Ian Yeo

Age-related macular degeneration and polypoidal choroidal vasculopathy in Asians.

Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in elderly people globally. It is estimated that there will be more Asians with AMD than the rest of the world combined by 2050. In Asian populations, polypoidal choroidal vasculopathy (PCV) is a common subtype of exudative AMD, while choroidal neovascularization secondary to AMD (CNV-AMD) is the typical subtype in Western populations. The two subtypes share many common clinical features and risk factors, but also have different epidemiological and clinical characteristics, natural history and treatment outcomes that point to distinct pathophysiological processes. Recent research in the fields of genetics, proteomics and imaging has provided further clarification of differences between PCV and CNV-AMD. Importantly, these differences have manifested as disparity in response to intravitreal injections of anti-vascular endothelial growth factor (anti-VEGF) treatment between PCV and CNV-AMD, emphasizing the need for accurate diagnosis of PCV and in distinguishing PCV from CNV-AMD, particularly in Asian patients. Current clinical trials of intravitreal anti-VEGF therapy and photodynamic therapy will provide clearer perspectives of evidence-based management of PCV and may lead to paradigm shifts in therapeutic strategies away from those currently employed in the treatment of CNV-AMD. Further research is needed to clarify the relative contribution of specific pathways in inflammation, complement activation, extracellular matrix dysregulation, lipid metabolism and angiogenesis to the pathogenesis of PCV. Findings from this research, together with improved diagnostic technology and new therapeutics, will facilitate more optimal management of Asian AMD.

A classification system for polypoidal choroidal vasculopathy.

Purpose: To describe the demographic features and clinical characteristics of polypoidal choroidal vasculopathy (PCV) in Chinese patients and define a new classification system. Methods: Retrospective review of 138 eyes of 123 patients presenting to the Singapore National Eye Center with PCV. Patients underwent ophthalmologic examination including digital color fundus photography and stereoscopic indocyanine green angiography. Classification based on indocyanine green angiography findings. Results: Mean age of patient 68.3 years and 62.4% were men. PCV was unilateral in 87.8% cases and age-related maculopathy was present in the unaffected fellow eye in 22.8%. Average largest size of polyp was 207 &mgr;m. PCV lesions were found in multiple discrete areas in 34.8%. Formation of lesion was cluster in 66.7%, single in 27.5%, and string in 5.8%. PCV lesions were found in the extrafoveal area in 63.0%, subfoveal in 29.7%, juxtafoveal in 15.9%, and peripapillary in 8.0%. Conclusions: Demographics of PCV, unilaterality and frequency of age-related maculopathy in fellow eye similar to other reports in Asians. We describe a classification system for PCV comprising polyp size, location, formation, and number of discrete polyp areas, which can be used for prospective interventional clinical studies and may aid in future prognosis and management of this condition.

Relationship of smoking and cardiovascular risk factors with polypoidal choroidal vasculopathy and age-related macular degeneration in Chinese persons.

PURPOSE Polypoidal choroidal vasculopathy (PCV) has been described as a distinct clinical entity from choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD). The present study aimed to determine risk factors for PCV and to compare associations with those for CNV secondary to AMD. DESIGN Case-control study. PARTICIPANTS Patients of Chinese ethnicity with clinically and angiographically diagnosed PCV (n = 123) or CNV secondary to AMD (n = 128) were recruited from a tertiary eye hospital in Singapore. Controls without signs of PCV, CNV secondary to AMD, or other retinal pathologic features (n = 1489) were selected from a population-based study. METHODS Patients underwent an ophthalmologic examination including digital color fundus photography, stereoscopic fluorescein angiography (FA), and indocyanine green angiography (ICGA). Classification into PCV or CNV secondary to AMD was based on FA and ICGA findings. Risk factors were determined from a standardized interview, with blood pressure recorded using a digital automatic blood pressure monitor. MAIN OUTCOME MEASURES Polypoidal choroidal vasculopathy or CNV secondary to AMD. RESULTS Persons who smoked were more likely to have PCV (39.9% vs. 13.4%) or CNV secondary to AMD (45.0% vs. 12.3%) than those who did not smoke. After controlling for age, gender, diabetes, hypercholesterolemia, and hypertension, persons who smoked were 4 times more likely to have PCV (odds ratio [OR], 4.4; 95% confidence interval [CI], 2.5-7.7; P<0.001) and CNV secondary to AMD (OR, 4.9; 95% CI, 2.7-8.8; P<0.001). A significant, negative association also was found between diastolic blood pressure and CNV secondary to AMD (OR, 0.7; 95% CI, 0.5-0.9; P = 0.017, adjusted for age, gender, smoking, diabetes, and hypercholesterolemia), but diastolic blood pressure was not associated with PCV. CONCLUSIONS Smoking but not other vascular risk factors is significantly associated with both PCV and CNV secondary to AMD in Chinese persons. The similarity of associations suggests that there may be common risk factors and pathological mechanisms.

Conversion to aflibercept for diabetic macular edema unresponsive to ranibizumab or bevacizumab

Background The purpose of this study was to determine if eyes with diabetic macular edema (DME) unresponsive to ranibizumab or bevacizumab would benefit from conversion to aflibercept. Methods This study was conducted as a retrospective chart review of subjects with DME unresponsive to ranibizumab and/or bevacizumab and subsequently converted to aflibercept. Results In total, 21 eyes from 19 subjects of mean age 62±15 years were included. The majority of subjects were male (63%). The median number of ranibizumab or bevacizumab injections before switching to aflibercept was six, and the median number of aflibercept injections after switching was three. Median follow-up was 5 months after the switch. Mean central foveal thickness (CFT) was 453.52±143.39 mm immediately prior to the switch. Morphologically, intraretinal cysts were present in all cases. Mean CFT after the first injection decreased significantly to 362.57±92.82 mm (Wilcoxon signed-rank test; P<0.001). At the end of follow-up, the mean CFT was 324.17±98.76 mm (P<0.001). Mean visual acuity was 0.42±0.23 logMAR just prior to the switch, 0.39±0.31 logMAR after one aflibercept injection, and 0.37±0.22 log-MAR at the end of follow-up. The final visual acuity was significantly better than visual acuity before the switch (P=0.04). Conclusion Eyes with DME unresponsive to multiple ranibizumab/bevacizumab injections demonstrate anatomical and visual improvement on conversion to aflibercept.

Impact of early and late age-related macular degeneration on vision-specific functioning

Aim To assess the impact of early and late age-related macular degeneration (AMD) on vision-specific functioning in Singapore Malays. Methods AMD was assessed from fundus photographs. The following endpoints were considered for (a) AMD: no AMD, early AMD, and late AMD; (b) drusen: absence and presence; and (c) retinal pigment epithelium (RPE) abnormality: absence and presence. Vision functioning was assessed using the modified VF-11 scale validated using the Rasch analysis. The overall functioning score was used as the main outcome measure. Results Retinal photographs and vision functioning data were available only for 3252 participants. After age standardisation, the prevalence of early AMD was 3.5% and late AMD 0.34%. In multivariate models, after adjusting for age, gender, education, level of income, smoking status, ocular condition and hypertension, only late AMD was independently associated with poorer vision functioning when compared with no AMD or early AMD (β (β regression coefficient)=−6.4 (CI −11.7 to −2.1; p=0.01)). Early AMD or its principal components, drusen or RPE abnormality, were not independently associated with vision functioning (p>0.05). In adjusted multinomial logistic regression models, people with late AMD were twice as likely (OR=2.23; 95% CI 1.16 to 7.11) to have low overall functioning than those without AMD. Conclusions Late AMD has a significant impact on visual functioning, but early AMD, drusen and RPE changes have no impact. These data highlight the importance of preventive public health strategies targeting patients with early AMD signs in order to prevent progression to late AMD when visual function is compromised.

A Prospective Study of Treatment Patterns and 1-Year Outcome of Asian Age-Related Macular Degeneration and Polypoidal Choroidal Vasculopathy

Objective To study the treatment patterns and visual outcome over one year in Asian patients with choroidal neovascular membrane secondary to age-related macular degeneration (AMD-CNV) and polypoidal choroidal vasculopathy (PCV). Design Prospective cohort, non-interventional study. Methods 132 treatment-naïve patients who received treatment for AMD-CNV and PCV were included. All patients underwent standardized examination procedures including retinal imaging at baseline and follow-up. AMD-CNV and PCV were defined on fundus fluorescein angiography and indocyanine green angiography at baseline. Patients were treated according to standard of care.We report the visual acuity (VA) and optical coherence tomography (OCT) measurements at baseline, month 3 and month 12 The factors influencing month 12 outcomes were analyzed. Main Outcome Measure Type of treatment, number of Anti-vascular endothelial growth factor (VEGF) treatments, visual outcome over one year. Results Anti-VEGF monotherapy was the initial treatment in 89.1% of AMD-CNV, but only 15.1% of PCV. The mean number of anti-VEGF injections up to month 12 was 3.97 (4.51 AMD-CNV, 3.43 PCV, p = 0.021). Baseline OCT, month 3 OCT and month 3 VA were significant in determining continuation of treatment after month 3. At month12, mean VA improved from 0.82 (∼20/132) at baseline to 0.68 (∼20/96) at month 12 (mean gain 6.5 ETDRS letters, p = 0.002). 34.2% of eyes (38/113 eyes) gained ≥15 ETDRS letters and 14.4% (16/113 eyes) lost ≥15 ETDRS letters. There were no significant differences in visual outcome between AMD-CNV and PCV (p = 0.51). Factors predictive of month 12 visual outcome were baseline VA, baseline OCT central macular thickness, month 3 VA and age. Conclusions There is significant variation in treatment patterns in Asian eyes with exudative maculopathy. There is significant visual improvement in all treatment groups at one year. These data highlight the need for high quality clinical trial data to provide evidence-based management of Asian AMD.

THREE-YEAR RESULTS OF POLYPOIDAL CHOROIDAL VASCULOPATHY TREATED WITH PHOTODYNAMIC THERAPY: Retrospective Study and Systematic Review.

Purpose: To evaluate the 3-year outcome in eyes with polypoidal choroidal vasculopathy (PCV) treated with photodynamic therapy with verteporfin. Methods: Retrospective study and review of the literature. We performed a retrospective study of patients with PCV who were treated with photodynamic therapy between January 2007 and December 2008. Patients were excluded if they had received photodynamic therapy before the study period, but those who received previous treatment with other modalities (thermal laser or intravitreal therapies) were allowed. The main outcome measures were best-corrected visual acuity, repeat photodynamic therapy, and recurrence of PCV at the end of Years 1, 2, and 3. We further conducted a systematic review of the literature using the terms “polypoidal choroidal vasculopathy” and “photodynamic therapy” and compared the visual outcome of studies over 3 years using meta-analytical methods. Results: The retrospective study included 68 eyes. The mean best-corrected visual acuity was 0.73 ± 0.56 logMAR (20/107, Snellen equivalent) at baseline, 0.73 ± 0.70 logMAR (20/107, Snellen equivalent) at 1 year, 0.96 ± 0.76 logMAR (20/182, Snellen equivalent) at 2 years, and 1.07 ± 0.81 logMAR (20/235, Snellen equivalent) at 3 years. The cumulative recurrence rates of PCV were 16.1% (1 year), 34.9% (2 years), and 52.7% (3 years) and eyes with recurrence were more likely to suffer ≥3 lines loss compared with eyes without recurrence (63.2 vs. 17.6%, P = 0.006). The systematic review summarized results from 48 published studies and our retrospective study. The pooled analysis from 29 studies (316 eyes reporting the 3-year visual outcome) reported mean best-corrected visual acuity improvement of 0.115 logMAR at 1 year (n = 1,669), 0.066 logMAR at 2 years (n = 701), and 0.027 logMAR at 3 years (n = 316). Reported recurrence rates were 5.9% to 50.0% after 1 year, 9.1% to 83.3% after 2 years, and 40.0% to 78.6% after 3 years or longer of follow-up. Conclusion: The visual outcome in eyes with PCV was stable until 2 years, but the outcome at 3 years worsened, particularly in eyes that experienced recurrence.

Prevalence and clinical correlates of focal choroidal excavation in eyes with age-related macular degeneration, polypoidal choroidal vasculopathy and central serous chorioretinopathy

Purpose To describe the prevalence and clinical characteristics of focal choroidal excavation (FCE) in patients with exudative maculopathy due to age-related macular degeneration with choroidal neovascularisation (AMD-CNV), polypoidal choroidal vasculopathy (PCV) and central serous chorioretinopathy (CSC). Methods Three hundred and forty-three patients (343 presenting eyes and 255 fellow unaffected eyes) from consecutive patients presenting with untreated AMD-CNV, PCV or CSC are prospectively recruited. Two independent retinal specialists masked to the clinical diagnosis graded the presence of FCE by examining the findings from spectral-domain optical coherence tomography (SD-OCT). The frequency and clinical characteristics of FCE in each of the three clinical diagnosis groups were compared. Results The diagnosis in the presenting eye was AMD-CNV in 92 patients, PCV in 149 patients, retinal angiomatous proliferation (RAP) in 3 patients and CSC in 99 patients; 255 fellow eyes free of clinical diseases were also graded. The prevalence of FCE was 2.3% (total 14 eyes; 10 presenting eyes, 4 fellow eyes) out of 598 eyes examined. In presenting eyes, FCE was most prevalent in PCV (6.0%), followed by AMD-CNV (1.0%) and CSC (0%), p=0.02. In fellow eyes, the prevalence of FCE was 2.9%, 0% and 1.2% in patients with PCV, AMD-CNV and CSC, respectively. Eyes with FCE had a significantly longer axial length (24.93±1.65 mm vs 23.49±1.10 mm, p<0.001), but otherwise, all other characteristics were similar. Conclusions FCE is more common in PCV than AMD-CNV and CSC. Disturbance in the choroid/retinal pigment epithelium/Bruch membrane interface affected by FCE may be linked to the pathogenesis of PCV and AMD-CNV.

Characterization And Differentiation Of Polypoidal Choroidal Vasculopathy Using Swept Source Optical Coherence Tomography Angiography

Purpose: To determine the correlation and agreement between swept-source optical coherence tomography angiography (SS-OCT-A) with fluorescein angiography (FA), indocyanine green angiography (ICGA) and spectral domain OCT (SD-OCT) in characterizing polypoidal choroidal vasculopathy (PCV) and in differentiating eyes with typical age-related macular degeneration (t-AMD). Methods: This study included 32 and 54 eyes with t-AMD and PCV, respectively, who underwent SS-OCT-A, SD-OCT, fluorescein angiography, and indocyanine green angiography. The images from these four techniques were compared. Results: On SS-OCT-A, flow signals with vascular network configuration were detected in 81.2% and 77.8% of eyes with t-AMD and PCV, respectively. 40.4% of polyps were detected as flow signals with polypoidal configuration. Compared with indocyanine green angiography, SS-OCT-A had sensitivity and specificity of 83.0% and 57.1%, respectively, for vascular network, and 40.5% and 66.7% for polyps. Longitudinal changes were in agreement between SS-OCT-A and SD-OCT in 90% of eyes. 88.2% of eyes with dry retina on SD-OCT had persistent vascular net on SS-OCT-A. In two cases with reactivation of PCV, SS-OCT-A was more sensitive at detecting recurrence than SD-OCT. Conclusion: Swept-source optical coherence tomography angiography is effective at detecting vascular network that correlate to conventional angiography in eyes with t-AMD and PCV. Swept-source optical coherence tomography angiography is inferior to indocyanine green angiography in detecting polyps and cannot replace indocyanine green angiography for differentiating PCV from t-AMD; however, SS-OCT-A may be more sensitive than SD-OCT in detecting early recurrence.

Systemic, Ocular and Genetic Risk Factors for Age-related Macular Degeneration and Polypoidal Choroidal Vasculopathy in Singaporeans

To examine the association of systemic, ocular and genetic risk factors in neovascular age-related macular degeneration (nAMD) in a large cohort of Asian patients, and to further compare risk factors between those with typical AMD and polypoidal choroidal vasculoapthy (PCV) subtypes. We recruited 456 cases and 1,824 controls matched for age, gender and ethnicity. Data on systemic and ocular risk factors were collected on questionnaires. In a subgroup of subjects, we included genetic data on four AMD-associated single nucleotide polymorphisms (SNPs). Risk factors for nAMD and subtypes were analyzed. Systemic risk factors for nAMD included older age, male gender, higher BMI and higher HDL-cholesterol. Ocular risk factors included pseudophakic and shorter axial length. Risk factors common to both typical AMD and PCV subtypes included age, BMI and HDL-cholesterol. Shorter axial length was only associated with PCV, while male gender and pseudophakia were only associated with typical AMD. In the subgroup with genotype data, ARMS2 rs10490924 and CFH rs800292 were associated with nAMD. None of the risk factors were significantly different between PCV and typical AMD. Systemic, ocular and genetic risk factors were largely similar for typical AMD and PCV subtypes in this Asian population based in Singapore.