Aqueous Humor Levels of Cytokines in Patients with Age-Related Macular Degeneration.

PURPOSE: To compare aqueous humor levels of various cytokines between patients with age-related macular degeneration (AMD) and cataract patients. METHODS: Thirteen eyes with wet-type AMD (AMD group) and 14 eyes with cataract (cataract group) were studied. Aqueous humor levels of 11 factors (vascular endothelial growth factor receptors, growth factors, and inflammatory factors) were measured by the suspension array method. RESULTS: Aqueous humor levels of vascular endothelial growth factor, soluble vascular endothelial growth factor receptor (sVEGFR)-1, sVEGFR-2, and inflammatory factors (monocyte chemotactic protein (MCP)-1, interleukin (IL)-6, and IL-8) were significantly higher in the AMD group than in the cataract group (all p < 0.05). In contrast, aqueous humor levels of placental growth factor (PGF), tumor necrosis factor-α, soluble intercellular adhesion molecule (sICAM)-1, IL-12 (p70), and IL-13 showed no significant difference between the two groups. There were significant correlations between sVEGFR-1 or sVEGFR-2 levels and some of the inflammatory molecules (PGF, sICAM-1, MCP-1, IL-6, and IL-8). CONCLUSIONS: These findings suggest that various cytokines/growth factors involved in inflammation and angiogenesis may be associated with the pathogenesis of AMD.

Glycolysis in patients with age-related macular degeneration.

PURPOSE: Retinal adenosine triphosphate is mainly produced via glycolysis, so inhibition of glycolysis may promote the onset and progression of age-related macular degeneration (AMD). When glycolysis is inhibited, pyruvate is metabolized by lactic acid fermentation instead of entering the mitochondrial tricarboxylic acid (TCA) cycle. We measured urinary pyruvate and lactate levels in patients with AMD. METHODS: Eight patients with typical AMD (tAMD group) and 9 patients with polypoidal choroidal vasculopathy (PCV group) were enrolled. Urinary levels of pyruvate, lactate, α-hydroxybutyrate, and ß-hydroxybutyrate were measured in all patients. RESULTS: The mean urinary levels of pyruvate and lactate were 8.0 ± 2.8 and 7.5 ± 8.3 µg/mg creatinine (reference values: 0.5-6.6 and 0.0-1.6), respectively, with the mean increase over the reference value being 83.6 ± 51.1% and 426.5 ± 527.8%, respectively. In 12 patients (70.6%), the lactate/pyruvate ratio was above the reference range. Urinary levels of α-hydroxybutyrate and ß-hydroxybutyrate were decreased by -31.9 ± 15.2% and -33.1 ± 17.5% compared with the mean reference values. There were no significant differences of any of these glycolysis metabolites between the tAMD and PCV groups. Multivariate analysis revealed that none of the variables tested, including patient background factors (age, hypertension, diabetes, hyperlipidemia, cerebrovascular disease, alcohol, smoking, visual acuity, and AMD phenotype), were significantly associated with the lactate/pyruvate ratio. CONCLUSION: A high lactate/pyruvate ratio is a well-known marker of mitochondrial impairment, and it indicates poor oxidative function in AMD. Our results suggest that increased lactate levels may be implicated in the pathogenesis of AMD.

The role of SIRT1 in ocular aging.

The sirtuins are a highly conserved family of nicotinamide adenine dinucleotide (NAD+)-dependent histone deacetylases that helps regulate the lifespan of diverse organisms. The human genome encodes seven different sirtuins (SIRT1-7), which share a common catalytic core domain but possess distinct N- and C-terminal extensions. Dysfunction of some sirtuins have been associated with age-related diseases, such as cancer, type II diabetes, obesity-associated metabolic diseases, neurodegeneration, and cardiac aging, as well as the response to environmental stress. SIRT1 is one of the targets of resveratrol, a polyphenolic SIRT1 activator that has been shown to increase the lifespan and to protect various organs against aging. A number of animal studies have been conducted to examine the role of sirtuins in ocular aging. Here we review current knowledge about SIRT1 and ocular aging. The available data indicate that SIRT1 is localized in the nucleus and cytoplasm of cells forming all normal ocular structures, including the cornea, lens, iris, ciliary body, and retina. Upregulation of SIRT1 has been shown to have an important protective effect against various ocular diseases, such as cataract, retinal degeneration, optic neuritis, and uveitis, in animal models. These results suggest that SIRT1 may provide protection against diseases related to oxidative stress-induced ocular damage, including cataract, age-related macular degeneration, and optic nerve degeneration in glaucoma patients.

Influence of pars plana vitrectomy on macular sensitivity and morphology in patients with branch retinal vein occlusion and serous retinal detachment.

BACKGROUND AND OBJECTIVE: To evaluate the influence of serous retinal detachment (SRD) on the outcome of pars plana vitrectomy (PPV) for macular edema in patients with branch retinal vein occlusion (BRVO). PATIENTS AND METHODS: In an interventional case series, 20 patients (20 eyes) with BRVO and macular edema underwent PPV, including 12 patients with SRD and eight with cystoid macular edema (CME). Microperimetry of the macular region and optical coherence tomography were performed before and 6 months after PPV. RESULTS: In both the CME and SRD groups, the mean macular thickness and macular volume decreased significantly from baseline to 3 and 6 months after PPV (all P < .01), while visual acuity improved significantly in both groups (both P < .01). However, mean macular sensitivity only increased significantly in the SRD group (P < .05). CONCLUSION: PPV achieves greater improvement of macular sensitivity in BRVO patients with SRD than in those with CME.

Changes of inflammatory factors after intravitreal triamcinolone acetonide for macular edema with central retinal vein occlusion.

PURPOSE: To investigate the effect of intravitreal triamcinolone acetonide (TA) on aqueous humor levels of vascular endothelial growth factor (VEGF), soluble intercellular adhesion molecule 1 (sICAM-1), and pigment epithelium-derived factor (PEDF) in patients with central retinal vein occlusion (CRVO) and macular edema. METHODS: We measured VEGF, sICAM-1, and PEDF levels in aqueous humor samples from 2 eyes of 2 CRVO patients during injection of TA. RESULTS: In both patients, the VEGF and sICAM-1 levels in aqueous humor samples obtained during initial injection of TA were higher than at the time of reinjection. Conversely, the initial PEDF levels were lower than those at reinjection. CONCLUSIONS: Aqueous humor levels of VEGF and sICAM-1 were decreased by TA treatment in 2 CRVO patients, while PEDF was increased. Intravitreal TA could be an option for CRVO patients with a low PEDF level and/or moderate VEGF and sICAM-1 levels.

Association of electroretinographic parameters and inflammatory factors in branch retinal vein occlusion with macular oedema.

BACKGROUND/AIMS: Branch retinal vein occlusion (BRVO) leads to retinal ischaemia, which then induces upregulation of various inflammatory factors, including vascular endothelial growth factor (VEGF). The aim of this study was to determine whether there was a correlation between inflammatory factors and components of the electroretinogram (ERG) in patients with BRVO. METHODS: In 19 BRVO patients with macular oedema, vitreous fluid samples were obtained during vitreoretinal surgery to measure the levels of four inflammatory factors (VEGF, soluble intercellular adhesion molecule-1 (sICAM-1), interleukin (IL)-6 and monocyte chemotactic protein (MCP)-1). The amplitude and implicit time of the a-wave cone, b-wave cone and 30 Hz flicker were calculated automatically from the ERG. Correlations between the different components of the ERG and the four inflammatory factors were investigated. RESULTS: Vitreous fluid levels of two factors (IL-6 and MCP-1) were significantly correlated with the implicit time of the cone b-wave (p=0.035 and p=0.016, respectively). Vitreous fluid levels of all four factors (VEGF, sICAM-1, IL-6, and MCP-1) were significantly correlated with the implicit time of 30 Hz flicker (p=0.047, p=0.031, p=0.002 and p=0.009, respectively). Vitreous fluid levels of VEGF, sICAM-1, IL-6, and MCP-1 were significantly higher in patients with an implicit time ≥36 ms than with an implicit time <36 ms (p=0.042, p=0.048, p=0.003 and p=0.024, respectively). CONCLUSIONS: These findings suggest that the implicit times of the cone b-wave and 30 Hz flicker can be used to detect BRVO patients with macular oedema who have a high risk of ischaemia.

Comparison of the efficacy of intravitreal triamcinolone acetonide for cystoid macular edema with versus without serous retinal detachment in branch retinal vein occlusion: influence on macular sensitivity and morphology.

BACKGROUND: The influence of serous retinal detachment (SRD) on visual acuity, macular sensitivity, and macular thickness is unclear after intravitreal injection of triamcinolone acetonide (IVTA) for macular edema with branch retinal vein occlusion (BRVO). METHODS: Twenty-one eyes of 21 BRVO patients with macular edema received IVTA. Patients were divided into two groups by optical coherence tomography findings: 11 patients who had cystoid macular edema (CME) with SRD (SRD (+) group) and 10 patients who had CME without SRD (SRD (-) group). Microperimetry was performed with a Micro Perimeter 1 before and at 3 and 6 months after IVTA. Macular thickness was measured by optical coherence tomography. We exchanged the superior and inferior regions to separate the regions into those with and without occlusion. As a result, the superior region was always the occluded region and the inferior region was non-occluded. RESULTS: In both the SRD (-) group and the SRD (+) group, the mean macular thickness within the central 4° field and the 10° and 20° fields of the occluded region decreased significantly from baseline to 3 and 6 months after IVTA (all P <0.01). Visual acuity also improved significantly in both groups from baseline to 3 and 6 months after IVTA (both P <0.05). In both groups, the mean macular sensitivity (measured with by microperimetry) within the central 4° field and the 10° and 20° fields of the occluded region showed a significant increase from baseline to 3 and 6 months after IVTA (all P <0.05). The trend profiles of macular thickness within the 10° and 20° fields of the occluded region showed significant differences, but there were no significant differences with respect to the trend profiles of visual acuity and macular sensitivity within the central 4° field and the 10° and 20° fields of the occluded region. CONCLUSIONS: These results suggest that IVTA may achieve more marked improvement of macular morphology in BRVO patients with SRD than in those without SRD, while this therapy may have a similar effect on macular function in BRVO patients with or without SRD.

Macular sensitivity and morphology after intravitreal injection of triamcinolone acetonide for macular edema with branch retinal vein occlusion.

PURPOSE: To evaluate the changes of macular sensitivity, thickness, and total macular volume after intravitreal injection of triamcinolone acetonide to treat macular edema with branch retinal vein occlusion. METHODS: Seventeen eyes of 17 patients with branch retinal vein occlusion with macular edema received intravitreal triamcinolone acetonide. Using capillary nonperfusion on fluorescein angiography, patients were classified into nonischemic or ischemic groups. Microperimetry was used to measure macular sensitivity within the central 4°, 10°, and 20° fields. Macular thickness and macular volume within these fields were measured by optical coherence tomography. RESULTS: The mean macular thickness within the central 4°, 10°, and 20° fields decreased significantly after intravitreal therapy (all Ps < 0.001) as did total macular volume (all Ps < 0.001). Visual acuity was significantly better at 3 and 6 months (P = 0.002) as was the mean macular sensitivity within the three fields (all Ps < 0.05). There were no significant differences in the trend profile of macular thickness and volume within the three fields between the ischemic and nonischemic groups. There were also no significant differences in the trend profile of visual acuity and macular sensitivity. CONCLUSION: Intravitreal triamcinolone acetonide may improve macular sensitivity and morphology in patients with ischemic and nonischemic branch retinal vein occlusion.

Pigment epithelium-derived factor is related to macular microcirculation in patients with macular edema and branch retinal vein occlusion.

To investigate the correlation between the perifoveal capillary blood flow velocity (BFV) and the vitreous level of pigment epithelium-derived factor (PEDF) in patients with branch retinal vein occlusion (BRVO) and macular edema. In a retrospective interventional study of patients with BRVO and macular edema, undiluted vitreous specimens were obtained from 12 eyes of 12 patients. The level of PEDF was then measured in vitreous samples by an enzyme-linked immunosorbent assay. Before vitreous fluid sampling, perifoveal capillary BFV was measured by fluorescein angiography with a scanning laser ophthalmoscope and the tracing method. Subsequently, the relationship between perifoveal capillary BFV and the vitreous level of PEDF was investigated. There was a significant positive correlation between BFV and the vitreous level of PEDF in the 12 patients (ρ = 0.75, p = 0.013). The vitreous level of PEDF may influence macular microcirculation in patients with BRVO and macular edema.

Pinguecula and diabetes mellitus.

PURPOSE: To assess the relationship between age and the incidence and severity of pinguecula in patients with diabetes mellitus, and to compare the grade of pinguecula between control subjects and patients with diabetes. METHODS: A total of 160 patients with type 2 diabetes aged 31 to 70 years (DM group) and 160 control subjects aged 31 to 70 years (control group) were enrolled. The grade of pinguecula at 2 locations (nasal and temporal) was assessed in all subjects by a grading system. RESULTS: There was an age-related increase in the grade of pinguecula in both the DMgroup (r = 0.52; P < 0.0001) and the control group (r = 0.51; P < 0.0001). The grade and prevalence of pinguecula were higher in the DM group than in the control group for pinguecula of the nasal conjunctiva (grade: P < 0.0001; and prevalence: 55.0% vs. 40.0%, P = 0.0072) and the temporal conjunctiva (grade: P < 0.0001; and prevalence: 54.4% vs. 40.0%, P = 0.0100). Multivariate logistic regression analysis revealed that age and diabetes were associated with an increased prevalence of nasal or temporal pinguecula (all P < 0.05). Diabetes mellitus was independently associated with the severity of pinguecula (nasal: odds ratio = 1.19; temporal: odds ratio = 1.22) after adjustment for age. CONCLUSIONS: This is the first assessment of the relationship between pinguecula and diabetes mellitus. Our results suggest that diabetes mellitus may be a factor associated with the development of pinguecula.

Vascular endothelial growth factor receptor-2 in macular oedema with retinal vein occlusion.

BACKGROUND: To evaluate the relationships among vitreous fluid levels of soluble vascular endothelial growth factor receptor-2 (sVEGFR-2), vascular endothelial growth factor (VEGF), and the severity of macular oedema secondary to branch retinal vein occlusion (BRVO). METHODS: Twenty-five BRVO patients with macular oedema were enrolled. Vitreous fluid samples were obtained during vitreoretinal surgery to measure the levels of sVEGFR-2 and VEGF. Macular oedema was examined by optical coherence tomography. RESULTS: The vitreous fluid levels of VEGF and sVEGFR-2 were significantly correlated with the severity of macular oedema (ρ = 0.54, p = 0.008 and ρ = 0.40, p = 0.047, respectively). The sVEGFR-2 × VEGF product was also significantly correlated with the severity of macular oedema (ρ = 0.62, p = 0.003). CONCLUSIONS: The severity of macular oedema was more closely associated with sVEGFR-2 × VEGF than sVEGFR-2 or VEGF alone, suggesting that macular oedema in BRVO patients may be influenced by both VEGF and sVEGFR-2.

Functional-morphological changes after intravitreal injection of triamcinolone acetonide for macular edema with branch retinal vein occlusion.

PURPOSE: To evaluate functional and morphological changes of the macula after intravitreal injection of triamcinolone acetonide (IVTA) for macular edema with branch retinal vein occlusion (BRVO). METHODS: Twenty patients with BRVO (mean age: 69.7 ± 9.8 years; 14 women and 6 men) received IVTA. Macular function was documented by microperimetry and best-corrected visual acuity (BCVA) was determined. Retinal thickness and retinal volume were measured by optical coherence tomography, and mean retinal sensitivity was calculated for each of 9 macular subfields. RESULTS: Mean BCVA significantly improved 6 months after IVTA. Mean retinal sensitivity, retinal thickness, and retinal volume significantly improved after 6 months in 4, 8, and 8 subfields, respectively. On multivariate analysis, improvement of retinal sensitivity was significantly correlated with the percent changes of both retinal thickness and retinal volume in 2 subfields [superior inner (the occlusion site) and temporal outer], although improvement of visual acuity was not significantly correlated with the percent change of macular edema in any of the 9 subfields. CONCLUSIONS: These findings suggest that IVTA can improve both functional and morphological changes due to macular edema in BRVO patients, and that morphological improvement after IVTA might be useful for assessing the functional prognosis of BRVO with macular edema.

Inflammatory factors in major and macular branch retinal vein occlusion.

Concentrations of inflammatory factors were measured in 40 patients with macular edema due to major branch retinal vein occlusion (BRVO) or macular BRVO who were treated by pars plana vitrectomy. Vitreous fluid levels of vascular endothelial growth factor (VEGF), soluble intercellular adhesion molecule-1 (sICAM-1), and pigment epithelium-derived factor (PEDF) were determined. Visual acuity and central macular thickness were significantly improved at 6 months in both groups. Vitreous fluid levels of VEGF and sICAM-1 were higher in the major BRVO group than the macular BRVO group, while the PEDF level was lower in the major group than the macular group. The mean visual acuity and central macular thickness at 6 months were not significantly different between the macular and major groups. In conclusion, patients with major BRVO had higher vitreous levels of inflammatory factors and lower vitreous levels of anti-inflammatory PEDF. Accordingly, regulating inflammatory factors might be more important in major BRVO than macular BRVO.

Conjunctivochalasis: associations with pinguecula in a hospital-based study.

PURPOSE: To assess the relationship between the prevalence and severity of conjunctivochalasis and pinguecula. METHODS: Cross-sectional, consecutive case study conducted at the university hospital of University of Tokyo Graduate School of Medicine. A total of 1061 patients aged from 1 to 94 years were enrolled. The grade and other parameters of conjunctivochalasis (classified into three locations: nasal, middle and temporal) and the grade of pinguecula located on the nasal or temporal conjunctiva were determined in all subjects. Patients were also divided into 5 or 10 age groups. RESULTS: The severity of conjunctivochalasis affecting the nasal and temporal bulbar conjunctiva was significantly correlated with the grade of pinguecula located on the nasal and temporal conjunctiva in each age group (p < 0.05). Pinguecula was independently associated with conjunctivochalasis (nasal: odds ratio [OR] = 1.44; temporal: OR = 1.43) after adjustment for age. CONCLUSION: This was the first assessment of the relation between the grade of conjunctivochalasis and pinguecula in a large consecutive series of patients. Our results suggest that the prevalence and severity of conjunctivochalasis are related to the presence of pinguecula.

Vitreous inflammatory factors and serous macular detachment in branch retinal vein occlusion.

PURPOSE: To investigate whether vascular endothelial growth factor, soluble intercellular adhesion molecule-1 (sICAM-1), and pigment epithelium-derived factor are associated with serous retinal detachment (SRD) secondary to branch retinal vein occlusion. METHODS: The subjects were 44 branch retinal vein occlusion patients with macular edema and 16 controls. Patients were divided into 2 groups by optical coherence tomography findings, that is, 18 patients with SRD and 26 with cystoid macular edema. The area of capillary nonperfusion was measured with fluorescein angiography and Scion Image software. Vitreous fluid samples obtained during pars plana vitrectomy were examined by enzyme-linked immunosorbent assay. RESULTS: The incidence of major branch retinal vein occlusion was significantly higher in SRD patients (17/18, 94%) than in cystoid macular edema patients (15/26, 58%, P = 0.007), while the nonperfused retinal area was significantly larger in SRD patients (P = 0.006). Vitreous fluid levels of vascular endothelial growth factor and soluble intercellular adhesion molecule-1 (sICAM-1) showed a significant increase across the 3 groups (control group, cystoid macular edema group, and SRD group) (P trend < 0.001 and P trend < 0.001, respectively), while the pigment epithelium-derived factor level showed a significant decrease across the 3 groups (P trend < 0.001). CONCLUSION: An excessive increase of vascular permeability secondary to upregulation of vascular endothelial growth factor and soluble intercellular adhesion molecule-1 (sICAM-1) along with downregulation of pigment epithelium-derived factor may contribute to the development of SRD in BRVO patients.

Vascular endothelial growth factor and interleukin-6 are correlated with serous retinal detachment in central retinal vein occlusion.

PURPOSE/AIM: To investigate aqueous humour and vitreous fluid levels of vascular endothelial growth factor (VEGF) and interleukin-6 (IL-6) in patients with central retinal vein occlusion (CRVO) and serous retinal detachment. MATERIALS AND METHODS: In twenty patients (20 eyes) with CRVO and 8 patients (8 eyes) with non-ischaemic ocular disease as controls, optical coherence tomography showed that 10 CRVO patients had serous retinal detachment (subretinal fluid with low reflectivity) and 10 patients had cystoid macular oedema (hyporeflective intraretinal cavities). Retinal ischaemia was evaluated from the area of capillary nonperfusion on fluorescein angiograms. To measure VEGF and IL-6 levels, aqueous humour and vitreous fluid samples were obtained during combined pars plana vitrectomy and cataract surgery. RESULTS: Ischaemia was significantly more frequent among the CRVO patients with serous retinal detachment than those with cystoid macular oedema (10/10 vs. 3/10, P = 0.001). Aqueous humour levels of VEGF and IL-6 were significantly higher in the serous patients than the cystoid patients (P = 0.004 and P < 0.001, respectively). Vitreous fluid levels of VEGF and IL-6 were also significantly higher in the serous patients than the cystoid patients (P = 0.007 and P < 0.001, respectively). CONCLUSIONS: These results suggest that a marked increase of vascular permeability due to upregulation of VEGF and IL-6 may contribute to serous retinal detachment in patients with CRVO.

Macular microcirculation in patients with epiretinal membrane before and after surgery.

BACKGROUND: To investigate blood flow velocity (BFV) in the perifoveal capillaries before and after vitreous surgery for patients with epiretinal membrane (ERM). METHODS: Twenty-one eyes in patients with ERM and 16 eyes in healthy subjects were involved in this study. Fluorescein angiography was performed using a scanning laser ophthalmoscope and BFV was analyzed by the tracing method. Foveal thickness (FT) was measured by optical coherence tomography. RESULTS: BFV was significantly slower in the ERM patients (1.04 ± 0.10 mm/s) than in the healthy subjects (1.49 ± 0.11 mm/s ) (p = 0.0010). BFV in the ERM patients 6 months after vitreous surgery (6 M) (1.21 ± 0.02 mm/s) significantly increased compared with BFV before surgery (0 M) (1.04 ± 0.10 mm/s) (p = 0.0061). BFV 1 year after vitreous surgery (1 Y) significantly increased (1.38 ± 0.02 mm/s) compared with BFV(6 M) (1.21 ± 0.02 mm/s) (p = 0.0235). FT was significantly greater in the ERM patients (351.7 ± 87.1 µm) than in the healthy subjects (158.9 ± 16.9 µm) (p = 0.0011). FT (6 M) significantly decreased (285.3 ± 36.9 µm) compared with FT before surgery (0 M) (351.7 ± 87.1 µm) (p = 0.0212). FT did not show significant differences between (6 M) and (1 Y). No significant correlation was found between BFV and FT before surgery. CONCLUSIONS: Perifoveal capillary BFV in patients with ERM was slower than that in the healthy subjects, and significantly improved after vitreous surgery as time progressed. It can be said that perifoveal capillary BFV is related to the development and improvement of ERM in the long term.