A Case of Acute Retinal Necrosis Associated with Reactivation of Varicella Zoster Virus after COVID-19 Vaccination.

PURPOSE: To report a case of acute retinal necrosis (ARN) after receiving COVID-19 vaccination. METHODS: A case report. RESULTS: A 78-year-old man complained of blurred vision and floaters in the right eye 2 days after receiving BNT162b2 mRNA-based COVID-19 vaccine and was referred to our hospital with worsening visual acuity after 7 days. He had no systemic symptoms and no history of systemic diseases. Ophthalmic examination revealed white-yellowish placoid lesions spreading to the entire circumference of the retina, and temporal and upper lesions extending to the posterior pole, although anterior inflammation and vitreous opacity were mild. Diagnostic and therapeutic vitrectomy was performed, and VZV-DNA was detected by comprehensive PCR using a vitreous fluid sample. The ocular inflammation subsided by systemic administration of antivirals and corticosteroids. However, total retinal detachment requiring repeat vitrectomy using silicone oil occurred after the second vaccination. CONCLUSION: ARN associated with VZV reactivation may develop after SARS-CoV-2 mRNA vaccination.

Epidemiology and characteristics of common forms of anterior uveitis at initial presentation in a tertiary facility in Japan.

PURPOSE: To elucidate detailed epidemiological profile of common types of anterior uveitis (AU) in real-world clinical setting of a tertiary facility in Japan, and to evaluate the characteristic clinical findings at initial presentation. STUDY DESIGN: Retrospective cohort study. METHODS: Clinical charts of 275 patients (335 eyes) aged 52.5 ± 19.1 years were reviewed retrospectively. Herpetic AU was diagnosed by multiplex polymerase chain reaction tests using aqueous humor. Time of uveitis onset, gender, laterality, disease course since the initial onset of AU, visual acuity (VA) and intraocular pressure (IOP) at first visit, and definitive diagnosis were collected from clinical charts. RESULTS: Acute AU (AAU) was the most common (21.8%) form of AU; followed by herpetic AU (20.7%) comprising Herpes Simplex Virus (HSV) (8.0%), Varicella Zoster Virus (VZV) (9.1%) and cytomegalo virus (CMV) (3.6%); scleritis (13.5%); diabetic iritis (7.6%), and Posner-Schlossman syndrome (5.5%). Unilateral AU constituted 78.2%, and VA less than 20/30 accounted for 31.2%. Of all the eyes, 16.1% had an IOP higher than 20 mmHg, out of which 37.0% had herpetic AU, followed by scleritis in 25.9%, and Posner-Schlossman syndrome (PSS) in 11.1%. AU patients over 60 years of age were 40.4%, in which 34.2% had herpetic AU, followed by scleritis in 14.4% and AAU in 13.5%. Herpetic AU patients were significantly older and had higher IOP compared with AAU patients. CONCLUSION: The most frequent AU was AAU, followed by herpetic AU. Herpetic AU patients were older and had higher intraocular pressure than AAU patients, although VA was equally impaired in both groups.

Dimethyl Fumarate Protects Retinal Pigment Epithelium from Blue Light-Induced Oxidative Damage via the Nrf2 Pathway.

The purpose of this study is to investigate the protective effect of dimethyl fumarate (DMF), the methyl-ester of fumaric acid, against blue-light (BL) exposure in retinal pigment epithelial (RPE) cells. ARPE-19 cells, a human RPE cell line, were cultured with DMF followed by exposure to BL. Reactive oxygen species (ROS) generation, cell viability, and cell death rate were determined. Real-time polymerase chain reaction and Western blotting were performed to determine the change in nuclear factor (erythroid-derived)-like 2 (NRF2) expression. Twenty-seven inflammatory cytokines in the supernatant of culture medium were measured. BL exposure induced ROS generation in ARPE-19 cells, which DMF alleviated in a concentration-dependent manner. BL exposure increased the ARPE-19 cell death rate, which DMF alleviated. BL exposure induced ARPE-19 cell apoptosis, again alleviated by DMF. Under BL exposure, DMF increased the NRF2 mRNA level and promoted NRF2 expression in the nucleus. BL also strongly increased interleukin (IL)-1ß and fibroblast growth factor (FGF) expression. BL strongly induced RPE cell damage with apoptotic change while DMF mainly reduced inflammation in BL-induced RPE damage, resulting in blockade of cell death. DMF has a protective effect in RPE cells against BL exposure via activation of the NRF2 pathway.

Background Factors Affecting Visual Acuity at Initial Visit in Eyes with Central Retinal Vein Occlusion: Multicenter Study in Japan.

PURPOSE: To determine the baseline characteristics of patients with central retinal vein occlusion (CRVO) that were significantly associated with the best-corrected visual acuity (BCVA) at the initial examination. METHODS: This was a retrospective multicenter study using the medical records registered in 17 ophthalmological institutions in Japan. Patients with untreated CRVO (≥20-years-of-age) who were initially examined between January 2013 and December 2017 were studied. The patients' baseline factors that were significantly associated with the BCVA at the initial examination were determined by univariate and multivariate linear regression analyses. RESULTS: Data from 517 eyes of 517 patients were analyzed. Univariate analyses showed that an older age (r = 0.194, p < 0.001) and the right eye (r = -0.103, p < 0.019) were significantly associated with poorer BCVA at the initial visit. Multivariate analyses also showed that an older age (ß = 0.191, p < 0.001) and the right eye (ß = -0.089, p = 0.041) were significantly associated with poorer BCVA at the initial visit. CONCLUSIONS: The results indicate that an older age, a known strong factor, and the right eye were significantly associated with poorer BCVA at the initial visit to the hospital. These results suggest that functional and/or anatomical differences between the right and left eyes may be involved in these results.

Inflammatory Factors of Macular Atrophy in Eyes With Neovascular Age-Related Macular Degeneration Treated With Aflibercept.

Background: Neovascular age-related macular degeneration (nAMD) is a leading cause of blindness in older people. Low-grade inflammation is well-known as one of the pathogenic mechanisms in nAMD. Anti-vascular endothelial growth factor (VEGF) therapy is the first-line treatment for nAMD, although macula atrophy (MA) developed under anti-VEGF therapy causes irreversible visual function impairment and is recognized as a serious disorder. Here, we show specific expression patterns of aqueous humor (AH) cytokines in nAMD eyes developing MA under intravitreal injection of aflibercept (IVA) as an anti-VEGF antibody and present predictive cytokines as biomarkers for the incidence of MA in nAMD eyes under IVA treatment. Methods: Twenty-eight nAMD patients received three consecutive monthly IVA, followed by a pro re nata regimen for 2 years. AH specimens were collected before first IVA (pre-IVA) and before third IVA (post-IVA). AH cytokine levels, visual acuity (VA), and central retinal thickness (CRT) were measured. Results: Two-year incidence of MA was 21.4%. In nAMD eyes developing MA [MA (+) group], pre-IVA levels of monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein (MIP)-1ß, VEGF and post-IVA level of MCP-1 were higher than those in nAMD eyes without MA [MA (-) group]. In hierarchical cluster analysis, pre-IVA MCP-1 and VEGF were grouped into the same subcluster, as were post-IVA MCP-1 and CRT. In principal component analysis, principal component loading (PCL) of pre-IVA interferon-γ-inducible protein 10 (IP-10) was 0.61, but PCL of post-IVA IP-10 decreased to -0.09. In receiver operating characteristic analysis and Kaplan-Meier curves, pre-IVA MCP-1, MIP-1ß, and VEGF and post-IVA interleukin-6, MCP-1, and MIP-1ß were detected as predictive factors for MA incidence. In 2-year clinical course, changes of VA in groups with high levels of pre-IVA MIP-1ß (over 39.9 pg/ml) and VEGF (over 150.4 pg/ml) were comparable to those in MA (+) group. Conclusion: Substantial loss of IP-10 effects and persistent inflammation contribute to incidence of MA, and screening of AH cytokine levels could be a useful method to predict MA incidence in nAMD eyes under anti-VEGF therapy.

Potential bias of preoperative intravitreal anti-VEGF injection for complications of proliferative diabetic retinopathy.

PURPOSE: Intravitreal anti-VEGF injection (IVI) is administered before vitrectomy to assist management of proliferative diabetic retinopathy (PDR)-related complications. In the clinical setting, retinal surgeons determine the use of preoperative IVI based on individual criteria. In this study, we investigated factors related to the potential bias of retinal surgeons in using IVI prior to vitrectomy for PDR-related complications, and evaluated the real-world outcomes of surgeon-determined preoperative IVI. METHODS: Medical records of 409 eyes of 409 patients who underwent 25-gauge vitrectomy for PDR complications at seven Japanese centers (22 surgeons) were retrospectively reviewed. Ocular factors, demographic and general clinical factors, surgical procedures, and postoperative complications were compared between IVI group (patients who received preoperative IVI; 87 eyes, 21.3%) and non-IVI group (patients who did not receive preoperative IVI; 322 eyes, 78.7%). In addition, baseline HbA1c in IVI group and non-IVI group was compared between eyes with and without postoperative complications. RESULTS: At baseline, IVI group was younger (P<0.001), had shorter duration of diabetes treatment (P = 0.045), and higher frequencies of neovascular glaucoma [NVG] (P<0.001) and tractional retinal detachment [TRD] (P<0.001) compared to non-IVI group. Although IVI group had higher frequencies of intraoperative retinal break and tamponade procedure, there were no significant differences in postoperative complications and additional treatments between two groups. Baseline HbA1c levels were also not correlated with postoperative complications of VH, NVG, and RD both in IVI group and non-IVI group. Logistic regression analysis identified age (P<0.001, odds ratio [OR] 0.95), presence of NVG (P<0.001, OR 20.2), and presence of TRD (P = 0.0014, OR 2.44) as preoperative factors in favor of IVI. CONCLUSIONS: In this multicenter real-world clinical study, younger age and presence of NVG and TRD were identified as potential biases in using IVI before vitrectomy for PDR complications. Eyes that received preoperative IVI had more intraoperative retinal breaks requiring tamponade than eyes not receiving IVI, but postoperative outcome was not different between the two groups.

Programmed Cell Death-1 Pathway Deficiency Enhances Autoimmunity Leading to Dacryoadenitis of Mice.

Programmed cell death protein (PD)-1 is a coinhibitory molecule that suppresses immune response and maintains immune homeostasis. Moreover, the PD-1 pathway blocks cancers from being attacked by immune cells. Anti-PD-1 antibody therapy such as nivolumab improves survival in cancer patients. However, the occurrence of autoimmune inflammatory disorders in various organs has been increasingly reported as an adverse effect of nivolumab. Of the disorders associated with nivolumab, Sicca syndrome occurs in 3% to 11% of cases and has unknown pathologic mechanisms. Whether the absence of the PD-1 pathway causes functional and morphologic disorders in lacrimal glands was determined by analyzing PD-1 gene-knockout (Pdcd1-/-) mice. Histopathologic analysis showed that Pdcd1-/- mice developed dacryoadenitis beginning at 3 to 4 months of age, and deteriorated with age. Flow-cytometric analysis confirmed that cells infiltrating the affected lacrimal glands consisted mainly of CD3+ T cells and only a small proportion of CD19+ B cells. Among infiltrating T cells, the CD4+ Th-cell subset consisted of Th1 cells producing interferon-γ in an early stage of dacryoadenitis in Pdcd1-/- mice. Experiments of lymphocyte transfer from Pdcd1-/- into irradiated wild-type mice confirmed that CD4+ T cells from Pdcd1-/- mice induced dacryoadenitis. These results indicate that PD-1 plays an important role in the prevention of autoimmune inflammatory disorders in lacrimal glands caused by activated CD4+ Th1 cells.

Caveolin-1 Promotes Cellular Senescence in Exchange for Blocking Subretinal Fibrosis in Age-Related Macular Degeneration.

Purpose: To determine whether caveolin-1 (i) prevents epithelial-mesenchymal transition in the RPE and laser-induced subretinal fibrosis and (ii) promotes or inhibits cellular senescence in the RPE. Methods: We examined laser-induced subretinal fibrosis and RPE cell contraction in wild-type and Caveolin-1 knockout (Cav-1-/-) mice treated with or without cavtratin, a cell-permeable peptide of caveolin-1. The senescence marker p16INK4a was measured in RPE tissues from patients with geographic atrophy and aged mice, laser-induced subretinal fibrosis, and primary human RPE cells. Human RPE was examined by TUNEL staining, reactive oxygen species generation, cell viability, and senescence-associated ß-galactosidase staining. Results: The volume of subretinal fibrosis was significantly smaller in cavtratin-injected eyes from wild-type mice than in control eyes from wild-type, P = 0.0062, and Cav-1-/- mice, P = 0.0095. Cavtratin treatment produced significant improvements in primary RPE cell contraction in wild-type, P = 0.04, and Cav-1-/- mice, P = 0.01. p16INK4a expression in the RPE was higher in patients with than without geographic atrophy. p16INK4a was expressed in 18-month-old but not 2-month-old wild-type mouse eyes. p16INK4a and collagen type I antibodies showed co-localization in subretinal fibrosis. Cavtratin did not affect RPE cell apoptosis or reactive oxygen species generation, but decreased cell viability and increased senescence-associated ß-galactosidase-positive cells. Conclusions: Enhanced expression of caveolin-1 successfully blocked epithelial-mesenchymal transition of RPE and the reduction of subretinal fibrosis in mice. Nevertheless, in exchange for blocking subretinal fibrosis, caveolin-1 promotes RPE cellular senescence and might affect the progression of geographic atrophy in AMD.

Lamivudine Inhibits Alu RNA-induced Retinal Pigment Epithelium Degeneration via Anti-inflammatory and Anti-senescence Activities.

Purpose: Accumulation of the long noncoding Alu element RNA activates the NLRP3 inflammasome and leads to retinal pigment epithelium (RPE) cell death, a key event in the pathogenesis of geographic atrophy during late-stage age-related macular degeneration. Lamivudine (3TC) is a nucleoside analog reverse transcriptase inhibitor known to inhibit the NLRP3 inflammasome. Currently, the intracellular response of the senescence marker p16Ink4a to the long noncoding RNA is being actively studied. The present study aimed to assess the efficacy of 3TC against Alu RNA-induced RPE inflammation and senescence by evaluating changes in expression of the proinflammatory cytokines IL-18 and IL-1ß and of p16INK4a in RPE cells. Methods: Cultured human RPE cells and in vivo mouse RPE cells were transfected with an in vitro-transcribed Alu RNA, and changes in IL-18, IL-1ß, and p16Ink4a expression measured in the presences of 3TC or 3,4-(M)CA as a negative control. Results: Treatment with 3TC markedly reduced Alu RNA-induced expression of IL-18 and IL-1ß in human and mouse RPE cells compared with the negative control. Further, Alu RNA-induced p16INK4a expression was suppressed by 3TC in human RPE cells. Conclusions: Our data suggest that Alu RNA accumulation contributes to RPE cell senescence in age-related macular degeneration and that this pathogenic process can be suppressed by 3TC. Translational Relevance: Further verifying this study leads to potential targets for age-related macular degeneration therapy.

Retinal changes in mice spontaneously developing diabetes by Th17-cell deviation.

Elevated level of interleukin (IL)-17, predominantly produced by T helper (Th) 17 cells, has been implicated in diabetic retinopathy (DR), but it remains unclear whether IL-17 is involved in the pathogenesis of DR. Ins2Akita (Akita) mice spontaneously develop diabetes, and show early pathophysiological changes in diabetic complications. On the other hand, interferon-γ knock out (GKO) mice exhibit high differentiation and activation of Th2 and Th17 cells as a result of Th1 cell inhibition. In this study, Ins2Akita IFN-γ-deficient (Akita-GKO) mice were established by crossbreeding Akita mice with GKO mice, and Th17-mediated immune responses on DR were investigated. Blood glucose levels (BGL) of Akita mice and Akita-GKO mice were significantly higher than those of age-matched wild type (WT) or GKO mice, and there was no significant difference in BGL between Akita and Akita-GKO mice. Relative mRNA expression of ROR-γt that is a transcriptional factor of Th17 cells but not GATA-3 that is for Th2 cells was significantly upregulated only in Akita-GKO mice compared with WT mice, and the proportions of IL-17 and IL-22-producing splenic CD4+ cells were significantly higher in Akita-GKO mice than in wild type (WT), Akita, or GKO mice. In the retina, mRNA expression of vascular endothelial growth factor (VEGF) and intercellular adhesion molecule-1 (ICAM-1) were increased in Akita-GKO mice more than in Akita or GKO mice, and statistically significant differences were observed between Akita-GKO mice and WT mice. Leukostasis in retinal vessels and ocular level of VEGF protein increased significantly in Akita-GKO mice compared with the other groups. Edematous change in the retinal surface layer, retinal exudative lesions depicted as areas of hyperfluorescence in fluorescein angiography (FA), and vascular basement membrane thickening in all layers of the retina were also observed in Akita-GKO mice at 9-week-old but not in age-matched Akita or GKO mice. These results suggested that Th17 cell-mediated immune responses might be involved in promotion of functional and morphological changes in the retina of mice spontaneously developing diabetes.

Functional and anatomical changes in diabetic macular edema after hemodialysis initiation: One-year follow-up multicenter study.

Diabetic nephropathy and retinopathy (DR) including diabetic macular edema (DME) are representative microvascular complications of diabetes. We conducted a retrospective multicenter study analyzing records from patients with DR (132 eyes in 70 patients) and end-stage renal diseases (ESRD) who underwent hemodialysis for the first time. We demonstrated that the central retinal thickness (CRT) values were significantly decreased (p < 0.0001), and the best-corrected visual acuity (BCVA) values were improved (p < 0.05) at 1, 3, 6, 9, and 12 months after hemodialysis initiation, in spite of a lack of specific ocular treatments for DME in 93.2% of eyes. We found a significant positive correlation in the rates of CRT changes between right and left eyes. The CRT reductions were greater in eyes with DME type subretinal detachment than in those with spongelike swelling and cystoid macular edema. The visual outcome gain was associated with the CRT reduction at 12 months in the eyes with good initial BCVA (≧20/50). Hemodialysis induction contributed to functional and anatomical improvements after 1 year, independently of initial laboratory values before the hemodialysis.

Changes in intraocular pressure and aqueous flare in eyes with multiple evanescent white dot syndrome.

PURPOSE: To study the changes in intraocular pressure (IOP) and aqueous flare in eyes with multiple evanescent white dot syndrome (MEWDS) during the disease course. STUDY DESIGN: Retrospective observational study. METHODS: Twenty-one patients with unilateral MEWDS were retrospectively evaluated. IOP values were compared between the affected and fellow eyes 2 weeks, 1 month, and 3 months following disease onset in 17 patients, and within 7 days from disease onset in 11 patients. Aqueous flare values measured using a laser flare-cell meter in ten eyes between 1 weeks and 1 month from disease onset were compared between the affected and fellow eyes. RESULTS: IOP values were significantly lower in the affected eyes than in the fellow eyes at both 2 weeks (P=0.002) and 1 month from disease onset (P=0.02). However, IOP values of affected eyes did not show significant differences from the fellow eyes within 7 days ((P=0.11) and 3 months of onset (P=0.30). Aqueous flare values were significantly increased in the affected eyes compared to those in the fellow eyes (P=0.010) and significantly correlated with IOP values (r=-0.67, P=0.035). CONCLUSION: IOP values mildly decreased in association with aqueous flare values in the acute phase in eyes with MEWDS.

n-3 Fatty Acid and Its Metabolite 18-HEPE Ameliorate Retinal Neuronal Cell Dysfunction by Enhancing Müller BDNF in Diabetic Retinopathy.

Diabetic retinopathy (DR) is a widespread vision-threatening disease, and neuroretinal abnormality should be considered as an important problem. Brain-derived neurotrophic factor (BDNF) has recently been considered as a possible treatment to prevent DR-induced neuroretinal damage, but how BDNF is upregulated in DR remains unclear. We found an increase in hydrogen peroxide (H2O2) in the vitreous of patients with DR. We confirmed that human retinal endothelial cells secreted H2O2 by high glucose, and H2O2 reduced cell viability of MIO-M1, Müller glia cell line, PC12D, and the neuronal cell line and lowered BDNF expression in MIO-M1, whereas BDNF administration recovered PC12D cell viability. Streptozocin-induced diabetic rats showed reduced BDNF, which is mainly expressed in the Müller glia cell. Oral intake of eicosapentaenoic acid ethyl ester (EPA-E) ameliorated BDNF reduction and oscillatory potentials (OPs) in electroretinography (ERG) in DR. Mass spectrometry revealed an increase in several EPA metabolites in the eyes of EPA-E-fed rats. In particular, an EPA metabolite, 18-hydroxyeicosapentaenoic acid (18-HEPE), induced BDNF upregulation in Müller glia cells and recovery of OPs in ERG. Our results indicated diabetes-induced oxidative stress attenuates neuroretinal function, but oral EPA-E intake prevents retinal neurodegeneration via BDNF in Müller glia cells by increasing 18-HEPE in the early stages of DR.

Diacron reactive oxygen metabolites and biological antioxidant potential tests for patients with age-related macular degeneration.

BACKGROUND: Previously, we showed that serum malondialdehyde (MDA) was significantly higher in patients with neovascular age-related macular degeneration (nAMD) than in those without AMD. The Diacron reactive oxygen metabolites (d-ROMs) and biological antioxidant potential (BAP) tests are known markers of oxidative stress. The aim of this study was to use d-ROMs and BAP tests to evaluate changes in systemic oxidative stress in patients with nAMD. METHODS: Blood serum samples were collected from 34 patients with nAMD (mean age: 76.5 ± 7.7 years; 22 men) and 20 control subjects (mean age: 62.9 ± 14.0 years; 10 men), and d-ROMs and BAP tests were examined. RESULTS: In men, the mean level of d-ROMs for the nAMD patients was significantly higher than that for the controls (312.0 ± 52.4 vs. 275.1 ± 45.5 U.CARR, respectively; P < .05). There was a significant correlation between d-ROM level and CNV lesion area in the male nAMD group (r = .42, P = .05). There were no significant differences in mean BAP test results between the nAMD patients and controls for either sex (men: 2241 ± 549 vs. 2136 ± 246 µmol/L; women: 2263 ± 292 vs. 2335 ± 161 µmol/L). CONCLUSION: The d-ROMs test may provide a useful indicator of nAMD in men but not in women.

Chronic chorioretinal detachment under normal intraocular pressure in eye with uveitic glaucoma after trabeculectomy: A case report.

RATIONALE: Choroidal detachment is a major postoperative complication of trabeculectomy. Postoperative choroidal detachment occurs with low intraocular pressure (IOP), and is naturally resolved by elevation of IOP. We report a case of chronic chorioretinal detachment (CRD) in the eye with uveitic glaucoma after trabeculectomy which persisted with normal IOP resistant for medication and required surgery. PATIENT CONCERNS: A 63-year-old man was referred to our department with uncontrolled uveitic glaucoma in his right eye. At first presentation, IOP was 62 mm Hg in the right eye with opened angle, and active ocular inflammation was presented by moderate cell infiltration to the anterior chamber. DIAGNOSIS: Uveitic glaucoma. INTERVENTIONS: Trabeculectomy with mitomycin-C combined with phacoemulsification were performed without any surgical trouble. Postoperative inflammation in the anterior segment was mild, and IOP decreased to the middle-teen. OUTCOMES: At 19 days after surgery, the depth of the anterior chamber changed to shallow and CRD occurred in the inferior quadrant area. This complication could not be resolved by additional systemic corticosteroid medication and scleral fenestration. Although IOP was maintained in middle-teen range, suture fixation of the sclera flap and additional scleral fenestration were necessary to resolve CRD at 191 days after primary surgery. LESSONS: In uveitic eye with uncontrolled ocular hypertension, severe CRD after trabeculectomy is able to occur even with normal IOP, which requires surgical procedure in addition to the medical treatment.

Prognostic factors of revitrectomy for complications in eyes with proliferative diabetic retinopathy: a retrospective multicentre study.

PURPOSE: To identify prognostic factors for revitrectomy in patients who underwent vitrectomy for complications with proliferative diabetic retinopathy (PDR) in multicentre study. METHODS: Consecutive 452 eyes of 452 patients with PDR undergoing 25-gauge microincision vitrectomy system (MIVS) in seven centres were retrospectivity reviewed. Preoperative ocular factors (baseline visual acuity [VA], vitreous haemorrhage [VH], tractional retinal detachment [TRD] and retinal photocoagulation), general factors (sex, age, diabetes duration, HbA1c level, hypertension, anti-coagulant medication and estimated glomerular filtration rate), surgical procedures (preoperative anti-vascular endothelial growth factor injection, internal limiting membrane peeling, combined cataract surgery, retinal break, and tamponade), postoperative complications for revitrectomy and postoperative VA at 6 months were evaluated. RESULTS: In the follow-up period of 6 months, revitrectomy was performed in 56 eyes (26.3%), and postoperative complications for revitrectomy were VH in 31 eyes (15%), TRD in 13 eyes (6.2%) and membrane proliferation in 12 eyes (5.2%). The mean LogMAR improvement from baseline to 6 months in revitrectomy group (0.39) was significantly worse than in single vitrectomy group (0.74). Diabetic duration, low baseline VA, less simple VH, TRD and air tamponade were statistical risk factors of revitrectomy, and logistic regression analysis identified low baseline VA and air tamponade also as prognostic factors of revitrectomy. CONCLUSION: Our results indicated that prognosis of VA was worse in PDR patients with revitrectomy and low baseline VA and air as the tamponade material were the potential prognostic factors of revitrectomy.

Efficacy of Adalimumab for Chronic Vogt-Koyanagi-Harada Disease Refractory to Conventional Corticosteroids and Immunosuppressive Therapy and Complicated by Central Serous Chorioretinopathy.

Purpose: To report the efficacy of adalimumab in a case of chronic Vogt-Koyanagi-Harada (VKH) disease refractory to conventional corticosteroids and immunosuppressive therapy and complicated by central serous chorioretinopathy (CSC).Case report: A 66-year-old woman diagnosed with VKH was treated with intravenous corticosteroids followed by oral corticosteroids and cyclosporine. However, systemic corticosteroids could not be tapered because of recurrent ocular inflammation and systemic complications (diabetes mellitus, moon face, bone weakness), while CSC appeared in both eyes. A diagnosis of chronic VKH resistant to medications complicated by corticosteroid-induced CSC was made. Systemic corticosteroids and cyclosporine were tapered and adalimumab initiated. Bilateral ocular inflammation and CSC were gradually reduced and visual acuity improved without any adverse effect. Twelve months after starting adalimumab monotherapy, no signs of active VKH and CSC were present.Conclusions: Adalimumab is one of the effective therapeutic options for refractory VKH disease complicated with corticosteroid-induced adverse effects.

Comprehensive expression patterns of inflammatory cytokines in aqueous humor of patients with neovascular age-related macular degeneration.

Neovascular age-related macular degeneration (nAMD) is a complex and multi-factorial disease, and low-grade inflammation is associated with pathogenesis of nAMD. Aqueous humor could reflect intraocular immune environments in various eye diseases. The research so far used aqueous humor samples and revealed that inflammation is involved in pathophysiology of nAMD, although immunological roles of cytokines were evaluated inadequately with aspect to individual effects. Here we used 27 kinds of cytokines covering general immunologic reactions, examined specific expression patterns of cytokines, and assessed relationships between inflammation and pathophysiology of nAMD by multivariate analyses. In nAMD eyes, principal component analysis showed that IL-7, MCP-1, MIP-1ß and VEGF had high principal component loadings of over 0.6 in the first principal component constituting 32.6% of all variability of the data. In exploratory factor analysis, IL-6, MCP-1 and MIP-1ß had high factor loadings (FL) of over 0.5 in Factor 1 constituting 32.6% of all variability, while VEGF had FL of over 1.0 in Factor 3 constituting 10.7% of all variability. In hierarchical cluster analysis, MCP-1 and VEGF were located in the cluster of first proximate mutual distance to central retinal thickness. These data could suggest that low-grade inflammation is a principal contributor in nAMD.

Outcomes of 25-Gauge Vitrectomy for Tractional and Nontractional Diabetic Macular Edema with Proliferative Diabetic Retinopathy.

The benefit of pars plana vitrectomy with internal limiting membrane peeling for tractional macular edema and diffuse nontractional macular edema in diabetic retinopathy has been reported. Although these studies had included various stages, use of conventional 20-gauge vitrectomy system, small number of cases, single-center study, and lack of retinal structure measurements were limitations. We compared one-year outcomes of 25-gauge vitrectomy for refractory diabetic macular edema with or without the tractional proliferative membrane in proliferative diabetic retinopathy (PDR) eyes and examined the prognostic factors for postoperative visual acuity. A total of consecutive 116 PDR eyes of 116 patients that underwent 25-gauge vitrectomy for tractional macular edema (TME group: 56 eyes) or nontractional macular edema (nTME group: 60 eyes) at six centers were retrospectively reviewed. Visual acuity (VA), central macular thickness (CMT), complications, and postoperative treatments before and 12 months after vitrectomy were compared. Mean VA improved significantly in each group (both P < 0.01), and mean CMT decreased significantly in each group (both P < 0.01). Thirteen eyes underwent additional vitrectomy, six eyes developed neovascular glaucoma, six eyes received intravitreal anti-VEGF injection, and thirteen eyes received subtenon triamcinolone acetonide injection. Multiple linear regression analysis showed that baseline VA and CMT in the TME group and kidney function in the nTME group were the predictable factors of the 12-month postoperative VA. Twenty-five-gauge vitrectomy effectively improved VA and macular structure both in TME and nTME groups. Baseline VA, CMT, and kidney function are important factors affecting postoperative VA.

Identification of Underlying Inflammation in Vogt-Koyanagi-Harada Disease with Sunset Glow Fundus by Multiple Analyses.

PURPOSE: To evaluate underlying subclinical ocular inflammation in Vogt-Koyanagi-Harada (VKH) disease with sunset glow fundus (SGF) by multiple analyses. STUDY DESIGN: Retrospective observational study. METHODS: Clinical records of 34 eyes of 17 VKH patients with SGF in whom laser flare photometry (LFP), enhanced depth imaging optical coherence tomography (EDI-OCT), and indocyanine green angiography (ICGA) were performed on the same day were reviewed. The mean age was 57.3 ± 16.3 years, and the mean duration from the initial onset of uveitis was 47.1 ± 22.1 months. Flare counts, ICGA scores, and subfoveal choroidal thickness (SFCT) were compared between eyes. RESULTS: Although clinical ocular inflammation was observed only in 4 eyes (11.8%), inflammatory signs were observed in 23 out of 34 eyes by LFP (67.6%), in 27 eyes by ICGA (79.4%), and in 10 eyes by SFCT (29.4%). Active inflammatory signs detected by ICGA were observed in 77.8% by LFP and in 25.9% by SFCT. The strength of agreement (Cohen's kappa coefficient) between positive ICGA score and positive flare score was 0.406 (95% CI: 0.076-0.7359, P < 0.01), but there was no association between positive ICGA score and increased SFCT. In addition, positive flare count was the significant prognostic factor of positive ICGA score with odds ratio 11.7. CONCLUSIONS: Subclinical ocular inflammation signs were detected in most VKH patients with SGF by ICGA and a substantial proportion of which were also detected by LFP, whereas SFCT was less sensitive to detect subclinical inflammation.