symptoms. Because of the likelihood that patients will develop corticosteroid-related complications from long-term administration, however, these drugs should be reserved for exacerbations that result in moderate to severe discomfort and/or decreased vision. During these exacerbations, intermittent (pulse) therapy is very effective. Topical corticosteroids (difluprednate ophthalmic emulsion 0.05%) can be used at relatively high frequency (eg, every 2 hours) for 5–7 days and then rapidly tapered. Because of the propensity of particles of suspended corticosteroid (eg, prednisolone acetate) to lodge between papillae, the use of less potent but soluble corticosteroids such as dexamethasone phosphate is generally preferred. To discourage indiscriminate use for relief of mild symptoms, the patient and family must be thoroughly informed of the potential dangers of long-term topical corticosteroid therapy. Systemic anti-inflammatory therapy should be reserved for very severe cases.

Cooperative patients can be offered an alternative to topical delivery that avoids the problem of continuing self-medication: supratarsal injection of corticosteroid. The supratarsal subconjunctival space is located superior to the upper border of the superior tarsus and is most easily reached by everting the upper eyelid. After the upper eyelid is everted and the supratarsal conjunctiva has been anesthetized, supratarsal injection of 0.5–1.0 mL of either a relatively short-acting corticosteroid such as dexamethasone phosphate (4 mg/mL) or a longer-acting corticosteroid such as triamcinolone acetonide (40 mg/mL) can be performed. Monitoring of intraocular pressure is mandatory, as corticosteroid-induced pressure spikes are possible.

Topical cyclosporine 2% applied 2–4 times daily or topical tacrolimus 0.1% applied twice daily can also be used to treat refractory cases of VKC. Reported adverse effects of cyclosporine include punctate epithelial keratopathy and ocular surface irritation. Systemic absorption after topical instillation is minimal.

Abu El-Asrar AM, Al-Mansouri S, Tabbara KF, Missotten L, Geboes K. Immunopathogenesis of conjunctival remodelling in vernal keratoconjunctivitis. Eye (Lond). 2006;20(1):71–79.

Amrane M, Bremond-Gignac D, Leonardi A, et al. The discordance between objective signs and giant papillae improvement in patients with vernal keratoconjunctivitis (VKC) participating in a randomized, controlled, clinical trial. Acta Ophthalmologica. 2011;89(Suppl s248):0. Epub 2011 Aug 11.

Mishra GP, Tamboli V, Jwala J, Mitra AK. Recent patents and emerging therapeutics in the treatment of allergic conjunctivitis.

Recent Pat Inflamm Allergy Drug Discov. 2011;5(1):26–36.

Ohashi Y, Ebihara N, Fujishima H, et al. A randomized, placebo-controlled clinical trial of tacrolimus ophthalmic suspension 0.1% in severe allergic conjunctivitis. J Ocul Pharmacol Ther. 2010;26(2):165–174.

Sangwan VS, Jain V, Vemuganti GK, Murthy SI. Vernal keratoconjunctivitis with limbal stem cell deficiency. Cornea. 2011;30(5):491–496.

Atopic Keratoconjunctivitis

PATHOGENESIS Approximately one-third of patients with atopic dermatitis develop one or more manifestations of atopic keratoconjunctivitis (AKC). Atopic individuals show signs of type I immediate hypersensitivity responses as well as depressed systemic cell-mediated immunity. As a consequence of this altered immunity, they are susceptible to herpes simplex virus keratitis and colonization of the eyelids with Staphylococcus aureus. Complications related to this predisposition to infection may contribute to, or compound, the primary immunopathogenic manifestations. AKC is primarily a type IV reaction; therefore, the use of mast-cell therapy may not be effective.

CLINICAL PRESENTATION Ocular findings are similar to those of VKC, with the following differences:

Patients with AKC frequently have disease year-round, with minimal seasonal exacerbation. Patients with AKC are older.

The papillae are more apt to be small or medium-sized than giant. The papillae occur in the upper and lower palpebral conjunctiva.

Milky conjunctival edema, with variable subepithelial fibrosis, is often present (Fig 7-6). Extensive corneal vascularization and opacification secondary to chronic epithelial disease (likely due to some degree of limbal stem cell dysfunction) can occur (Fig 7-7). Eosinophils in conjunctival cytology specimens are less numerous and are less often degranulated.

Conjunctival scarring often occurs, with occasional symblepharon formation.

Characteristic posterior subcapsular and/or multifaceted or shield-shaped anterior subcapsular lens opacities may occasionally develop.

Corneal findings include punctate erosions, persistent epithelial defects, an increased incidence of ectatic corneal diseases such as keratoconus and pellucid marginal degeneration, and an increased incidence of staphylococcal and herpes simplex infections.

Figure 7-6 Atopic keratoconjunctivitis demonstrating small papillae, edema, and subepithelial fibrosis.

Figure 7-7 Severe corneal vascularization and scarring with atopic keratoconjunctivitis.

MANAGEMENT Treatment of AKC involves allergen avoidance and the use of pharmacotherapeutic agents similar to those used in the treatment of VKC. Cold compresses may also be of benefit. In addition, patients should be carefully monitored for complications of infectious diseases that may warrant specific therapy, such as secondary staphylococcal infections. In these severe cases, the indications for systemic therapy include chronic ocular surface inflammation unresponsive to topical treatment, discomfort, progressive cicatrization, and peripheral ulcerative keratopathy. Systemic

immune suppression (eg, by oral cyclosporine 2.0–2.5 mg/kg daily) should be monitored in coordination with an internist or rheumatologist. Systemic treatment of AKC may be beneficial in suppressing the interleukin-2 (IL-2) response, which promotes lymphocyte proliferation. Topical therapy with tacrolimus has been helpful for the dermatitis.

García DP, Alperte JI, Cristóbal JA, et al. Topical tacrolimus ointment for treatment of intractable atopic keratoconjunctivitis: a case report and review of the literature. Cornea. 2011;30(4):462–465.

Ligneous Conjunctivitis

PATHOGENESIS Ligneous conjunctivitis is a rare chronic disorder characterized by the formation of firm (“woody”), yellowish fibrinous pseudomembranes on the conjunctival surface (Fig 7-8). These membranes are composed of an admixture of fibrin, fibrin-bound tissue plasminogen activator (tPA), epithelial cells, and mixed inflammatory cells that adhere to the conjunctival surface. Latent and activated forms of matrix metalloproteinase-9 have also been identified. The cause of ligneous conjunctivitis has recently been linked to severe deficiency in type I plasminogen, with hypofibrinolysis as the primary defect. More than 12% of patients have severe hypoplasminogenemia. The genetic defect in the plasminogen gene (PLG) is located at band 6q26.

Figure 7-8 Ligneous conjunctivitis: papillary white-red lesions of firm consistency in both eyelids of the left eye. (Courtesy of

Mission for Vision, www.missionforvision.org.)

CLINICAL PRESENTATION Ligneous conjunctivitis can affect patients of all ages. Patients present with symptoms of ocular irritation and foreign-body sensation. The cardinal finding consists of yellowish, platelike masses that overlie one or more of the palpebral surfaces and are readily visible with eversion of the eyelid (see Fig 7-8). Ligneous conjunctivitis is generally bilateral and can recur after excision.

MANAGEMENT Cultures can be taken at initial diagnosis to exclude a bacterial pseudomembranous or membranous conjunctivitis. Surgical excision with or without adjunctive cryotherapy has been advocated. However, recurrences are frequent. Use of purified plasminogen, fresh frozen plasma, heparin, corticosteroids, azathioprine, and amniotic membrane has been reported. No single treatment has been shown to be consistently effective or superior. Many cases of ligneous conjunctivitis eventually resolve spontaneously after several months to a few years.

The incidence of SJS has been shown to be approximately 5 cases per million per year. Recent reports have suggested that patients with acquired immunodeficiency syndrome (AIDS), particularly those who have been treated for Pneumocystis jiroveci pneumonia, are at a higher risk of developing erythema multiforme.

SJS occurs most commonly in children and young adults and occurs more often in females than males. Fever, arthralgia, malaise, and upper or lower respiratory symptoms are usually sudden in onset. Skin eruption follows within a few days, with a classic “target” lesion consisting of a red center surrounded by a pale ring and then a red ring, although maculopapular or bullous lesions are also common. The mucous membranes of the eyes, mouth, and genitalia may be affected by bullous lesions with membrane or pseudomembrane formation. New lesions may appear over 4–6 weeks, with approximately 2-week cycles for each crop of lesions.

The primary ocular finding is a mucopurulent conjunctivitis and episcleritis. Conjunctival and corneal epithelial sloughing and necrosis with severe inflammation and scarring may develop (Fig 7- 9). Long-term ocular complications result from ocular surface cicatrization, resulting in conjunctival shrinkage, keratinization of the eyelid margins, trichiasis, and tear deficiency. Eyelid margin keratinization and scarring is an important risk factor for poor long-term outcomes in these patients. Patients with SJS are at higher risk of infection due to loss of the epithelial barrier and hence may develop severe ocular infection concurrently with the ocular surface disease. Mucous membrane pemphigoid has also been reported as a rare sequela of SJS (see the following section).

Figure 7-9 Stevens-Johnson syndrome with severe ocular surface disease.

MANAGEMENT Management of acute and chronic disease should be distinguished. Management of acute SJS is similar to that of extensive thermal burns; patients are often treated in burn units at major tertiary care centers. Immediate discontinuation of the offending agent has been associated with reduced mortality and improved outcome. Systemic therapy is mainly supportive and is aimed at managing dehydration and superinfection. Systemic prednisone (1 mg/kg per day for 3 days) and

intravenous immunoglobulin have been reported to be effective in reducing mortality and morbidity, but no consensus has been established. Even when used for short periods, however, high doses of systemic corticosteroids are associated with serious complications: gastrointestinal hemorrhage, electrolyte imbalance, and even sudden death. Moreover, they may increase the likelihood of infection.

The mainstay of acute ocular therapy includes lubrication with preservative-free artificial tears and ointments and vigilant surveillance for the early manifestations of ocular infections. Topical antibiotics are occasionally used as prophylaxis. More recently, significant long-term benefit has been demonstrated from the early transplantation of amniotic membrane over the entire ocular surface, including the eyelid margins. This is one of the few potentially beneficial therapeutic interventions for this devastating disease. Indications for amniotic membrane transplantation include severe epithelial defects of the cornea and/or conjunctiva. A second amniotic membrane grafting may be necessary for severe cases. The efficacy of topical corticosteroids for the ocular manifestations of this condition has not been established and remains controversial. Corticosteroids may decrease surface inflammation and corneal angiogenesis.

Symblephara may form during the acute phase because the raw, necrotic palpebral and bulbar conjunctival surfaces can adhere to one another (Fig 7-10). Repeated conjunctival lysis of the symblepharon may exacerbate inflammation and surface morbidity.

Figure 7-10 Stevens-Johnson syndrome demonstrating inferior eyelid symblepharon as well as ocular surface

keratinization. (Courtesy of Charles S. Bouchard, MD.)

Late eyelid sequelae, such as entropion, trichiasis, and keratinization, result in chronic ocular surface inflammation that is difficult to manage. Attempts to reconstruct the symblepharon and eyelid margins with mucous membrane grafting may result in further inflammation and scarring. Therapeutic contact lenses may offer temporary help. Scleral contact lenses can play a critical role in the long-term rehabilitation of these patients. Systemic immunosuppression is often required to suppress the severe inflammatory response in these cases. Eyelid reconstruction for severe disease needs to be performed prior to any ocular surface management, such as limbal stem cell transplantation or penetrating keratoplasty (PK). Because of the altered ocular surface and the corneal neovascularization that frequently develops in these patients, PK is associated with an extremely poor prognosis and is generally reserved for progressive thinning or perforation. Rare favorable results in desperate cases have been achieved with the use of a keratoprosthesis, including an osteo-odonto- keratoprosthesis, although the long-term stability of such devices is poor. The Boston Type I