Epidemiology of age-related maculopathy

In 1875, Pagenstecher and Gentll provided the first description of age-related maculopathy (ARM). Nowadays, hundred and twenty years after the first description, ARM is one of the major causes of severe irreversible visual loss in the elderly in western countries. It has been estimated that there are 640000 people aged 75 years or older in the United States who have signs of the endstage of this disease. Still, Olll' knowledge about the etiology of ARM is very limited and treatment is only possible in a minority of patients. The Framingham Eye Study was the first population-based study that provided information about prevalence and risk factors for ARM. Since then, several epidemiologic studies on the disease have been performed, most of them in the USA. A review of the epidemiological knowledge obtained in these studies is given in chapter 2 of this thesis. Since until recently a uniform classification of ARM has not been available, comparison of the results of different studies has for years been a problem. Chapter 3 presents the results of several international meetings of six research groups with the aim to develop a uniform classification system for ARM. Little information was available on the prevalence of ARM in the Netherlands. The Rotterdam Study, however, provided an excellent opportunity to answer several research questions into the epidemiology of the disease. The results of the prevalence study are presented in chapter 4. The remainder of this thesis focuses on risk factors of the late stages of the disease, atrophic and neovascular agerelated macular degeneration (AMD). In chapter 5, the associations of various indicators of atherosclerosis and the late stages of the disease are described. Chapter 6 presents the association between smoking and AMD and in chapter 7 the relation with age of menopause and is described. Methodological issues related to the presented studies are discussed in chapter 8, together with a review of the results of these studies and suggestions for future research

Growth in foetal life, infancy, and early childhood and the association with ocular biometry

Purpose: Ocular biometry varies within groups of emmetropic, hyperopic or myopic children. The aim of this study was to quantify the effect of foetal and infant growth on ocular biometry in early childhood, to determine the most important period for this association, and to examine genetic overlap with height and birth weight. Methods: 5931 children (50.1% girls) from a population-based prospective birth cohort study underwent intra-uterine and infant growth measurements at second and third trimester, and from birth to 72 months. An ophthalmic examination including axial length (mm) and corneal radius of curvature (mm) was performed at 6 years of age. The associations between prenatal and postnatal growth variables and axial length and corneal radius of curvature were assessed with conditional linear regression analyses. Weighted genetic risk scores for birth weight and height were calculated and causality was tested with Mendelian randomisation. Results: Weight and length from mid-pregnancy to 2 years of age were most important prognostic factors for axial length and corneal radius of curvature at age 4.9–9 years (mean 6.2 years S.D. 0.5). For height (Standard deviation score), the association with axial length and corneal radius of curvature was highest for the measurement at 12 months (β 0.171 p < 0.001 and 0.070 p < 0.001). The genetic height and birth weight risk scores were both significantly associated with ocular biometry. Conclusions: Larger neonates had longer axial length and greater corneal radius of curvature. Growth during pregnancy and 2 years postnatally is the most important period underlying this association and may be partly genetically determined by genes associated with height

Blood pressure, atherosclerosis, and the incidence of age-related maculopathy: the Rotterdam Study

PURPOSE: To determine whether blood pressure and subclinical atherosclerosis are associated with incident age-related maculopathy (ARM). METHODS: The study was performed within the Rotterdam Study, a population-based, prospective cohort study in Rotterdam, The Netherlands. A total of 4822 subjects who at baseline were aged 55 years more, were free of ARM, and participated in at least one of two follow-up examinations after a mean of 2 and 6.5 years, were included in the study. At baseline, blood pressure and the presence of atherosclerosis were determined. ARM was assessed according to the International Classification and Grading System and defined as large, soft drusen with pigmentary changes; indistinct drusen; or atrophic or neovascular age-related macular degeneration. RESULTS: After a mean follow-up of 5.2 years, incident ARM was diagnosed in 417 subjects. Increased systolic blood pressure or pulse pressure was associated with a higher risk of ARM. Adjusted for age, gender, smoking, total and high-density lipoprotein cholesterol, body mass index, and diabetes mellitus, odds ratios (OR) per 10-mm Hg increase were 1.08 (95% confidence interval [CI]: 1.03-1.14) and 1.11 (95% CI: 1.04-1.18), respectively. Moreover, different measures of atherosclerosis were associated with the risk of ARM. An increase in carotid wall thickness (OR per 1 SD, 1.15; 95% CI: 1.03-1.28) increased the risk of ARM. The lowest compared with the highest tertile of ankle-arm index had an OR of 1.32 (95% CI: 1.00-1.75). A weak association was found between aortic calcifications and the risk of ARM. CONCLUSIONS: Elevated systolic blood or pulse pressure or the presence of atherosclerosis may increase the risk of development of ARM

Low serum vitamin D is associated with axial length and risk of myopia in young children

The aim of the study was to investigate the relationship between serum 25(OH)D levels and axial length (AL) and myopia in 6-year-old children. A total of 2666 children aged 6 years participating in the birth-cohort study Generation R underwent a stepwise eye examination. First, presenting visual acuity (VA) and AL were performed. Second, automated cycloplegic refraction was measured if LogMAR VA > 0.1. Serum 25-hydroxyvitamin D [25(OH)D] was determined from blood using liquid chromatography/tandem mass spectrometry. Vitamin D related SNPs were determined with a SNP array; outdoor exposure was assessed by questionnaire. The relationships between 25(OH)D and AL or myopia were investigated using linear and logistic regression analysis. Average 25(OH)D concentration was 68.8 nmol/L (SD ± 27.5; range 4–211); average AL 22.35 mm (SD ± 0.7; range 19.2–25.3); and prevalence of myopia 2.3 % (n = 62). After adjustment for covariates, 25(OH)D concentration (per 25 nmol/L) was inversely associated with AL (β −0.043; P < 0.01), and after additional adjusting for time spent outdoors (β −0.038; P < 0.01). Associations were not different between European and non-European children (β −0.037 and β −0.039 respectively). Risk of myopia (per 25 nmol/L) was OR 0.65 (95 % CI 0.46–0.92). None of the 25(OH)D related SNPs showed an association with AL or myopia. Lower 25(OH)D concentration in serum was associated with longer AL and a higher risk of myopia in these young children. This effect appeared independent of outdoor exposure and may suggest a more direct role for 25(OH)D in myopia pathogenesis

Incidence of glaucomatous visual field loss after two decades of follow-up: the Rotterdam Study

To determine the incidence of glaucomatous visual field loss (GVFL) two decades after the start of the Rotterdam Study, and to compare known risk factors for open-angle glaucoma (OAG) between different clinical manifestations of OAG. Of 6806 participants aged 55 years and older from the population-based Rotterdam Study, 3939 underwent visual field testing at baseline and at least one follow-up round. The ophthalmic examinations included optic disc assessment and measurements of intraocular pressure (IOP), refractive error, diastolic blood pressure (DBP), and height and weight. The incidence rate of GVFL was calculated. Associations with the risk factors age, gender, baseline IOP, family history, myopia, DBP, and body-mass index [BMI] were assessed using Cox regression, with different clinical manifestations of OAG as outcome measure (glaucomatous optic neuropathy (GON), GVFL, GVFL and GON, GVFL without GON, and GON without GVFL). Median follow-up was 11.1 (IQR 6.8–17.2; range 5.0–20.3) years. The incidence rate of GVFL was 2.9 (95% confidence interval 2.4–3.4) per 1000 person years (140 cas

Axial length growth and the risk of developing myopia in European children

Purpose: To generate percentile curves of axial length (AL) for European children, which can be used to estimate the risk of myopia in adulthood. Methods: A total of 12 386 participants from the population-based studies Generation R (Dutch children measured at both 6 and 9 years of age; N = 6934), the Avon Longitudinal Study of Parents and Children (ALSPAC) (British children 15 years of age; N = 2495) and the Rotterdam Study III (RS-III) (Dutch adults 57 years of age; N = 2957) contributed to this study. Axial length (AL) and corneal curvature data were available for all participants; objective cycloplegic refractive error was available only for the Dutch participants. We calculated a percentile score for each Dutch child at 6 and 9 years of age. Results: Mean (SD) AL was 22.36 (0.75) mm at 6 years, 23.10 (0.84) mm at 9 years, 23.41 (0.86) mm at 15 years and 23.67 (1.26) at adulthood. Axial length (AL) differences after the age of 15 occurred only in the upper 50%, with the highest difference within the 95th percentile and above. A total of 354 children showed accelerated axial growth and increased by more than 10 percentiles from age 6 to 9 years; 162 of these children (45.8%) were myopic at 9 years of age, compared to 4.8% (85/1781) for the children whose AL did not increase by more than 10 percentiles. Conclusion: This study provides normative values for AL that can be used to monitor eye growth in European children. These results can help clinicians detect excessive eye growth at an early age, thereby facilitating decision-making with respect to interventions for preventing and/or controlling myopia

Thyroid function and age-related macular degeneration: A prospective population-based cohort study - the Rotterdam Study

Background: In animal models, lack of thyroid hormone is associated with cone photoreceptor preservation, while administration of high doses of active thyroid hormone leads to deterioration. The association between thyroid function and age-related macular degeneration (AMD) has not been investigated in the general population. Methods: Participants of age ≥55 years from the Rotterdam Study with thyroid-stimulating hormone (TSH) and/or free thyroxine (FT4) measurements and AMD assessment were included. We conducted age- and sex-adjusted Cox proportional hazards models to explore the association of TSH or FT4 with AMD, in the full range and in those with TSH (0.4-4.0 mIU/L) and/or FT4 in normal range (11-25 pmol/L). Cox proportional hazards models were performed for the association of TSH or FT4 with retinal pigment alterations (RPA), as an early marker of retinal changes. Multivariable models additionally included cardiovascular risk factors and thyroid peroxidase antibodies positivity. We also performed stratification by age and sex. A bidirectional look-up in genome-wide association study (GWAS) data for thyroid parameters and AMD was performed. Single nucleotide polymorphisms (SNPs) that are significantly associated with both phenotypes were identified. Results: We included 5,573 participants with a median follow-up of 6.9 years (interquartile range 4.4-10.8 years). During follow-up 805 people developed AMD. TSH levels were not associated with increased risk of AMD. Within normal range of FT4, participants in the highest FT4 quintile had a 1.34-fold increased risk of developing AMD, compared to individuals in the middle group (95% confidence interval [CI] 1.07-1.66). Higher FT4 values in the full range were associated with a higher risk of AMD (hazard ratio 1.04, CI, 1.01-1.06 per 1 pmol/L increase). Higher FT4 levels were similarly associated with a higher risk of RPA. Restricting analyses to euthyroid individuals, additional multivariable models, and stratification did not change estimates. We found a SNP (rs943080) in the VEGF-A gene, associated with AMD, to be significant in the TSH GWAS (P = 1.2 x 10-4). Adding this SNP to multivariable models did not change estimates. Conclusions: Higher FT4 values are associated with increased risk of AMD - even in euthyroid individuals - and increased risk of RPA. Our data suggest an important role of thyroid hormone in pathways leading to AMD

Comparing the effectiveness of bevacizumab to ranibizumab in patients with exudative age-related macular degeneration. The BRAMD study

Purpose: To compare the effectiveness of bevacizumab and ranibizumab in the treatment of exudative age-related macular degeneration (AMD). Design: Multicentre, randomized, controlled, double-masked clinical trial in 327 patients. The noninferiority margin was 4 letters. Patients: Patients ≥ 60 years of age with primary or recurrent sub- or juxtafoveal choroidal neovascularization (CNV) secondary to AMD with a total area of CNV < 12 disc areas and a best corrected visual acuity (BCVA) score between 20 and 78 letters on an EDTRS like chart in the study eye. Methods: Monthly intravitreal injections with 1.25 mg bevacizumab or 0.5 mg ranibizumab were given during one year. Intention to treat with last observation carried forward analysis was performed. Main Outcome Measures: Primary outcome was the change in BCVA in the study eye from baseline to 12 months. Results: The mean gain in BCVA was 5.1 (±14.1) letters in the bevacizumab group (n = 161) and 6.4 (±12.2) letters in the ranibizumab group (n = 166) (p = 0.37). The lower limit of the 95% confidence interval of the difference in BCVA gain was 3.72. The response to bevacizumab was more varied; 24% of patients showed a gain of ≥15 letters, 11% a loss of ≥15 letters and 65% a gain or loss < 15 letters compared to 19%, 5% and 76% respectively for ranibizumab (p = 0.038). No significant differences in absolute CRT and CRT change (p = 0.13) or in the presence of subretinal or intraretinal fluid (p = 0.14 and 0.10, respectively) were observed. However, the presence of any fluid on SD-OCT (subretinal and/or intraretinal) differed significantly (p = 0.020), with definite fluid on SD-OCT in 45% of the patients for bevacizumab versus 31% for ranibizumab. The occurrence of serious adverse events and adverse events was similar, with 34 SAEs and 256 AEs in the bevacizumab group and 37 SAEs and 299 AEs in the ranibizumab group (p = 0.87 and p = 0.48, respectively). Conclusions: Bevacizumab was not inferior to ranibizumab. The response to bevacizumab was more varied with higher percentages of both gainers and losers and more frequently observed retinal fluid on SD-OCT at 12 months when compared to the ranibizumab group. Trial Registration: Trialregister.nl NTR1704

Comparing the effectiveness and costs of Bevacizumab to Ranibizumab in patients with Diabetic Macular Edema: A randomized clinical trial (the BRDME study)

Background: The effectiveness of ranibizumab in the treatment of diabetic macular edema has been proven with large clinical trials. For bevacizumab only two clinical trials have been published and a head-to-head comparison is lacking to date. However, if proved non-inferior to ranibizumab, use of the off-label bevacizumab could reduce costs enormously without a loss in visual acuity. A cost-effectiveness study has been designed to substantiate this hypothesis. Aim: To compare the effectiveness and costs of 1.25 mg of bevacizumab to 0.5 mg ranibizumab given as monthly intravitreal injections during 6 months in patients with diabetic macular edema. It is hypothesized that bevacizumab is non-inferior to ranibizumab regarding its effectiveness. Design: This is a randomized, controlled, double masked, clinical trial in 246 patients in seven academic trial centres in The Netherlands. Outcomes: The primary outcome measure is the change in best-corrected visual acuity (BCVA) in the study eye from baseline to month 6. Secondary outcomes are the proportions of patients with a gain or loss of 15 letters or more or a BCVA of 20/40 or more at 6 months, the change in leakage on fluorescein angiography and the change in foveal thickness by optical coherence tomography at 6 months, the number of adverse events in 6 months, and the costs per quality adjusted life-year of the two treatments