Risk factors for progression of normal‐tension glaucoma under β‐blocker monotherapy

Purpose: To prospectively study prognostic factors for normal‐tension glaucoma (NTG) under treatment with topical β‐blocker. Methods: One hundred and forty‐six eyes of 146 patients with NTG with a mean untreated intraocular pressure (IOP) of 14 mmHg, mild to moderate visual field damage and mean spherical equivalent refraction of ?3.5 (?8.0 to +2.0) dioptre were randomized to topical nipradilol or timolol and followed for 3 years. The Humphrey full threshold 30‐2 visual field test was performed every 6 months, and optic disc photographs were obtained every 12 months. Progression was defined as visual field progression, optic disc and/or peripapillary nerve fibre layer change, and factors relating to progression were evaluated using Cox proportional hazards models. Results: IOP decreased by 1.0 mmHg over the 3‐year period, during which 35% showed progression according to the aforementioned criteria. Optic disc haemorrhage (hazard ratio [HR] 4.00, p < 0.001) and less extent of myopia (per dioptre, HR 1.15, p = 0.013) were significant risk factors. When progression was defined by visual field progression only, less extent of myopia was again a significant risk factor (HR 1.17, p = 0.038). Conclusion: Beside optic disc haemorrhage, less extent of myopia was a risk factor for progression in the current NTG population where most patients were mildly myopic and IOP during follow‐up averaged 13.2 mmHg under topical β‐blocker.     

Risk factors for incident open‐angle glaucoma: a population‐based 20‐year follow‐up study

Purpose:  To study the effect of potential risk factors on the development of open‐angle glaucoma (OAG) in a population in which pseudoexfoliation (PEX) is a common finding. Methods: In 1984–1986, a population‐based survey of 760 people aged 65–74 years was conducted in the municipality of Tierp, Sweden. From 1988 to 2006, a follow‐up study of the 530 people with normal visual fields has been in progress. To increase the cohort, 273 ophthalmic outpatients were enroled. Reliable visual fields were available for 679 people, representing 6 126 person‐years at risk. A time‐weighted mean intraocular pressure (IOP) for all visits was calculated. Results: Sixty‐four subjects developed definite OAG, 29 of whom were exposed to PEX. Risk factors associated with OAG were higher age, a positive family history, increased IOP and PEX. The age‐standardized rate ratio (SRR) was 14.8 times (95% confidence interval [CI] 7.92–27.8) greater in subjects with mean IOP ≥20 mmHg than in those with mean IOP <20 mmHg. When subjects with IOP <20 mmHg at baseline were affected by PEX, the SRR increased 5.01‐fold (95% CI 1.97–12.8), compared with the unaffected group. However, when mean IOP at follow‐up was taken into account, there was no relationship between OAG and PEX as a distinct risk factor. Among participants in the population survey, 69% of all cases were attributable to a mean IOP ≥20 mmHg. Conclusion: Increased IOP and PEX were serious risk factors for incident OAG. The effect of PEX was mediated by increased IOP.     

Pseudoexfoliation and Alzheimer’s disease: a population‐based 30‐year follow‐up study

Purpose: To determine the effect of pseudoexfoliation (PEX) on the development of Alzheimer’s disease (AD) in a population in which PEX is a common finding. The relationship between open‐angle glaucoma (OAG) and AD was also studied. Methods: Predictors of incident AD, including mixed and unspecified dementia, were analysed in a cohort of 679 residents 65–74 years of age, examined in a population survey in the municipality of Tierp, Sweden, 1984–1986. To expand the cohort, participants in other studies in Tierp were enrolled. In this way, the cohort embraced 1123 people, representing more than 15 700 person‐years at risk. Medical records were reviewed to identify subjects diagnosed with dementia. Those with a follow‐up time shorter than 2 years were excluded from the study. Results: By the conclusion of the study, in December 2011, 174 new cases of AD, including mixed and unspecified dementia, had been detected, 41 of whom were affected by PEX at baseline. Higher age and female gender were the only predictors identified. No association between PEX and AD was found (hazard ratio 0.98; 95% confidence interval 0.69–1.40). Newly diagnosed OAG at baseline did not increase the risk (hazard ratio 1.09; 95% confidence interval 0.69–1.74). Conclusion: Pseudoexfoliation is not a predictor of AD. No association was found between OAG and AD.     

Bevacizumab modulates epithelial‐to‐mesenchymal transition in the retinal pigment epithelial cells via connective tissue growth factor up‐regulation

Purpose: To investigate the effect of bevacizumab treatment on connective tissue growth factor (CTGF) expression and the induction of epithelial‐to‐mesenchymal transition in ARPE‐19 cells and human donor retinal pigment epithelium (HRPE) cells in vitro. Methods: We quantitated the protein and gene expression level of CTGF by ELISA. The effect of Fc–Fc receptor (Fc–FcR) interaction on CTGF expression was evaluated by CD64 siRNA silencing. Expression of epithelial‐to‐mesenchymal transition markers, alpha‐smooth muscle actin (α‐SMA) and zona occludens protein (ZO‐1) was evaluated by Western blot. Cell migration and collagen gel contraction assay were examined by light microscopy, and collagen production was measured by ELISA. Results: Bevacizumab stimulation increased CTGF expression in ARPE‐19 and HRPE cells in a dose‐dependent manner. CD64 gene silencing inhibited the effect of bevacizumab‐induced CTGF up‐regulation. Bevacizumab increased the expression of α‐SMA and decreased the expression of ZO‐1 in ARPE‐19 cells. Bevacizumab also caused the release of type‐1 collagen and increased cell migration and contraction of collagen. Conclusions: Bevacizumab exerts pro‐fibrotic effects on human RPE cells at clinical doses by up‐regulation of CTGF expression via an Fc–FcR interaction. This effect of bevacizumab may be one of the underlying mechanisms involved in age‐related macular degeneration therapy or intravitreal bevacizumab‐associated complications.     

Differential effects of TGF‐β and FGF‐2 on in vitro proliferation and migration of primate retinal endothelial and Müller cells

Purpose: During retinal development, the pattern of blood vessel formation depends upon the combined effects of proliferation and migration of endothelial cells, astrocytes and Müller cells. In this study, we investigated the potential for transforming growth factor‐β (TGF‐β) and fibroblast growth factor (FGF‐2) to influence this process by regulating proliferation and migration of retinal endothelial and macroglial cells. Methods: We assessed the effects of exogenous TGF‐β and FGF‐2 on the proliferation and migration of cultured endothelial (RF/6A) and Müller cell (MIO‐M1) lines. Cell proliferation was measured using a MTT [3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide) colorimetric assay over 72 hr. Cell migration was measured using a scratch‐wound assay over 72 hr. Results: Transforming growth factor‐β inhibited the proliferation of endothelial and Müller cells and inhibited the migration of Müller cells, but not endothelial cells, compared to untreated controls. Conversely, FGF‐2 increased endothelial cell proliferation but inhibited endothelial cell migration. Fibroblast growth factor‐2 increased migration of Müller cells but had little effect on proliferation except at higher concentrations (20 ng/ml). Conclusion: Taken together, these observations indicate that TGF‐β and FGF could work in concert to inhibit endothelial cell proliferation and migration, respectively; this may have implications for establishing and maintaining the avascular zone of primate fovea.     

Ophthalmic manifestations and risk factors for mortality of HIV patients in the post‐highly active anti‐retroviral therapy era

Background: To evaluate the ophthalmic manifestations and risk factors for mortality in HIV patients in the post‐highly active anti‐retrovirus therapy (HAART) era. Design: Retrospective study. Samples: 151 patients with HIV infection. Methods: Review of all HIV patients who have attended the Hong Kong Eye Hospital between 2000 and 2007. Main Outcome Measures: Ocular findings especially opportunistic infections and medical information including mortality during follow up. Results: At presentation, 139 (92.1%) patients were already diagnosed with HIV and 58 (41.7%) had an AIDS indicator condition. Fifty‐one (33.8%) patients had HIV‐related eye disease on presentation and the leading manifestations were cytomegalovirus (CMV) retinitis and HIV microangiopathy. Low baseline CD4 cell count <100 cells/L was significantly related with HIV‐related ophthalmic manifestations and CMV retinitis at presentation (P < 0.013). 105 patients were followed for 6 months or more and the mean follow‐up was 4.8 years. There was no significant change in visual acuity compared with baseline (P = 0.13). 20 (19.0%) patients had one eye with final visual acuity of 20/200 or worse and the leading cause for poor vision was CMV retinitis. 11 (10.5%) patients died during the follow‐up due to complications of HIV/AIDS. The presence of HIV retinal microangiopathy was significantly associated with mortality (P = 0.005). Conclusions: CMV retinitis remains the main HIV‐related ocular disease in the post‐HAART era. HIV retinal microangiopathy might be an important prognostic factor for mortality. Appropriate ophthalmic monitoring is justified to detect for ophthalmic complications in HIV patients regardless of HAART use in order for prompt initiation of treatment.     

Circulating bone‐marrow‐derived endothelial precursor cells contribute to neovascularization in diabetic epiretinal membranes

Purpose: The role of vasculogenesis, recruitment and differentiation of circulating bone‐marrow‐derived endothelial precursor cells into mature endothelium in proliferative diabetic retinopathy (PDR) remains undefined. We investigated the presence of bone‐marrow‐derived endothelial precursor cells and the expression of the chemotactic pathway SDF‐1/CXCL12?CXCR4 in PDR epiretinal membranes. Methods: Membranes from eight patients with active PDR and nine patients with inactive PDR were studied by immunohistochemistry using antibodies against CD133, vascular endothelial growth factor receptor‐2 (VEGFR‐2), CD14, SDF‐1 and CXCR4. Results: Blood vessels expressed CD133, VEGFR‐2, CD14, SDF‐1 and CXCR4 in 10, 10, 10, seven and seven out of 17 membranes, respectively. There were significant correlations between number of blood vessels expressing CD34 and number of blood vessels expressing CD133 (r_s = 0.646; p = 0.005), VEGFR‐2 (r_s = 0.704; p = 0.002), CD14 (r_s = 0.564; p = 0.018) and SDF‐1 (r_s = 0.577; p = 0.015). Stromal cells in close association with blood vessels expressed CD133, VEGFR‐2, CD14 and CXCR4 in 10, 12, 13 and 14 membranes, respectively. The number of blood vessels expressing CD133 (p = 0.013), VEGFR‐2 (p = 0.005), CD14 (p = 0.008) and SDF‐1 (p = 0.005), and stromal cells expressing CD133 (p = 0.003), VEGFR‐2 (p = 0.013) and CD14 (p = 0.002) was significantly higher in active membranes than in inactive membranes. Conclusion: Bone‐marrow‐derived CD133⁺ endothelial progenitor cells and CD14⁺ monocytes may contribute to vasculogenesis in PDR.     

Circulating antiretinal antibodies predict the outcome of anti‐VEGF therapy in patients with exudative age‐related macular degeneration

Purpose: To determine serum antiretinal antibody (ARA) levels in response to treatment with intravitreal bevacizumab of exudative age‐related macular degeneration (AMD). Methods: The study comprised 22 patients treated with intravitreal bevacizumab (Avastin) 1.25 mg. In all patients, serum ARA levels were assessed by indirect immunofluorescence on normal monkey retina substrate. The ophthalmic examination including best corrected visual acuity (BCVA), fundoscopy, fluorescein angiography, optical coherence tomography (OCT) and immunohistochemical investigations. These were repeated at 4‐week intervals during a loading phase of antiangiogenic therapy. Sera of 22 sex‐ and age‐matched healthy subjects were used as controls for immunohistochemical studies. Results: Before bevacizumab therapy, ARAs were detected in the sera of all patients at titres ranging from 1:40 to 1:1280. The titres were significantly higher (p < 0.01) than in controls (1:10–1:40). There was no significant correlation between serum ARA titres and neither the type nor the dimensions of choroidal neovascularization, as well as central retinal thickness. Following treatment, all patients demonstrated significant decrease in ARA levels. This correlated with improvement of BCVA, decreased leakage of fluorescein and reduction of subretinal fluid on OCT. Conclusion: Serum ARA levels demonstrate a dynamic change which occurs in parallel with clinical outcomes of antiangiogenic therapy. They also may act as markers of the therapeutic benefits of vascular endothelial growth factor inhibition.     

Three‐year results of visual outcome with disease activity–guided ranibizumab algorithm for the treatment of exudative age‐related macular degeneration

Purpose: To evaluate 3‐year follow‐up treatment outcomes with ranibizumab (Lucentis^®) 0.5 mg administered either monthly or quarterly on a pro re nata (PRN) basis according to a disease activity–guided monitoring and treatment algorithm. Methods: A total of 316 treatment‐naive eyes of 316 patients with exudative age‐related macular degeneration met the criteria for inclusion in this retrospective, interventional case series. Patients were treated with ranibizumab 0.5 mg according to a disease activity–guided algorithm with monthly monitoring. Optical coherence tomography and fluorescein angiography were routinely used to assess disease activity: active lesions were treated with a series of three monthly injections, whereas inactive lesions were treated with quarterly injections. Results: Mean Early Treatment Diabetic Retinopathy Study best‐corrected visual acuity improved from 52 letters at baseline to 59 letters at 12 months, achieved with a mean of 7.1 injections, 61 letters at 24 months with a mean of 5.0 injections administered in the second year and 60 letters at 36 months with a mean number of 5.2 injections. Conclusions: Monthly visits and a morphology‐driven PRN regimen with 3 injections in case of recurrence plus quarterly injections in case of inactive CNV resulted in an average VA gain of 7–9 letters that could be maintained over 3 years.