Pretreatment ocular blood flow and retinal oxygen metabolism in the acute uveitic phase is associated with final outcome in Vogt-Koyanagi-Harada disease.

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.

Comparisons of choroidal blood flow velocity between initial-onset acute uveitis associated with Vogt-Koyanagi-Harada disease and acute central serous chorioretinopathy.

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.

CD40 Ligand-CD40 Interaction Is an Intermediary between Inflammation and Angiogenesis in Proliferative Diabetic Retinopathy.

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.

Macrophage-Myofibroblast Transition Contributes to Myofibroblast Formation in Proliferative Vitreoretinal Disorders.

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-Ä¸ß 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.

Occlusive Retinal Vasculitis in Patients with Multiple Sclerosis.

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.

Acute uveitic phase of Vogt-Koyanagi-Harada disease: optic nerve head swelling, ocular blood flow and retinal oxygen metabolism.

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.

Outcomes of initial-onset acute uveitis associated with Vogt-Koyanagi-Harada disease occurred during pregnancy.

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.

Therapeutic window of opportunity in the acute uveitic phase of Vogt-Koyanagi-Harada disease: Prevention of late autoimmune complications by early intervention.

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.

Optic Nerve Head Infiltration in Presumed Tuberculous Uveitis.

To report the clinical and multimodal imaging findings of presumed tuberculous optic nerve head (ONH) infiltration in 3 patients at a tertiary eye care center. In addition to unilateral presumed tuberculous ONH infiltration, all patients had clinical findings suggestive of tuberculous choroidal involvement which was confirmed by Indocyanine green angiography (ICGA). All patients were treated successfully with a combination of antituberculous regimen and systemic corticosteroids.

Clinical Findings Predicting Posttraumatic Endophthalmitis after Repair of Open Globe Injuries.

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.

Differential Expression and Localization of ADAMTS Proteinases in Proliferative Diabetic Retinopathy.

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.

Proprotein convertase furin is a driver and potential therapeutic target in proliferative diabetic retinopathy.

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.

A novel mechanism of macular holes in patients with Behçet's uveitis.

To describe two cases of Behçet's retinitis lesions in the macula causing sloughing of retinal tissue forming a full-thickness macular hole. This was a case series study. Case 1 was a 26-year-old presented, known case of Behçet's disease, presented with a large area of retinitis involving the center of the macula with overlying vitritis. One day after the initiation of treatment, vitritis improved, but the retinitis patch sloughed and created a full-thickness macular hole. Case 2 was a 31-year-old male, known case of Behçet's uveitis, who presented vitritis and multiple retinitis patches involving the macula of the left eye. Two weeks after infliximab infusion, the inflammation resolved with medical management, however, the retinitis patch was complicated by a full-thickness macular hole with an inferior rhegmatogenous retinal detachment. Retinitis at the macula can be complicated by a full-thickness macular hole.

Branch Retinal Artery Occlusion Following Cocaine Inhalation: Case Report and Review of the Literature.

Cocaine abuse has been reported to cause devastating systemic and ocular side effects. Retinal vascular occlusion following cocaine abuse has been scarcely reported in the literature. Herein, we are describing a rare case of branch retinal artery occlusion (BRAO) following intranasal cocaine use in a young female. She presented to the emergency department 1 month after having blurred vision in the left eye, which started 1 day after cocaine nasal inhalation. Fundus examination of the left eye showed an inferotemporal BRAO. In conclusion, cocaine should be considered in the differential diagnosis of retinal arterial occlusion in young healthy patients.

Implications of COVID-19 infection on patients with uveitis under biologic treatment.

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.

Efficacy of B Cell Depletion Therapy with Rituximab in Refractory Chronic Recurrent Uveitis Associated with Vogt-Koyanagi-Harada Disease.

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.

Varicella Zoster Viral Retinitis following Chimeric Antigenic Response T-cell Therapy for B-cell Lymphoma.

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.

Long-term Outcomes of Uveitis Associated with Vogt-Koyanagi-Harada Disease in the Pediatric Age Group.

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.