Epidemiology and course of disease in childhood uveitis.

PURPOSE: To describe the disease characteristics and visual outcome of pediatric uveitis. DESIGN: Retrospective, longitudinal observation. PARTICIPANTS: Five hundred twenty-seven pediatric uveitis patients from the National Eye Institute, University of Illinois, Chicago, and Oregon Health Sciences University. METHODS: Retrospective chart review. MAIN OUTCOME MEASURES: Demographics, uveitis disease characteristics, complications, treatments, and visual outcomes were determined at baseline and at 1-, 3-, 5-, and 10-year time points. RESULTS: The patient population was 54% female; 62.4% white, 12.5% black, 2.7% Asian, 2.1% multiracial, and 14.61% Hispanic. Median age at diagnosis was 9.4 years. The leading diagnoses were idiopathic uveitis (28.8%), juvenile idiopathic arthritis-associated uveitis (20.9%), and pars planitis (17.1%). Insidious onset (58%) and persistent duration (75.3%) were most common. Anterior uveitis was predominant (44.6%). Complications were frequent, and cystoid macular edema (odds ratio [OR] 2.94; P = 0.006) and hypotony (OR, 4.54; P = 0.026) had the most significant visual impact. Ocular surgery was performed in 18.9% of patients. The prevalence of legal blindness was 9.23% at baseline, 6.52% at 1 year, 3.17% at 3 years, 15.15% at 5 years, and 7.69% at 10 years. Posterior uveitis and panuveitis had more severe vision loss. Hispanic ethnicity was associated with a higher prevalence of infectious uveitis and vision loss at baseline. CONCLUSIONS: The rate and spectrum of vision threatening complications of pediatric uveitis are significant. Prospective studies using standard outcome measures and including diverse populations are needed to identify children most at risk.

Effects of topical anti-inflammatory agents in a botulinum toxin B-induced mouse model of keratoconjunctivitis sicca.

PURPOSE: The aim of this study was to compare the effects of topical nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroid, doxycycline, and artificial tears for the treatment of ocular surface damage in the Botulinum toxin B (BTX-B)-induced mouse model of dry eye. METHODS: CBA/J mice were randomized into 2 experimental groups of 35 animals each. The control group received a transconjunctival injection of 0.05 mL of saline into the left lacrimal gland, and another group was injected with 0.05 mL of 20 milliunits BTX-B solution (SPSS, Inc., Chicago, IL). Three (3) days after intralacrimal gland injections, each group was equally randomized into 7 subgroups (n=5 each) to receive treatment unilaterally into their left eyes with topical artificial tears (0.5% carboxymethylcellulose sodium), 0.1% fluorometholone, 0.1% nepafenac, 0.4% ketorolac, 0.09% bromfenac, 0.1% diclofenac, or 0.025% doxycycline. Tear volume, ocular surface changes, and spontaneous blink rate were evaluated in each of the 14 experimental subgroups. RESULTS: Topical fluorometholone, nepafenac, and doxycycline significantly improved corneal surface staining in the BTX-B-injected mice within 2 weeks of treatment. Topical ketorolac, diclofenac, and bromfenac, applied twice-daily, partially reduce corneal staining, and did so more slowly by the 4-week time point. In comparison, topical artificial tear-treated mice did not demonstrate significant improvement of the corneal surface at any time point. Aqueous tear production in the BTX-B-injected fluorometholone-treated group started to return to baseline level within 2 weeks, although not significantly. Meanwhile, BTX-B-injected mice treated with artificial tears, topical NSAIDs, and doxycycline still exhibited a reduction in tear production up to 4 weeks. No significant differences in blink rate between the control and study groups undergoing the various treatments were noted at all time points. CONCLUSIONS: This study suggests the potential usefulness of topical NSAIDs, corticosteroid, and doxycycline for the clinical treatment of ocular surface epithelial disorders associated with dry eye.

Microarray and protein analysis of human pterygium.

PURPOSE: Pterygium is a sunlight-related, ocular-surface lesion that can obscure vision. In order to identify specific genes that may play a role in pterygium pathogenesis, we analyzed the global gene expression profile of pterygium in relation to autologous conjunctiva. METHODS: Oligonucleotide microarray hybridization was used to compare the gene expression profile between human whole pterygium and autologous conjunctiva. Selected genes were further characterized by RT-PCR, western blot, and immunohistochemistry, and comparisons were made with limbal and corneal tissues. RESULTS: Thirty-four genes exhibited a 2 fold or greater difference in expression between human whole pterygium and autologous conjunctiva. Twenty-nine transcripts were increased and five transcripts were decreased in pterygium. Fibronectin, macrophage-inflammatory protein-4 (MIP-4), and lipocalin 2 (oncogene 24p3; NGAL) were increased 9, 5, and 2.4 fold, respectively, while Per1 and Ephrin-A1 were decreased 2 fold in pterygium. Western blots showed that fibronectin and MIP-4 were increased in pterygium compared to limbus, cornea, and conjunctiva. Immunohistochemical analysis showed fibronectin in the stroma; lipocalin 2 in the basal epithelial cells, basement membrane, and extracellular stroma; and MIP-4 in all areas of the pterygium. CONCLUSIONS: These data show both novel and previously identified extracellular-matrix-related, proinflammatory, angiogenic, fibrogenic, and oncogenic genes expressed in human pterygium. Comparisons of selected genes with limbal and corneal tissues gave results similar to comparisons between pterygium and normal conjunctiva. The increased expression of lipocalin 2, which activates matrix metalloproteinases (MMP), is consistent with our previous findings that MMP-9 and other MMPs are highly expressed in pterygium basal epithelium.

Hypergammaglobulinemia and corneal opacities in patients with human T-cell lymphotrophic virus type-1.

PURPOSE: To investigate the relationship between serum immunoglobulin levels and corneal opacities in a cohort of patients with human T-cell lymphotrophic virus type-1 (HTLV-1). DESIGN: Retrospective case series. METHODS: Complete ophthalmologic examination was performed on 44 patients with HTLV-1 infection (25 patients with adult T-cell leukemia/lymphoma [ATL], 18 patients with HTLV-1 that was associated myelopathy/tropical spastic paraparesis [HAM/TSP], and one patient who was asymptomatic). Corneal opacities were described by shape, size, color, and location. Serum immunoglobulin (Ig) levels (IgG, IgM, and IgA) were measured by nephelometry. RESULTS: Corneal opacities were identified in 15 of 25 patients (60%) with ATL and five of 18 patients (28%) with HAM/TSP. The prevalence of corneal opacities was associated statistically with elevated IgG level (P = .023) in patients with ATL, but not in patients with HAM/TSP (P > .99). CONCLUSION: Although the mechanism remains unclear, hypergammaglobulinemia is associated with the development of the corneal opacities in patients of African descent with ATL.

Inhibition of inflammatory cytokine production in human corneal cells by dexamethasone, but not cyclosporin.

PURPOSE: To evaluate the modulatory effects of anti-inflammatory agents, dexamethasone (Dex) and cyclosporin A (CsA), on the production of cytokines and chemokines by human corneal cells in vitro following stimulation by the pro-inflammatory cytokine after interleukin 1beta (IL-1beta). METHODS: A human corneal epithelial (HCE) cell line and human corneal fibroblasts (HCFs) were stimulated in culture with IL-1beta and treated with Dex or CsA. The gene expression for selected cytokines and chemokines was determined by reverse transcriptase-polymerase chain reaction (RT-PCR). The secretion of cytokines and chemokines was measured by enzyme-linked immunosorbent assay. RESULTS: IL-1beta enhanced the mRNA and/or protein levels of granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-8, and monocyte chemotactic protein (MCP)-1 in HCE and IL-6, IL-8, MCP-3, and regulated on T-cell activation expressed secreted (RANTES) in HCFs. Treatment with CsA did not inhibit cytokine production in either HCE or HCFs. In contrast, Dex treatment inhibited the IL-1beta-induced production of GM-CSF, IL-6, IL-8, MCP-3, and RANTES, but not MCP-1. CONCLUSION: These results show that Dex, but not CsA, has direct immunosuppressive effects on the resident corneal cells, HCE and HCFs. This suggests that the clinically observed immunosuppressive effects of topical CsA are mediated primarily through the immune cells.

Conjunctival T-cell subpopulations in Sjögren's and non-Sjögren's patients with dry eye.

PURPOSE: To examine the conjunctiva of patients with Sjögren's syndrome keratoconjunctivitis sicca (SS-KCS) and non-Sjögren's keratoconjunctivitis sicca (NS-KCS) for evidence of immune-based inflammation. METHODS: Conjunctival biopsy specimens were obtained from 15 patients with SS-KCS and 15 with NS-KCS. Immunohistochemistry was performed on frozen sections to characterize and quantify T-cell subtypes (CD3, CD4, and CD8) and markers of immune activation (major histocompatibility complex [MHC] class II: HLA-DR, HLA-DQ) and inflammation (intercellular adhesion molecule [ICAM]-1). The numbers of cells positive for each marker were counted by two masked observers and averaged. RESULTS: Conjunctival biopsy specimens from patients with SS-KCS or NS-KCS revealed lymphocytic infiltration and increased immunoreactivity for the markers of inflammation and immune activation. The extent of cellular immunoreactivity did not differ significantly between SS-KCS and NS-KCS tissue samples. CONCLUSIONS: The authors' findings indicate that patients with SS-KCS or NS-KCS have conjunctival inflammation manifested by inflammatory cell infiltrates and upregulation of expression in markers of immune activation. Clinical symptoms of KCS may be more dependent on T-cell activation and resultant inflammation than previously believed. In addition to tear substitutes, anti-inflammatory therapeutics should be investigated for the treatment of KCS.

Dry eye signs and symptoms in women with premature ovarian failure.

OBJECTIVE: To examine whether women with premature ovarian failure (POF) have abnormal findings in ocular surface or tear parameters and whether they report symptoms of ocular discomfort compared with age-matched controls. METHODS: Sixty-five patients with POF and 36 age-matched healthy controls were examined for signs and symptoms of dry eye. The Ocular Surface Disease Index questionnaire and the 25-item National Eye Institute Visual Function Questionnaire (NEI-VFQ 25) were administered to the participants. Assessments of ocular surface damage (Oxford and van Bijsterveld scores of vital dye staining) and tear status (Schirmer tests 1 [without anesthesia] and 2 [with anesthesia] and tear breakup time) were performed. RESULTS: Women with POF scored significantly worse than controls on all ocular surface damage parameters: Oxford score (3.2 vs 1.7; P =.001), conjunctival lissamine green (2.1 vs 1.3; P =.02), corneal fluorescein staining (1.2 vs 0.4; P =.005), and van Bijsterveld score (2.1 vs 1.3; P =.02). Further, the proportion of patients with POF meeting the dry eye diagnostic criterion of a van Bijsterveld score greater than or equal to 4 was significantly greater among women with POF than among controls (20% vs 3%; P =.02). The POF group also tended to have worse scores than controls on self-reported symptoms, as measured by the overall Ocular Surface Disease Index (12.5 vs 2.1; P<.001) and the overall NEI-VFQ (94 vs 98; P =.001) after adjustment for age and race. Schirmer test scores and tear breakup time did not differ. CONCLUSIONS: Women with POF were more likely to exhibit ocular surface damage and symptoms of dry eye than age-matched controls. They were not, however, more likely to have reduced tear production. To our knowledge, this association between ocular surface disease and POF has not been previously reported. These data provide further evidence of the multifaceted role of sex hormones in the health and disease of the ocular surface.

Comparison of the NEI-VFQ and OSDI questionnaires in patients with Sjögren's syndrome-related dry eye.

BACKGROUND: To examine the associations between vision-targeted health-related quality of life (VT-HRQ) and ocular surface parameters in patients with Sjögren's syndrome, a systemic autoimmune disease characterized by dry eye and dry mouth. METHODS: Forty-two patients fulfilling European / American diagnostic criteria for Sjögren's syndrome underwent Schirmer testing without anesthesia, ocular surface vital dye staining; and measurement of tear film breakup time (TBUT). Subjects were administered the Ocular Surface Disease Index (OSDI) and the 25-item National Eye Institute Vision Functioning Questionnaire (NEI-VFQ). Main outcome measures included ocular surface parameters, OSDI subscales describing ocular discomfort (OSDI-symptoms), vision-related function (OSDI-function), and environmental triggers, and NEI-VFQ subscales. RESULTS: Participants (aged 31-81 y; 95% female) all had moderate to severe dry eye. Associations of OSDI subscales with the ocular parameters were modest (Spearman r (rho) < 0.22) and not statistically significant. Associations of NEI-VFQ subscales with the ocular parameters reached borderline significance for the near vision subscale with TBUT (rho = 0.32, p =.05) and for the distance vision subscale with van Bijsterveld score (rho = 0.33, p =.04). The strongest associations of the two questionnaires were for: ocular pain and mental function with OSDI-symptoms (rho = 0.60 and 0.45, respectively); and general vision, ocular pain, mental function, role function, and driving with OSDI-function (rho = 0.60, 0.50, 0.61, 0.64, 0.57, and 0.67, respectively). CONCLUSIONS: Associations between conventional objective measures of dry eye and VT-HRQ were modest. The generic NEI-VFQ was similar to the disease-specific OSDI in its ability to measure the impact of Sjögren's syndrome-related dry eye on VT-HRQ.

Grading of corneal and conjunctival staining in the context of other dry eye tests.

PURPOSE: To describe the Oxford Scheme for grading ocular surface staining in dry eye and to discuss optimization of stain detection using various dyes and filters. Also, to propose a sequence of testing for dry eye diagnosis. METHODS: The grading of corneal and conjunctival staining is described, using the Oxford Scheme, including biomicroscopy, optical filters, illumination conditions, and the characteristics of and instillation techniques used for, selected clinical dyes. RESULTS: A series of panels, labeled A-E, in order of increasing severity, reproducing the staining patterns encountered in dry eye, are used as a guide to grade the degree of staining seen in the patient. The amount of staining seen in each panel, represented by punctate dots, increases by 0.5 of the log of the number of dots between panels B to E. The use of the vital dyes fluorescein, lissamine green, and rose Bengal is described; fluorescein and lissamine green, used in conjunction with appropriate absorption filters, are recommended for use in clinical trials. The placement of staining in relation to the sequence of other diagnostic tests is discussed. CONCLUSIONS: The monitoring and assessment of corneal and conjunctival staining can be greatly enhanced by the use of a grading scale, controlled instillation of dyes, and standard evaluation techniques. This is of particular benefit in clinical trials, where ocular surface staining is commonly employed as an outcome measure

Corneal verticillata after dual anti-epidermal growth factor receptor and anti-vascular endothelial growth factor receptor 2 therapy (vandetanib) for anaplastic astrocytoma.

PURPOSE: To describe a patient with a history of epithelial basement membrane dystrophy who developed symptomatic corneal verticillata after vandetanib therapy for anaplastic astrocytoma. METHODS: Retrospective interventional case report. RESULTS: A 48-year-old female patient with a history of anaplastic astrocytoma status post resection, external beam radiation, and chemotherapy presented with glare symptoms, decreased contrast sensitivity, and increased lacrimation after approximately 12 months of therapy with the anti-epidermal growth factor receptor (EGFR) and anti-vascular endothelial growth factor receptor 2 protein tyrosine kinase inhibitor, vandetanib. Ophthalmic examination revealed diffuse corneal verticillata and fine subepithelial opacities. Schirmer 1 testing was normal bilaterally. Therapy with carboxymethylcellulose, 5% sodium chloride ointment, and a decrease in the dose of vandetanib led to an improvement in the patient's ophthalmic symptoms despite persistence of the corneal findings. The patient remained under surveillance for tumor recurrence. CONCLUSIONS: Vandetanib (ZD6474), a protein tyrosine kinase inhibitor with dual anti-EGFR and anti-vascular endothelial growth factor receptor 2 action, may have contributed to the formation of corneal verticillata in our patient. Inhibition of EGFR, which is involved with corneal epithelial cell migration and wound healing, may play a role in the pathogenesis underlying corneal vortex keratopathy and ocular surface conditions with significant epithelial turnover.

Management of acute hydrops with perforation in a patient with keratoconus and cone dystrophy: case report and literature review.

PURPOSE: To describe a patient with cone dystrophy who presented with acute hydrops and perforation, leading to the diagnosis of keratoconus. METHODS: Case report and literature review. RESULTS: A 21 -year-old male patient with a history of cone dystrophy presented with a flat anterior chamber, diffuse corneal stromal edema with an intrastromal cleft, and ruptured Descemet membrane, findings consistent with acute hydrops with corneal perforation. After bandage contact lens placement and instillation of a cycloplegic agent, the anterior chamber reformed within 24 hours. Over the next week, conservative management with a bandage lens, pressure patching, topical fluoroquinolone antibiotic, and topical cycloplegic led to the reformation and maintenance of anterior chamber stability. Corneal topography of the unaffected eye showed global corneal thinning and steep sim K readings suspicious for early keratoconus. CONCLUSIONS: Although the association between keratoconus and cone dystrophy is extremely rare, our patient's vision-threatening complication of acute hydrops with corneal perforation highlights the importance of corneal evaluation including topography in cone dystrophy. Conservative management was successful in the restoration of anatomic integrity in this situation.