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Purpose: To investigate the association between pretreatment blood flow velocity in the choroid and optic nerve head (ONH) and retinal oxygen metabolism in the acute uveitic phase and the development of 'sunset glow fundus' in Vogt-Koyanagi-Harada (VKH) disease., Methods: Retrospective analysis of 41 patients (82 eyes). Laser speckle flowgraphy and retinal oximetry measurements were performed at the presentation. The main outcome measure was the development of 'sunset glow fundus'., Results: Twenty patients (40 eyes) presented in the phase preceding anterior segment inflammation (early presentation), and 21 patients (42 eyes) presented with anterior segment inflammation (late presentation). In ONH, mean blur rate (MBR)-vessel, representing blood flow velocity in retinal vessels, was significantly lower in the late presentation group, while choroidal MBR was not significantly different. The late presentation group had significantly lower oxygen saturation in retinal venules, a higher arteriovenous oxygen saturation difference and a smaller calibre of retinal arterioles compared with the early presentation group. Eyes that subsequently developed 'sunset glow fundus' had significantly lower ONH MBR-vessels, lower oxygen saturation in retinal venules, a higher arteriovenous oxygen saturation difference and a smaller calibre of retinal arterioles compared with eyes without 'sunset glow fundus'. ONH MBR-vessel had a significant negative correlation with arteriovenous oxygen saturation difference and a significant positive correlation with calibre of retinal arterioles., Conclusions: In the acute uveitic phase of VKH disease, the development of 'sunset glow fundus' is associated with pretreatment reduced retinal blood flow velocity, calibre of retinal arterioles and oxygen saturation in retinal venules, as well as an increased arteriovenous oxygen saturation difference., (© 2024 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Background: To evaluate risk factors for developing endophthalmitis after repair of open globe injuries., Methods: Retrospective chart analysis of 1303 patients from May 1996 till December 2019., Results: All patients received prophylactic intravenous broad-spectrum antibiotics for 5-7 days. Endophthalmitis was clinically suspected in 37 (2.8%) eyes and was culture proven in 14 of these eyes (1.1%). Univariate analysis identified poor initial visual acuity at presentation, rural setting of injury, contaminated wound and lens injury as significant predictors for the development of clinically suspected endophthalmitis. Intravitreal antibiotics at the time of primary repair in eyes with high-risk characteristics decreased risk of developing endophthalmitis (OR: 2.28;95% CI,1.07-4.86; p = .033)., Conclusions: Poor initial visual acuity, rural setting of injury, contaminated wound, and lens injury increased risk of suspected posttraumatic endophthalmitis. Prophylactic intravitreal antibiotics at the time of primary repair in eyes with high-risk characteristics reduced the risk of posttraumatic endophthalmitis.

Objectives: Acute central serous chorioretinopathy (CSC) and Vogt-Koyanagi-Harada (VKH) disease in the acute uveitic phase are characterized by serous retinal detachment caused by dysfunction of the choroid. The aim of this study is to compare blood flow velocity and pulse waveform parameters in the choroid between these two diseases., Methods: In this study, 25 patients (50 eyes) with VKH disease, 21 patients (27 eyes) with CSC and 15 healthy controls (30 eyes) were studied. Laser speckle flowgraphy (LSFG) was performed at presentation., Results: Choroidal mean blur rate (MBR), representing blood flow velocity in choroidal vessels, was significantly lower in the eyes affected by VKH disease compared with the healthy control and CSC eyes. CSC eyes had a significantly higher MBR compared with healthy controls. Among the analyzed pulse waveform parameters, blow-out time (BOT), falling rate (FR) and flow acceleration index (FAI) changed significantly. BOT value was significantly lower in CSC eyes than in healthy control and VKH eyes. FR and FAI values were significantly lower in VKH eyes than in healthy control and CSC eyes. There was a strong positive correlation between MBR and FAI., Conclusions: Our findings confirm different pathophysiology of these two diseases. Assessment of choroidal blood flow velocity and haemodynamics with LSFG provides useful information to differentiate acute CSC and initial-onset acute uveitis associated with VKH disease., (© 2023. The Author(s), under exclusive licence to The Royal College of Ophthalmologists.)

Purpose: To investigate the frequency, clinical findings and outcomes of occlusive retinal vasculitis in patients with multiple sclerosis (MS)., Methods: A retrospective case series., Results: During the period between January 2000 and December 2021, we identified 24 patients who were diagnosed to have uveitis associated with MS. Among them, four (16.6%) patients presented with bilateral occlusive retinal vasculitis who were diagnosed to have MS prior to presentation. All patients were treated successfully with a combination of systemic corticosteroids combined with mycophenolate mofetil. In addition, scatter laser photocoagulation was applied to the ischemic retina in all eyes., Conclusions: Early recognition and prompt treatment with systemic immunosuppressive agents and scatter laser photocoagulation prevent complications and improve outcomes in MS patients with occlusive retinal vasculitis.

We aimed to investigate the role of the CD40-CD40 ligand (CD40L) pathway in inflammation-mediated angiogenesis in proliferative diabetic retinopathy (PDR). We analyzed vitreous fluids and epiretinal fibrovascular membranes from PDR and nondiabetic patients, cultures of human retinal microvascular endothelial cells (HRMECs) and Müller glial cells and rat retinas with ELISA, immunohistochemistry, flow cytometry and Western blot analysis. Functional tests included measurement of blood-retinal barrier breakdown, in vitro angiogenesis and assessment of monocyte-HRMEC adherence. CD40L and CD40 levels were significantly increased in PDR vitreous samples. We demonstrated CD40L and CD40 expression in vascular endothelial cells, leukocytes and myofibroblasts in epiretinal membranes. Intravitreal administration of soluble (s)CD40L in normal rats significantly increased retinal vascular permeability and induced significant upregulation of phospho-ERK1/2, VEGF, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). sCD40L induced upregulation of VEGF, MMP-9, MCP-1 and HMGB1 in cultured Müller cells and phospo-ERK1/2, p65 subunit of NF-ĸB, VCAM-1 and VEGF in cultured HRMECS. TNF-α induced significant upregulation of CD40 in HRMECs and Müller cells and VEGF induced significant upregulation of CD40 in HRMECs. sCD40L induced proliferation and migration of HRMECs. We provide experimental evidence supporting the involvement of the CD40L-CD40 pathway and how it regulates inflammatory angiogenesis in PDR.

Inflammation and fibrosis are key features of proliferative vitreoretinal disorders. We aimed to define the macrophage phenotype and investigate the role of macrophage-myofibroblast transition (MMT) in the contribution to myofibroblast populations present in epiretinal membranes. Vitreous samples from proliferative diabetic retinopathy (PDR), proliferative vitreoretinopathy (PVR) and nondiabetic control patients, epiretinal fibrovascular membranes from PDR patients and fibrocellular membranes from PVR patients, human retinal Müller glial cells and human retinal microvascular endothelial cells (HRMECs) were studied by ELISA, immunohistochemistry and flow cytometry analysis. Myofibroblasts expressing α-SMA, fibroblast activation protein-α (FAP-α) and fibroblast-specific protein-1 (FSP-1) were present in all membranes. The majority of CD68 + monocytes/macrophages co-expressed the M2 macrophage marker CD206. In epiretinal membranes, cells undergoing MMT were identified by co-expression of the macrophage marker CD68 and myofibroblast markers α-SMA and FSP-1. Further analysis revealed that CD206 + M2 macrophages co-expressed α-SMA, FSP-1, FAP-α and ß-catenin. Soluble (s) CD206 and sFAP-α levels were significantly higher in vitreous samples from PDR and PVR patients than in nondiabetic control patients. The proinflammatory cytokine TNF-α and the hypoxia mimetic agent cobalt chloride induced upregulation of sFAP-α in culture media of Müller cells but not of HRMECs. The NF-ĸß inhibitor BAY11-7085 significantly attenuated TNF-α-induced upregulation of sFAP-α in Müller cells. Our findings suggest that the process of MMT might contribute to myofibroblast formation in epiretinal membranes, and this transition involved macrophages with a predominant M2 phenotype. In addition, sFAP-α as a vitreous biomarker may be derived from M2 macrophages transitioned to myofibroblasts and from Müller cells.

Objectives: To investigate the association of optic nerve head (ONH) swelling in the acute uveitic phase of Vogt-Koyanagi-Harada (VKH) disease with blood flow velocity in the choroid and ONH and oxygen saturation and diameter of retinal vessels., Methods: In this prospective study, 25 patients (50 eyes) were studied. Thirteen patients (26 eyes) had ONH swelling and 12 patients (24 eyes) had no ONH swelling. Laser speckle flowgraphy (LSFG) and retinal oximetry measurements were performed at presentation., Results: In the ONH, mean blur rate (MBR)-vessel, representing blood flow velocity in retinal vessels, was significantly lower in the eyes affected by ONH swelling, while choroidal MBR was not significantly different. Eyes with ONH swelling had a significantly lower oxygen saturation in retinal venules, a significantly higher arteriovenous oxygen saturation difference and a significantly smaller calibre of retinal arterioles compared with eyes without ONH swelling. There were significant positive correlations between the MBR-vessel of the ONH and venular oxygen saturation and calibre of retinal arterioles. In addition, MBR-vessel of the ONH had a significant negative correlation with arteriovenous oxygen saturation difference., Conclusions: The occurrence of ONH swelling in the acute uveitic phase of VKH disease is associated with lower retinal blood flow velocity and smaller calibre of retinal arterioles as well as lower oxygen saturation in retinal venules and higher arteriovenous difference in oxygen saturation., (© 2022. The Author(s), under exclusive licence to The Royal College of Ophthalmologists.)

Purpose: To determine relationship between timing of treatment initiation and disease outcomes and whether a therapeutic window of opportunity exists in initial-onset acute uveitis associated with Vogt-Koyanagi-Harada disease., Methods: Retrospective analysis of 112 patients (224 eyes). Main outcome measures were final visual acuity, progression to chronic recurrent evolution, development of complications, particularly 'sunset glow fundus', and drug-free remission cure of uveitis., Results: Forty-six patients (92 eyes) presented in the phase preceding anterior segment (AS) inflammation (early presentation) and 66 patients (132 eyes) had AS inflammation at presentation (late presentation). In significantly more eyes in the early presentation group (85.9%), final visual acuity of 20/20 was achieved compared with those in the late presentation group (66.7%) (p = 0.001). None of the eyes in the early presentation group progressed to chronic recurrent evolution and none developed 'sunset glow fundus', whereas in the late presentation group, 28.8% of the eyes progressed to chronic recurrent evolution (p < 0.001) and 56.1% developed 'sunset glow fundus' (p < 0.001). Patients in the early presentation group were able to discontinue treatment without relapse of inflammation at significantly shorter time intervals compared to patients in the delayed presentation group (p < 0.001). In the late presentation group, logistic regression analysis demonstrated that presenting clinical features predicting unfavourable outcomes were posterior synechiae (odds ratio = 4.03; 95% confidence interval [CI] = 1.29-12.23), bullous exudative retinal detachment extending to the periphery (odds ratio = 3.35; 95% CI = 1.53-7.32) and female gender (odds ratio = 2.05; CI = 1.08-3.90)., Conclusions: Our findings suggest that the window of opportunity lies in the phase preceding AS inflammation and initiation of effective treatment during this phase results in cure of uveitis and prevents blinding complications., (© 2022 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Purpose: To investigate the outcomes of initial-onset acute uveitis associated with Vogt-Koyanagi-Harada (VKH) disease that occurred during pregnancy., Methods: This is a retrospective case series., Results: During the period between January 2001 and December 2021, we identified 112 patients with initial-onset acute uveitis associated with VKH disease, 67 (59.8%) were females. Among the female patients, 10 (14.9%) patients (20 eyes) were pregnant. Of these patients, 5 patients presented in the first trimester, 3 in the second trimester and 2 in the third trimester. The follow-up period ranged from 8 to 108 months (mean 35.2 ± 28.3 months). At presentation, 8 (80%) patients had initial-onset acute VKH disease with anterior segment (AS) inflammation and 2 (20%) initial-onset acute VKH disease without AS inflammation. All patients were initially treated with systemic corticosteroids combined with cyclosporine. During follow-up period, none of the patients with initial-onset acute VKH disease without AS inflammation developed any complications. Complications including "sunset glow fundus" in 8 (40%) eyes, cataract in 2 (10%) eyes and subretinal fibrosis in 1 (5%) eye were recorded in patients with initial-onset acute VKH disease with AS inflammation. Four (40%) patients developed pregnancy-related complications, including abortion in 1 patient, systemic hypertension in 1 patient and premature rupture of membrane in 2 patients. There were no documented congenital anomalies in all born babies. Best-corrected visual acuity of ≥ 20/20 was achieved in 16 (80%) eyes at the final follow-up., Conclusion: Primary treatment with combined systemic corticosteroids and cyclosporine in initial-onset acute uveitis associated with VKH disease was safe and effective., (© 2022. The Author(s), under exclusive licence to Springer Nature B.V.)

Background/aims: To investigate the incidence, severity of COVID-19 infection and the outcomes in patients with uveitis treated with biologic agents during COVID-19 pandemic., Methods: In this prospective study, we included all patients with uveitis treated with biologic agents and tested for COVID-19 infection between May 2020 and October 2020., Results: A total of 59 patients were identified. Behçet's disease was the most common diagnosis (64.4%). Infliximab was the most frequent biologic agent used (61%). Nine (15.3%) patients were tested positive for COVID-19. None of the patients with positive COVID-19 test developed any COVID-19-related symptoms during follow-up. Of the nine patients with positive COVID-19 test, only two patients had uveitis flare-up after the biologic suspension., Conclusion: Uveitis patients under biologic therapy can be silent carriers for COVID-19., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: To investigate the outcomes of uveitis associated with Vogt-Koyanagi-Harada (VKH) disease in pediatric age group (aged 16 years and under)., Methods: A retrospective review of patients with VKH disease., Results: Among the 244 patients identified, 38 (76 eyes) were children. Among them, five had insulin-dependent diabetes mellitus. 21 presented with initial-onset acute disease and 17 with chronic recurrent disease. The mean follow-up period was 59.1 months. At presentation, chronic recurrent disease was associated with more severe inflammation as indicated by the presence of mutton-fat keratic precipitates ( p < .001), iris nodules ( p = .005) and posterior synechiae ( p < .001). During follow-up, the rate of complications was higher in children with chronic recurrent disease compared with initial-onset acute disease ( p < .001). 92.4% of the eyes with initial-onset acute disease achieved a final visual acuity of ≥20/40 compared with 70.6% of the eyes with chronic recurrent disease ( p = .013)., Conclusions: Chronic recurrent VKH disease in children is associated with worse outcomes.

We analyzed the expression of ADAMTS proteinases ADAMTS-1, -2, -4, -5 and -13; their activating enzyme MMP-15; and the degradation products of proteoglycan substrates versican and biglycan in an ocular microenvironment of proliferative diabetic retinopathy (PDR) patients. Vitreous samples from PDR and nondiabetic patients, epiretinal fibrovascular membranes from PDR patients, rat retinas, retinal Müller glial cells and human retinal microvascular endothelial cells (HRMECs) were studied. The levels of ADAMTS proteinases and MMP-15 were increased in the vitreous from PDR patients. Both full-length and cleaved activation/degradation fragments of ADAMTS proteinases were identified. The amounts of versican and biglycan cleavage products were increased in vitreous from PDR patients. ADAMTS proteinases and MMP-15 were localized in endothelial cells, monocytes/macrophages and myofibroblasts in PDR membranes, and ADAMTS-4 was expressed in the highest number of stromal cells. The angiogenic activity of PDR membranes correlated significantly with levels of ADAMTS-1 and -4 cellular expression. ADAMTS proteinases and MMP-15 were expressed in rat retinas. ADAMTS-1 and -5 and MMP-15 levels were increased in diabetic rat retinas. HRMECs and Müller cells constitutively expressed ADAMTS proteinases but not MMP-15. The inhibition of NF-κB significantly attenuated the TNF-α-and-VEGF-induced upregulation of ADAMTS-1 and -4 in a culture medium of HRMECs and Müller cells. In conclusion, ADAMTS proteinases, MMP-15 and versican and biglycan cleavage products were increased in the ocular microenvironment of patients with PDR.

Purpose: To describe the first case of varicella zoster virus (VZV) retinitis following chimeric antigenic response (CAR) T-cell therapy., Methods: Case review., Results: A 53-year-old male was treated with CAR T-cell therapy for refractory diffuse large B-cell lymphoma. Nine months after CAR T-cell therapy, he developed VZV skin infection and retinitis. The retinitis responded to systemic acyclovir therapy and intravitreal ganciclovir., Conclusion: VZV retinitis can occur following CAR T-cell immunotherapy.

Background: Furin converts inactive proproteins into bioactive forms. By activating proinflammatory and proangiogenic factors, furin might play a role in pathophysiology of proliferative diabetic retinopathy (PDR)., Methods: We studied vitreous samples from PDR and nondiabetic patients, epiretinal membranes from PDR patients, retinal microvascular endothelial cells (HRMECs), retinal Müller cells and rat retinas by ELISA, Western blot analysis, immunohistochemistry and immunofluorescence microscopy. We performed in vitro angiogenesis assays and assessed adherence of monocytes to HRMECs., Results: Furin levels were significantly increased in PDR vitreous samples. In epiretinal membranes, immunohistochemistry analysis revealed furin expression in monocytes/macrophages, vascular endothelial cells and myofibroblasts. Furin was significantly upregulated in diabetic rat retinas. Hypoxia and TNF-α induced significant upregulation of furin in Müller cells and HRMECs. Furin induced upregulation of phospho-ERK1/2, p65 subunit of NF-κB, ADAM17 and MCP-1 in cultured Müller cells and phospho-ERK1/2 in cultured HRMECs and induced HRMECs migration. Treatment of monocytes with furin significantly increased their adhesion to HRMECs. Intravitreal administration of furin in normal rats induced significant upregulation of p65 subunit of NF-κB, phospho-ERK1/2 and ICAM-1 in the retina. Inhibition of furin with dec-CMK significantly decreased levels of MCP-1 in culture medium of Müller cells and HRMECs and significantly attenuated TNF-α-induced upregulation of p65 subunit of NF-κB, ICAM-1 and VCAM-1 in HRMECs. Dec-CMK significantly decreased adherence of monocytes to HRMECs and TNF-α-induced upregulation of adherence of monocytes to HRMECs. Treatment of HRMECs with dec-CMK significantly attenuated migration of HRMECs., Conclusions: Furin is a potential driver molecule of PDR-associated inflammation and angiogenesis., (© 2022 Royal Australian and New Zealand College of Ophthalmologists.)

Purpose: To evaluate the efficacy of B cell depletion therapy with the chimeric mouse/human anti-CD20 monoclonal antibody rituximab for refractory chronic recurrent granulomatous uveitis associated with Vogt-Koyanagi-Harada (VKH) disease., Methods: Retrospective study of 9 patients (18 eyes) who failed to respond to conventional combination immunosuppressive therapy., Results: All the patients received 3 rituximab infusions. The follow-up period after initiation of rituximab therapy ranged from 9 to 36 months (mean ±SD, 19.2 ± 10.1). All patients achieved remission and visual acuity significantly improved ( p < .001). Rituximab provided corticosteroid-sparing effect along with control of inflammation. No rituximab-related complications were observed., Conclusions: Rituximab is effective for the treatment of refractory chronic recurrent granulomatous uveitis associated with VKH disease.

Purpose: Endogenous tissue inhibitor of matrix metalloproteinase-3 (TIMP-3) has powerful regulatory effects on inflammation and angiogenesis. In this study, we investigated the role of TIMP-3 in regulating inflammation in the diabetic retina. Methods: Vitreous samples from patients with proliferative diabetic retinopathy (PDR) and non-diabetic patients were subjected to Western blot analysis. Streptozotocin-treated rats were used as a preclinical diabetic retinopathy (DR) model. Blood-retinal barrier (BRB) breakdown was assessed with fluorescein isothiocyanate (FITC)-conjugated dextran. Rat retinas, human retinal microvascular endothelial cells (HRMECs) and human retinal Müller glial cells were studied by Western blot analysis and ELISA. Adherence of human monocytes to HRMECs was assessed and in vitro angiogenesis assays were performed. Results: Tissue inhibitor of matrix metalloproteinase-3 in vitreous samples was largely glycosylated. Intravitreal injection of TIMP-3 attenuated diabetes-induced BRB breakdown. This effect was associated with downregulation of diabetes-induced upregulation of the p65 subunit of NF-κB, intercellular adhesion molecule-1 (ICAM-1), and vascular endothelial growth factor (VEGF), whereas phospho-ERK1/2 levels were not altered. In Müller cell cultures, TIMP-3 significantly attenuated VEGF upregulation induced by high-glucose (HG), the hypoxia mimetic agent cobalt chloride (CoCl 2 ) and TNF-α and attenuated MCP-1 upregulation induced by CoCl 2 and TNF-α, but not by HG. TIMP-3 attenuated HG-induced upregulation of phospho-ERK1/2, caspase-3 and the mature form of ADAM17, but not the levels of the p65 subunit of NF-κB and the proform of ADAM17 in Müller cells. TIMP-3 significantly downregulated TNF-α-induced upregulation of ICAM-1 and VCAM-1 in HRMECs. Accordingly, TIMP-3 significantly decreased spontaneous and TNF-α- and VEGF-induced adherence of monocytes to HRMECs. Finally, TIMP-3 significantly attenuated VEGF-induced migration, chemotaxis and proliferation of HRMECs. Conclusion: In vitro and in vivo data point to anti-inflammatory and anti-angiogenic effects of TIMP-3 and support further studies for its applications in the treatment of DR., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Abu El-Asrar, Ahmad, Nawaz, Siddiquei, De Zutter, Vanbrabant, Gikandi, Opdenakker and Struyf.)

Purpose: To investigate the effect of immunosuppressive therapy on blood flow and waveform parameters in the choroid and optic nerve head (ONH) in patients with initial-onset acute uveitis associated with Vogt-Koyanagi-Harada (VKH) disease., Methods: In this prospective study, 18 patients (36 eyes) were studied. Laser speckle flowgraphy was performed at baseline and at 4 weeks, 8 weeks and 12 weeks after treatment. We analysed longitudinal changes in mean blur rate (MBR), blow-out time, blow-out score (BOS), acceleration time index (ATI), flow acceleration index (FAI), resistivity index (RI) and blood flow fluctuation., Results: After immunosuppressive therapy, MBR, representing blood flow velocity, in the choroid and ONH significantly increased at each post-treatment time point compared to baseline values. Among the analysed pulse waveform parameters, BOS significantly increased, while RI and fluctuation significantly decreased. Increased BOS and decreased RI indicate decreased vascular resistance following treatment. There was a strong negative correlation between BOS and RI. Additionally, FAI increased in the choroid and ATI increased in ONH., Conclusions: Immunosuppressive therapy in the acute uveitic phase of VKH disease improved inflammation-related impairment in choroidal and ONH blood flow., (© 2021 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Purpose: To investigate the frequency of initial-onset acute uveitis associated with Vogt-Koyanagi-Harada (VKH) disease presenting with unilateral exudative retinal detachment., Methods: A retrospective case series., Results: During the period between January 1998 and December 2020, we identified 135 patients with initial-onset acute uveitis associated with VKH disease. Among them, 5 (3.7%) patients were referred to have unilateral uveitis due to the presence of exudative retinal detachment in only one eye. Optical coherence tomography confirmed the presence of unilateral exudative retinal detachment, however, indocyanine green angiography (ICGA) revealed characteristic findings of bilateral granulomatous choroidal inflammation typical for initial-onset acute uveitis associated with VKH disease., Conclusions: Patients with initial-onset acute uveitis associated with VKH disease can present with unilateral exudative retinal detachment. ICGA assessment of the choroid revealed the presence of subclinical involvement of the fellow eyes., (© 2021. The Author(s), under exclusive licence to Springer Nature B.V.)

Uveitis associated with Vogt-Koyanagi-Harada (VKH) disease is a bilateral, chronic, granulomatous autoimmune disease associated with vitiligo, poliosis, alopecia, and meningeal and auditory manifestations. The disease affects pigmented races with a predisposing genetic background. Evidence has been provided that the clinical manifestations are caused by a T-lymphocyte-mediated autoimmune response directed against antigens associated with melanocytes in the target organs. Alongside of T lymphocytes, autoreactive B cells play a central role in the development and propagation of several autoimmune diseases. The potential role of B lymphocytes in the pathogenesis of granulomatous uveitis associated with VKH disease is exemplified within several studies. The early initial-onset acute uveitic phase typically exhibits granulomatous choroiditis with secondary exudative retinal detachment and optic disc hyperemia and swelling, subsequently involving the anterior segment if not adequately treated. The disease eventually progresses to chronic recurrent granulomatous anterior uveitis with progressive posterior segment depigmentation resulting in "sunset glow fundus" appearance and chorioretinal atrophy if not properly controlled. Chronically evolving disease is more refractory to treatment and, consequently, vision-threatening complications have been recognized to occur in the chronic recurrent phase of the disease. Conventional treatment with early high-dose systemic corticosteroids is not sufficient to prevent chronic evolution. Addition of immunomodulatory therapy with mycophenolate mofetil as first-line therapy combined with systemic corticosteroids in patients with acute initial-onset disease prevents progression to chronic evolution, late complications, vitiligo, and poliosis. Furthermore, patients under such combined therapy were able to discontinue treatment without relapse of inflammation. These findings suggest that there is a therapeutic window of opportunity for highly successful treatment during the early initial-onset acute uveitic phases, likely because the underlying disease process is not fully matured. It is hypothesized that early and aggressive immunosuppressive therapy will prevent remnant epitope generation in the initiation of the autoimmune process, the so-called primary response. B cell depleting therapy with the anti-CD20 monoclonal antibody rituximab is effective in patients with refractory chronic recurrent granulomatous uveitis. The good response after rituximab therapy reinforces the idea of an important role of B cells in the pathogenesis or progression of chronic recurrent uveitis associated with VKH disease., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Abu El-Asrar, Van Damme, Struyf and Opdenakker.)

Growth factors such as vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF) and epidermal growth factor (EGF) are important angiogenesis-mediating factors. They exert their effects not only through their respective receptor tyrosine kinases (RTKs), but they also require molecular pairing with heparan sulfate proteoglycans (HSPGs). Angiogenic growth factors and their signaling pathways are commonly targeted in current anti-angiogenic cancer therapies but have unfortunately insufficient impact on patient survival. Considering their obvious role in pathological angiogenesis, HS-targeting drugs have become an appealing new strategy. Therefore, we aimed to reduce angiogenesis through interference with growth factor-HS binding and downstream signaling using a CXCL9-derived peptide with a high affinity for glycosaminoglycans (GAGs), CXCL9(74-103). We showed that CXCL9(74-103) reduced EGF-, VEGF165- and FGF-2-mediated angiogenic processes in vitro, such as endothelial cell proliferation, chemotaxis, adhesion and sprouting, without exerting cell toxicity. CXCL9(74-103) interfered with growth factor signaling in diverse ways, e.g., by diminishing VEGF165 binding to HS and by direct association with FGF-2. The dependency of CXCL9(74-103) on HS for binding to HMVECs and for exerting its anti-angiogenic activity was also demonstrated. In vivo, CXCL9(74-103) attenuated neovascularization in the Matrigel plug assay, the corneal cauterization assay and in MDA-MB-231 breast cancer xenografts. Additionally, CXCL9(74-103) reduced vascular leakage in the retina of diabetic rats. In contrast, CXCL9(86-103), a peptide with low GAG affinity, showed no overall anti-angiogenic activity. Altogether, our results indicate that CXCL9(74-103) reduces angiogenesis by interfering with multiple HS-dependent growth factor signaling pathways.

Purpose: Inflammation, angiogenesis and fibrosis are pathological hallmarks of proliferative diabetic retinopathy (PDR). The CD146/sCD146 pathway displays proinflammatory and proangiogenic properties. We investigated the role of this pathway in the pathophysiology of PDR., Methods: Vitreous samples from 41 PDR and 27 nondiabetic patients, epiretinal fibrovascular membranes from 18 PDR patients, rat retinas, human retinal microvascular endothelial cells (HRMECs) and human retinal Müller glial cells were studied by ELISA, Western blot analysis, immunohistochemistry and immunofluorescence microscopy analysis. Blood-retinal barrier breakdown was assessed with fluorescein isothiocyanate-conjugated dextran., Results: sCD146 and VEGF levels were significantly higher in vitreous samples from PDR patients than in nondiabetic patients. In epiretinal membranes, immunohistochemical analysis revealed CD146 expression in leukocytes, vascular endothelial cells and myofibroblasts. Significant positive correlations were detected between numbers of blood vessels expressing CD31, reflecting angiogenic activity of PDR, and numbers of blood vessels and stromal cells expressing CD146. Western blot analysis showed significant increase of CD146 in diabetic rat retinas. sCD146 induced upregulation of phospho-ERK1/2, NF-κB , VEGF and MMP-9 in Müller cells. The hypoxia mimetic agent cobalt chloride, VEGF and TNF-α induced upregulation of sCD146 in HRMECs. The MMP inhibitor ONO-4817 attenuated TNF-α-induced upregulation of sCD146 in HRMECs. Intravitreal administration of sCD146 in normal rats significantly increased retinal vascular permeability and induced significant upregulation of phospho-ERK1/2, intercellular adhesion molecule-1 and VEGF in the retina. sCD146 induced migration of HRMECs., Conclusions: These results suggest that the CD146/sCD146 pathway is involved in the initiation and progression of PDR.

Purpose: To study features of Indocyanine green angiography (ICGA) in patients with presumed intraocular tuberculosis., Methods: Retrospective study of 48 consecutive patients (77 eyes) who underwent ICGA. The following signs were analysed: choroidal perfusion inhomogeneity, early hyperfluorescent stromal vessels, round or oval hypofluorescent dark dots (HDDs), hypofluorescent geographic lesions (HGLs), fuzzy or lost pattern of large stromal choroidal vessels, disc hyperfluorescence and diffuse late choroidal hyperfluorescence., Results: Among 44 eyes of 29 patients with no clinical evidence of choroidal involvement, only 7 eyes of 6 patients had no ICGA evidence of choroidal involvement. On the other hand, ICGA findings suggesting choroidal involvement were noted in 37 (84.1%) eyes of 23 patients in the form of HDDs in all 37 (100%) eyes, HGLs in 7 (18.9%) eyes, disc hyperfluorescence in 20 (45.5%) eyes, fuzzy stromal vessels in 17 (38.6%) eyes, early hyperfluorescent stromal vessels in 13 (29.5%) eyes, late pinpoint hyperfluorescence in 11 (25%) eyes and late diffuse choroidal hyperfluorescence in 7 (15.9%) eyes. Among 33 eyes of 19 patients with clinically evident choroidal involvement, the following findings were identified; HDDs in 12 (36.4%) eyes, HGLs in 10 (30.3%) eyes, both HDDs and HGLs in 9 (27.3%) eyes, disc hyperfluorescence in 11 (33.3%) eyes, early hyperfluorescent stromal vessels in 7 (21.2%) eyes, fuzzy stromal vessels in 6 (18.2%) eyes and late diffuse choroidal hyperfluorescence was present in 2 (6.1%) eyes., Conclusions: ICGA is necessary in identifying and diagnosing subclinical tuberculous choroidal involvement. The most prevalent ICGA finding was persistent HDDs.

NADPH oxidase (NOX) is a main producers of reactive oxygen species (ROS) that may contribute to the early pathogenesis of diabetic retinopathy (DR). ROS has harmful effects on endogenous neuro-survival factors brain-derived neurotrophic factor (BDNF) and sirtuin 1 (SIRT1) are necessary for the growth and survival of the retina. The role of NOX isoforms NOX4 in triggering ROS in DR is not clear. Here we determine the protective effects of a plant-derived NOX inhibitor apocynin (APO) on NOX4-induced ROS production which may contribute to the depletion of survival factors BDNF/SIRT1 or cell death in the diabetic retinas. Human retinal Müller glial cells (MGCs) were treated with hypoxia mimetic agent cobalt chloride (CoCl 2 ) in the absence or presence of APO. Molecular analysis demonstrates that NOX4 is upregulated in CoCl 2 -treated MGCs and in the diabetic retinas. Increased NOX4 was accompanied by the downregulation of BDNF/SIRT1 expression or in the activation of apoptotic marker caspase-3. Whereas, APO treatment downregulates NOX4 and subsequently upregulates BDNF/SIRT1 or alleviate caspase-3 expression. Accordingly, in the diabetic retina we found a positive correlation in NOX4 vs ROS (p = 0.025; R 2  = 0.488) and caspase-3 vs ROS (p = 0.04; R 2  = 0.428); whereas a negative correlation in BDNF vs ROS (p = 0.009; R 2  = 0.596) and SIRT1 vs ROS (p = 0.0003; R 2  = 0.817) respectively. Taken together, NOX4-derived ROS could be a main contributor in downregulating BDNF/SIRT1 expression or in the activation of caspase-3. Whereas, APO treatment may minimize the deleterious effects occurring due to hyperglycemia and/or diabetic mimic hypoxic condition in early pathogenesis of DR.

Purpose: To describe the clinical findings and outcomes in patients who presented with uveitis associated with multiple sclerosis., Methods: Retrospective review of 20 patients (38 eyes)., Results: The most frequent ocular finding was multifocal elongated retinal perivenous "sheathing" with focal vascular leakage on fundus fluorescein angiography in 29 eyes followed by vitreous snowballs and debris in 26 eyes, anterior chamber inflammation in 15 eyes, mutton-fat keratic precipitates in 14 eyes, posterior synechiae in 13 eyes, cystoid macular edema in 9 eyes, iris nodules in 4 eyes, and optic neuritis in 3 eyes. Patients with cystoid macular edema were treated successfully with systemic corticosteroids combined with mycophenolate mofetil. Ocular complications were cataract in 6 eyes, glaucoma in 2 eyes and vitreous hemorrhage in 1 eye., Conclusions: Multifocal elongated retinal perivenous "sheathing" with focal vascular leakage on fundus fluorescein angiography is the most frequent finding in uveitis associated with multiple sclerosis.

Purpose: To demonstrate changes in oxygen saturation and calibre of retinal vessels in initial-onset acute uveitis associated with Vogt-Koyanagi-Harada (VKH) disease at baseline and during immunosuppressive therapy., Methods: In this prospective study, 22 patients (44 eyes) were studied. Retinal oximetry measurements were performed using the noninvasive spectrophotometric retinal oximeter (Oxymap T1) at baseline and at 1-3 months, 4-6 months, 5-7 months and more than 9 months after treatment., Results: At baseline, mean logarithm of the minimum angle of resolution (logMAR) best-corrected visual acuity (BCVA) was 1.12 ± 0.78 (Snellen equivalent, 20/265). Arteriolar and venular oxygen saturations were 108 ± 7% and 70 ± 9%, respectively and calibres of arterioles and venules were 12.1 ± 1.1 pixels and 16.9 ± 1.4 pixels, respectively. At 4-6 months of follow-up, logMAR BCVA was almost maximum (0.08 ± 0.1, Snellen equivalent 20/24; p < 0.001) and thereafter remained almost unchanged. After immunosuppressive therapy, arteriolar and venular oxygen saturation values continued to decrease up to >9 months of follow-up (92 ± 7% and 56 ± 10%, respectively; p < 0.001 for both arterioles and venules). Similarly, arteriolar and venular calibres continued to decrease up to >9 months of follow-up to 11.4 ± 0.9 pixels (p = 0.006) and 15.6 ± 1.3 pixels (p = 0.001), respectively., Conclusions: Eyes with initial-onset acute uveitis associated with VKH disease have increased oxygen saturation and calibres of retinal vessels at baseline. Immunosuppressive therapy normalizes these changes and in a similar pattern improves BCVA., (© 2020 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

The transmembrane chemokine pathways CXCL16/CXCR6 and CX3CL1/CX3CR1 are strongly implicated in inflammation and angiogenesis. We investigated the involvement of these chemokine pathways and their processing metalloproteinases ADAM10 and ADAM17 in the pathophysiology of proliferative diabetic retinopathy (PDR). Vitreous samples from 32 PDR and 24 non-diabetic patients, epiretinal membranes from 18 patients with PDR, rat retinas, human retinal Müller glial cells and human retinal microvascular endothelial cells (HRMECs) were studied by enzyme-linked immunosorbent assay, immunohistochemistry and Western blot analysis. In vitro angiogenesis assays were performed and the adherence of leukocytes to CXCL16-stimulated HRMECs was assessed. CXCL16, CX3CL1, ADAM10, ADAM17 and vascular endothelial growth factor (VEGF) levels were significantly increased in vitreous samples from PDR patients. The levels of CXCL16 were 417-fold higher than those of CX3CL1 in PDR vitreous samples. Significant positive correlations were found between the levels of VEGF and the levels of CXCL16, CX3CL1, ADAM10 and ADAM17. Significant positive correlations were detected between the numbers of blood vessels expressing CD31, reflecting the angiogenic activity of PDR epiretinal membranes, and the numbers of blood vessels and stromal cells expressing CXCL16, CXCR6, ADAM10 and ADAM17. CXCL16 induced upregulation of phospho-ERK1/2, p65 subunit of NF-κB and VEGF in cultured Müller cells and tumor necrosis factor-α induced upregulation of soluble CXCL16 and ADAM17 in Müller cells. Treatment of HRMECs with CXCL16 resulted in increased expression of intercellular adhesion molecule-1 (ICAM-1) and increased leukocyte adhesion to HRMECs. CXCL16 induced HRMEC proliferation, formation of sprouts from HRMEC spheroids and phosphorylation of ERK1/2. Intravitreal administration of CXCL16 in normal rats induced significant upregulation of the p65 subunit of NF-κB, VEGF and ICAM-1 in the retina. Our findings suggest that the chemokine axis CXCL16/CXCR6 and the processing metalloproteinases ADAM10 and ADAM17 might serve a role in the initiation and progression of PDR., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Abu El-Asrar, Nawaz, Ahmad, De Zutter, Siddiquei, Blanter, Allegaert, Gikandi, De Hertogh, Van Damme, Opdenakker and Struyf.)

Retinal arterial macroaneurysm with supravalvular pulmonic stenosis (RAMSVPS), also known as familial retinal arterial macroaneurysm syndrome, is an autosomal recessive disorder associated with many life-threatening complications. The disease is characterized by progressive multiple retinal arterial macroaneurysms, retinal arterial beading, and recurrent vitreous hemorrhage. Here, we describe the first case of RAMSVPS associated with peripheral ischemia evident on ultra-widefield fluorescein angiography. A 23-year-old otherwise healthy woman presented to our ophthalmology emergency room with a 1-week history of right eye floaters and decreased vision. Dilated fundoscopic examination showed right eye vitreous and preretinal hemorrhage with bilateral active and involuted retinal arterial macroaneurysms, arterial beading, and sclerosed vessels. Ultra-widefield fluorescein angiography demonstrated multiple macroaneurysms on the optic discs and along the major retinal arteries in addition to significant peripheral retinal ischemia in both eyes. Echocardiography showed severe supravalvular pulmonic stenosis that required urgent pulmonary valvuloplasty. Indeed, peripheral retinal ischemia is an additional finding in RAMSVPS., Competing Interests: There are no conflicts of interest., (Copyright: © 2021 Middle East African Journal of Ophthalmology.)

Purpose : To investigate risk factors and surgical outcomes of cataract in Vogt-Koyanagi-Harada (VKH) disease. Methods : Review of 187 patients (374 eyes). Results : At presentation, cataract was diagnosed in 56 (14.9%) eyes all had chronic recurrent VKH. During follow-up, cataract developed in additional 51 (13.6%) eyes. Fifteen (13.6%) of these had initial-onset acute VKH with anterior segment (AS) inflammation and 36 (19.4%) had chronic recurrent VKH. No patient with initial-onset acute VKH without AS inflammation developed cataract. Risk factors for cataract development during follow-up included female gender, keratic precipitates, anterior chamber reaction ≥2+, chronic recurrent VKH, posterior synechiae, iris nodules, glaucoma, glaucoma surgery, choroidal neovascular membrane, "sunset glow fundus" and chorioretinal atrophy. Thirty-two eyes underwent cataract extraction. Fourteen (43.8%) eyes achieved ≥20/40. Posterior segment complications of chronic recurrent VKH accounted for <20/40 outcome. Conclusions : Poor outcome after surgery is secondary to posterior segment complications of chronic recurrent VKH.

Purpose: To describe distinctive stages of Vogt-Koyanagi-Harada (VKH) disease: initial-onset acute versus chronic recurrent disease., Methods: A comprehensive literature review regarding stages and clinical presentations of VKH disease was conducted., Results: Despite a list of signs that has been described as characteristic features of early or late phases of VKH disease, the current classification -developed by an international committee and published in 2001- does not consider a distinction regarding the time from onset of disease symptoms, and specific findings observed at certain time point from the symptoms presentation and outcomes related to the stage of VKH disease. In that sense, chronic recurrent VKH disease is more refractory to treatment and is associated with a higher rate of complications. Accordingly, this subset of VKH patients has poorer functional and anatomical outcomes than patients with an initial-onset acute disease., Conclusions: An early clear distinction of VKH phenotype [Initial-onset acute versus chronic recurrent disease] should be considered in each clinical scenario, evaluating the delay in diagnosis and the clinical presentation, since it may help clinicians to perform a correct disease prognosis categorization and thus to make treatment decisions in terms of potential refractoriness or expected clinical outcomes.

Background/Purpose Vogt-Koyanagi-Harada (VKH) disease is a primary autoimmune stromal choroiditis producing a spill-over panuveitis. For initial-onset VKH disease, it is increasingly thought that corticosteroid therapy is not sufficient and additional non-steroidal immunosuppressive therapy is needed. At the 11th workshop on VKH, the disease was said to be well controlled with corticosteroids alone in Japanese patients. The aim of this study was to review the literature to determine whether different levels of severity exist in different geographical areas., Methods: Literature was reviewed for studies on the evolution of initial-onset VKH disease, looking at treatment modalities and proportion of cases with chronic evolution and/or sunset-glow fundus (SGF)., Results: PubMed search yielded 1249 references containing the term of Vogt-Koyanagi-Harada. Twenty references (15 from outside of Japan and 5 from Japan) contained information on the evolution of treated initial-onset disease. For the "international" group, percentage of chronic evolution after systemic corticosteroid monotherapy was 61%, and after combined steroidal and non-steroidal therapy it fell to 2% (0% in 3/4 studies). In the Japanese studies where all patients received systemic corticosteroids alone, chronic evolution was reported in 25%; however, SGF amounted to 61%., Conclusion: In the world at large, chronic evolution of initial-onset VKH disease treated with corticosteroids alone concerned two-thirds of patients. Japanese studies showed that chronic evolution was substantially less frequent, indicating possibly less severe disease in Japan. This proportion fell to almost zero when dual steroidal and non-steroidal immunosuppression was given at onset.

Purpose: Soluble cytokine receptors are potential biomarkers for immune activation and have a promising potential as immunotherapeutic agents. We investigated the levels of soluble cytokine receptors in aqueous humour (AH) samples from patients with specific autoimmune uveitic entities., Methods: Patients with active uveitis associated with Behçet's disease (BD) (n = 13), sarcoidosis (n = 8), HLA-B27-related inflammation (n = 12), Vogt-Koyanagi-Harada (VKH) disease (n = 12) and control subjects (n = 9) were included. AH samples were analyzed with the use of multiplex assays for the proinflammatory cytokine tumour necrosis factor (TNF)-α and the soluble cytokine receptors sCD30, sCD163, sgp130, sIL-6 receptor-α (sIL-6R), sTNFRI and sTNFRII., Results: TNF-α and soluble cytokine receptor AH levels were significantly higher in uveitis patients (n = 45) compared with controls (n = 9). When nongranulomatous uveitis (BD and HLA-B27-associated uveitis) was compared with granulomatous uveitis (sarcoidosis and VKH disease), the levels of sCD30 and sTNFRI/TNF-α and sTNFRII/TNF-α ratios were significantly enhanced in granulomatous uveitis. Finally, when comparing the profile in the specific uveitis entities, sCD30 levels were highest in patients with VKH disease. sgp130, sCD163, sIL-6R, sTNFRI and sTNFRII did not differ significantly between the four different clinical uveitic subgroups., Conclusions: Soluble cytokine receptors are significantly upregulated in autoimmune uveitis. CD30 + T cells might contribute to the inflammatory process in granulomatous uveitis, particularly in VKH disease. Granulomatous uveitis is also characterized by significantly higher sTNFRs/TNF-α ratios than nongranulomatous uveitis.

Nodular posterior scleritis represents a small percentage of all cases of posterior scleritis. Because of the scarcity of nodular posterior scleritis, it may be confused or even misdiagnosed as an intraocular tumor or posterior uveitis. Here, we are reporting a case of nodular posterior scleritis in a 25-year-old medically free male. Furthermore, we reviewed previously reported cases of nodular posterior scleritis. Our patient presented with a choroidal mass of about one disc diameter in size. In addition, the patient had exudative retinal detachment and chorioretinal folds. B scan ultrasonography showed subretinal fluid, macular nodular thickening and underlying echolucent area along with medium internal reflectivity on A scan. Fluorescein angiography revealed early pinpoint areas of hyperfluorescence and late pooling under the detached retina. Indocyanine green angiography demonstrated early diffuse hypofluorescence corresponding to the area of detachment and late multiple pinpoint spots of hyperfluorescence. After intravenous methylprednisolone 1 g for 3 days followed by a course of oral prednisolone along with mycophenolate mofetil, the patient experienced rapid recovery with improvement in vision and complete resolution of subretinal fluid. On further follow-up, the patient regained 20/20 vision. Nodular posterior scleritis is a rare unilateral disease with strong female predominance. Multimodal imaging should be employed to confirm the diagnosis. The disease must be diagnosed correctly to avoid any unnecessary diagnostic work-up and aggressive management. Most cases carry excellent prognosis with no recurrence., Competing Interests: There are no conflicts of interest., (Copyright: © 2020 Middle East African Journal of Ophthalmology.)

Purpose: To investigate the expression of IL-11 and its receptor IL-11Rα and to quantify density of CD163 + M2 macrophages in proliferative diabetic retinopathy (PDR)., Methods: Vitreous samples from 29 PDR and 19 nondiabetic patients, epiretinal fibrovascular membranes from 15 patients with PDR and Müller cells were studied by enzyme-linked immunosorbent assay, immunohistochemistry and Western blot analysis., Results: We showed a significant increase in expression of IL-11, soluble(s) IL-11Rα, sCD163 and VEGF in vitreous samples from PDR patients compared to nondiabetic controls. Significant positive correlations were found between levels of VEGF and levels of IL-11 and sCD163. Significant positive correlations were found between microvessel density and number of blood vessels and stromal cells expressing IL-11, IL-11Rα and CD163 in PDR epiretinal membranes. The hypoxia mimetic agent cobalt chloride induced upregulation of IL-11 and IL-11Ra in cultured Müller cells., Conclusions: IL-11/IL-11Rα signaling and CD163 + M2 macrophages might be involved in PDR angiogenesis.