Stephen Beatty

The Role of Oxidative Stress in the Pathogenesis of Age-Related Macular Degeneration

Age-related macular degeneration (AMD) is the leading cause of blind registration in the developed world, and yet its pathogenesis remains poorly understood. Oxidative stress, which refers to cellular damage caused by reactive oxygen intermediates (ROI), has been implicated in many disease processes, especially age-related disorders. ROIs include free radicals, hydrogen peroxide, and singlet oxygen, and they are often the byproducts of oxygen metabolism. The retina is particularly susceptible to oxidative stress because of its high consumption of oxygen, its high proportion of polyunsaturated fatty acids, and its exposure to visible light. In vitro studies have consistently shown that photochemical retinal injury is attributable to oxidative stress and that the antioxidant vitamins A, C, and E protect against this type of injury. Furthermore, there is strong evidence suggesting that lipofuscin is derived, at least in part, from oxidatively damaged photoreceptor outer segments and that it is itself a photoreactive substance. However, the relationships between dietary and serum levels of the antioxidant vitamins and age-related macular disease are less clear, although a protective effect of high plasma concentrations of alpha-tocopherol has been convincingly demonstrated. Macular pigment is also believed to limit retinal oxidative damage by absorbing incoming blue light and/or quenching ROIs. Many putative risk-factors for AMD have been linked to a lack of macular pigment, including female gender, lens density, tobacco use, light iris color, and reduced visual sensitivity. Moreover, the Eye Disease Case-Control Study found that high plasma levels of lutein and zeaxanthin were associated with reduced risk of neovascular AMD. The concept that AMD can be attributed to cumulative oxidative stress is enticing, but remains unproven. With a view to reducing oxidative damage, the effect of nutritional antioxidant supplements on the onset and natural course of age-related macular disease is currently being evaluated.

Macular pigment and age related macular degeneration

The yellow coloration of the macula lutea is attributable to the presence of macular pigment in the axons of its photoreceptors.1 In the 1980s several investigators demonstrated that macular pigment consists of the xanthophyll isomers, lutein and zeaxanthin.2 3 Although the role of the macular pigment remains uncertain, several functions have been hypothesised and these include reduction of the effects of light scatter and chromatic aberration on visual performance,4 5 limitation of the damaging photo-oxidative effects of blue light through its absorption,6-8 and protection against the adverse effects of photochemical reactions because of the antioxidant properties of the carotenoids.9 10 Age related macular degeneration (AMD) is the leading cause of visual loss in people over the age of 65 years in the Western world.11 Although the aetiopathogenesis of AMD remains a matter of debate, there is a growing body of evidence to indicate that oxidative damage plays a role.12-14 Consequently, the possibility that the absorption characteristics and antioxidant properties of macular pigment confer protection against AMD has been postulated.10 15 A proved protective effect of macular pigment may be of therapeutic value, as it has recently been reported that human macular pigment can be augmented with dietary modification.16 In this article we review the current literature germane to macular pigment and AMD, and examine the evidence that retinal carotenoids are protective against AMD. The absorption of blue light by the macular pigment was first described in 1866 by Max Schultze who concluded: “Therefore, under an otherwise equal organisation, a retina without a yellow spot would see more blue light than one with such a spot”.17 He believed that absorption of the “most refractable violet” reduced chromatic aberration, but also hypothesised that macular pigment might provide some protection against the hazards …

Multi-country real-life experience of anti-vascular endothelial growth factor therapy for wet age-related macular degeneration

Background/aims Real-life anti-vascular endothelial growth factor (VEGF) therapy use in patients with wet age-related macular degeneration (wAMD) was assessed in a retrospective, observational study in Canada, France, Germany, Ireland, Italy, the Netherlands, UK and Venezuela. Methods Medical records of patients with wAMD, who started ranibizumab treatment between 1 January 2009 and 31 August 2009, were evaluated. Data were collected until the end of treatment and/or monitoring or until 31 August 2011. Results 2227 patients who received ≥1 anti-VEGF injection with a baseline visual acuity assessment and ≥1 postbaseline visual acuity assessment for the treated eye were evaluated. Visual acuity improved until about day 120; thereafter, visual acuity gains were not maintained. Mean change in visual acuity score from baseline to years 1 and 2 was +2.4 and +0.6 letters, respectively. Patients received a mean of 5.0 and 2.2 injections in the first and second year, respectively. There were substantial differences in visual outcomes and injection frequency between countries. More frequent visits and injections were associated with greater improvements in visual acuity. Conclusions In clinical practice, fewer injections are administered than in clinical trials. Anti-VEGF treatment resulted in an initial improvement in visual acuity; however, this was not maintained over time. Trial registration number NCT01447043.

A novel index for predicting intraocular pressure reduction following cataract surgery

Aim: The results of a study designed to investigate the predictive value of preoperative anterior chamber depth (ACD) and intraocular pressure (IOP) are reported. The relation between these factors and their effect on the reduction in IOP following phacoemulsification cataract surgery was also studied. Methods: The ACD and IOP were prospectively measured in 103 non-glaucomatous eyes of 103 patients who underwent uneventful phacoemulsification and posterior chamber intraocular lens (PCIOL) implantation. Other data which were recorded included best corrected visual acuity, axial length, lens thickness, and severity of lens opacity. Results: The ACD increased by a mean (SD) of 1.10 (0.44) mm (p<0.00001) and this increase was significantly and inversely related to preoperative ACD (r2 = 68%; p<0.01). IOP dropped by a mean of 2.55 (1.78) mm Hg following cataract surgery (p<0.0001), and this reduction was significantly and positively related to preoperative IOP (r2 = 56%; p<0.01), and significantly and inversely related to preoperative ACD (r2 = 21%; p<0.01). A novel ratio, the pressure to depth (PD) ratio (preoperative IOP/preoperative ACD), was found to be significantly and positively related to the surgically induced reduction in IOP (r2 = 73%; p<0.01), and IOP was reduced by ⩾4 mm Hg in all patients with a PD ratio >7. Conclusion: The reduction in IOP following cataract surgery was found to be positively related to preoperative IOP, and inversely related to preoperative ACD. Furthermore, these results indicate that a novel index, the PD ratio, is strongly predictive for IOP reduction following cataract extraction, and may prove useful in surgical decision making.

Local intra-arterial fibrinolysis for acute occlusion of the central retinal artery: a meta-analysis of the published data

BACKGROUND/AIM Central retinal artery occlusion (CRAO) is typically associated with a poor visual outcome. Several favourable reports of local intra-arterial fibrinolysis (LIF), which involves the superselective administration of a thrombolytic agent directly into the ophthalmic artery, have appeared in the recent literature. The aim of this study was to critically appraise these studies in a collective fashion. METHODS A meta-analysis was performed of all the published literature germane to LIF in cases of CRAO. RESULTS Of the 16 studies identified, all were retrospective and non-randomised. After correction for data duplication, the results of LIF in 100 patients can be reported. A final acuity of 6/6 or better was seen in 14% of patients following LIF, and a visual result of 6/12 or better was seen in 27% of subjects. A poor final acuity of 3/60 or worse was seen in 60.6% of eyes treated with local intra-arterial fibrinolysis. These results compare favourably with conventional forms of therapy. Potentially serious complications were seen in four patients, but no patient suffered a permanent neurological deficit. CONCLUSION The results of this study suggest that there may be a marginal visual benefit associated with LIF compared with conventional management of CRAO. However, the methodology of the cited studies was often unsatisfactory, and a randomised controlled trial of LIF in cases of CRAO is justified. Outside of a randomised clinical trial, the use of superselective fibrinolytic therapy for CRAO cannot be recommended on the basis of current evidence.

Augmentation of Macular Pigment Following Supplementation with All Three Macular Carotenoids: An Exploratory Study

Purpose: At the macula, the carotenoids meso-zeaxanthin (MZ), lutein (L), and zeaxanthin (Z) are collectively referred to as macular pigment (MP). This study was designed to measure serum and macular responses to a macular carotenoid formulation. Materials and Methods: Ten subjects were recruited into this study (five normal and five with early age-related macular degeneration [AMD]). Subjects were instructed to consume a formulation containing 7.3 mg of MZ, 3.7 mg of L, and 0.8 mg of Z everyday over an eight-week period. The spatial profile of MP optical density (i.e., MPOD at 0.25°, 0.5°, 1°, and 1.75°) was measured using customized heterochromatic flicker photometry, and a blood sample was collected at each study visit in order to analyze serum concentrations of MZ, L, and Z. Results: There was a significant increase in serum concentrations of MZ and L after two weeks of supplementation (p < 0.05). Baseline serum carotenoid analysis detected a small peak eluting at the same time as MZ in all subjects, with a mean ± SD of 0.02 ± 0.01 μmol/L. We report significant increases in MPOD at 0.25°, 0.5°, 1°, and average MPOD across its spatial profile after just two weeks of supplementation (p < 0.05, for all). Four subjects (one normal and three AMD) who had an atypical MPOD spatial profile (i.e., central dip) at baseline had the more typical MPOD spatial profile (i.e., highest MPOD at the center) after eight weeks of supplementation. Conclusion: We report significant increases in serum concentrations of MZ and L following supplementation with MZ, L, and Z and a significant increase in MPOD, including its spatial profile, after two weeks of supplementation. Also, this study has detected the possible presence of MZ in human serum pre-supplementation and the ability of the study carotenoid formulation to rebuild central MPOD in subjects who have atypical profiles at baseline.

Transport and Retinal Capture of Lutein and Zeaxanthin with Reference to Age-related Macular Degeneration

Age-related macular degeneration (AMD) is the most common cause of irreversible blindness in the elderly population in the western world. The etiology and pathogenesis of this disease remain unclear. However, there is an increasing body of evidence supporting the hypothesis that the macular pigment carotenoids, lutein and zeaxanthin, play an important role in protection against AMD, by filtering out blue light at a pre-receptoral level, or by quenching free radicals. Lutein and zeaxanthin are dietary xanthophyll carotenoids, which are delivered to the retina via plasma lipoproteins. The biological mechanisms governing retinal capture and accumulation of lutein and zeaxanthin, to the exclusion of other carotenoids, are still poorly understood. Although these mechanisms remain unclear, it is possible that selective capture of these carotenoids is related to lipoprotein, or apolipoprotein, function and profile. Xanthophyll-binding proteins appear to play an important role in the retinal capture of the xanthophyll carotenoids. The Pi isoform of GSTP1 has been isolated as a specific binding protein for zeaxanthin. The binding protein responsible for retinal uptake of lutein remains elusive. This article reviews the literature germane to the mechanisms involved in the capture, accumulation and stabilization of lutein and zeaxanthin by the retina, and the processes involved in their transport in serum.

The rationale and evidence base for a protective role of macular pigment in age-related maculopathy

Age-related maculopathy (ARM) remains the most common cause of blind registration in people aged 50 years or over in the developed world, and its prevalence continues to rise. Although effective new treatments have become available in the recent past, these are expensive and cumbersome to the healthcare provider and to the patient, and many cases remain resistant to such therapy. There is a biologically plausible rationale whereby macular pigment, which is entirely of dietary origin, may prevent or delay the onset, or ameliorate the clinical course, of ARM. In this article, we review this rationale, and critically appraise the current evidence base germane to the use of supplements containing the macular carotenoids in patients with, or at risk of developing, ARM.

Low macular pigment optical density is associated with lower cognitive performance in a large, population-based sample of older adults

Macular pigment (MP) is comprised of the carotenoids lutein (L), zeaxanthin (Z), and meso-zeaxanthin (MZ), which selectively accumulate at the macula (central retina) of the eye and are neuroprotective. These carotenoids are also present in the brain, and evidence suggests a close correlation between retinal and brain concentrations. We investigated the relationship between MP and cognitive function in 4453 adults aged ≥ 50 years as part of The Irish Longitudinal Study on Aging. Macular pigment optical density (MPOD) was determined using customized heterochromatic flicker photometry-a quick and noninvasive way of measuring the concentration of the pigment. Lower MPOD was associated with poorer performance on the mini-mental state examination (p = 0.026) and on the Montreal cognitive assessment (p = 0.016). Individuals with lower MPOD also had poorer prospective memory (p = 0.011), took longer time to complete a trail-making task (p = 0.003), and had slower and more variable reaction times on a choice reaction time task (p = 0.000 and 0.001). These associations were only slightly attenuated following adjustment for physical and mental health. There was no significant association between MPOD and verbal fluency, word recall, visual reasoning, or picture memory. Overall, the findings support the theory that xanthophyll carotenoids impact on cognitive function, underscoring the need for exploration of novel, noninvasive biomarkers for cognitive vulnerability and preventive strategies.

Risk factors for endothelial cell loss after phacoemulsification surgery by a junior resident

Purpose: To assess the risk factors for endothelial cell loss after phacoemulsification cataract surgery performed by a junior resident. Setting: Ophthalmic teaching hospital, Dublin, Ireland. Methods: This prospective study included 40 eyes having divide‐and‐conquer phacoemulsification cataract surgery by a junior resident under the supervision of an experienced surgeon. Nine variables were examined to assess the risk for corneal endothelial cell loss postoperatively. Results: The mean overall endothelial cell loss was 11.6%. Longer surgery time, longer absolute and effective phaco time, higher mean ultrasound power, and higher cataract density were significantly associated with endothelial cell loss on univariate analysis. Multivariate analysis identified a grade 3 nucleus (severely dense) and long absolute phaco time as independent predictors for endothelial cell loss, with longer absolute phaco time the stronger predictor. Conclusions: Divide‐and‐conquer phacoemulsification cataract surgery was a safe technique in the hands of an ophthalmic trainee. This study supports advice to junior surgeons to choose cases with less dense cataracts as this will help reduce the absolute phaco time and thus minimize endothelial cell loss.