Macular Degeneration: Chong NV

Fletcher EC, Chong NV. · Oxford Eye Hospital, Oxford, UK. · Eye. · Pubmed #18188178 No free full text.

Abstract: PURPOSE: Age-related macular degeneration (AMD) is the leading cause of blindness in the developed world. In the past decade, AMD research has improved our understanding of the pathogenesis of the condition. There is no doubt that anti-VEGF therapies will play a major role in the reduction of blindness, but it needs close monitoring and frequent treatments. In this review we summarise the key pathophysiology of the condition and some of the new treatment strategies under development. METHODS: Literature review. RESULTS: Oxidative stress, inflammation, hypoxia, and angiogenesis are key pathophysiological processes in AMD, this diversity has provided a variety of possible areas amenable to modification to enhance the treatment options for AMD.

Patel N, Adewoyin T, Chong NV. · Laser and Retinal Research Unit, Kings College Hospital, London, UK. · Eye. · Pubmed #17491602 No free full text.

Abstract: AIM: Age-related macular degeneration (AMD) is a common macular disease in the developed world and recent studies have shown that specific genes may be associated with it and may contribute to a higher risk of developing AMD. OBJECTIVE: Our objective was to review systematically recent publications related to the genetics of AMD and provide relevant information that would help both scientists and clinicians in advising patients. METHOD: A systematic search was performed on PubMed, Medline, and National Library of Medicine as well as ARVO abstracts using key words relevant to the genetic associations of AMD. RESULTS: The most important genetic associations in AMD involved the complement factor H (CFH) gene, which showed that possession of the variant Y402H polymorphism significantly increases the risk for AMD. Protective genes have also been identified such as those on either factor B (BFor complement factor B (CFB)) or complement component 2 (C2) genes. The genes involved in inherited macular dystrophies such as ATP-binding cassette, subfamily A (ABC1), member 4 (ABCA4), vitelliform macular dystrophy (VMD2), tissue inhibitor of matrix metalloproteinase-3 (TIMP3), and EFEMP1have yielded some important information but further confirmatory work has yet to establish a clear association with AMD. CONCLUSION: Patients with AMD possess specific genetic variants of the CFHgene, which put them at a higher risk of developing the disease. Other unaffected individuals may possess certain protective genetic variants, which could prevent them from developing AMD. Further research will no doubt shed light on other such mechanisms and these will be useful in identifying possible direct targets for drugs or indirectly through modulation of the genes responsible for disease presentation.

Chong NV. · Oxford Eye Hospital, University of Oxford, England, Oxford, UK. · Eye. · Pubmed #19407836 No free full text.

This publication has no abstract.

Fletcher EC, Lade RJ, Adewoyin T, Chong NV. · King's College Hospital, London, United Kingdom. · Ophthalmology. · Pubmed #18930556 No free full text.

Abstract: PURPOSE: To present a computerized model assessing individualized cost utility for current treatments for neovascular age-related macular degeneration (AMD) to enhance discussion regarding treatment options. DESIGN: Case- and eye-specific cost-utility analysis using individual case scenarios. PARTICIPANTS: Visual acuity data from published randomized controlled trials are incorporated into this analysis. METHODS: Computerized model (Microsoft Visual Basic 6.0 programming) to establish preference-based cost-utility analysis in association with individual cost of treatment and blindness for neovascular AMD for both the better and worst seeing eye, with extrapolation of results over a 5-year term. MAIN OUTCOME MEASURES: Cost per quality-adjusted life-year (QALY) and cost per QALY gained for comparison of treatments for specific visual acuities. RESULTS: All treatments show an increase in utility in comparison with best supportive care (BSC) if the better-seeing eye is treated. Ranibizumab, using the Phase IIIb, Multicenter, Randomized, Double-Masked, Sham Injection-Controlled Study of the Efficacy and Safety of Ranibizumab in Subjects with Subfoveal Choroidal Neovascularisation (CNV) with or without Classic CNV Secondary to AMD (PIER) regimen, is the most cost effective at $626 938 per QALY gained for treatment of the better seeing eye. To increase utility value when treating the worst seeing eye, the vision must improve to such a degree that it becomes the better seeing eye. This level of improvement is only possible if there is <9 letters difference between the 2 eyes and treated with ranibizumab. Over 5 years, increasing influence from the cost of blindness results in increasing costs for those treatments unable to stabilize vision. Within 5 years, the cost per QALY for the BSC is greater than all treatments except monthly ranibizumab injections. CONCLUSIONS: Assessment of cost of treatment incorporates both effectiveness of treatment, cost of treatment, and cost of blindness. Cost analysis enables incorporation of these aspects of treatment with the quality of life data to provide a better comparison of treatments over time. This analysis has provided a method for individual analysis and therefore can provide the structure for resource allocation. FINANCIAL DISCLOSURE(S): The authors have no proprietary or commercial interest in any materials discussed in this article.

Chau KY, Sivaprasad S, Patel N, Donaldson TA, Luthert PJ, Chong NV. · Institute of Ophthalmology, University College, London, UK. · Eye. · Pubmed #18597988 No free full text.

Abstract: BACKGROUND: Several studies indicate that age-related macular degeneration (AMD) and atherosclerosis may share common pathogenetic pathways. The aim of this study was to determine the role of systemic matrix metalloproteinases (MMPs) in AMD, given that MMPs are implicated in the pathogenesis of atherosclerosis. METHODS: This study determined the plasma matrix metalloproteinases (MMP-2 and MMP-9) levels in three groups of subjects: group 1 included subjects with age-related maculopathy (ARM), group 2 included subjects with choroidal neovascularization (CNV) owing to AMD and group 3 consisted of age-matched controls. RESULTS: The mean plasma levels of MMP-2 were not significantly different in the three groups. In contrast, the mean plasma MMP-9 levels were significantly higher in ARM and CNV groups compared to that of the control group. However, there was no significant difference in MMP-9 levels between ARM and CNV groups. CONCLUSION: This is the first study that reveals a link between raised plasma MMP-9 levels with AMD. Further studies are required to identify the factors that contribute to this association.

Scholl HP, Charbel Issa P, Walier M, Janzer S, Pollok-Kopp B, Börncke F, Fritsche LG, Chong NV, Fimmers R, Wienker T, Holz FG, Weber BH, Oppermann M. · Department of Ophthalmology, University of Bonn, Bonn, Germany. · PLoS One. · Pubmed #18596911 links to  free full text

Abstract: Dysregulation of the alternative pathway (AP) of complement cascade has been implicated in the pathogenesis of age-related macular degeneration (AMD), the leading cause of blindness in the elderly. To further test the hypothesis that defective control of complement activation underlies AMD, parameters of complement activation in blood plasma were determined together with disease-associated genetic markers in AMD patients. Plasma concentrations of activation products C3d, Ba, C3a, C5a, SC5b-9, substrate proteins C3, C4, factor B and regulators factor H and factor D were quantified in patients (n = 112) and controls (n = 67). Subjects were analyzed for single nucleotide polymorphisms in factor H (CFH), factor B-C2 (BF-C2) and complement C3 (C3) genes which were previously found to be associated with AMD. All activation products, especially markers of chronic complement activation Ba and C3d (p<0.001), were significantly elevated in AMD patients compared to controls. Similar alterations were observed in factor D, but not in C3, C4 or factor H. Logistic regression analysis revealed better discriminative accuracy of a model that is based only on complement activation markers Ba, C3d and factor D compared to a model based on genetic markers of the complement system within our study population. In both the controls' and AMD patients' group, the protein markers of complement activation were correlated with CFH haplotypes.This study is the first to show systemic complement activation in AMD patients. This suggests that AMD is a systemic disease with local disease manifestation at the ageing macula. Furthermore, the data provide evidence for an association of systemic activation of the alternative complement pathway with genetic variants of CFH that were previously linked to AMD susceptibility.

Sivaprasad S, Adewoyin T, Bailey TA, Dandekar SS, Jenkins S, Webster AR, Chong NV. · Laser and Retinal Research Unit, King's College Hospital, King's College London, England. · Arch Ophthalmol. · Pubmed #17420372 links to  free full text

Abstract: OBJECTIVES: To determine the role of systemic complement activation in the pathogenesis of age-related macular degeneration and to examine whether serum C3a des Arg reflects systemic complement activation, independent of individual complement component levels. METHODS: Plasma complement C3a des Arg levels and a single nucleotide polymorphism at position 402 of the complement factor H gene (CFH) were determined in 3 groups of subjects: 42 subjects with early age-related maculopathy, 42 subjects with neovascular (wet) age-related macular degeneration, and a control group of 38 subjects with no clinical evidence of age-related changes at the macula. RESULTS: The median (range) of plasma complement C3a des Arg levels in the age-related maculopathy and neovascular age-related macular degeneration groups were 52.6 (2.8-198.1) ng/mL and 60.9 (3.1-173.1) ng/mL, respectively. The levels were significantly raised compared with the control group (n = 38), which had a median (range) plasma complement C3a des Arg level of 40.3 (6.1-81.7) ng/mL (analysis of variance, P = .02). The concentration of plasma C3a des Arg did not differ significantly between those with different CFH genotypes (P = .07). CONCLUSION: Systemic activation of the complement system may contribute to the pathogenesis of age-related macular degeneration independent of CFH polymorphism. CLINICAL RELEVANCE: The results of this study may be relevant to aiming new treatment strategies toward reducing systemic low-grade inflammation.

Chau KY, Sivaprasad S, Patel N, Donaldson TA, Luthert PJ, Chong NV. · Institute of Ophthalmology, University College, London, UK. · Eye. · Pubmed #17304258 No free full text.

Abstract: BACKGROUND: Several studies indicate that age-related macular degeneration (AMD) and atherosclerosis may share common pathogenetic pathways. The aim of this study was to determine the role of systemic matrix metalloproteinases (MMPs) in AMD, given that MMPs are implicated in the pathogenesis of atherosclerosis. METHODS: This study determined the plasma matrix metalloproteinases (MMP-2 and MMP-9) levels in three groups of subjects: group 1 included subjects with age-related maculopathy (ARM), group 2 included subjects with choroidal neovascularization (CNV) owing to AMD and group 3 consisted of age-matched controls. RESULTS: The mean plasma levels of MMP-2 were not significantly different in the three groups. In contrast, the mean plasma MMP-9 levels were significantly higher in ARM and CNV groups compared to that of the control group. However, there was no significant difference in MMP-9 levels between ARM and CNV groups. CONCLUSION: This is the first study that reveals a link between raised plasma MMP-9 levels with AMD. Further studies are required to identify the factors that contribute to this association.

Smith RT, Chan JK, Busuoic M, Sivagnanavel V, Bird AC, Chong NV. · Department of Ophthalmology, Columbia University, Harkness Eye Institute, New York, New York 10032, USA. · Invest Ophthalmol Vis Sci. · Pubmed #17122141 links to  free full text

Abstract: PURPOSE: To assess the relationships of drusen, pigment, and focally increased autofluorescence (FIAF) and the reticular pattern of hypoautofluorescence, to distinguish the combined photographic and AF characteristics of early, atrophic, and high-risk fellow eyes in AMD. METHODS: In a retrospective interinstitutional clinical study, AF and color photograph pairs of 221 eyes were examined: 166 eyes of 83 patients with bilateral large, soft drusen, with and without geographic atrophy (GA), and 55 fellow eyes of 55 patients with unilateral choroidal neovascularization (CNV). Forty-two eyes (one eye from each of 42 patients with early or atrophic AMD) were divided into four groups: 14 with drusen only, 9 with drusen and pigment abnormalities, 11 fellow eyes of patients with unilateral GA, and 8 eyes of patients with bilateral GA (acronyms for the groups: D-D, D-Pig, D-GA and GA-GA, respectively). The 55 fellow eyes of patients with CNV were divided into three groups: 19 eyes with no FIAF (CNV-0), 16 with FIAF without reticular AF (CNV-1), and 20 eyes with reticular AF and/or pseudodrusen (CNV-R). Image pairs of eyes with FIAF were registered, and drusen, pigment, and FIAF were segmented using automated background leveling and thresholding. All 221 eyes were surveyed for reticular AF and reticular pseudodrusen. The main outcome measures were (1) the fraction and relative probability of FIAF colocalizing with drusen and pigment and (2) the presence or absence of reticular AF and reticular pseudodrusen. RESULTS: The mean fractions of FIAF that colocalized with large drusen were: D-D group, 0.46 +/- 0.21; D-Pig group, 0.42 +/- 0.29; D-GA group, 0.13 +/- 0.09; and GA-GA group, 0.11 +/- 0.12. Comparisons between groups showed significant differences when comparing either the D-D group or the D-Pig group with either the D-GA group or the GA-GA group (P between 0.0001 and 0.015), whereas other comparisons were nonsignificant (Mann-Whitney rank sum test). The mean probabilities of FIAF colocalizing with large drusen relative to chance (1.0) were: D-D group, 4.7 +/- 2.5; D-Pig group, 4.3 +/- 2.3; D-GA group, 1.4 +/- 0.8; and GA-GA group, 1.8 +/- 1.3, with similar significant differences as for the colocalization fractions. The mean probability of FIAF colocalizing with small to intermediate drusen in the D-D group was 1.5 +/- 1.3, which was not significantly different from chance. In the D-Pig group, the median probability of FIAF colocalizing with pigment abnormalities was 10.0 (range, 1.1-51.0). The AF patterns in 15 of 19 eyes in the CNV-0 group were normal; the remainder had nonreticular hypoautofluorescence only. In the CNV-1 group, the relations of FIAF with drusen and pigment were similar to those in the early AMD groups. CNV-R comprised 20 of 55 eyes in the CNV group, but reticular autofluorescence and/or pseudodrusen were found in only 14 of 166 eyes of the early and atrophic groups. Of the 34 total eyes with reticular AF or pseudodrusen, 28 had both, 4 had reticular AF only, and 2 had reticular pseudodrusen only. CONCLUSIONS: There are clear relationships between AF patterns and clinical AMD status. In early AMD, FIAF's colocalization with large, soft drusen and hyperpigmentation is several times greater than chance, suggesting linked disease processes. In advanced atrophic AMD, FIAF is found mostly adjacent to drusen and GA, suggesting that dispersal of drusen-associated lipofuscin is a marker of atrophic disease progression. In the neovascular case, a large group of fellow eyes have no FIAF abnormalities, suggesting that lipofuscin is not a major determinant of CNV. However, reticular hypoautofluorescence, consistent with widespread inflammatory damage to the RPE, appears to be a highly sensitive imaging marker for the disease that determines reticular pseudodrusen and is strongly associated with CNV.

Sandhu R, Sivaprasad S, Shah SP, Adewoyin T, Chong NV. · Retinal Research Unit, Department of Ophthalmology, King's College Hospital, Denmark Hill, London, UK. · Eye. · Pubmed #16456596 No free full text.

Abstract: PURPOSE: Ocular perfusion abnormalities have been proposed in the pathogenesis of age-related macular degeneration (AMD) with differences in pulsatile ocular blood flow (POBF) in eyes with asymmetric AMD in Japanese and Taiwanese patients. The purpose of our study was to observe POBF difference in the fellow eyes of Caucasians with asymmetric AMD. METHODS: This was a cross-sectional study comparing POBF in three groups of patients with asymmetric AMD in the fellow eyes: Group 1 (n=21) with drusen and active choroidal neovascularisation (CNV); Group 2 (n=18) with drusen and disciform scar; Group 3 (n=8) with CNV and disciform scar. The POBF was adjusted for intraocular pressure (IOP), pulse rate (PR), and axial length using multiple regression analysis. Generalised estimation equation model was used to include both eyes in each group. RESULTS: The geometric mean (95% confidence interval) POBF values were as follows: Group 1 with drusen 1097.9 microl/min (957.0, 1259.7) in one eye and the fellow eye with CNV 1090.1 microl/min (932.3, 1274.7); Group 2 with drusen 946.0 microl/min (794.2, 1126.7) and disciform scar 966.2 microll/min (780.3, 1196.4); Group 3 with CNV 877.1 microl/min (628.3, 1224.6) and disciform scar 767.2 microl/min (530.5, 1109.7). Adjusting for differences in axial length, pulse rate and intraocular pressure, no statistically significant difference in POBF was found between fellow eyes in the same subject. CONCLUSIONS: POBF is not different between fellow eyes of Caucasian patients with asymmetric AMD.

Sivaprasad S, Chong NV. · Laser and Retinal Research Unit, King's College Hospital, Denmark Hill, London, UK. · Eye. · Pubmed #16410816 No free full text.

Abstract: PURPOSE: Age-related macular degeneration (AMD) is the leading cause of blindness in the developed world. There are increasing evidences to suggest the complement system may play a significant role on the pathogenesis of AMD. In this review, we summarise the current research in this area. METHODS: Review of literature. RESULTS: The complement system is a complex system with several activation pathways. Complement factor H (CFH) polymorphisms has been associated with increase risk of AMD. CFH is an inhibitor protein; the polymorphisms might cause uncontrolled activation by initiation events. CONCLUSION: Further studies on the molecular basis of the complement-mediated pathogenesis of AMD may offer novel therapy to AMD.

Sivaprasad S, Membrey WL, Sivagnanavel V, Gonzalez JG, Liu DT, Chan WM, Lam DS, Jackson H, Chong NV. · Retinal Research Unit, King's College Hospital, Denmark Hill, London, UK. · Eye. · Pubmed #16123783 No free full text.

Abstract: PURPOSE: To investigate the correlation between morphological features of choroidal neovascularisation (CNV) secondary to age-related macular degeneration (AMD) in the first eye and the severity of age-related maculopathy (ARM) in the fellow eyes in two racial groups: Caucasians and Chinese. PARTICIPANTS: A total of 135, fluorescein angiograms of patients with unilateral neovascular AMD and ARM in the fellow eyes were included in the study: 38 Caucasians from King's College Hospital, UK; 45 Caucasians from West Kent Eye Centre, UK; 52 Chinese from Hong Kong Eye Hospital, Hong Kong. MAIN OUTCOME MEASURES: CNV subtype in the affected eye and ARM severity in the second eyes. RESULTS: Although the proportion of CNV subtypes in the three groups were similar, the Chinese cohort showed significantly less ARM severity compared to the Caucasian cohorts (P < 0.05). CONCLUSION: Although drusen and retinal pigmentary changes may be prognostic indicators of CNV, this study suggest that other factors contribute significantly to the pathogenesis of CNV in AMD.

Sivaprasad S, Chong NV, Bailey TA. · Laser and Retinal Research Unit, King's College Hospital, University of London, Denmark Hill, London SE5 9RS, UK. · Invest Ophthalmol Vis Sci. · Pubmed #16123400 links to  free full text

Abstract: PURPOSE: Dysregulation of the extracellular matrix (ECM) plays an important role in the pathogenesis of age-related macular degeneration (AMD). Elastin is a fibrous protein constituent of the ECM, degradation of which may be detected by the presence of serum elastin-derived peptides (S-EDPs) in circulation. This study was undertaken to estimate levels of S-EDPs in patients with AMD compared with age-matched control subjects. METHODS: Fifty-six patients with AMD were classified into two groups: early age-related maculopathy (ARM) and neovascular AMD. The control group consisted of 15 age-matched subjects with no AMD. S-EDP levels in the serum of these subjects was estimated by competitive ELISA, using solubilized alpha-elastin from human aorta and polyclonal antibodies to this antigen. RESULTS: S-EDPs were significantly higher in patients with AMD than in control subjects. In addition, subjects with neovascular AMD had higher levels of S-EDPs than did those with early disease. CONCLUSIONS: The cause of this association between S-EDPs and AMD is unknown, but it suggests that systemic elastin degradation may increase the risk of conversion from early ARM to neovascular AMD. Further studies are needed to confirm whether the serum level of S-EDPs is a useful predictor of conversion from early ARM to neovascular AMD.

Sivagnanavel V, Smith RT, Lau GB, Chan J, Donaldson C, Chong NV. · Retinal Research Unit, King's College Hospital, University of London, UK. · Br J Ophthalmol. · Pubmed #15834083 links to  free full text

Abstract: AIMS: To assess the portability and clinical applicability of a software program based on Photoshop (Adobe Systems Inc, San Jose, CA, USA) for digital drusen quantification. METHODS: Independent graders from the Digital Fundus Photo Reading Center of Columbia University and King's College Hospital used macular background levelling software to quantify the percentage of drusen in the central and middle Wisconsin subfields. 100 images of consecutive patients with choroidal neovascularisation in one eye and significant drusen in the other eye were analysed to determine suitability, and 10 were chosen for assessment by this software. RESULTS: Of the 10 images used in the interinstitutional validation, the random effects ANOVA for the central and middle subfields showed a high degree of interobserver agreement. The ICC for interobserver reliability was 0.83 (95% CI: 67 to 95) for the central subfield and 0.84 (95% CI: 69 to 99) for the middle subfield. Overall agreement with the manual grading results was good and the within patient coefficient of variation was about 20% for all the pairwise comparisons between observers and the manual stereo gradings. Of the 100 images used to assess practical applicability of the software, 79 were suitable for semiautomated analysis. 13 had extensive mixed retinal pigment epithelial (RPE) changes limiting drusen identification, five had a significant number of reticular drusen, which are poorly identified by the software, and three had multiple small areas of RPE atrophy, which are difficult to distinguish from drusen. CONCLUSIONS: The software was successfully used by two institutions demonstrating portability, with good correlation between graders and to the manual stereo grading. Digital drusen quantification was possible in 79% of the images analysed.

Hamada S, Jain S, Sivagnanavel V, Patel N, Chong NV. · Retinal Research Unit, King's College Hospital, University of London, UK. · Eye. · Pubmed #15746948 No free full text.

Abstract: AIM: To assess the value of the modified international classification system in screening high-risk patients with bilateral age-related maculopathy (ARM) from those with lower risk characteristics. METHODS: In total, 164 digital images of 106 patients with either bilateral ARM (group A) or the fellow eyes of unilateral exudative age-related macular degeneration (AMD) (Group B) were included. Patients with no signs of ARM in both eyes or those with bilateral late AMD were excluded. The images were randomised and then graded by two masked ophthalmologists based on the modified International Classification of ARM. RESULTS: The interobserver consistency between the two graders was high with a Kappa value of 0.82 (SE 0.34, P<0.0001). There were no significant differences in the distribution of the stages of ARM between the two subgroups. Stage 3 was the most common stage in each group for both graders followed by stage 2a in the bilateral drusen group. Stages 1a, 2a and 2b were equally the next common stage in the fellow eye of chordial neovascularisation group. CONCLUSION: A screening system based on clinical characteristics would be of value in risk prediction in a clinical setting. Type of Drusen alone, as identified by the modified International grading system, may not be reliably predictive in screening for patients who are at high risk of developing choroidal neovascularisation.