Foveal relocation by redistribution of the neurosensory retina

Aim - To describe a new surgical technique for foveal relocation, and to report the outcome in nine patients treated with this procedure. Methods - Nine consecutive patients with subfoveal choroidal neovascular membranes (CNVMs) secondary to age related macular degeneration underwent foveal relocation surgery by redistribution of the neurosensory retina (RNR). The technique involved induction of a retinal detachment via a single retinotomy, relocation of the fovea by 'sweeping' the retinal tissue with a retinal brush, and stabilisation of the retina in its new location using perfluorocarbon liquid peroperatively and silicone oil postoperatively. Results - In eight of nine eyes successful relocation of the fovea was achieved; in one eye the CNVM remained in a subfoveal location postoperatively. Visual acuity improved in two eyes, remained unchanged in three, and decreased in four eyes after a median follow up of 4 months (range 2.5-6 months). Complications included rupture of a foveal cyst with the development of a macular hole in one eye and epimacular membrane formation in another eye. In two eyes, macular retinal vessel closure occurred at the time of laser photocoagulation; one of these eyes later developed cystoid macular oedema and the other an epiretinal membrane. Recurrence of the CNVM was observed in one eye, but was controlled with further laser treatment. Conclusions - Foveal relocation by RNR appears to be feasible, obviating the need for extensive retinotomies or scleral shortening.

Quantitative evaluation of fundus autofluorescence imaged 'in vivo' in eyes with retinal disease

Aim - To describe a new method of evaluating the topographic distribution of fundus autofluorescence in eyes with retinal disease. Methods - Images of fundus autofluorescence were obtained in five patients and 34 normal volunteers using a confocal scanning laser ophthalmoscope (cSLO). To evaluate the topographic distribution of fundus autofluorescence throughout the posterior pole a rectangular box, 10 x 750 pixels, was used as the area of analysis. The box was placed, horizontally, across the macular region. The intensity of fundus autofluorescence of each pixel within the rectangular box was plotted against its degree of eccentricity. Profiles of fundus autofluorescence from patients were compared with those obtained from the age matched control group and with cSLO images. Results - Profiles of fundus autofluorescence appeared to represent the topographic distribution of fundus autofluorescence throughout the posterior pole appreciated in the cSLO images, and allowed rapid identification and quantification of areas of increased or decreased fundus autofluorescence. Conclusions - Fundus autofluorescence profiles appear to be useful to study the spatial distribution of fundus autofluorescence in eyes with retinal disease.

Interventions for prevention of giant retinal tear in the fellow eye.

BACKGROUND: A giant retinal tear is a full-thickness retinal break that extends circumferentially around the retina for 90 degrees or more in the presence of a posteriorly detached vitreous. It causes significant visual morbidity from retinal detachment and proliferative vitreoretinopathy. The fellow eye of patients who have had a spontaneous giant retinal tear has an increased risk of developing a giant retinal tear, a retinal detachment or both. Interventions such as 360-degree encircling scleral buckling, 360-degree cryotherapy and 360-degree laser photocoagulation have been advocated by some ophthalmologists as prophylaxis for the fellow eye against the development of a giant retinal tear and/or a retinal detachment, or to prevent its extension. OBJECTIVES: To evaluate the effectiveness of prophylactic 360-degree interventions in the fellow eye of patients with unilateral giant retinal tear to prevent the occurrence of a giant retinal tear and/or a retinal detachment. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library 2008, Issue 4), MEDLINE (January 1950 to December 2008), EMBASE (January 1980 to December 2008) and Latin American and Caribbean Literature on Health Sciences (LILACS) (January 1982 to December 2008). In addition, we searched the proceedings of the Annual Meeting of the Association for Research in Vision and Ophthalmology (ARVO) up to 2008 for information about other relevant studies. There were no language or date restrictions in the search for trials. The electronic databases were last searched on 15 December 2008. SELECTION CRITERIA: Prospective randomised controlled trials (RCTs) comparing one prophylactic treatment for fellow eyes of patients with giant retinal tear against observation (no treatment) or another form of prophylactic treatment. In the absence of RCTs, we planned to discuss case-control studies that met the inclusion criteria but we would not conduct a meta-analysis using these studies. DATA COLLECTION AND ANALYSIS: We did not find any studies that met the inclusion criteria for the review and therefore no assessment of methodological quality or meta-analysis could be performed. MAIN RESULTS: No studies met the inclusion criteria for this review. AUTHORS' CONCLUSIONS: No strong evidence in the literature was found to support or refute prophylactic 360-degree treatments to prevent a giant retinal tear or a retinal detachment in the fellow eye of patients with unilateral giant retinal tears.

Interventions for prevention of giant retinal tear in the fellow eye.

A giant retinal tear is a full-thickness retinal break that extends circumferentially around the retina for 90 degrees or more in the presence of a posteriorly detached vitreous. It causes significant visual morbidity from retinal detachment and proliferative vitreoretinopathy. The fellow eye of patients who have had a spontaneous giant retinal tear has an increased risk of developing a giant retinal tear, a retinal detachment or both. Interventions such as 360-degree encircling scleral buckling, 360-degree cryotherapy and 360-degree laser photocoagulation have been advocated by some ophthalmologists as prophylaxis for the fellow eye against the development of a giant retinal tear and/or a retinal detachment, or to prevent its extension. To evaluate the effectiveness of prophylactic 360-degree interventions in the fellow eye of patients with unilateral giant retinal tear to prevent the occurrence of a giant retinal tear, a retinal detachment or both. We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library 2011, Issue 11), MEDLINE (January 1950 to December 2011), EMBASE (January 1980 to December 2011), Latin American and Caribbean Literature on Health Sciences (LILACS) (January 1982 to December 2011), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov) and the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). There were no date or language restrictions in the electronic searches for trials. The electronic databases were last searched on 6 December 2011. In addition, we searched the proceedings of the Annual Meeting of the Association for Research in Vision and Ophthalmology (ARVO) up to 2008 for information about other relevant studies. Prospective randomised controlled trials (RCTs) comparing one prophylactic treatment for fellow eyes of patients with giant retinal tear against observation (no treatment) or another form of prophylactic treatment. In the absence of RCTs, we planned to discuss case-control studies that met the inclusion criteria but we would not conduct a meta-analysis using these studies. We did not find any studies that met the inclusion criteria for the review and therefore no assessment of methodological quality or meta-analysis could be performed. No studies met the inclusion criteria for this review. No strong evidence in the literature was found to support or refute prophylactic 360-degree treatments to prevent a giant retinal tear or a retinal detachment in the fellow eye of patients with unilateral giant retinal tears.

Treatment of age-related subfoveal neovascular membranes by teletherapy:a pilot study

This investigation was designed to determine whether low dose radiation to the macular region could influence the natural course of age-related subfoveal neovascularisation. Nineteen patients with subfoveal membranes due to age-related macular degeneration (ARMD) were treated with 10 or 15 Gy of 6 MV photons and seven patients who declined treatment were followed up as controls. Six controls and all treated patients had completed follow up times of at least 12 months. Visual acuity was maintained or improved in 78% and 63% of treated patients at their 6 and 12 month follow up examinations respectively. By contrast visual acuity showed steady deterioration in six of seven controls. Significant neovascular membrane regression, as measured by image analysis, was recorded in 68% and 77% of treated patients at 6 and 12 months post-radiation, whereas the membranes in all seven control patients showed progressive enlargement. This study suggests that low doses of radiation can maintain central vision and induce regression of subfoveal neovascular membranes of ARMD in a significant proportion of patients. We now believe it appropriate to proceed to a prospective randomised study to test this hypothesis further.

External beam radiotherapy in exudative age-related macular degeneration: a pooled analysis of phase I data

In recent years external beam radiotherapy (EBRT) has been proposed as a treatment for the wet form of age-related macular degeneration (AMD) where choroidal neovascularization (CNV) is the hallmark. While the majority of pilot (Phase I) studies have reported encouraging results, a few have found no benefit, i.e. EBRT was not found to result in either improvement or stabilization of visual acuity of the treated eye. The natural history of visual loss in untreated CNV of AMD is highly variable. Loss of vision is influenced mainly by the presenting acuity, and size and composition of the lesion, and to a lesser extent by a variety of other factors. Thus the variable outcome reported by the small Phase I studies of EBRT published to date may simply reflect the variation in baseline factors. We therefore obtained information on 409 patients treated with EBRT from eight independent centres, which included details of visual acuity at baseline and at subsequent follow-up visits. Analysis of the data showed that 22.5% and 14.9% of EBRT-treated eyes developed moderate and severe loss of vision, respectively, during an average follow-up of 13 months. Initial visual acuity, which explained 20.5% of the variation in visual loss, was the most important baseline factor studied. Statistically significant differences in loss of vision were observed between centres, after considering the effects of case mix factors. Comparisons with historical data suggested that while moderate visual loss was similar to that of the natural history of the disease, the likelihood of suffering severe visual loss was halved. However, the benefit in terms of maintained/improved vision in the treated eye was modest.

Complement expression in retinal pigment epithelial cells is modulated by activated macrophages

Complement activation is involved in a variety of retinal diseases. We have shown previously that a number of complement components and regulators can be produced locally in the eye, and that retinal pigment epithelial (RPE) cells are the major source of complement expression at the retina-choroidal interface. The expression of complement components by RPE cells is regulated by inflammatory cytokines. Under aging or inflammatory conditions, microglia and macrophages accumulate in the subretinal space, where they are in close contact with RPE cells. In this study, we investigated the effect of activated macrophages on complement expression by RPE cells. Mouse RPE cells were treated with the supernatants from un-activated bone marrow-derived macrophages (BM-DMs), the classically activated BM-DMs (M1) and different types of the alternatively activated BM-DMs (M2a by IL-4, M2b by immune complex and lipopolysaccharide (LPS), M2c by IL-10). The expression of inflammatory cytokines and complement genes by RPE cells were determined by real-time RT-PCR. The protein expression of CFB, C3, C1INH, and C1r was examined by Western blot. Our results show that un-stimulated RPE cells express a variety of complement-related genes, and that the expression levels of complement regulators, including C1r, factor H (CFH), DAF1, CD59, C1INH, Crry, and C4BP genes are significantly higher than those of complement component genes (C2, C4, CFB, C3, and C5). Macrophage supernatants increased inflammatory cytokine (IL-1ß, IL-6, iNOS), chemokine (CCL2) and complement expression in RPE cells. The supernatants from M0, M2a and M2c macrophages mildly up-regulated (2~3.5-fold) CFB, CFH and C3 gene expression in RPE cells, whereas the supernatants from M1 and M2b macrophages massively increased (10~30-fold) CFB and C3 gene expression in RPE cells. The expression of other genes, including C1r, C2, C4, CFH, Masp1, C1INH, and C4BP in RPE cells was also increased by the supernatants of M1 and M2b macrophages; however, the increment levels were significantly lower than CFB and C3 genes. M1 and M2b macrophage supernatants enhanced CFB (Bb fragment) protein expression and C3 secretion by RPE cells. M1 macrophages may affect complement expression in RPE cells through the STAT1 pathway. Our results suggest that under inflammatory conditions, activated macrophages could promote the alternative pathway of complement activation in the retina via induction of RPE cell CFB and C3 expression.

Quantitative estimation of retinal nerve fiber layer height in glaucoma and the relationship with optic nerve head topography and visual field

Purpose: The authors estimated the retinal nerve fiber layer height (RNFLH) measurements in patients with glaucoma compared with those in age-matched healthy subjects as obtained by the laser scanning tomography and assessed the relationship between RNFLH measurements and optic and visual field status. Methods: Parameters of optic nerve head topography and RNFLH were evaluated in 125 eyes of 21 healthy subjects and 104 patients with glaucoma using the Heidelberg Retina Tomograph ([HRT] Heidelberg Engineering GmbH, Heidelberg, Germany) for the entire disc area and for the superior 70°(50°temporal and 20°nasal to the vertical midline) and inferior 70°sectors of the optic disc. The mean deviation of the visual field, as determined by the Humphrey program 24-2 (Humphrey Instruments, Inc., San Leonardo, CA, U.S.A) was calculated in the entire field and in the superior and inferior Bjerrum area. Result: Retinal nerve fiber layer height parameters (mean RNFLH and RNFL cross-sectional area) were decreased significantly in patients with glaucoma compared with healthy individuals. Retinal nerve fiber layer height parameters was correlated strongly with rim volume, rim area, and cup/disc area ratio. Of the various topography measures, retinal nerve fiber layer (RNFL) parameters and cup/disc area ratio showed the strongest correlation with visual field mean deviation in patients with glaucoma. Conclusion: Retinal nerve fiber layer height measures were reduced substantially in patients with glaucoma compared with age-matched healthy subjects. Retinal nerve fiber layer height was correlated strongly with topographic optic disc parameters and visual field changes in patients with glaucoma.

Lymphocyte subsets in conjunctival mucosa-associated-lymphoid-tissue after exposure to retinal-S-antigen

Purpose: To evaluate the immune cell subsets in conjunctival mucosa-associated-lymphoid-tissue (C-MALT) following challenge with antigen. Methods: Ten adult female Lewis rats were studied. Five rats received one drop (5 µL) of retinal S-antigen (500 µg/mL in phosphate buffered saline, PBS) instilled into the lower fornix twice daily for 10 consecutive days. Five rats received PBS only and served as controls for the experiment. Two days after the last instillation the animals were sacrificed and the orbital contents prepared for immunohistological staining. A panel of monoclonal antibodies was used: CD5, CD4, CD8, CD25, and CD45RA. The number of positive cells were counted in sections of epibulbar, forniceal, and tarsal conjunctiva. Results: There was a significant increase in the number of CD8 T lymphocytes in the conjunctiva of animals receiving retinal S-antigen when compared to control animals. Conclusion: Conjunctival instillation of retinal S-antigen causes an immune response in the C-MALT with a significant increase in the CD8 T lymphocyte subset in this tissue. This response may be involved in the induction of tolerance to the encountered antigen.

Association of retinal arteriolar dilatation with lower verbal memory::The Edinburgh Type 2 Diabetes Study

Abstract


AIMS/HYPOTHESIS:

Retinal vascular calibre changes may reflect early subclinical microvascular disease in diabetes. Because of the considerable homology between retinal and cerebral microcirculation, we examined whether retinal vascular calibre, as a proxy of cerebral microvascular disease, was associated with cognitive function in older people with type 2 diabetes.

METHODS:

A cross-sectional analysis of 954 people aged 60-75 years with type 2 diabetes from the population-based Edinburgh Type 2 Diabetes Study was performed. Participants underwent standard seven-field binocular digital retinal photography and a battery of seven cognitive function tests. The Mill Hill Vocabulary Scale was used to estimate pre-morbid cognitive ability. Retinal vascular calibre was measured from an image field with the optic disc in the centre using a validated computer-based program.

RESULTS:

After age and sex adjustment, larger retinal arteriolar and venular calibres were significantly associated with lower scores for the Wechsler Logical Memory test, with standardised regression coefficients -0.119 and -0.084, respectively (p?<?0.01), but not with other cognitive tests. There was a significant interaction between sex and retinal vascular calibre for logical memory. In male participants, the association of increased retinal arteriolar calibre with logical memory persisted (p?<?0.05) when further adjusted for vocabulary, venular calibre, depression, cardiovascular risk factors and macrovascular disease. In female participants, this association was weaker and not significant.

CONCLUSIONS/INTERPRETATION:

Retinal arteriolar dilatation was associated with poorer memory, independent of estimated prior cognitive ability in older men with type 2 diabetes. The sex interaction with stronger findings in men requires confirmation. Nevertheless, these data suggest that impaired cerebral arteriolar autoregulation in smooth muscle cells, leading to arteriolar dilatation, may be a possible pathogenic mechanism in verbal declarative memory decrements in people with diabetes.

Role of vascular endothelial growth factor and placental growth factors during retinal vascular development and hyaloid regression

PURPOSE. Vascular endothelial growth factor (VEGF)-A and placental growth factor (PIGF) are members of a large group of homologous peptides identified as the VEGF family. Although VEGF-A is known to act as a potent angiogenic peptide in the retina, the vasoactive function of PIGF in this tissue is less well defined. This study has sought to elucidate the expression patterns and modulatory role of these growth factors during retinal vascular development and hyaloid regression in the neonatal mouse. METHODS. C57BL6J mice were killed at postnatal days (P)1, P3, P5, P7, P9, and P11. The eyes were enucleated and processed for in situ hybridization and immunocytochemistry and the retinas extracted for total protein or RNA. Separate groups of neonatal mice were also injected intraperitoneally daily from P2 through P9 with either VEGF-neutralizing antibody, PIGF-neutralizing antibody, isotype immunoglobulin (Ig)-G, or phosphate-buffered saline (PBS). The mice were then perfused with fluorescein isothiocyanate (FITC)-dextran, and the eyes were subsequently embedded in paraffin wax or flat mounted. RESULTS. Quantitative (real-time) reverse transcription-polymerase chain reaction (RT-PCR) demonstrated similar expression patterns of VEGF-A and PIGF mRNA during neonatal retinal development, although the fluctuation between time periods was greater overall for VEGF-A. The localization of VEGF-A and PIGF in the retina, as revealed by in situ hybridization and immunohistochemistry, was also similar. Neutralization of VEGF-A caused a significant reduction in the hyaloid and retinal vasculature, whereas PIGF antibody treatment caused a marked persistence of the hyaloid without significantly affecting retinal vascular development. CONCLUSIONS. Although having similar expression patterns in the retina, these growth factors appear to have distinct modulatory influences during normal retinal vascular development and hyaloid regression.

Effects of modified LDL and HDL on retinal pigment epithelial cells: a role in diabetic retinopathy?

Aims/hypothesis: Blood–retina barrier leakage in diabetes results in extravasation of plasma lipoproteins. Intra-retinal modified LDLs have been implicated in diabetic retinopathy (DR), but their effects on retinal pigment epithelial (RPE) cells and the added effects of extravasated modified HDLs are unknown.

Methods: In human retinas from individuals with and without diabetes and DR, immunohistochemistry was used to detect ApoB, ApoA1 and endoplasmic reticulum (ER) stress markers. In cell culture, human RPE cells were treated with native LDL (N-LDL) or heavily-oxidised glycated LDL (HOG-LDL) with or without pretreatment with native HDL (N-HDL) or heavilyoxidised glycated HDL (HOG-HDL). Cell viability, oxidative stress, ER stress, apoptosis and autophagy were assessed by Cell Counting Kit-8 assay, dichlorofluorescein assay, western blotting, immunofluorescence and TUNEL assay. In separate
experiments, RPE cells were treated with lipid oxidation products, 7-ketocholesterol (7-KC, 5–40 µmol/l) or 4-hydroxynonenal (4-HNE, 5–80 µmol/l), with or without pretreatment with N-HDL or HOG-HDL.

Results: ApoB, ApoA1 staining and RPE ER stress were increased in the presence of DR. HOG-LDL but not N-LDL significantly decreased RPE cell viability and increased reactive oxygen species generation, ER stress, apoptosis and autophagy. Similarly, 4-HNE and 7-KC decreased viability and induced ER stress. Pretreatment with N-HDL mitigated these effects, whereas HOG-HDL was less effective by most, but not all, measures.

Conclusions/interpretation: In DR, extravascular modified LDL may promote RPE injury through oxidative stress, ER stress, autophagy and apoptosis. N-HDL has protective effects, but HOG-HDL is less effective. Extravasation and modification of HDL may modulate the injurious effects of extravasated modified LDL on the retinal pigment epithelium.

Mechanisms of modified LDL-induced pericyte loss and retinal injury in diabetic retinopathy

Aims/hypothesis: In previous studies we have shown that extravasated, modified LDL is associated with pericyte loss, an early feature of diabetic retinopathy (DR). Here we sought to determine detailed mechanisms of this LDLinduced pericyte loss.

Methods: Human retinal capillary pericytes (HRCP) were exposed to ‘highly-oxidised glycated’ LDL (HOG-LDL) (a model of extravasated and modified LDL) and to 4-hydroxynonenal or 7-ketocholesterol (components of oxidised LDL), or to native LDL for 1 to 24 h with or without 1 h of pretreatment with inhibitors of the following: (1) the scavenger receptor (polyinosinic acid); (2) oxidative stress (N-acetyl cysteine); (3) endoplasmic reticulum (ER) stress (4-phenyl butyric acid); and (4) mitochondrial dysfunction (cyclosporin A). Oxidative stress, ER stress, mitochondrial dysfunction, apoptosis and autophagy were assessed using techniques including western blotting, immunofluorescence, RT-PCR, flow cytometry and TUNEL assay. To assess the relevance of the results in vivo, immunohistochemistry was used to detect the ER stress chaperon, 78 kDa glucose-regulated protein, and the ER sensor, activating transcription factor 6, in retinas from a mouse model of DR that mimics exposure of the retina to elevated glucose and elevated LDL levels, and in retinas from human participants with and without diabetes and DR.

Results: Compared with native LDL, HOG-LDL activated oxidative and ER stress in HRCP, resulting in mitochondrial dysfunction, apoptosis and autophagy. In a mouse model of diabetes and hyperlipidaemia (vs mouse models of either condition alone), retinal ER stress was enhanced. ER stress was also enhanced in diabetic human retina and correlated with the severity of DR.

Conclusions/interpretation: Cell culture, animal, and human data suggest that oxidative stress and ER stress are induced by modified LDL, and are implicated in pericyte loss in DR.

Oxidative and endoplasmic reticulum stresses mediate apoptosis induced by modified LDL in human retinal Müller cells

We previously showed that extravasated, modified LDL is implicated in pericyte loss in diabetic retinopathy (DR). Here, we investigate whether modified LDL induces apoptosis in retinal Müller glial cells.

Tyrosine nitration of prostacyclin synthase is associated with enhanced retinal cell apoptosis in diabetes

The risk of diabetic retinopathy is associated with the presence of both oxidative stress and toxic eicosanoids. Whether oxidative stress actually causes diabetic retinopathy via the generation of toxic eicosanoids, however, remains unknown. The aim of the present study was to determine whether tyrosine nitration of prostacyclin synthase (PGIS) contributes to retinal cell death in vitro and in vivo. Exposure of human retinal pericytes to heavily oxidized and glycated LDL (HOG-LDL), but not native forms of LDL (N-LDL), for 24 hours significantly increased pericyte apoptosis, accompanied by increased tyrosine nitration of PGIS and decreased PGIS activity. Inhibition of the thromboxane receptor or cyclooxygenase-2 dramatically attenuated HOG-LDL-induced apoptosis without restoring PGIS activity. Administration of superoxide dismutase (to scavenge superoxide anions) or L-N(G)-nitroarginine methyl ester (L-NAME, a nonselective nitric oxide synthase inhibitor) restored PGIS activity and attenuated pericyte apoptosis. In Akita mouse retinas, diabetes increased intraretinal levels of oxidized LDL and glycated LDL, induced PGIS nitration, enhanced apoptotic cell death, and impaired blood-retinal barrier function. Chronic administration of tempol, a superoxide scavenger, reduced intraretinal oxidized LDL and glycated LDL levels, PGIS nitration, and retina cell apoptosis, thereby preserving the integrity of blood-retinal barriers. In conclusion, oxidized LDL-mediated PGIS nitration and associated thromboxane receptor stimulation might be important in the initiation and progression of diabetic retinopathy.