembranous conjunctivitis. Erythema multiforme occurs more frequently in men than in women.

Diagnosis

SJS and TEN are systemic disorders typically presenting with constitutional signs, including fever, malaise, headache, loss of appetite, nausea, and vomiting.The skin is involved with inflammatory vesiculobullous lesions, frequently accompanied by hemorrhage and necrosis. In contrast, EMM usually presents with a diffuse erythematous papular and macular eruption that evolves into characteristic target or bull’s-eye lesions with an erythematous center surrounded by a zone of normal skin and then by an erythematous ring. The soles of the feet and the palms of the hands often are affected in EMM. Mucous membranes of the nose and mouth are the most commonly affected, and conjunctival involvement is common in both EMM and SJS/TEN.At least two mucous membranes surfaces are involved in SJS and TEN.

EMM has an associated purulent conjunctivitis in approximately 10% of cases.SJS andTEN have a bacteria-like

pseudomembranous conjunctivitis frequently associated with significant discharge. The onset is rapid. As the disorder progresses, bullae formation followed by rapid rupture and subsequent scarring in the area of the epithelial erosions characterize the disease. It is typical for the conjunctiva to show vascular changes with necrosis and subsequent scarring. If the eyelids are involved in the cicatricial process, entropion and trichiasis frequently are noted, and in many individuals an ulcerative bullous-type process develops near or on the eyelid margin. The condition may include a wide spectrum of clinical manifestations not unlike those encountered with OCP.These may range from minimal punctal stenosis to severe corneal opacification and infiltration with scarring. More remarkable ocular involvement typically occurs only in individuals with extremely severe disease.

Management

Immediate withdrawal of suspected causative agents appears to improve outcome and survival in SJS. The condition is treated similarly to OCP: Although still controversial, the use of systemic steroids and, in some instances of severe disease, immunosuppressive agents has been successful. Tetracycline and fluoroquinolone antibiotics may be used to combat any secondary infections of the bullous regions of the epidermis. Fluid and electrolyte levels must be monitored to assess potential dehydration secondary to the skin lesions, and intravenous fluids should be administered as necessary.

Ocular therapy is directed primarily at the prevention of infectious complications secondary to the colonization of organisms such as Staphylococcus species and other skin flora.This can be accomplished with topical fluoroquinolones or other broad-spectrum antibiotics. Dosage frequencies are variable depending on the severity of the disease, but in most instances a dosage regimen of every 3 to 4 hours is recommended.The use of topical steroids has been advocated in managing the inflammatory components of this disease. Prednisolone acetate 1% used every 2 to 3 hours initially and tapered after the inflammatory response begins to subside is a reasonable adjunct to antibiotic therapy.The use of eyelid scrubs, epilation in the case of trichiasis, sweeping of the fornices with a glass rod to prevent adhesions between raw surfaces, and the use of cool compresses to provide symptomatic relief can prove extremely valuable in conjunction with topical pharmacotherapy.

The management of dry eye associated with SJS can be accomplished in an aggressive fashion with the use of nonpreserved lubricant solutions and bland ointments. Unfortunately, patients with SJS or OCP frequently have chronic severe dry eye. The challenge in managing this condition is to provide the best environment and visual performance possible in the face of rather severe compromise of the ocular surface.The best approach may entail using a variety of mechanisms to preserve lacrimal function, such as moisture chambers, lacrimal occlusion,