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.

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.

Menisci and fullness of the blink in dry eye.

PURPOSE: This study was to investigate the role of the upper meniscus in tear film formation and blinking. METHODS: One microliter of 2% fluorescein was instilled under the upper lid of 15 dry eye (DE) and 15 control subjects. Subjects were instructed to blink partially and hold the eye open as long as possible, and analysis of tear breakup dynamics was used to quantify the area of breakup. This procedure was repeated following a full blink. Meniscus height was measured from digital videos. RESULTS: Both menisci were significantly decreased in DE compared with controls (p < 0.02, t test). Tear breakup dynamics analysis showed that significantly greater areas of breakup occurred with full compared with incomplete blinks in DE (p < 0.003 Mann Whitney U test), but not in controls. CONCLUSIONS: A stable tear film can be deposited by the upper meniscus alone following a partial blink, without contribution from the lower meniscus. The increased tear stability of partial blinks in DE may be due to less stretching of the already fragile tear film compared with a full blink, which covers more surface area.

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.

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.

Diagnosis and treatment of vasculitis of the central nervous system in a patient with systemic lupus erythematosus.

BACKGROUND: A 23-year-old white woman with a 3-year history of systemic lupus erythematosus and a 15-month history of lupus nephritis and retinal vasculitis was successfully treated with antibiotics for Pseudomonas aeruginosa pneumonia while on moderate doses of corticosteroids. Even though her pneumonia had improved, she developed acute changes in her mental status that rapidly progressed to encephalopathy with coma. INVESTIGATIONS: Physical examination, fundoscopic examination, laboratory tests for metabolic abnormalities, cerebrospinal fluid analysis, microbiology and serologic testing, electroencephalogram, tests for IgM and IgG anticardiolipin antibodies, neuroimaging including CT of the brain and T1-weighted MRI before and after gadolinium contrast, and flow-attenuated inversion recovery MRI. DIAGNOSIS: Vasculitis of the central nervous system associated with systemic lupus erythematosus. MANAGEMENT: Intravenous methylprednisolone 1,000 mg/day for 3 days, one dose of intravenous pulse cyclophosphamide 750 mg/m(2), intravenous immunoglobulin 400 mg/kg/day for 4 days, plasmapheresis on alternate days for five cycles, and prednisone 40 mg/day. She continued monthly doses of intravenous pulse cyclophosphamide and intravenous pulse methylprednisolone for 6 months, followed by maintenance infusions every 3 months over 2 years. Prednisone was tapered over 18 months. Cyclophosphamide was discontinued after 2 years because of poor bone-marrow tolerance, and was replaced with mycophenolate mofetil 3,000 mg/ day and ciclosporin 50 mg twice daily.

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.

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.

Management of chronic pediatric uveitis.

PURPOSE OF REVIEW: The diagnosis and management of chronic pediatric uveitis can be particularly challenging, with an estimated 25-33% of childhood uveitis cases resulting in severe, life-long visual disability. This paper reviews the recent literature on the management of chronic pediatric uveitis. RECENT FINDINGS: This review highlights recent advances in the diagnosis and medical and surgical management of pediatric uveitis. Several systemic diseases associated with chronic uveitis in children are highlighted, including juvenile idiopathic arthritis, sarcoidosis and Behçet's disease. The treatment of primary ocular diseases associated with chronic pediatric uveitis such as intermediate uveitis and Fuchs' heterochromic iridocyclitis is discussed. The management of infectious causes of pediatric uveitis is not covered in this review. SUMMARY: Knowledge of the ocular complications of chronic pediatric uveitis can help to customize efficacious therapeutic regimens for each patient, maximize the visual potential and minimize complications of these diseases. In addition a close relation should be fostered between pediatricians, pediatric rheumatologists and ophthalmologists to effectively monitor these patients who have multiple medical, surgical and refractive needs. Finally, surgical intervention must be appropriately timed with expert perioperative management of immunosuppressive medications with pediatric concerns in mind.

X-linked anhidrotic ectodermal dysplasia disruption yields a mouse model for ocular surface disease and resultant blindness.

X-linked anhidrotic/hypohidrotic ectodermal dysplasia (EDA) is caused by mutations in the (EDA) gene, which is required for the morphogenesis of ectoderm-derived tissues. Although EDA function in skin appendage development has been studied in Eda mutant "Tabby" mice, we have recently identified characteristic abnormalities in the ocular surface, an ectoderm-derived tissue. Histology of eyes of Tabby males revealed that 1) as previously reported, mice lacked meibomian glands; 2) >80% developed corneal lesions such as neovascularization, keratitis, ulceration, and keratinization identifiable from 9 weeks of age; and 3) > 80% showed ocular surface inflammation (blepharitis and conjunctivitis) when housed in a standard environment. Strikingly, both corneal defects and inflammation were prevented in Tabby mice bearing a transgene for the Eda-A1 isoform, but meibomian glands were restored little if at all. These findings suggest that intact ocular surface health is EDA dependent and that Tabby corneal abnormalities are not solely dependent on meibomian gland lipid secretion. Alternatively, susceptibility to inflammation and other phenotypes could result from failure of the usual EDA receptor to activate nuclear factor-kappaB transcription factors. This can be further tested in Tabby and Tabby-EDA transgenic mice, which provide unique models of severe ocular surface disease.

A randomized, placebo-controlled, double-masked clinical trial of etanercept for the treatment of uveitis associated with juvenile idiopathic arthritis.

OBJECTIVE: To investigate the safety and efficacy of etanercept in the treatment of uveitis associated with juvenile idiopathic arthritis (JIA). METHODS: Children who met the American College of Rheumatology diagnostic criteria for JIA with active uveitis, who had anterior chamber cells of >/=1+ or requiring topical corticosteroid >/=3 times daily, and who were on a stable regimen for arthritis treatment were eligible. Study participants received etanercept (0.4 mg/kg) or placebo administered subcutaneously twice weekly for 6 months. All participants received open-label etanercept for an additional 6 months. RESULTS: Five patients received placebo and 7 received etanercept. Three of the 7 patients treated with etanercept and 2 of the 5 placebo-treated patients were considered ophthalmic successes (P = 1.0). One patient in each treatment group was considered a treatment failure. Three of the 7 etanercept-treated and 2 of the 5 placebo-treated patients were neither successes nor failures by our definition. There were no serious adverse events for any patient during the entire study period. Reports of minor infections were comparable in each treatment group, 71% for etanercept and 60% for placebo (P = 0.58). CONCLUSION: In this small pilot study there was no apparent difference in the anterior segment inflammation between patients treated with etanercept and placebo. The stringent criteria used to measure ophthalmic success of treatment and the small patient population limit the implications of our findings.

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.

Pilot clinical trial of dehydroepiandrosterone (DHEA) versus placebo for Sjögren's syndrome.

OBJECTIVE: To screen for potential efficacy and assess feasibility and safety of dehydroepiandrosterone (DHEA) as a treatment for Sjögren's syndrome (SS). METHODS: A 24-week randomized, double-blinded, pilot trial of oral DHEA (200 mg/day) versus placebo was conducted. The primary comparison was to a hypothesized 20% placebo response rate. If 14 consecutive subjects on DHEA did not respond, a Phase III trial would be considered futile. A placebo group of 14 subjects was planned to verify placebo response rate and estimate sample size required for a definitive trial. Response criteria required 20% improvement in at least 2 of 3 domains. Analysis of covariance was used to adjust for baseline differences and for stratified randomization. Outcome measures included visual analog scale questionnaires for dry eye and dry mouth symptoms, lissamine green ocular dye staining and Schirmer I tests, stimulated salivary flow, IgG, and erythrocyte sedimentation rate (ESR). RESULTS: Randomization resulted in 14 DHEA and 14 placebo group subjects. At baseline, mean +/- SD for DHEA versus placebo groups were Schirmer I tests 4.5 +/- 4.5 versus 5.4 +/- 6.1 mm/5 minutes; Van Bijsterveld score 5.3 +/- 2.1 versus 5.5 +/- 2.2; unstimulated saliva 0.03 +/- 0.05 versus 0.04 +/- 0.10 ml/minute; IgG 1,699 +/- 749 versus 1,712 +/- 621 g/dl; and ESR 40 +/- 31 versus 44 +/- 28 mm/hour. Apart from changes over the trial in dry mouth symptoms, no significant differences were noted between the DHEA and placebo groups for dry eye symptoms, objective measures of ocular dryness, stimulated salivary flow; IgG, or ESR. Four DHEA and one placebo group patient dropped out because of adverse effects. Although 7 subjects met response criteria in the DHEA group, 5 met the criteria in the placebo group, and there was no significant difference between groups. CONCLUSION: DHEA showed no evidence of efficacy in SS. Without evidence for efficacy, patients with SS should avoid using unregulated DHEA supplements, since long-term adverse consequences of exposure to this hormone are unknown.

Etanercept in Sjögren's syndrome: a twelve-week randomized, double-blind, placebo-controlled pilot clinical trial.

OBJECTIVE: To assess the safety and potential efficacy of etanercept in the treatment of Sjögren's syndrome (SS). METHODS: This pilot study was a 12-week randomized, double-blind, placebo-controlled trial of etanercept, with 14 subjects in each group. Patients received 25 mg of etanercept or placebo (vehicle) by twice-weekly subcutaneous injection. Patients met the American-European Consensus Group criteria for SS. The primary outcome required at least 20% improvement from baseline values for at least 2 of the following 3 domains: subjective or objective measures of dry mouth, subjective or objective measures of dry eyes, and IgG level or erythrocyte sedimentation rate (ESR). RESULTS: Of the 14 patients taking etanercept, 11 had primary SS and 3 had SS secondary to rheumatoid arthritis. Baseline measures did not differ between the 2 groups. Three etanercept-treated patients and 1 placebo-treated patient did not complete the trial. Five etanercept-treated patients and 3 placebo-treated patients showed improvement from baseline in the primary outcome variable at 12 weeks, but the difference was not statistically significant. There were no significant differences between the groups for changes in subjective measures of oral or ocular symptoms (by visual analog scale), the IgG level, Schirmer I test result, van Bijsterveld score, or salivary flow. At 12 weeks, the ESR had decreased in the etanercept group compared with baseline (P = 0.004); however, the mean reduction was only 18.6%. CONCLUSION: We found no evidence to suggest that treatment with etanercept at a dosage of 25 mg twice weekly for 12 weeks was clinically efficacious in SS. A larger trial will be necessary to definitively address the efficacy of etanercept in the treatment of SS.