The use of weighted health-related Quality of Life scores in people with diabetic macular oedema at baseline in a randomized clinical trial.

AIMS: To examine the relationship between visual acuity in each eye and Quality of Life (QoL) outcomes in people with diabetic macular oedema. METHODS: Cross sectional retrospective analysis of data collected at baseline in 289 people entered into a randomized clinical trial with diabetic macular oedema which investigated the safety and efficacy of a vascular endothelial growth factor inhibitor, pegaptanib sodium. At the baseline visit, visual acuity was measured through refraction and using retro-illuminated modified Early Treatment Diabetic Retinopathy Study Log MAR charts, and patient health-related QoL was determined using the European Quality of Life EQ-5D-3L and the Visual Functioning Questionnaire-25 (NEI-VFQ25). A regression analysis with QoL score from each vision-related domain as the dependent variable was fitted using linear and quadratic terms of the better and worse eye, age, gender, adjusted for number of concurrent conditions, ethnicity and level of diabetes control. RESULTS: For all vision-related QoL domains from NEI-VFQ25 and EQ-5D-3L except ocular pain, both visual acuity in the better-seeing and the worse-seeing eye gave a significant increase in correlation coefficient over that obtained from clinical and demographic data. The NEI-VFQ25 correlation was most closely associated with a weighted visual acuity measure of 0.75 in the better and 0.25 in the worse eye or 0.60 in the better and 0.40 in the worse eye. CONCLUSIONS: We recommend that a weighted visual acuity measure from both eyes is considered in future diabetic macular oedema trials.

Macromolecular diffusion characteristics of ageing human Bruch's membrane: implications for age-related macular degeneration (AMD).

Macromolecular species such as retinal binding protein, transferrin, ceruloplasmin, etc., released by the fenestrated choroidal capillaries must diffuse across Bruch's membrane for interaction with the basal membranes of the retinal pigment epithelium (RPE) for delivery of essential metabolites to the neural retina. The patency of this pathway through ageing Bruch's was examined by quantifying the diffusional flux of a 21.2 kDa fluorescein-isothiocyanate labelled dextran. Dextran flux measurements across Bruch's membrane from the macular region of the human fundus showed a highly significant decrease (p < 0.001) with ageing of donor such that diffusional transport in the ninth decade was about 6.5% of that in the first decade of life. Peripheral regions also showed a highly significant decline (p < 0.001) but ageing changes were considerably slowed in comparison to the macula with diffusional rates in the ninth decade being about 44% of that in the first decade. Peripheral samples from AMD donors displayed diffusional rates that were lower than the control population. The age-related decline in macromolecular diffusion across Bruch's membrane suggests that in the elderly, the patency of the conducting pathways may be compromised and in the more advanced ageing of Bruch's associated with AMD, the metabolic trafficking of carrier proteins may be severely impaired.

Localization of the site of major resistance to fluid transport in Bruch's membrane.

PURPOSE: To determine the site of highest resistance to the movement of water across Bruch's membrane in humans. METHODS: A hydraulic conductivity chamber was designed that enabled us to measure flow across Bruch's membrane while ablating its subepithelial aspect using an excimer laser (193 nm). When resistance was lost, samples were fixed and processed for electron microscopy. RESULTS: Changes in the hydraulic conductivity of Bruch's membrane in response to the excimer-mediated sequential removal of tissue layers was studied in four control eyes of donors 26, 46, 61, and 76 years of age and in one eye of an 83-year-old donor with age-related macular degeneration. The number of laser pulses required to abolish the resistance in Bruch's membrane was found to be dependent on the age of the donor. The ablation rate was approximately 0.11 micron per pulse. Loss of resistance correlated with removal of layers internal to the layer of elastin. CONCLUSIONS: This study indicates that the inner collage-nous layer imparts the major resistance to fluid movement between the retinal pigment epithelium and the choroid. Aging changes in the ultrastructure of these compartments could be responsible for the decrease in hydraulic conductivity observed in early life in previous studies.

Hydrodynamics of ageing Bruch's membrane: implications for macular disease.

The hydrodynamic properties of isolated human Bruch's membrane and choroid were investigated as a function of age and retinal location. Macular and peripheral regions of the fundus showed an exponential decline of hydraulic conductivity with half-lives of 15 and 22 years respectively. Comparison of age profiles for hydraulic conductivity and lipid deposits suggests the involvement of two discrete processes for reduction in transport capability. The first appears to involve 'membrane remodelling' with a programmed decay rate leading to a major reduction in hydraulic conductivity by the fifth decade of life. The second commences in the fourth decade and is apparently dependent on the lipid content of Bruch's membrane.

Decreasing hydraulic conductivity of Bruch's membrane: relevance to photoreceptor survival and lipofuscinoses.

Deterioration of visual performance leading to blindness is particularly severe in the early-onset forms of Batten disease. Metabolic support of the neural retina is critically dependent on the choroidal blood supply and on efficient transport pathways through Bruch's membrane and the retinal pigment epithelium (RPE). Conversely, degradation products and, in particular, damaged membranous components of photoreceptor outer segments must be removed in the opposite direction. Incomplete breakdown of damaged "spent" discs leads to the age-related accumulation of lipofuscin-like pigments in the RPE, and these in turn influence the degenerative changes in Bruch's membrane. The generalized and extensive deposition of lipofuscin-like material in Batten disease is therefore likely to exacerbate the degenerative changes in Bruch's membrane, and thereby compromise local fluid dynamics. The hydrodynamic properties of Bruch's membrane were examined in normal donor eyes and showed a precipitous decline of hydraulic conductivity during early life. In fact, the maximal capacity for fluid transport was halved for every 17 years of life. This finding is therefore highly relevant to the development of ensuing pathology in the neuronal ceroid-lipofuscinoses.