Age-related macular degeneration in very old individuals with family history.

PURPOSE: To study age-related macular degeneration (AMD) in old and very old individuals with family history of AMD to find the proportion of those with early and advanced AMD. DESIGN: Retrospective cross-sectional cohort study of individuals with family history of AMD. METHODS: Database of 897 AMD patients ages 75 to 102 years with family history of AMD was compiled. Color fundus photographs were graded in a masked fashion according to the International Classification of AMD. RESULTS: With increasing age, a gradually larger proportion of participants had advanced AMD; 54% (469 of 863) of all those 75 years and older had advanced AMD, 64% (258 of 406) of all those 85 years and older, 74% (37 of 50) of all those 95 years and older, and all (eight of eight) 100 years and older had advanced AMD. CONCLUSIONS: All the centenarians in the present study had advanced AMD.

Enucleation in Iceland 1992-2004: study in a defined population.

PURPOSE: To determine the incidence rate as well as causative diagnoses and surgical indications of enucleation in Iceland during the years 1992-2004. METHODS: A retrospective population-based incidence study involving the entire population of Iceland. Medical records of all patients who underwent enucleation in Iceland from January 1992 through December 2004 were reviewed. The annually updated Icelandic census was used as a denominator data. RESULTS: Fifty-six eyes were enucleated during 1992-2004. No eviscerations were done, and the three exenterations performed were not included in the study. The mean annual age-adjusted incidence rate of enucleation in Iceland was 1.48 enucleations per 100 000 population in comparison with 2.66 enucleations per 100 000 for the time period 1964-1991. With advancing age, a significant increasing linear trend existed (p < 0.001). The median age at enucleation was 51 years (SD 22; mean 55 years; 16-91 years). The three most common surgical indications for enucleation were blind painful eye, suspected ocular malignancy and acute trauma. The most common causative diagnosis for enucleation was traumatic lesion (39%). The annual incidence was 2.00 enucleations per 100 000 for men and 0.95 for women. There were significantly more men in the traumatic lesion group (p < 0.001), but no gender predominance was found in the other groups of causative diagnoses (p = 0.8). CONCLUSION: The overall mean annual incidence of enucleation in Iceland is continually decreasing, although the incidence of severe ocular trauma and ocular malignancy is fairly stable.

Retinal oxygen metabolism in exudative age-related macular degeneration.

PURPOSE: To determine whether retinal vessel oxygen saturation in patients with exudative age-related macular degeneration (AMD) is different from that of a healthy population. METHODS: Oxygen saturation was measured in retinal arterioles and venules in 46 eyes of 46 treatment-naïve exudative AMD patients and 120 eyes of 120 healthy controls. Simple and multiple linear regression analyses were used to compare the two study groups. RESULTS: Oxygen saturation in retinal venules increases with age in patients with exudative AMD (0.45 ± 0.19% per year; p = 0.026), while it decreases with age in healthy individuals (-0.13 ± 0.03% per year; p = 0.0002). The slopes are statistically different (ANCOVA; p = 0.0003). The reverse is true for the arteriovenous difference in oxygen saturation, which decreases with age in AMD patients (-0.29 ± 0.16% per year; p = 0.065) and increases in healthy individuals (0.12 ± 0.03% per year; p < 0.0001). At age 80 years, AMD patients have 2.7 percentage points higher venous oxygen saturation than healthy persons and 4.2 percentage points less arteriovenous difference. CONCLUSIONS: The data suggest that retinal oxygen metabolism may be altered in exudative AMD. The arteriovenous difference is smaller in exudative AMD than in a healthy cohort, consistent with reduced oxygen extraction by retinal vessels in AMD patients. Further studies are needed to fully understand the role of retinal oxygen metabolism in the pathophysiology of exudative AMD.

Retinal oxygen metabolism in healthy subjects and glaucoma patients.

BACKGROUND: To test whether retinal oxygen metabolism is different in glaucoma patients compared with healthy subjects. METHODS: This was a two-centre study where retinal vessel oxygen saturation was measured in glaucoma patients and healthy individuals with a non-invasive spectrophotometric retinal oximeter. Visual fields were obtained in the glaucoma patients. RESULTS: No statistical difference was found in retinal oxygen saturation in arterioles (p=0.16), venules (p=0.16) and arteriovenous difference (p=0.24) when all glaucoma patients (n=74) were compared with healthy individuals (n=89). When patients with advanced glaucoma (visual field mean defect (MD ≥ 10 dB, n=21)) were compared with healthy individuals, the oxygen saturation in venules was higher in glaucoma patients (58.2% ± 5.4% vs 53.8% ± 6.4%; p=0.0054, mean ± SD) and the arteriovenous difference was lower in glaucoma patients (36.4% ± 4.7% vs 39.5% ± 5.7%; p=0.021). In glaucoma patients with mild glaucoma (visual field MD ≤ 5 dB, n=33), no statistical differences were found in retinal oxygen saturation compared with healthy individuals. CONCLUSIONS: Glaucoma patients with advanced glaucoma have higher oxygen saturation in venules and lower arteriovenous difference in oxygen saturation compared with healthy individuals. The decreased arteriovenous difference in severe glaucoma may be related to lower oxygen consumption secondary to neuropathy.

A rare nonsynonymous sequence variant in C3 is associated with high risk of age-related macular degeneration.

Through whole-genome sequencing of 2,230 Icelanders, we detected a rare nonsynonymous SNP (minor allele frequency = 0.55%) in the C3 gene encoding a p.Lys155Gln substitution in complement factor 3, which, following imputation into a set of Icelandic cases with age-related macular degeneration (AMD) and controls, associated with disease (odds ratio (OR) = 3.45; P = 1.1 × 10(-7)). This signal is independent of the previously reported common SNPs in C3 encoding p.Pro314Leu and p.Arg102Gly that associate with AMD. The association of p.Lys155Gln was replicated in AMD case-control samples of European ancestry with OR = 4.22 and P = 1.6 × 10(-10), resulting in OR = 3.65 and P = 8.8 × 10(-16) for all studies combined. In vitro studies have suggested that the p.Lys155Gln substitution reduces C3b binding to complement factor H, potentially creating resistance to inhibition by this factor. This resistance to inhibition in turn is predicted to result in enhanced complement activation.

Seven new loci associated with age-related macular degeneration.

Age-related macular degeneration (AMD) is a common cause of blindness in older individuals. To accelerate the understanding of AMD biology and help design new therapies, we executed a collaborative genome-wide association study, including >17,100 advanced AMD cases and >60,000 controls of European and Asian ancestry. We identified 19 loci associated at P < 5 × 10(-8). These loci show enrichment for genes involved in the regulation of complement activity, lipid metabolism, extracellular matrix remodeling and angiogenesis. Our results include seven loci with associations reaching P < 5 × 10(-8) for the first time, near the genes COL8A1-FILIP1L, IER3-DDR1, SLC16A8, TGFBR1, RAD51B, ADAMTS9 and B3GALTL. A genetic risk score combining SNP genotypes from all loci showed similar ability to distinguish cases and controls in all samples examined. Our findings provide new directions for biological, genetic and therapeutic studies of AMD.

Population-based incidence of exudative age-related macular degeneration and ranibizumab treatment load.

BACKGROUND/AIMS: The use of intravitreal vascular endothelial growth factor antibodies for exudative age-related macular degeneration (AMD) has stressed ophthalmology services and drug budgets throughout the world. The authors study the population-based incidence of exudative AMD in Iceland and the use of intravitreal ranibizumab in a defined population. METHODS: This is a prospective study of 439 consecutive patients aged 60 years and older with exudative AMD starting intravitreal ranibizumab for exudative AMD in Iceland from March 2007 to December 2009. All patients initially received three consecutive ranibizumab injections, with regular follow-up visits and re-treatment as needed. RESULTS: In total, 517 eyes from 439 patients received treatment for exudative AMD (mean age 79 years). The annual incidence of exudative AMD in the population 60 years and older is 0.29%. The incidence increased with advancing age, double for patients 85 years and older compared with those 75-79 years. Approximately 2400 ranibizumab injections per 100,000 persons aged 60 years and older were given each year for exudative AMD. CONCLUSIONS: These data allow an estimation of the incidence of exudative AMD in a Caucasian population and the treatment load with ranibizumab, which may help plan anti-vascular endothelial growth factor treatment programmes and estimate costs.

Retinal oximetry images must be standardized: a methodological analysis.

PURPOSE: Retinal vessel oximetry is a new technology and needs detailed methodological scrutiny. We determine (1) the repeatability of retinal vessel oxygen saturation measurements, (2) whether measured saturation is different between retinal quadrants, and (3) whether the angle of gaze changes measurements of the same vessels. METHODS: Fundus oximetry images were obtained from 26 healthy individuals, 18 to 30 years old, using the Oxymap retinal oximeter. Oxygen saturation in the same vessel segments was compared between two similar images of each individual to determine repeatability. Vessel oxygen saturation was also compared between different quadrants of the retina in the same oximetry image. Finally, oxygen saturation measurements were made on the same vessel segments at different angles of gaze. RESULTS: Mean and standard deviation of saturation measurements was 93.1% ± 2.3% in arterioles and 64.9% ± 3.3% in venules. Standard deviation of repeated saturation measurements on the same vessel segment was 1.0% in arterioles and 1.4% in venules. Significant differences were seen between retinal quadrants. When angle of gaze was altered, measured saturation was lower in the same vessels when they were located in the inferior portion compared with other parts of the image (-1.3% ± 1.7%, P = 0.0004 in arterioles and -1.9 ± 2.4%, P = 0.0007 in venules). CONCLUSIONS: Retinal vessel oxygen saturation measurements are repeatable with a small standard deviation. When oximetry results are compared between time points or eyes, the imaging must be standardized and similar parts of the images analyzed.

Retinal vessel oxygen saturation in healthy individuals.

PURPOSE: We measured oxygen saturation in retinal vessels of healthy eyes to determine the effects of age, sex, and cardiovascular parameters, as well as the reliability of the measurements and topographic differences. METHODS: The Oxymap T1 retinal oximeter is based on a fundus camera. It simultaneously captures retinal images at two different wavelengths and estimates retinal vessel oxygen saturation. Mean saturation of main retinal arterioles and venules was measured in 120 healthy individuals aged 18-80 years (median 47 years). Of the 120 participants 44 (37%) were male (49 years) and 76 (63%) female (44 years). RESULTS: Oxygen saturation was 92.2 ± 3.7% (mean ± SD) in retinal arterioles and 55.6 ± 6.3% in venules. No significant difference in oxygen saturation was found between left and right eyes. The inferotemporal quadrant had lower oxygen saturation in arterioles and venules (P < 0.0001). Arteriolar oxygen saturation was stable with age. Venular oxygen saturation in males decreased by 1.9 ± 0.6% (mean ± SEM) per 10 years of age (P = 0.003) and by 0.7 ± 0.4% in females (P = 0.068). Arteriovenous (AV) difference increased by 1.5 ± 0.5% per 10 years in males (P = 0.004) and 1.0 ± 0.4% (P = 0.007) in females. For every 10 mm Hg increase in ocular perfusion pressure, oxygen saturation in arterioles increased by 0.9 ± 0.4% (P = 0.024) and in venules by 1.2 ± 0.7% (P = 0.075). CONCLUSIONS: Retinal arteriolar oxygen saturation is stable in healthy individuals, while there is a significant decrease in venular oxygen saturation with age in males and a similar trend in females. AV difference increases significantly with age for both sexes. Our study provided normative data for spectrophotometric retinal oximetry in the Caucasian population.

Metabolic physiology in age related macular degeneration.

Ischemia and hypoxia have been implicated in the pathophysiology of age related macular degeneration (AMD). This has mostly been based on studies on choroidal perfusion, which is not the only contributor to retinal hypoxia found in AMD eyes. Other features of AMD may also interfere with retinal oxygen metabolism including confluent drusen, serous or hemorrhagic retinal detachment, retinal edema and vitreoretinal adhesion. Each of these features contributes to retinal hypoxia: the drusen and retinal elevation by increasing the distance between the choriocapillaris and retina; vitreoretinal adhesion by reducing diffusion and convection of oxygen towards and vascular endothelial growth factor (VEGF) away from hypoxic retinal areas. Hypoxia-inducible-factor is known to exist in subretinal neovascularization and hypoxia is the main stimulus for the production of VEGF. Each feature may not by itself create enough hypoxia and VEGF accumulation to stimulate wet AMD, but they may combine to do so. Choroidal ischemia in AMD has been demonstrated by many researchers, using different technologies. Choroidal ischemia obviously decreases oxygen delivery to the outer retina. Confluent drusen, thickening of Bruch's membrane and any detachment of retina or retinal pigment epithelium, increases the distance between the choriocapillaris and the retina and thereby reduces the oxygen flux from the choroid to the outer retina according to Fick's law of diffusion. Retinal elevation and choroidal ischemia may combine forces to reduce choroidal oxygen delivery to the outer retina, produce retinal hypoxia. Hypoxia leads to production of VEGF leading to neovascularization and tissue edema. A vicious cycle may develop, where VEGF production increases effusion, retinal detachment and edema, further increasing hypoxia and VEGF production. Adhesion of the viscous posterior vitreous cortex to the retina maintains a barrier to diffusion and convection currents in the vitreous cavity according to the laws of Fick's, Stokes-Einstein and Hagen-Poiseuille. If the vitreous is detached from the surface of the retina, the low viscosity fluid transports oxygen and nutrients towards an ischemic area of the retina, and cytokines away from the retina, at a faster rate than through attached vitreous gel. Vitreoretinal adhesion can exacerbate retinal hypoxia and accumulation of cytokines, such as VEGF. Vitreoretinal traction can also cause hypoxia by retinal elevation. Conceivably, the basic features of AMD, drusen, choroidal ischemia, and vitreoretinal adhesion are independently determined by genetics and environment and may combine in variable proportions. If the resulting hypoxia and consequent VEGF accumulation crosses a threshold, this will trigger effusion and neovascularization.