Optimisation of an automated drusen-quantifying software for the analysis of drusen distribution in patients with age-related macular degeneration.

PURPOSE: The purpose of this study is to optimise the settings of the Retinal Image Analysis Laboratory (RIALAB), a semi-automatic drusen quantification software, in planning for high-throughput quantification of drusen in clinical studies of age-related macular degeneration (AMD). PATIENTS AND METHODS: A comparison of five different settings in RIALAB was made on 67 images from the Rotterdam eye study (population-based study) and 56 images from the fellow eye of patients with active neovascular AMD in King's College Hospital, London (hospital-based study). RESULTS: The 'Few Outer' setting was the best setting, with it being most appropriate for 52 (77.6%) of the Rotterdam cohort and 47 (83.9%) for the London cohort. Pearson's χ(2)-test revealed both results to be statistically significant (P<0.0001). CONCLUSIONS: RIALAB is a viable algorithm and software package that can detect, quantify, and analyse drusen efficiently in both population-based and hospital-based studies. We have shown that the 'Few Outer' drusen setting can be employed as the default setting, with fine-tuning only needed in a minority of cases, thus helping to speed up workflow.

Two-wavelength fundus autofluorescence and macular pigment optical density imaging in diabetic macular oedema.

PURPOSE: To evaluate the application of 488 and 514 nm fundus autofluorescence (FAF) and macular pigment optical density (MPOD) imaging in diabetic macular oedema (DMO) and to demonstrate the typical imaging features. PATIENTS AND METHODS: A hundred and twenty-five eyes of 71 consecutive patients with diabetic retinopathy who underwent examination at a specialist university clinic employing a modified Heidelberg Retina Angiograph, using two different light sources of 488 and 514 nm wavelength, were retrospectively reviewed. MPOD images were calculated using modified Heidelberg Eye Explorer software. All images were evaluated by two independent masked graders. Features from FAF and MPOD images were correlated with optical coherence tomography (OCT) imaging findings and inter-grader variability, sensitivity and specificity were calculated using OCT as reference. RESULTS: Sixty-seven eyes had DMO on OCT. The inter-grader variability was 0.84 for 488 nm FAF, 0.63 for 514 nm FAF and 0.79 for MPOD imaging. Sensitivity and specificity for detection of DMO were 80.6 and 89.7% for 488 nm FAF; 55.2 and 94.8% for 514 nm FAF; and 80.6 and 91.4% for MPOD imaging. In 488 nm FAF and MPOD imaging, DMO was better visualised in comparison with 514 nm FAF imaging, P<0.01. MPOD revealed displacement of macular pigment by intraretinal cysts. CONCLUSION: MPOD imaging, and particularly its combination with 488 nm and 514 nm FAF, provides a valuable addition to OCT in the evaluation of DMO and is clinically useful in rapid en-face assessment of the central macula.

New approaches for the treatment of diabetic macular oedema: recommendations by an expert panel.

The current standard therapy for patients with diabetic macular oedema (DME)--focal/grid laser photocoagulation--usually does not improve impaired vision, and many patients lose vision despite laser therapy. Recent approval of ranibizumab by the European Medicines Agency to treat visual impairment due to DME fulfils the previously unmet medical need for a treatment that can improve visual acuity (VA) in these patients. We reviewed 1- and 2-year clinical trial findings for ranibizumab used as treatment for DME to formulate evidence-based treatment recommendations in the context of this new therapy. DME with or without visual impairment should be considered for treatment when it fulfils the Early Treatment Diabetic Retinopathy Study (ETDRS) criteria for clinically significant oedema. For DME with centre involvement and associated vision loss due to DME, monthly ranibizumab monotherapy with treatment interruption and re-initiation based on VA stability is recommended. Laser therapy based on ETDRS guidelines is recommended for other forms of clinically significant DME without centre involvement or when no vision loss has occurred, despite centre involvement. Because these recommendations are based on randomised controlled trials of 1-2 years duration, guidance may need updating as long-term ranibizumab data become available and as additional therapeutic agents are assessed in clinical trials.

A pilot study on the combination treatment of reduced-fluence photodynamic therapy, intravitreal ranibizumab, intravitreal dexamethasone and oral minocycline for neovascular age-related macular degeneration.

AIM: To assess the safety and efficacy of the combined treatment of reduced-fluence verteporfin photodynamic therapy (PDT), intravitreal ranibizumab, intravitreal dexamethasone and oral minocycline for choroidal neovascularisa- tion (CNV) secondary to age-related macular degeneration (AMD). METHODS: Nineteen patients with subfoveal CNV secondary to AMD were recruited into the trial. All study eyes (n = 19) received a single cycle of reduced-fluence (25 mJ/cm(2)) PDT with verteporfin followed by an intravitreal injection of ranibizumab 0.3 mg/0.05 ml and dexamethasone 200 µg at baseline. Oral minocycline 100 mg daily was started the following day and continued for 3 months. Patients were followed up monthly for 12 months. Repeat intravitreal ranibizumab was given if best-corrected visual acuity (BCVA) deteriorated by >5 letters on the Early Treatment Diabetic Retinopathy Study (ETDRS) chart or central retinal thickness (CRT) on ocular coherence tomography increased >100 µm. RESULTS: Eighteen patients completed the 12-month study. Stable vision (loss of ≤15 ETDRS letters) was maintained in 89% eyes (16/18). The mean change in BCVA was -5.0 ± 10.5 ETDRS letters. The mean number of ranibizumab injections was 3.4 (range 2-6). The mean reduction in the CRT was 66.3 µm (±75). CONCLUSION: This open-label clinical trial has demonstrated the safety in terms of adverse effects and maintenance of stable vision of combination treatment with verteporfin, ranibizumab, dexamethasone and minocycline in exudative AMD. However, the outcomes with reduced-fluence PDT combination therapy does not differ significantly with outcomes of clinical trials on combination treatment with standard dose PDT and intravitreal ranibizumab in neovascular AMD.

Comparing fixation location and stability in patients with neovascular age-related macular degeneration treated with or without Ranibizumab.

PURPOSE: To compare fixation location and stability in patients with neovascular age-related macular degeneration (AMD) treated with or without ranibizumab. METHODS: Patients were recruited from the Macular Clinic of the King's College Hospital in London. Two groups of patients with neovascular AMD with at least 12 months of follow-up were included in the study. The treated group was treated with ranibizumab while the untreated group did not have any treatment. Best corrected visual acuity (BCVA) with modified ETDRS chart, fixation location and stability as measured with Nidek MP1, central retinal thickness as measured by Zeiss Cirrus SD-optical coherent tomography (OCT), and lesion size as measured by Topcon TRC-50IX camera were analysed and correlated. RESULTS: In total, 102 eyes were included in the study with 76 in the ranibizumab-treated group and 26 in the untreated group. There were no significantly demographic differences between the two groups. However, as expected, the treated group has significantly better vision (48.5 vs 15.5 letters, P < 0.0001) and smaller lesions (10.8 vs 18.3 mm(2), P = 0.004), the central macular thickness as measured by OCT also showed a trend of normalised macular thickness (252 vs 282 microns, P = 0.07). The location of fixation was significantly more central in the ranibizumab-treated group (χ(2) 17.9, P < 0.0001) with over 50% of eyes with predominantly central fixation. Majority (84.6%) of the patients in the untreated group had predominantly eccentric fixation. Fixation stability was significantly better in the ranibizumab-treated group as compared with the untreated group, using both the software provided by the MP1 machine (χ(2) 21.8, P < 0.0001) and the mean log bivariate contour ellipse area calculated from the raw data obtained from the machine (3.64 vs 4.39 in treated and untreated group respectively, P < 0.0001). CONCLUSION: Low vision rehabilitation strategy for this group of patients in the ranibizumab era will be very different from those used in untreated patients with dense central scotoma. Further studies on the visual rehabilitation in the ranibizumab-treated patients should consider fixation characteristics of the patients.

Prospective randomised controlled trial comparing sub-threshold micropulse diode laser photocoagulation and conventional green laser for clinically significant diabetic macular oedema.

AIM: The study was a prospective randomised controlled double-masked trial performed in two centres to compare sub-threshold micropulse diode laser photocoagulation (MPDL) with conventional green laser photocoagulation (CGL) in the treatment of clinically significant diabetic macular oedema (CSMO). METHODS: Fifty-three patients (84 eyes) with diabetic CSMO were randomly assigned to MPDL (n = 44) or CGL (n = 40) according to the modified Early Treatment Diabetic Retinopathy Study (ETDRS) protocol. Treatments were performed after baseline and re-treatments were allowed at or after the 4 month visit if necessary. Parameters noted included the best corrected visual acuity (BCVA), colour fundus photographs, central retinal thickness using optical coherence tomography (OCT), vision contrast sensitivity with Pelli-Robson charts and presence of visible laser scars at baseline and at 4 and 12 months. The primary outcome was BCVA at 12 months. RESULTS: All patients completed 12 months of follow-up after treatment at baseline. There were no statistically significant differences in BCVA, contrast sensitivity and retinal thickness between the two laser modalities at 0, 4 and 12 months. We found that laser scarring was much more apparent with CGL than with the sub-threshold approach (MPDL). Laser scars were identified at the 12 month visits in 13.9% of the MPDL-treated eyes compared with 59.0% of the CGL-treated eyes (p<0.001). CONCLUSION: Sub-threshold micropulse diode laser photocoagulation is equally as effective as CGL treatment for CSMO. TRIAL REGISTRATION NUMBER: ISTRN 90646644.

Computerized model of cost-utility analysis for treatment of age-related macular degeneration.

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.

Plasma levels of matrix metalloproteinase-2 and -9 (MMP-2 and MMP-9) in age-related macular degeneration.

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.

Looking beyond Lucentis on the management of macular degeneration.

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.

Age-related macular degeneration: a perspective on genetic studies.

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.

Plasma levels of matrix metalloproteinase-2 and -9 (MMP-2 and MMP-9) in age-related macular degeneration.

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.

Pulsatile ocular blood flow in asymmetric age-related macular degeneration.

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.

The complement system and age-related macular degeneration.

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.

Second eye of patients with unilateral neovascular age-related macular degeneration: Caucasians vs Chinese.

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.

Drusen classification in bilateral drusen and fellow eye of exudative age-related macular degeneration.

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.

An interinstitutional comparative study and validation of computer aided drusen quantification.

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.