Hyperbaric Oxygen Therapy for Mumps-Associated Outer Retinitis with Frosted Branch Angiitis.

PURPOSE: To describe a case of outer retinitis with frosted branch angiitis associated with mumps infection treated with hyperbaric oxygen (HBO) therapy. METHODS: Observational case report. CASE REPORT: A four-year-old boy with bilateral blindness was diagnosed with necrotizing outer retinitis with frosted branch angiitis associated with serologically confirmed mumps virus infection. He was treated with HBO therapy. Visual acuity subsequently improved to 20/40 in the right eye and to 20/320 in the left eye. Sequential follow-up optical coherence tomography examinations showed progressive recovery of the outer retinal layers in the right eye. CONCLUSION: HBO therapy appears to be a feasible and safe treatment that might improve the anatomical and functional outcome in patients with mumps retinitis.

Multimodal imaging-guided diagnosis, management and follow-up of a case of diffuse unilateral subacute neuroretinitis.

A 45-year-old woman presented with diminished vision in the left eye. Visual acuity was 6/9 and fundus showed a very large live nematode near the macula along with inflammatory outer retinal lesions in the periphery. We diagnosed the case as diffuse unilateral subacute neuroretinitis and treated with immediate focal photocoagulation of the worm along with oral antihelminthic drugs and corticosteroids. The report highlights the importance of prompt laser and steroids in achieving good structural as well as the functional outcome, and the added significance of advanced imaging techniques in prognosticating such patients.

Presumed ocular histoplasmosis syndrome in a commercially insured population, United States.

PURPOSE: To describe epidemiologic features of patients with presumed ocular histoplasmosis syndrome (POHS) in the United States using insurance claims data and compare POHS patients with and without choroidal neovascularization (CNV). DESIGN: Retrospective cohort study. METHODS: Patients with International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis codes for histoplasmosis retinitis on an outpatient claim in the 2014 IBM® MarketScan® Commercial Database and the Medicare Supplemental Database who were enrolled for at least 2 years after the POHS code. MAIN OUTCOME MEASURES: Data related to testing, treatment, and direct medical costs. RESULTS: Among >50 million total MarketScan enrollees, 6,678 (13 per 100,000) had a POHS diagnosis code. Of those, 2,718 were enrolled for 2 years; 698 (25%) of whom had a CNV code. Eleven of the 13 states with the highest POHS rates bordered the Mississippi and Ohio rivers. CNV patients had significantly more eye care provider visits (mean 8.8 vs. 3.2, p<0.0001), more ophthalmic imaging tests, higher rates of treatment with anti-vascular endothelial growth factor injections (45% vs. 4%, p<0.0001), and incurred higher mean total yearly costs ($1,251.83 vs. $251.36, p<0.0001) than POHS patients without CNV. CONCLUSIONS: Although the relationship between Histoplasma and POHS remains controversial, geographic patterns of POHS patient residence were consistent with the traditionally reported range of the fungus. CNV in the context of POHS was associated with additional healthcare use and costs. Further research to understand POHS etiology, risk factors, prevalence, and complications is needed, along with early diagnosis and treatment strategies.

TREATMENT OF IDIOPATHIC RETINAL VASCULITIS, ANEURYSMS, AND NEURORETINITIS (IRVAN) WITH PHOTOCOAGULATION IN COMBINATION WITH SYSTEMIC IMMUNOSUPPRESSION.

BACKGROUND: Idiopathic retinal vasculitis, aneurysms, and neuroretinitis syndrome is a very rare primary retinal vasculitis. It seems to evolve in stages, where there is initially a florid vasculitis associated with aneurysm formation. Neuroretinitis and macula edema are common features. Subsequently, retinal ischemia ensues, leading to neovascularization. If untreated, further sight-threatening complications occur, including traction retinal detachment and secondary glaucoma. METHODS AND RESULTS: Here, we describe a patient with early idiopathic retinal vasculitis, aneurysms, and neuroretinitis syndrome, who was treated with a combination of systemic immunosuppression and localized photocoagulation. There was substantial regression of the aneurysms and improvement of the macular edema. Treatment of the disorder should be based on the clinical stage and complications of the disorder. CONCLUSIONS: As shown here, a multidisciplinary approach can be very helpful in managing patients with this severe sight-threatening disorder.

Fungal retinitis following influenza virus type A (H1N1) infection.

A 43-year-old male presented with left eye foveal retinits causing an acute visual loss following influenza virus type A infection (H1N1 infection or Swine flu). Considering viral (influenza) etiology, a prompt treatment with oral corticosteroids was started. But an initial poor response prompted an immediate diagnostic vitrectomy, which revealed Candida albicans. The retinitis healed with scar formation following anti-fungal therapy. This case highlights that even in the setting of an acute retinitis in an immunocompetent patient with recent history of viral systemic illness, a high index of suspicion of a fungal (rather than viral) infection should be kept in mind.

Adenovirus-mediated down-regulation of miR-21-5p alleviates experimental autoimmune uveoretinitis in mice.

MiR-21-5p has been found to be up-regulated in the retina of experimental autoimmune uveoretinitis (EAU) mice and correlated with the pathogenesis of EAU. The objective of the present study is to explore the role of miR-21-5p in EAU. C57 mice were immunized with residue1-20 (IRBP1-20) in complete Freund's adjuvant supplemented with Mycobacterium tuberculosis H37Ra to induce EAU, and miR-21-5p was knocked down via subretinal injection of anti-miR-21-5p adenovirus. The pathological score, TUNEL positive cells and the expression of pro-inflammatory factors in the retina were reduced, and the expression of IL-10 was increased by down-regulation of miR-21-5p. Up-regulation of miR-21-5p significantly decreased the mRNA and protein levels of IL-10 in ARPE-19 cells. The binding activity of miR-21-5p on the 3'UTR of IL-10 mRNA was confirmed by luciferase reporter assay. Moreover, the miR-21-5p level in splenic lymphocytes of EAU mice was increased at the 7th day after immunization and reached its peak at the 14th day, that was in accordance with the changing trend with the Th17 cell frequency in the spleen. Besides, lentivirus-mediated down-regulation of miR-21-5p reduced the Th17 cell frequency and increased the Treg cell fraction of IRBP1-20-stimulated lymphocytes in vitro. Taken together, in situ down-regulation of miR-21-5p attenuates EAU by inhibiting inflammatory responses and reducing retinal cell apoptosis. miR-21-5p may also participate in the progress of EAU by affecting Th17/Treg balance via the regulation of IL-10. Therefore, we demonstrate that miR-21-5p can serve as a therapeutic target in the management of uveitis and other autoimmune diseases.

Ophthalmic manifestations of bartonella infection.

PURPOSE OF REVIEW: The eye is commonly affected in disseminated cat scratch disease (CSD) caused by Bartonella species. This article reviews recently published data on epidemiology of CSD, clinical features of ocular involvement, diagnosis and treatment. RECENT FINDINGS: The annual incidence of CSD has been estimated as 4.7 per 100 000 in the United States. It occurs predominantly in the southern states, with a peak in January, and disproportionately affects children. Retinal infiltrates, neuroretinitis and branch retinal artery occlusions have been reported as common manifestations of ocular bartonellosis in recent series. The use of different antigens for serodiagnosis and new real-time PCR assays for molecular diagnosis have been described. Despite lack of a standard treatment, good visual outcomes were generally reported in patients with ocular bartonellosis. SUMMARY: Bartonella infections continue to be a burden worldwide and epidemiologic features may guide preventive measures in high-risk regions and populations. An increased awareness of diverse posterior segment manifestations will lead to an early diagnosis of ocular bartonellosis. Laboratory diagnostic methods continue to evolve and may be applied to the investigation of ocular fluids for a definitive diagnosis of ocular bartonellosis. Well designed clinical trials are required to establish the optimum treatment of especially sight-threatening manifestations.

MSC-derived Extracellular Vesicles Attenuate Immune Responses in Two Autoimmune Murine Models: Type 1 Diabetes and Uveoretinitis.

Accumulating evidence shows that extracellular vesicles (EVs) produced by mesenchymal stem/stromal cells (MSCs) exert their therapeutic effects in several disease models. We previously demonstrated that MSCs suppress autoimmunity in models of type 1 diabetes (T1D) and experimental autoimmune uveoretinitis (EAU). Therefore, here, we investigated the therapeutic potential of MSC-derived EVs using our established mouse models for autoimmune diseases affecting the pancreas and the eye: T1D and EAU. The data demonstrate that MSC-derived EVs effectively prevent the onset of disease in both T1D and EAU. In addition, the mixed lymphocyte reaction assay with MSC-derived EVs indicated that EVs inhibit activation of antigen-presenting cells and suppress development of T helper 1 (Th1) and Th17 cells. These results raise the possibility that MSC-derived EVs may be an alternative to cell therapy for autoimmune disease prevention.

A novel bispecific molecule delivered by recombinant AAV2 suppresses ocular inflammation and choroidal neovascularization.

Elevated vascular endothelial growth factor (VEGF) and complement activation are implicated in the pathogenesis of different ocular diseases. The objective of this study was to investigate the hypothesis that dual inhibition of both VEGF and complement activation would confer better protection against ocular inflammation and neovascularization. In this study, we engineered a secreted chimeric VEGF inhibitor domain (VID), a complement inhibitor domain (CID) and a dual inhibitor (ACVP1). Vectors expressing these three inhibitors were constructed and packaged into AAV2 (sextY-F) particles. The expression and secretion of the proteins were validated by Western blot. The effects of these inhibitors expressed from AAV2 vectors were examined in endotoxin-induced uveitis (EIU), experimental autoimmune uveoretinitis (EAU) and choroidal neovascularization (CNV) mouse models. The AAV2 vectors expressing the CID- and ACVP1-attenuated inflammation in EIU and EAU model, whereas the vector expressing VID showed improved retinal structure damaged by EAU, but not affect the infiltration of inflammatory cells in EAU or EIU eyes. Both VID and CID vectors improved laser-induced retinal and choroid/RPE injuries and CNV, whereas ACVP1 vector provided significantly better protection. Our results suggest that gene therapy targeting VEGF and complement components could provide an innovative and long-term strategy for ocular inflammatory and neovascular diseases.

Targeting inflammation in the retina: a new therapeutic approach in diabetic retinopathy / El tratamiento de la inflamación en la retina: una nueva estrategia terapéutica en la retinopatía diabética

Retinal diseases linked to inflammation, including diabetic retinopathy (DR), are often accompanied by resident macrophage/microglial cells activation. During DR, there are substantial changes in the polarization status of the microglia from the M2 (anti-inflammatory) to the M1 (pro-inflammatory) stage. However, the dynamics between M1 and M2 polarization of microglia during DR has not been investigated and it might be therapeutically useful. In this study, we have characterized the evolution of microglia polarizarion during the early stages of DR in the retina of diabetic db/db mice. Moreover, we have analyzed microglia polarization in response to pro- (bacterial lipopolysaccharide; LPS) or anti-(IL4/IL13 cytokines or the bicyclic nojirimycin derivative (1R)-1- dodecylsulfinyl-5N,6O-oxomethylidenenojirimycin (RDS-ONJ)) inflammatory stimuli. For this goal, we have performed in vitro experiments in Bv-2 murine microglial cells as well as ex vivo experiments in retinal explants from db/db mice. Treatment of Bv-2 cells with LPS together with IL4/IL13 or R-DS-ONJ switched the M1 response towards M2. In retinal explants from db/db mice, R-DS-ONJ induced a M2 response. In conclusion, the modulation of microglia polarization dynamics towards a M2 status at early stages of DR offers novel therapeutic interventions (AU)

Las enfermedades retinianas, entre las que se encuentra la retinopatía diabética (RD), están vinculadas a un contexto inflamatorio en el cual existe una activación de los macrófagos residentes en la retina (microglia). Durante la retinopatía diabética se producen cambios de polarización de la microglia, definiéndose éstos como transiciones entre el estado M1 (proinflamatorio) y el estado M2 (anti-inflamatorio), estando aún por determinar los tiempos de aparición y actuación de la microglia en cada uno de ellos. La identificación espacio-temporal de la transición de la microglía de un estado a otro podría constituir una potente herramienta clínica para diferentes abordajes terapéuticos. En este trabajo se ha caracterizado el estado de polarización de la microgía en la retina durante las primeras fases de la RD en el modelo de ratón diabético db/db. Además, se ha estudiado la polarización de la microglia en presencia de estímulos pro-inflamatorios (lipopolisacárido bacteriano; LPS) o anti-inflamatorios (citoquinas IL4/IL13 o un compuesto natural derivado de la casternospermina, R-DS-ONJ). Para ello, se ha realizado un abordaje in vitro utilizando la línea celular de microglia murina Bv-2 y un abordaje ex vivo con explantes de retinas procedentes de ratones diabéticos db/db. El tratamiento de las células Bv-2 con LPS en combinación con IL4/IL13 o alternativamente con el compuesto R-DS-ONJ indujo la transición en la polarización de la microglia desde el estado proinflamatorio M1, inducido por el LPS, al estado antiinflamatorio M2. En los explantes de retinas de ratones db/db, el compuesto R-DS-ONJ indujo la respuesta M2 disminuyendo la respuesta M1. En conclusión, la polarización de la microglia hacía un estado M2 durante los estadíos tempranos de la RD ofrece una nueva ventana terapéutica de actuación (AU)

Internal limiting membrane: The innermost retinal barrier.

Recently, peeling of internal limiting membrane (ILM) has become one of the most common and effective surgical procedures for macular disorders. The authors discuss the adverse effects of such procedures and explore the possible functions of the membrane. We also suggest a barrier function of this membrane in addition to its possible other physiological roles. Thus, apart from the well-known inner and outer retinal barriers, ILM might be the third and innermost retinal barrier. The possible evidences supporting this hypothesis are presented.

Fluorescein photodiagnosis of idiopathic retinal vasculitis, aneurysms, and neuroretinitis (IRVAN) syndrome: A case report and long-term outcome of photocoagulation therapy.

Idiopathic retinal vasculitis, aneurysms, and neuroretinitis (IRVAN) syndrome is a disease characterized by multiple retinal macroaneurysms, neuroretinitis and peripheral capillary non-perfusion, leading to irreversible visual loss. It includes five stages and has previously been rarely reported. IRVAN syndrome is especially rare in Asia. In this report, we describe laser diagnosis and therapy in an Asian patient with IRVAN syndrome over two years of follow-up. We observed non-perfusion retina and dilated retinal capillaries in the contralateral eye. Photocoagulation is an effective therapy to control retinal macroaneurysms and nonperfusions and to prevent visual loss, particularly in the early stages of IRVAN syndrome (stages 2 & 3). To the best of our knowledge, this is the first long-term observation of photocoagulation in IRVAN syndrome. We discovered the early signs of such lesions, which may be beneficial for clinical diagnosis and therapy.

Diffuse unilateral subacute neuroretinitis in a healthy Korean male: the first case report in Korea.

A 52-yr-old male was referred for progressive visual loss in the left eye. The decimal best-corrected visual acuity (BCVA) was 0.01. Fundus examination revealed diffuse retinal pigment epithelial degeneration, focal yellow-white, infiltrative subretinal lesion with fuzzy border and a live nematode within the retina. Diffuse unilateral subacute neuroretinitis (DUSN) was diagnosed and the direct laser photocoagulation was performed to destroy the live nematode. During eight months after treatment, BCVA gradually improved to 0.2 along with the gradual restoration of outer retinal layers on SD-OCT. We report on the first case of DUSN in Korea. DUSN should be included in the differential diagnosis of unexplained unilateral visual loss in otherwise healthy subjects.

Oral delivery of ACE2/Ang-(1-7) bioencapsulated in plant cells protects against experimental uveitis and autoimmune uveoretinitis.

Hyperactivity of the renin-angiotensin system (RAS) resulting in elevated Angiotensin II (Ang II) contributes to all stages of inflammatory responses including ocular inflammation. The discovery of angiotensin-converting enzyme 2 (ACE2) has established a protective axis of RAS involving ACE2/Ang-(1-7)/Mas that counteracts the proinflammatory and hypertrophic effects of the deleterious ACE/AngII/AT1R axis. Here we investigated the hypothesis that enhancing the systemic and local activity of the protective axis of the RAS by oral delivery of ACE2 and Ang-(1-7) bioencapsulated in plant cells would confer protection against ocular inflammation. Both ACE2 and Ang-(1-7), fused with the non-toxic cholera toxin subunit B (CTB) were expressed in plant chloroplasts. Increased levels of ACE2 and Ang-(1-7) were observed in circulation and retina after oral administration of CTB-ACE2 and Ang-(1-7) expressing plant cells. Oral feeding of mice with bioencapsulated ACE2/Ang-(1-7) significantly reduced endotoxin-induced uveitis (EIU) in mice. Treatment with bioencapsulated ACE2/Ang-(1-7) also dramatically decreased cellular infiltration, retinal vasculitis, damage and folding in experimental autoimmune uveoretinitis (EAU). Thus, enhancing the protective axis of RAS by oral delivery of ACE2/Ang-(1-7) bioencapsulated in plant cells provide an innovative, highly efficient and cost-effective therapeutic strategy for ocular inflammatory diseases.

Management of IRVAN syndrome with observation.

A 7-year-old girl with IRVAN (idiopathic retinal vasculitis, aneurysms, and neuroretinitis) syndrome was monitored for 9 years. The patient had symmetric multiple aneurysmal dilations, retinal vasculitis, and severe hard exudation in the macula bilaterally. Long-term visual acuity in her untreated right eye was 20/25. In the left eye, treated with laser panretinal photocoagulation and intravitreal vascular endothelial growth factor inhibitor therapy, visual acuity decreased to 20/200 from macular hard exudates and central fibrovascular tissue. Observation is a consideration in IRVAN syndrome if the vision remains good with hard exudation.

Abrogation of Rbpj attenuates experimental autoimmune uveoretinitis by inhibiting IL-22-producing CD4+ T cells.

Experimental autoimmune uveoretinitis (EAU) is an organ-specific T cell-mediated disease induced by immunizing mice with interphotoreceptor retinoid binding protein (IRBP). Autoaggressive CD4(+) T cells are the major pathogenic population for EAU. We investigated the contribution of Notch signaling in T cells to EAU pathogenesis because Notch signaling regulates various aspects of CD4(+) T cell functions. Rbpj is required for Notch signaling, and Rbpj deficiency in T cells inhibited EAU disease severity. The amelioration of EAU in T cell-specific Rbpj-deficient mice correlated with low levels of IL-22 production from CD4(+) T cells, although IRBP-specific CD4(+) T cell proliferation and Th17 differentiation were unaffected. Administration of recombinant IL-22 during the late phase, but not the early phase, of EAU increased EAU clinical scores in T cell-specific Rbpj-deficient mice. Notch inhibition in mice immunized with IRBP with a γ-secretase inhibitor (GSI) suppressed EAU progression, even when GSI was administered as late as 13 days after IRBP immunization. Our data demonstrate that Rbpj/Notch-mediated IL-22 production in T cells has a key pathological role in the late phase of EAU, and suggest that Notch blockade might be a useful therapeutic approach for treating EAU.