Gene expression profiling in autoimmune noninfectious uveitis disease.

Noninfectious uveitis is a predominantly T cell-mediated autoimmune, intraocular inflammatory disease. To characterize the gene expression profile from patients with noninfectious uveitis, PBMCs were isolated from 50 patients with clinically characterized noninfectious uveitis syndrome. A pathway-specific cDNA microarray was used for gene expression profiling and real-time PCR array for further confirmation. Sixty-seven inflammation- and autoimmune-associated genes were found differentially expressed in uveitis patients, with 28 of those genes being validated by real-time PCR. Several genes previously unknown for autoimmune uveitis, including IL-22, IL-19, IL-20, and IL-25/IL-17E, were found to be highly expressed among uveitis patients compared with the normal subjects with IL-22 expression highly variable among the patients. Furthermore, we show that IL-22 can affect primary human retinal pigment epithelial cells by decreasing total tissue resistance and inducing apoptosis possibly by decreasing phospho-Bad level. In addition, the microarray data identified a possible uveitis-associated gene expression pattern, showed distinct gene expression profiles in patients during periods of clinical activity and quiescence, and demonstrated similar expression patterns in related patients with similar clinical phenotypes. Our data provide the first evidence that a subset of IL-10 family genes are implicated in noninfectious uveitis and that IL-22 can affect human retinal pigment epithelial cells. The results may facilitate further understanding of the molecular mechanisms of autoimmune uveitis and other autoimmune originated inflammatory diseases.

Ocular Autoimmune Systemic Inflammatory Infectious Study (OASIS) - Report 2: Pattern of Uveitis Investigations in Singapore.

Purpose: To analyze the pattern of laboratory investigations of uveitis at a tertiary referral eye care center in Singapore.Methods: Retrospective analysis of 2040 uveitis cases from the Ocular Autoimmune Systemic Inflammatory Infectious Study (OASIS) database over a 12-year period (2004 - 2015).Results: Patients with retinal vasculitis (RV) had the most tests utilized per patient (6.79), followed by intermediate uveitis (IU) (5.25), panuveitis (Pan) (5.12), posterior uveitis (PU) (4.17), anterior uveitis (AU) (2.75), and keratouveitis (KU) (1.10). The most frequently utilized test for infective etiology were the VDRL (41.3%), Syphilis IgG (29.5%), and T-SPOT.TB (24.6%). For autoimmune tests, ANA was most utilized (18.2%), followed by anti-dsDNA (14.8%), and HLA-B27 (12.4%).Conclusion: There was high utilization of autoimmune tests such as ANA, anti-dsDNA, RF, and ANCA, despite its limited yield. Rationalization of investigations in patients with ocular inflammation via a stepladder approach may help optimize the use of limited resources.

Ocular Autoimmune Systemic Inflammatory Infectious Study - Report 3: Posterior and Panuveitis.

PURPOSE: To report the pattern of posterior and panuveitis at a tertiary referral center in Singapore. METHODS: Subgroup retrospective analysis of 334 new posterior and panuveitis cases, from the Ocular Autoimmune Systemic Inflammatory Infectious Study (OASIS) database. Descriptive analysis was performed and visual outcome and complications were reported. RESULTS: The etiology for posterior uveitis and panuveitis was infectious in 162 patients (48.5%), non-infectious in 144 patients (43.1%), and idiopathic in 28 patients (8.4%). More patients with bilateral disease had a non-infectious etiology (n = 82, 50.9%) (p = 0.012). The most common complication was epiretinal membrane (n = 20, 12.3%) for the infectious group and cystoid macular edema (n = 12, 8.3%) for the non-infectious group. CONCLUSIONS: The proportion of etiologies in our cohort varies from other studies. Understanding the variations and demographic associations allows the diagnosis and management of posterior and panuveitis to be further improved.

Ocular Autoimmune Systemic Inflammatory Infectious Study (OASIS) - Report 1: Epidemiology and Classification.

PURPOSE: To report the epidemiology and classification of ocular inflammation at a tertiary eye care center in Singapore. METHODS: Retrospective cohort study of the clinical records of consecutive new cases from the Ocular Autoimmune Systemic Inflammatory Infectious Study (OASIS) database from 2004-2015. RESULTS: A total of 2200 patients were studied from the OASIS database. The most common anatomic diagnosis was anterior uveitis (55.9%), posterior uveitis (17.5%), panuveitis (9.6%), and intermediate uveitis (4.7%). In addition, scleritis (6.1%), keratouveitis (2.8%), retinal vasculitis (2.2%), and episcleritis (1.2%) were observed. Etiology was established in 65.1%, with 35.2% of patients associated with non-infectious etiologies. The most common etiologies found were presumed tuberculosis (7.2%), followed by cytomegalovirus infection (6.9%), herpetic infection (6.3%), HLA-B27-associated anterior uveitis (4.2%), and ankylosing spondylitis (3.8%). CONCLUSIONS: The pattern of ocular inflammation in Singapore has similarities with both Western and Asian populations. Anterior uveitis was the most common, with non-infectious etiologies being slightly more common than infectious etiologies.

Prevalence of dengue maculopathy in patients hospitalized for dengue fever.

OBJECTIVE: Dengue fever causes numerous systemic manifestations, including maculopathy, with loss of vision. This study sought to determine the prevalence of dengue maculopathy in patients hospitalized with dengue fever. DESIGN: Cross-sectional observational study in which consecutive patients hospitalized with dengue fever during a dengue epidemic were enrolled over a 3-week period. PARTICIPANTS: Patients hospitalized in 2 general hospitals in Singapore with dengue fever. TESTING: Patients completed a standardized questionnaire and underwent tests for near and distance visual acuity (VA), Amsler grid testing, dilated retinal examination, serum complements C3 and C4, and urinary microalbumin. MAIN OUTCOME MEASURES: Dengue maculopathy found on retinal examination. RESULTS: One hundred ninety-seven patients were enrolled, of whom 119 (60.4%) were male and 78 (39.6%) female. The patients ranged between 12 and 67 years old (mean, 32.65). One hundred sixty of 197 patients had positive dengue immunoglobulin M serology. Dengue maculopathy was detected in 27 eyes of 16 of the seropositive patients, giving a prevalence of 10% (95% confidence interval, 6.03%-15.40%). None of the patients who were dengue immunoglobulin M negative had dengue maculopathy. Dengue maculopathy eyes were more likely to have distance acuity worse than logarithm of the minimal angle of resolution 0.15 (Snellen 6/9 or worse) (P = 0.005) and abnormalities on Amsler grid testing (P = 0.001), with a greater proportion of these patients having visual complaints (P = 0.002) and lower mean complement C3 levels (P = 0.008) as compared with patients without maculopathy. Logistic regression analysis showed Amsler grid abnormalities to be the most consistent factor associated with dengue-related maculopathy (P<0.001), with a hazard ratio of 8.669; sensitivity, 29.6%; and specificity, 95.4%. CONCLUSION: The prevalence of dengue maculopathy among patients hospitalized for dengue fever is 10% in our series. Amsler grid abnormalities, reduced distance VA, and the presence of visual symptoms are associated with dengue maculopathy. Low complement C3 levels in these patients suggest that this is an immune-mediated disease.

Epithelium-on photorefractive intrastromal cross-linking (PiXL) for reduction of low myopia.

PURPOSE: To report the 9-12-month outcomes of a novel procedure for reduction of low myopia through epithelium-on photorefractive intrastromal cross-linking (PiXL) with customized control of topographic distribution of ultraviolet (UV)-fluence. METHOD: Myopic patients with normal (non-ectatic) corneas underwent the PiXL procedure for reduction of low myopia. PiXL treatments were delivered through selective application of UVA light based on the refractive error of each patient. Clinical evaluation included safety (corrected distance visual acuity, endothelial cell count, central corneal thickness, anterior ocular health) and efficacy (uncorrected distance visual acuity, manifest refraction, K-mean) examinations. In addition, a patient satisfaction survey was conducted at 9 months post-procedure to evaluate patients' subjective experience with the procedure. RESULTS: Fourteen myopic eyes (mean manifest refraction spherical equivalent -1.62±0.6D; range -0.75 to -2.65D) of 8 subjects (mean age 30 years old; range 24-51 years old) were enrolled in the study. At 12 months post-procedure, a mean manifest refraction spherical equivalent reduction of 0.72±0.43D (P<0.001) was observed, with a corresponding gain in uncorrected visual acuity of 0.25 logMAR and mean K-mean flattening of 0.47±0.46D. All patients achieved best corrected visual acuity of 20/20 or better from 1 month onward. There were no cases of ocular infection or secondary changes to the crystalline lens and retina due to UV exposure, while transient corneal haze subsided gradually. CONCLUSION: The epithelium-on PiXL procedure was safe and effective in reducing myopic refractive error in this study with up to 12 months follow-up. Early results of this novel application of collagen cross-linking are encouraging but longer-term data in larger studies are required. PRECIS: This paper serves to introduce and report the early clinical results of epithelium-on PiXL, a novel application of cornea cross-linking, in reducing low myopia in Asian eyes, which are under-represented in studies of similar design.

Ocular Autoimmune Systemic Inflammatory Infectious Study (OASIS)-report 4: analysis and outcome of scleritis in an East Asian population.

BACKGROUND: The purpose of this study is to evaluate the spectrum of scleritis from database of Ocular Autoimmune Systemic Inflammatory Infectious Study (OASIS) at a tertiary eye referral eye institute in Singapore. Clinical records of 120 patients with scleritis from a database of 2200 patients from Ocular Autoimmune Systemic Inflammatory Infectious Study (OASIS) were reviewed. RESULTS: 56.6% were females, with a mean age of 48.6 ± 15.9 years. 75 (62.5%) had diffuse anterior scleritis, 25 (20.8%) had nodular anterior scleritis, 7 (5.8%) had necrotizing anterior scleritis and 13 (10.8%) had posterior scleritis. Ocular complications were observed in 53.3% of patients, including anterior uveitis (42.5%), raised intraocular pressure (12.5%), and corneal involvement (11.7%). Autoimmune causes were associated with 31 (25.8%) of patients, and 10 (8.3%) patients had an associated infective etiology, much higher than Caucasian studies. 53.3% of patients were treated with oral corticosteroids while 26.7% required immunosuppressives. CONCLUSIONS: Infective etiology needs to be considered in patients of scleritis from Asian origin. In our study and in OASIS database, scleritis was associated with systemic autoimmune disease and ocular complications.

Gamma interferon assay as an alternative to PPD skin testing in selected patients with granulomatous intraocular inflammatory disease.

BACKGROUND: To evaluate the QuantiFERON-TB test (gamma interferon assay), approved by the Centers for Disease Control and Prevention for the detection of latent tuberculosis (LTB), in patients who potentially may require immunosuppressive therapy for ocular inflammatory disease. METHODS: Blood samples from 12 consecutive patients with granulomatous ocular inflammatory disease were evaluated first with the purified protein derivative (PPD) skin test and then with the QuantiFERON-TB test (11 of 12 patients, 1 declined). The results of the 2 tests in both U.S.- and non-U.S.-born patients were compared with their Bacillus Calmette-Guérin (BCG) vaccination status and chest x-rays. RESULTS: In our small series there was a high degree of concordance between the QuantiFERON-TB assay and the PPD skin test. INTERPRETATION: The QuantiFERON-TB test did not demonstrate intrinsic merit over PPD skin testing for screening for LTB in selected patients when immunosuppressive therapy is considered. The confounding effect of BCG vaccination renders interpretation of both tests difficult. Early reports suggest the second-generation tests that are now available may hold promise for use in the uveitis clinic and should be formally evaluated.

Concurrent intermediate uveitis and an enhancing intracranial lesion as the initial manifestation of sarcoidosis.

INTRODUCTION: Posterior segment involvement has been described to be associated with central nervous system involvement in sarcoidosis as a result of direct sarcoid tissue infiltration or mass effect of a cerebral lesion. However, isolated intermediate uveitis occurring concurrently with central nervous system involvement prior to extensive systemic disease is rare. CLINICAL PICTURE: We describe a patient with neuro-ophthalmic manifestations of intermediate uveitis and an enhancing basal ganglia lesion at initial presentation, in the absence of extensive systemic disease. TREATMENT: He was treated with high-dose systemic steroids which was progressively tailed down over 6 months. OUTCOME: There was prompt resolution of vitritis with good preservation of visual acuity. CONCLUSION: The difficulties of the initial diagnosis of sarcoidosis and the indications for initiation of steroid therapy are illustrated. We use this case to emphasise the need for a high clinical suspicion of sarcoidosis in the presence of similar unusual and seemingly unrelated combinations of neurological manifestations so as to facilitate the prompt institution of appropriate treatment when indicated.

Suppression of immune-mediated ocular inflammation in mice by interleukin 1 receptor antagonist administration.

OBJECTIVE: To evaluate the effects of an interleukin 1 receptor antagonist (IL-1RA) on the development of immune-mediated ocular inflammation in mice. METHODS: Recombinant, human, nonglycosylated IL-1RA (anakinra [kineret]) was tested for its inhibitory effects in 2 systems: (1) experimental autoimmune uveitis induced by interphotoreceptor retinoid-binding protein in B10.A mice using routine procedures and evaluated by clinical and histological examination, and (2) ocular inflammation in mice induced by transfer of hen egg lysozyme-specific T cells to hen egg lysozyme-transgenic mice. Treatment with IL-1RA included daily subcutaneous injections of the drug, at 300 and 500 mg/kg, or phosphate-buffered saline as control. RESULTS: Mean +/- SE experimental autoimmune uveitis scores of histological ocular changes of the mice at day 14 postimmunization with interphotoreceptor retinoid-binding protein were 1.5 +/- 0.3 in control mice; 1.0 +/- 0.4 in 300-mg/kg anakinra-treated mice; and 0.5 +/- 0.2 in 500- mg/kg anakinra-treated mice (P = .004). There was a corresponding decrease in the cellular immune response and cytokine production of immune cells in treated mice. Suppression of ocular inflammation by anakinra in the transfer system was also observed (P = .04). CONCLUSION: Human IL-1RA suppresses immune-mediated ocular inflammation in mice, affecting both the afferent and efferent components of the pathogenic immune response.Clinical Relevance Systemic administration of IL-1RA may have clinical application in the management of patients with uveitis.

Serpiginous choroiditis.

Serpiginous choroiditis is a rare, usually bilateral, chronic, progressive, recurrent inflammation of the choroid, retinal pigment epithelium, and choriocapillaris of unknown etiology. Based on clinical presentation, it can be classified into 1) peripapillary, 2) macular, and 3) ampiginous types. The clinical course, regardless of the presentation, is progressive with multiple recurrences leading to potentially significant visual loss. Visual outcome is directly related to the involvement of the para-fovea and fovea by the lesions or secondary choroidal neovascularization. The histological findings of the lesions are atrophy of the choriocapillaris, retinal pigment epithelium and photoreceptor cells, and moderate diffuse lymphocytic infiltrates throughout the choroid. Multiple etiologies including autoimmunity, infection, vasculopathy, and degeneration were proposed but none is well supported by clinical and laboratory evidence. Fluorescein and indocyanine green angiography have been useful in the assessment of the extent and the activity of lesions. Due to the insidious and progressive clinical course, an assessment of treatment outcomes needs long term follow-up. Currently, treatment with immunosuppressive and alkylating agents have shown possible efficacy in small case series. Larger clinical studies and interventional trials are required to further our understanding of the pathogenesis, etiology, and for the evaluation of treatment strategies.

Bilateral uveitis in a patient with autoimmune lymphoproliferative syndrome.

PURPOSE: We report a case of autoimmune lymphoproliferative syndrome (ALPS) presenting with bilateral uveitis. DESIGN: Observational case report. METHODS: Review of case record, serum and aqueous IL-10 and IL-6 cytokine results, and immunosuppressive treatment of a patient with a mutation in the gene encoding Fas. RESULTS: Control of the intermediate uveitis required sustained doses of topical and periocular corticosteroids as well as systemic cyclosporine. The serum IL-10 level was elevated, as commonly seen in ALPS, but the aqueous IL-10 was not. CONCLUSIONS: Despite a Th2 immune predominance in ALPS, uveitis, a Th1-mediated disease, may still manifest in these patients. The pathogenesis of uveitis in ALPS may differ from that of the systemic disease overall. Long-term follow-up is required for patients with uveitis associated with ALPS.

Progression of varicella-zoster virus necrotizing retinopathy in an HIV-negative patient with transient immune deviation.

PURPOSE: To report a case of unilateral varicella-zoster virus (VZV) necrotizing retinopathy that progressed from outer retinitis with features of progressive outer retinal necrosis (PORN) to typical acute retinal necrosis (ARN) in an HIV-negative patient with a transient decrease in CD4 lymphocyte counts and CD4/CD8 ratio. METHOD: Case report. RESULTS: A 41-year-old Chinese man presenting with blurred vision in the right eye was diagnosed with herpetic necrotizing retinitis without vitritis. Fundus examination revealed retinal arteritis and extensive deep whitish retinal lesions in the mid-periphery with minimal vitritis. Aqueous humor and vitreous PCR were positive for VZV. His CD4 count on presentation was depressed (239 cells/ul) and the CD4/CD8 ratio was low (0.8). The referring ophthalmologist had treated him with prednisolone 60 mg/day. At our institution, when intravenous acyclovir was started and the steroid therapy discontinued, he developed severe vitritis and the deep retinal lesions progressed to full-thickness retinitis typical of ARN. Repeat CD4 count was 512 cells/ul at day 14. In total, he was treated with 14 days of i.v. acyclovir (12 mg/kg 8-hourly) followed by oral valaciclovir 500 mg three times a day for 3 months. Prednisolone 30 mg once daily was restarted and tapered over 3 months. Despite prophylactic argon retinal photocoagulation to the edge of the retinitis, the patient developed a total retinal detachment at 3 months. CONCLUSIONS: VZV retinal infection in an HIV-negative patient with transient immune deviation can manifest initially as outer retinitis with features similar to PORN and progress to typical ARN when CD4 counts return to normal.

Ocular manifestations of dengue fever.

PURPOSE: To evaluate ocular manifestations associated with dengue fever. DESIGN: Retrospective case series and literature review. METHODS: Clinical records of patients with dengue fever who subsequently had ocular symptoms and signs develop were reviewed. The clinical presentation and ocular complications were evaluated. RESULTS: Six patients, 5 females and 1 male, were seen with a sudden decrease in vision 6 to 7 days after the initial manifestations of dengue fever were identified. The diagnosis was confirmed by detection of dengue-specific IgM antibodies (IgM enzyme-linked immunoassay). The presenting best-corrected visual acuity ranged from 20/30 to counting fingers, and ocular involvement was bilateral but asymmetric in 5 cases and unilateral in 1 case. Fundus findings included small, intraretinal, whitish lesions, with localized retinal and retinal pigment epithelium (RPE) disturbance, small dot hemorrhages, and vascular sheathing around the macula and the papillomacular bundle. Fluorescein angiography showed arteriolar focal knobby hyperfluorescence at the macula with mild staining of the vascular walls and leakage at the level of the RPE. All 5 cases that had indocyanine green angiography done showed early diffuse choroidal hyperfluorescence with late silhouetting of the larger choroidal vessels. Five patients received steroid therapy: 1 topical, 2 periocular, and 2 oral. Over 2 to 4 months, RPE discoloration was observed over the affected areas. After the acute episode, 3 patients showed partial recovery of vision, and in the remaining patients, the visual acuity remained stable. CONCLUSIONS: Ocular complications associated with dengue fever are rare but may result in permanent visual impairment.

Immunopathology of progressive subretinal fibrosis: a variant of sympathetic ophthalmia.

PURPOSE: We report the immunopathology of progressive subretinal fibrosis, a variant of sympathetic ophthalmia. DESIGN: Brief case report. METHOD: Review of medical record and immunopathology of a chorioretinal biopsy of a 40-year-old man who presented with left total retinal detachment (RD) following multiple vitrectomies in the right eye for RD. Small peripherally retinal holes, snow banks, and inflammatory nodules along the ora serrata were observed during left vitrectomy. Both eyes deteriorated rapidly to blindness with progressive subretinal fibrosis and inflammation over 3 months, and the patient was unresponsive to systemic prednisolone and azathioprine. RESULT: Immunopathology of the chorioretinal biopsy of the right eye revealed aggregates of CD20+ B cells, surrounded by CD3+ T cells. CD68+ macrophages were scattered throughout. CONCLUSION: The rapid clinical course described in this case may be related to the unique immunopathology of rapidly forming peudogerminal centers in the choroids and retina.

Causes of visual loss associated with uveitis in a singapore tertiary eye center.

PURPOSE: To identify the causes of visual loss associated with uveitis and its risk factors. METHODS: Review of 359 patients attending a uveitis service. RESULTS: Anterior uveitis (n = 229, 63.8%) was most common, followed by panuveitis (n = 55, 15.3%). There were 82 infective cases with 29.3% associated with tuberculosis. Visual loss occurred in 100 (27.9%) patients, of which 27 (7.5%) had severe visual loss. The main causes of visual loss were cataract (26%) and glaucoma (12%). Cystoid macular edema (14.8%) accounted for severe visual loss. Panuveitis was predictive for visual loss (p = 0.022, odds ratio (OR) 2.22) and severe visual loss (p = 0.01, OR 3.47). Posterior uveitis (p = 0.005, OR 5.01) and chronic uveitis (p = 0.008, OR 3.83) also showed higher risk for severe visual loss. CONCLUSION: With panuveitis being the second most common presentation, early specialist referral is essential in preventing visual loss.

Trends in patterns of anterior uveitis in a tertiary institution in singapore.

PURPOSE: To report the trends in etiology of patients with anterior uveitis (AU) in Singapore over 6 years. METHODS: A retrospective review of the clinical records of all new patients who presented with anterior uveitis to the uveitis subspecialty clinic from 2005 to 2010 at Tan Tock Seng Hospital, Singapore. RESULTS: There were 552 new cases of AU. This comprised 59.5% of a total of 928 new patients diagnosed with uveitis from 2005 to 2010. The mean age was 48.0 ± 17.2 years. There was a male predominance (62.5%), with a male:female ratio of 1.7:1. The majority were of Chinese ethnicity (69%), followed by Malays (13.2%). Most cases were unilateral (79.5%) and idiopathic (50.4%). Common etiological causes included Fuchs heterochromic iridocyclitis (FHI) (5.6%), ankylosing spondylitis (AS)-related AU (5.1%), herpes simplex virus (HSV) (4.7%), and herpes zoster virus (HZV) (4.5%). There were increasing trends in AS-related AU from 3.2% in 2008 to 6.5% in 2010, and psoriasis-associated AU from 1.7% in 2005 to 4.0% in 2008. There were decreasing trends in the incidence of FHI from 10.6% in 2006 to 4.7% in 2009. No change in incidence of viral etiologies was noted, but cytomegalovirus-related immune-recovery uveitis (IRU) comprised 7.4%. IRU showed an increasing trend from 1.7% in 2005 to 11.9% in 2007, then decreased to 3.3% in 2010. Using the Pearson chi-square test, there was no statistically significant association between ethnicities (Chinese, Malay, Indian) comparing infectious and noninfectious cases (p = 0.788), idiopathic and nonidiopathic cases (p = 0.170), or between the various etiologies of uveitis (p = 0.168). CONCLUSIONS: AU was the predominant form of uveitis seen at our centers. Infectious etiologies (18.5%) are the most common among nonidiopathic cases, with herpes viruses (9.2%) being most prevalent. Despite increased use of polymerase chain reaction (PCR) in the detection of microbial and viral DNA, there was no overall increase in detection of infectious causes for uveitis. The changes in CMV-related immune recovery uveitis from 2005 to 2010 could reflect a change in HIV management in Singapore.

Optic nerve toxoplasmosis and orbital inflammation as initial presentation of AIDS.

PURPOSE: To report a case of toxoplasmosis with optic nerve and orbital involvement as the initial presentation of HIV infection. METHOD: Case report. RESULTS: A 46-year-old zookeeper, who had had right central retinal vein occlusion (CRVO) 2 weeks previously, presented with painless lid and conjunctival swelling and profound visual loss in his right eye (RE). Examination revealed no light perception (NLP) RE with axial proptosis and ocular motility restriction; fundal examination revealed a clinical picture of an ischaemic CRVO. MRI of the brain and orbit showed ring-enhancing targetoid lesions in the brain and inflammatory changes in the right optic nerve, extraocular muscles and orbital fat. He was subsequently found to be HIV positive and had positive toxoplasma IgG serology. CONCLUSIONS: Immunocompromised individuals have an increased likelihood for more severe and atypical presentations; this highlights the need for increased index of suspicion for HIV infection as ocular or orbital disease may be the first manifestation of life-threatening systemic toxoplasmosis.