Topical ciclosporin in the treatment of ocular surface disorders.

Mounting evidence suggests that inflammation is the key factor in the pathogenesis of various ocular surface diseases, with a complex interplay of genetic, environmental, and psychosocial factors. Management of these conditions is often challenging. Topical corticosteroids, with their associated side effects, are the mainstay of current treatments for patients with vision threatening disease. Ciclosporin A is an immunomodulator that specifically inhibits T lymphocyte proliferation. Recently, a topical ciclosporin preparation was approved by the US Food and Drug Administration and became available for use in ophthalmology. Given the increasing use of ciclosporin eye drops, the goal of this article is to provide the reader with an overview of the well established uses of ciclosporin and to help refine the questions that should be addressed by future investigations.

Induction of experimental autoimmune keratitis by adoptive transfer of human corneal antigen-specific T-cell line.

PURPOSE: To establish a permanent human corneal antigen (HuCOAg)-specific T-cell line and to determine whether line cells are capable of inducing inflammatory keratitis by adoptive transfer. METHODS: Lymphoid cells harvested from HuCOAg-immunized Lewis rats were expanded to a permanent T-cell line by repetitive cycles of restimulation with HuCOAg and irradiated antigen-presenting cells and propagation in interleukin 2-containing medium. The phenotype and epitope specificity of the line cells were determined. Adoptive transfer was performed after seven cycles by intraperitoneal injection of activated T cells into irradiated recipient rats. RESULTS: A panel of 11 overlapping synthetic HuCOAg peptides to identify T-cell epitopes recognized by the line cells was used. The cells responded selectively to a synthetic peptide containing an immunodominant epitope of HuCOAg (peptides 69-83). Line cells bore the surface phenotype of the T-helper/inducer marker (W 3/25(+) or CD4(+)). Intraperitoneal inoculation of naive rats with 5 x 10(7) activated line cells led to maximal clinical signs of stromal keratitis 7 to 9 days after transfer, characterized by corneal haze, conjunctival and episcleral injection, corneal infiltrates, and neovascularization. Histopathologic examination of the tissues revealed numerous lymphocytes and macrophages and some polymorphonuclear leukocytes along with neovascularization. The pathologic lesions were confined to the peripheral corneal stroma. Immunohistochemical studies demonstrated that the overwhelming majority of the inflammatory cells were CD4(+) T lymphocytes and macrophages; an upregulation of major histocompatibility complex class II antigen expression was also noted. CONCLUSIONS: A long-term, rat T-cell line of CD4(+) phenotype specific for HuCOAg that can induce autoimmune keratitis by adoptive transfer of the line cells to naive syngeneic recipients is described. With the development of this cell line, the mechanisms by which T cells exert their immunopathologic effects in experimental autoimmune keratitis models can be studied.

Bilateral acute retinal necrosis caused by cytomegalovirus in an immunocompromised patient.

PURPOSE: To report a case of bilateral acute retinal necrosis caused by cytomegalovirus. METHODS: A diagnostic vitrectomy was performed on a patient with non-Hodgkin lymphoma who presented with a bilateral, rapidly progressing necrotizing retinitis and uveitis. RESULTS: Immunohistochemical studies and polymerase chain reaction disclosed cytomegalovirus as the cause of retinitis. The patient was treated with intravitreal and intravenous ganciclovir. CONCLUSIONS: Although rare, cytomegalovirus may lead to an appearance identical to acute retinal necrosis and should be considered among the viral etiologies of this syndrome.

Peripheral ulcerative keratitis after clear corneal cataract extraction(1).

A previously healthy 80-year-old man had uneventful clear corneal cataract extraction. An extensive peripheral corneal infiltrate with overlying epithelial defect at the incision site was noted at the regular follow-up visit 1 week after surgery. Corneal cultures showed no evidence of infectious keratitis. A systemic evaluation uncovered early-stage, active rheumatoid arthritis. This case illustrates that peripheral ulcerative keratitis may occur with a small clear corneal incision and may be the presenting sign of a previously undiagnosed rheumatoid disease.

Spontaneous corneal perforation in a patient with unusual unilateral pellucid marginal degeneration.

A 56-year-old man presented with acute loss of vision and tearing in his left eye. Slitlamp examination demonstrated peripheral corneal edema extending between the 2 and 6 o'clock positions as well as a perforation located inferiorly. The right eye was unremarkable. An emergent crescentic lamellar keratoplasty was performed. The patch graft remained clear during the 30-month follow-up, and visual acuity improved significantly. No changes occurred in the right eye. This case represents an unusual, unilateral corneal ectatic disorder, most likely pellucid marginal degeneration.

Postoperative topical mitomycin C in conjunctival squamous cell neoplasia.

PURPOSE: To report the efficacy of topical mitomycin C in preventing local recurrences after incomplete surgical excision of conjunctival squamous cell neoplasia. METHODS: Four patients presented with unilateral conjunctival tumors. Excisional biopsy results revealed conjunctival intraepithelial neoplasia with an intact basement membrane. Neoplastic cells were present in at least one of the surgical borders of the excised conjunctiva in all four cases. Patients were treated with topical mitomycin C 0.02% three times daily for 2 weeks to prevent recurrences. RESULTS: All four patients were free of clinically detectable tumors after a mean follow-up period of 20 months (range, 16-23 months). Side effects included mild discomfort, redness, photophobia, and punctate epithelial keratopathy that subsided on discontinuation of the medication. CONCLUSION: Postoperative topical mitomycin C application may be a useful adjunct to prevent recurrences in patients with incompletely excised conjunctival squamous cell neoplasia.

Ocular surface neoplasia masquerading as chronic blepharoconjunctivitis.

PURPOSE: To present the clinical characteristics and difficulties in the diagnosis of various ocular surface malignancies mimicking features of chronic blepharoconjunctivitis and to summarize the current therapeutic approach and prognosis of patients. METHODS: Six patients with slowly evolving signs of persistent inflammation underwent a conjunctival biopsy after a prolonged course of medical treatment. The medical records of the patients were reviewed. RESULTS: Histopathologic examination of the biopsy specimens revealed intraepithelial squamous neoplasia (one patient), invasive squamous cell carcinoma (one patient), sebaceous carcinoma (two patients), and conjunctival lymphoma (two patients). CONCLUSION: Although uncommon, ocular surface malignancies may involve the conjunctiva diffusely and present as chronic conjunctivitis. A high index of suspicion and an early histopathologic examination are essential to not delay diagnosis.

Krill protease effects on wound healing after corneal alkali burn.

PURPOSE: To study the effect of a novel protease in the development and progression of corneal ulceration secondary to alkali burning. METHODS: By using a 4N alkali burn model of corneal ulceration in rabbits, the effects and efficacy of topical application of a novel protease (PHM-101) capable of degrading metalloproteinases was studied for 28 days of treatment and 7 days off treatment for its effect on corneal ulceration and recurrent erosion. RESULTS: At day 28, both the protease- and placebo-treated groups had different numbers of eyes showing reepithelialization (nine (45%) of 20 and six (33%) of 18, respectively]. By day 35 the protease-treated group had significantly fewer recurrent epithelial defects [two (13%) of 15 vs. eight (61%) of 13; p = 0.02]. Similarly, at day 35 the protease-treated group showed significantly less corneal ulceration [two (13%) of 15 vs. six (46%) of 13; p = 0.02], and those ulcers were of a lesser severity (three units vs. 17.76 units). No difference was found in the degree of stromal edema or neovascularization, nor was there any difference in histopathologic characteristics of inflammatory cell infiltration and corneal scarring. CONCLUSION: We conclude that this novel protease is efficient in reducing recurrent corneal epithelial defects and stromal ulceration after alkali burning.

Herpes zoster sine herpete presenting with hyphema.

PURPOSE: To report a case of herpes zoster sine herpete presenting with hyphema. METHODS: A 69-year-old man was referred for traumatic hyphema and corneal edema in his left eye after a sandblast exposure three weeks previously. Slit-lamp examination demonstrated hyphema, anterior chamber inflammation, mid-dilated pupil, impaired corneal sensation, and high intraocular pressure, without any facial skin lesions. Iris fluorescein angiography revealed tortuosity and extensive occlusion of iris vessels. The patient was treated with oral acyclovir and intensive topical steroids with a presumed diagnosis of severe herpes zoster uveitis. RESULTS: Clinical findings improved dramatically within several days. Typical sectorial iris atrophy with pupillary sphincter dysfunction and complete loss of corneal sensation developed after the resolution of intraocular inflammation. CONCLUSION: Herpes zoster should be considered in patients with uveitis and hyphema even in the absence of typical skin rash.

Long-term immunosuppressive treatment of serpiginous choroiditis.

OBJECTIVE: To determine the efficacy of immunosuppressive treatment in serpiginous choroiditis. DESIGN: The clinical courses were reviewed of six consecutive patients (12 eyes) with vision-threatening, steroid-dependent/resistant serpiginous choroiditis treated with a combination of immunosuppressive agents including azathioprine, cyclosporine, and cyclophosphamide. All patients underwent treatment for at least 12 months. RESULTS: The follow-up period ranged from 17 to 105 months (mean 57, median 43). All patients were able to taper oral steroids. Five patients discontinued all immunosuppressive medications after a treatment period of 12 to 69 months (mean 39 months). Immunosuppressive treatment was continued in one patient at a "low" maintenance dose. Ten eyes had improved visual acuities, while vision remained impaired in two due to macular scars. Recurrence was noted in two patients when an attempt was made to decrease the dose of immunosuppressive medication. Two patients experienced side effects which were reversed by decreasing the dose of the medications. CONCLUSION: Long-term immunosuppressive treatment appears to prolong remission and preserve vision in patients with serpiginous choroiditis.

Topical cyclosporin stimulates neovascularization in resolving sterile rheumatoid central corneal ulcers.

OBJECTIVE: To report the successful use of topical cyclosporin for treatment of central sterile corneal ulcers associated with rheumatoid disease. DESIGN: Retrospective, noncomparative case series. PARTICIPANTS/INTERVENTION: Five patients (7 eyes) with collagen vascular disorders presented with central, sterile corneal ulcers. An extensive medical evaluation did not reveal active underlying rheumatoid disease in any patient. Inadequate clinical response with use of topical steroids and lubricants led to corneal perforations requiring multiple tectonic procedures. Systemic immunosuppressive therapy either could not be initiated owing to a systemic contraindication or was discontinued owing to intolerance and side effects. The patients were ultimately treated with topical cyclosporin. RESULTS: Six of the 7 eyes responded favorably. An intense limbal vascularization began within 48 hours of treatment. The neovascularization progressed centrally with the simultaneous arresting of epithelial and stromal ulceration. Over a 2-week period, re-epithelization occurred with vascularization proceeding throughout the cornea. After several months, the corneal vessels attenuated, and all signs of inflammation subsided. Intrastromal bleeding with corneal blood staining occurred in 1 patient; this resolved over several months. No recurrences of corneal ulceration occurred in a mean follow-up period of 28 months (range, 7 to 60 months). None of the 5 patients have had a reactivation of their rheumatoid disease in the follow-up period. CONCLUSION: The clinical response in these patients contrasts with previous animal studies demonstrating an anti-angiogenic property of cyclosporin. We report that an immediate intense neovascularization is the first sign of a favorable clinical response. Treatment with topical cyclosporin alone may be considered in patients with sterile corneal ulcers associated with rheumatoid disease in the absence of systemic activation.

Immune defense at the ocular surface.

The ocular surface is constantly exposed to a wide array of microorganisms. The ability of the outer ocular system to recognize pathogens as foreign and eliminate them is critical to retain corneal transparency, hence preservation of sight. Therefore, a combination of mechanical, anatomical, and immunological defense mechanisms has evolved to protect the outer eye. These host defense mechanisms are classified as either a native, nonspecific defense or a specifically acquired immunological defense requiring previous exposure to an antigen and the development of specific immunity. Sight-threatening immunopathology with autologous cell damage also can take place after these reactions. This article discusses the innate and acquired corneal elements of the immune defense at the ocular surface. The relative roles of the various factors contributing to prevention of eye infection remain to be fully defined.

A randomized trial of low-dose, topical mitomycin-C in the treatment of severe vernal keratoconjunctivitis.

OBJECTIVE: To evaluate the efficacy and safety of low-dose, topical mitomycin-C in patients with severe vernal keratoconjunctivitis. DESIGN: Placebo-controlled, double-masked, randomized clinical trial. PARTICIPANTS: Twenty-six patients with vernal keratoconjunctivitis refractory to combination of steroid and mast-cell stabilizer treatment. INTERVENTION: Patients were randomly assigned (2:1) to treatment with topical 0.01% mitomycin-C eye drops (n = 17) or placebo (n = 9) three times daily for 2 weeks. MAIN OUTCOME MEASURES: Symptoms (itching, tearing, photophobia, ropy mucous discharge, foreign body sensation) and signs (conjunctival hyperemia, epithelial punctate keratitis, Trantas' dots, limbal edema, and palpebral conjunctival giant papillae) of vernal keratoconjunctivitis recorded on the day of enrollment and at the end of the treatment period. RESULTS: There was a statistically significant decrease in ropy mucous discharge, photophobia, conjunctival hyperemia, and limbal edema in the mitomycin-C treated group compared with the placebo group at the end of the 2-week treatment period. In addition, none of the 17 treated patients, but all 9 of the placebo patients, required medication during the 4-week posttreatment follow-up period. No adverse effects of treatment with mitomycin-C were observed. CONCLUSIONS: Short-term, low-dose, topical mitomycin-C may be considered in the acute exacerbation periods of patients with severe vernal keratoconjunctivitis refractory to conventional treatment.

Bilateral consecutive central corneal perforations associated with hypogammaglobulinemia.

OBJECTIVE: To describe the presentation and the clinical course of a patient with consecutive central sterile corneal perforations associated with common variable immunodeficiency. DESIGN: Case report. METHODS: Multiple corneal cultures and scrapings were performed in an effort to identify an infectious cause and all were negative. Corneal biopsy did not demonstrate any evidence of micro-organisms. An extended investigation failed to uncover a collagen vascular cause or atopy. RESULTS: Progressive sterile stromal thinning with intact epithelium in the left eye proceeded to perforation despite topical treatment, and cyanoacrylate gluing was performed. However, a secondary Haemophilus influenza endophthalmitis developed, and the eye was eventually lost. The fellow eye proceeded along the same clinical course with sterile stromal thinning. A lamellar patch graft was performed when the central ulceration progressed to a descemetocele. The eye remained quiet with 20/25 vision for 2 years, until the patient died from complications of a liver transplant. CONCLUSIONS: Devastating central sterile corneal thinning leading to perforation may occur in patients with hypogammaglobulinemia.

Severity of episcleritis and systemic disease association.

OBJECTIVE: To analyze patient characteristics and correlate between the site and severity of the inflammation and ocular and/or systemic disease association in a cohort of patients with episcleritis. DESIGN: Retrospective case series. METHODS: Medical records of 100 patients with episcleritis were reviewed. Data were analyzed using a customized database software. RESULTS: The age range at presentation was 18 to 76 years (mean, 43; median, 44). Sixty-nine percent of the patients were female. Thirty-two (32%) patients had bilateral involvement. The episcleritis was nodular in 23 eyes (16%). Half of the patients had a concurrent eye disease. Associated systemic disease was found in 36 patients (36%). In two patients, episcleritis preceded a systemic vasculitic disease (Wegener granulomatosis and Cogan syndrome). Ocular complications included uveitis (11.4%), corneal involvement (15%), and glaucoma (7.8%). No significant correlation of the site and severity of inflammation to the presence of associated systemic or ocular diseases was found. The mean follow-up was 16.5 months. Twenty-eight patients experienced recurrence of episcleritis during the follow-up. Half of the patients required treatment with oral nonsteroidal anti-inflammatory drugs. CONCLUSIONS: Episcleritis is usually a benign, self-limited disease, but it should not be trivialized since it may be associated with systemic disease and ocular complications. A careful review of systems should be performed in all patients presenting with episcleritis, and this should be repeated at least annually during the follow-up. A thorough eye examination is obviously essential to detect and treat ocular complications.