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The role of oxidative stress in the pathogenesis of age-related macular degeneration.

Beatty S, Koh H, Phil M, Henson D, Boulton M. Academic Department of Ophthalmology, Manchester Royal Eye Hospital, Manchester, United Kingdom.

Surv Ophthalmol 2000 Sep-Oct;45(2):115-34

Age-related macular degeneration (AMD) is the leading cause of blind registration in the developed world, and yet its pathogenesis remains poorly understood. Oxidative stress, which refers to cellular damage caused by reactive oxygen intermediates (ROI), has been implicated in many disease processes, especially age-related disorders. ROIs include free radicals, hydrogen peroxide, and singlet oxygen, and they are often the byproducts of oxygen metabolism. The retina is particularly susceptible to oxidative stress because of its high consumption of oxygen, its high proportion of polyunsaturated fatty acids, and its exposure to visible light. In vitro studies have consistently shown that photochemical retinal injury is attributable to oxidative stress and that the antioxidant vitamins A, C, and E protect against this type of injury. Furthermore, there is strong evidence suggesting that lipofuscin is derived, at least in part, from oxidatively damaged photoreceptor outer segments and that it is itself a photoreactive substance. However, the relationships between dietary and serum levels of the antioxidant vitamins and age-related macular disease are less clear, although a protective effect of high plasma concentrations of alpha-tocopherol has been convincingly demonstrated. Macular pigment is also believed to limit retinal oxidative damage by absorbing incoming blue light and/or quenching ROIs. Many putative risk-factors for AMD have been linked to a lack of macular pigment, including female gender, lens density, tobacco use, light iris color, and reduced visual sensitivity. Moreover, the Eye Disease Case-Control Study found that high plasma levels of lutein and zeaxanthin were associated with reduced risk of neovascular AMD. The concept that AMD can be attributed to cumulative oxidative stress is enticing, but remains unproven. With a view to reducing oxidative damage, the effect of nutritional antioxidant supplements on the onset and natural course of age-related macular disease is currently being evaluated.

Macular pigment and risk for age-related macular degeneration in subjects from a Northern European population.

Beatty S, Murray IJ, Henson DB, Carden D, Koh H, Boulton ME. University Department of Ophthalmology, Manchester Royal Eye Hospital, Manchester, UK. stephen@stiofanbetagh.demon.co.uk

Invest Ophthalmol Vis Sci 2001 Feb;42(2):439-46

PURPOSE: Age and advanced disease in the fellow eye are the two most important risk factors for age-related macular degeneration (AMD). In this study, the authors investigated the relationship between these variables and the optical density of macular pigment (MP) in a group of subjects from a northern European population.

METHODS: The optical density of MP was measured psychophysically in 46 subjects ranging in age from 21 to 81 years with healthy maculae and in 9 healthy eyes known to be at high-risk of AMD because of advanced disease in the fellow eye. Each eye in the latter group was matched with a control eye on the basis of variables believed to be associated with the optical density of MP (iris color, gender, smoking habits, age, and lens density).

RESULTS: There was an age-related decline in the optical density of macular pigment among volunteers with no ocular disease (right eye: r(2) = 0.29, P = 0.0006; left eye: r(2) = 0.29, P < 0.0001). Healthy eyes predisposed to AMD had significantly less MP than healthy eyes at no such risk (Wilcoxon's signed rank test: P = 0.015).

CONCLUSIONS: The two most important risk factors for AMD are associated with a relative absence of MP. These findings are consistent with the hypothesis that supplemental lutein and zeaxanthin may delay, avert, or modify the course of this disease.

Lutein and zeaxanthin in the eyes, serum and diet of human subjects.

Bone RA, Landrum JT, Dixon Z, Chen Y, Llerena CM. Department of Physics, Florida International University, Miami, FL 33199, USA.

Exp Eye Res 2000 Sep;71(3):239-45

Inverse associations have been reported between the incidence of advanced, neovascular, age-related macular degeneration (AMD) and the combined lutein (L) and zeaxanthin (Z) intake in the diet, and L and Z concentration in the blood serum. We suggest that persons with high levels of L and Z in either the diet or serum would probably have, in addition, relatively high densities of these carotenoids in the macula, the so-called 'macular pigment'. Several lines of evidence point to a potential protective effect by the macular pigment against AMD. In this study we examined the relationship between dietary intake of L and Z using a food frequency questionnaire; concentration of L and Z in the serum, determined by high-performance liquid chromatography, and macular pigment optical density, obtained by flicker photometry. Nineteen subjects participated. We also analysed the serum and retinas, as autopsy samples, from 23 tissue donors in order to obtain the concentration of L and Z in these tissues. The results reveal positive, though weak, associations between dietary intake of L and Z and serum concentration of L and Z, and between serum concentration of L and Z and macular pigment density. We estimate that approximately half of the variability in the subjects' serum concentration of L and Z can be explained by their dietary intake of L and Z, and about one third of the variability in their macular pigment density can be attributed to their serum concentration of L and Z. These results, together with the reported associations between risk of AMD and dietary and serum L and Z, support the hypothesis that low concentrations of macular pigment may be associated with an increased risk of AMD.

Macular pigment in donor eyes with and without AMD: a case-control study.

Bone RA, Landrum JT, Mayne ST, Gomez CM, Tibor SE, Twaroska EE. Department of Physics, Florida International University, Miami, Florida 33199, USA. bone@fiu.edu

Invest Ophthalmol Vis Sci 2001 Jan;42(1):235-40

PURPOSE: To determine whether there is an association between the density of macular pigment in the human retina and the risk of age-related macular degeneration (AMD).

METHODS: Retinas from 56 donors with AMD and 56 controls were cut into three concentric regions centered on the fovea. The inner, medial, and outer regions covered the visual angles 0 degrees to 5 degrees, 5 degrees to 19 degrees, and 19 degrees to 38 degrees, respectively. The amounts of lutein (L) and zeaxanthin (Z) extracted from each tissue sample were determined by high-performance liquid chromatography.

RESULTS: L and Z levels in all three concentric regions were less, on average, for the AMD donors than for the controls. The differences decreased in magnitude from the inner to medial to outer regions. The lower levels found in the inner and medial regions for AMD donors may be attributable, in part, to the disease. Comparisons between AMD donors and controls using the outer (peripheral) region were considered more reliable. For this region, logistic regression analysis indicated that those in the highest quartile of L and Z level had an 82% lower risk for AMD compared with those in the lowest quartile (age- and sex-adjusted odds ratio = 0.18, 95% confidence interval = 0.05-0.64).

CONCLUSIONS: The results are consistent with a theoretical model that proposes an inverse association between risk of AMD and the amounts of L and Z in the retina. The results are inconsistent with a model that attributes a loss of L and Z in the retina to the destructive effects of AMD.

Photodynamic therapy with verteporfin (Visudyne): impact on ophthalmology and visual sciences.

Bressler, N.M., Bressler, S.B.

Invest. Ophthalmol. Vis. Sci. 2000 Mar; 41(3): 624 8.

No abstract available.

Nutrition supplements and the eye.

Brown NA, Bron AJ, Harding JJ, Dewar HM. Clinical Cataract Research Unit, Nuffield Laboratory of Ophthalmology, Oxford, UK.

Eye 1998;12 ( Pt 1):127-33

PURPOSE: A review of the role of vitamins, minerals, carotenoids and essential fatty acids in relation to eye health. The mode of action may be directly on the eye or by promoting bodily health on which the eye depends.

RESULTS: The lens and retina suffer oxidative damage and the anti-oxidant vitamins A, C and E are implicated as protective. Studies in man give indifferent support to the role of nutrition in the development of cataract. In the elderly, vitamin intake may be inadequate, so that a vitamin supplement may be reasonable. Zinc has a role in retinal metabolism and may be beneficial in macular degeneration. Selenium has an anti-oxidant role. Other minerals including copper have a less defined role. Carotenoids are concentrated at the macula and have an anti-oxidant role. A reduced risk of macular degeneration is found in relation to a high serum level. The essential fatty acid, gamma-linolenic acid (GLA), is useful in Sjogren's syndrome and may help in other dry eye conditions. Omega-3 fatty acids are important in retinal development and have a role in preventing cardiovascular disease.

CONCLUSION: All persons should be encouraged to maintain healthy nutrition. Middle-aged and elderly patients may benefit from a supplement. An intake in excess of the recommended daily intake may be beneficial, but this is not proven. Further clinical trials are indicated to define the advisability of vitamin, mineral and other supplements. Dosages for recommended intake and for supplements are given.

Ascorbic acid content of human corneal epithelium.

Brubaker RF, Bourne WM, Bachman LA, McLaren JW. Department of Ophthalmology, Mayo Clinic and Mayo Foundation, Rochester, Minnesota 55905, USA. brubaker.richard@mayo.edu

Invest Ophthalmol Vis Sci 2000 Jun;41(7):1681-3

PURPOSE: To measure the concentration of ascorbic acid in the human corneal epithelium.

METHODS: Corneal epithelium was removed from postmortem eyes 4 to 16 hours after death and ascorbate measured by high-performance liquid chromatography.

RESULTS: The concentration of ascorbate was 1.33 +/- 0.48 mg/gm wet weight (mean +/- SD), estimated to be 14 times its concentration in the aqueous humor.

CONCLUSIONS: Ascorbate can protect the basal layer of the epithelium by absorption of incident ultraviolet radiation.

Glutathione: a vital lens antioxidant.

Giblin FJ. Eye Research Institute, Oakland University, Rochester, Michigan 48309-4401, USA. giblin@oakland.edu

J Ocul Pharmacol Ther 2000 Apr;16(2):121-35

The reducing compound glutathione (GSH) exists in an unusually high concentration in the lens where it functions as an essential antioxidant vital for maintenance of the tissue's transparency. In conjunction with an active glutathione redox cycle located in the lens epithelium and superficial cortex, GSH detoxifies potentially damaging oxidants such as H2O2 and dehydroascorbic acid. Recent studies have indicated an important hydroxyl radical-scavenging function for GSH in lens epithelial cells, independent of the cells' ability to detoxify H2O2. Depletion of GSH or inhibition of the redox cycle allows low levels of oxidant to damage lens epithelial targets such as Na/K-ATPase, certain cytoskeletal proteins and proteins associated with normal membrane permeability. The level of GSH in the nucleus of the lens is relatively low, particularly in the aging lens, and exactly how the compound travels from the epithelium to the central region of the organ is not known. Recently, a cortical/nuclear barrier to GSH migration in older human lenses was demonstrated by Sweeney et al. The relatively low ratio of GSH to protein -SH in the nucleus of the lens, combined with low activity of the glutathione redox cycle in this region, makes the nucleus especially vulnerable to oxidative stress, as has been demonstrated with use of in vivo experimental animal models such as hyperbaric oxygen, UVA light and the glutathione peroxidase knockout mouse. Effects observed in these models, which are currently being utilized to investigate the mechanism of formation of human senile nuclear cataract, include an increase in lens nuclear disulfide, damage to nuclear membranes and an increase in nuclear light scattering. A need exists for development of therapeutic agents to slow age-related loss of antioxidant activity in the nucleus of the human lens to delay the onset of cataract.

[Antioxidants and angiogenetic factor associated with age-related macular degeneration (exudative type)]

Ishihara N; Yuzawa M; Tamakoshi A Department of Ophthalmology, Nihon University School of Medicine, Tokyo, Japan.

Nippon Ganka Gakkai Zasshi (Japan) Mar 1997, 101 (3) p248-51

To confirm the hypothesis that antioxidants and angiogenetic factors may be associated with the development of age-related macular degeneration (exudative type), we compared serum levels of vitamins A, C, and E and carotinoid, zinc, selenium and b-FGF (basic-fibroblast growth factor) in 35 patients with age-related macular degeneration (exudative type) with the levels in 66 controls. The average serum zinc level was significantly lower in the patient group than in the control group. Serum vitamin E-alpha levels also tended to be lower. Most serum b-FGF levels were below the standard value in each group. Based on the above results, we conclude that subnormal levels of zinc and vitamin E may be associated with the development of age-related macular degeneration.

Thalidomide and prednisolone inhibit growth factor-induced human retinal pigment epithelium cell proliferation in vitro.

Kaven C, Spraul CW, Zavazava N, Lang GK, Lang GE. Department of Ophthalmology, University of Ulm, Germany.

Ophthalmologica 2001 Jul-Aug;215(4):284-9

Thalidomide and prednisolone were recently introduced as treatment modalities in age-related macular degeneration (AMD). Growth factor-induced activation of retinal pigment epithelial (RPE) cells is a crucial event in this disease. The purpose was to examine the effect of thalidomide and prednisolone on growth factor-preactivated RPE cells. Human RPE cells were stimulated with 10 ng/ml platelet-derived growth factor (PDGF), basic fibroblast growth factor (bFGF), or vascular endothelial growth factor (VEGF) for 24 h. Afterwards, thalidomide (50 microg/ml) or prednisolone (100 ng/ml) were added for 24 h. RPE cell proliferation was determined by [3H]-thymidine incorporation. PDGF and bFGF significantly stimulated human RPE cell proliferation (p < 0.005), the value for VEGF stimulation was not significant (p = 0.3). The effect of the growth factors was diminished after addition of thalidomide and prednisolone (p < 0.005). The current study shows that the inhibitory properties of thalidomide and prednisolone remain even after growth factor activation of the cells.

Lutein, zeaxanthin, and the macular pigment.

Landrum JT, Bone RA. Department of Chemistry, Florida International University, Miami 33199, USA. landrumj@fiu.edu

Arch Biochem Biophys 2001 Jan 1;385(1):28-40

The predominant carotenoids of the macular pigment are lutein, zeaxanthin, and meso-zeaxanthin. The regular distribution pattern of these carotenoids within the human macula indicates that their deposition is actively controlled in this tissue. The chemical, structural, and optical characteristics of these carotenoids are described. Evidence for the presence of minor carotenoids in the retina is cited. Studies of the dietary intake and serum levels of the xanthophylls are discussed. Increased macular carotenoid levels result from supplementation of humans with lutein and zeaxanthin. A functional role for the macular pigment in protection against light-induced retinal damage and age-related macular degeneration is discussed. Prospects for future research in the study of macular pigment require new initiatives that will probe more accurately into the localization of these carotenoids in the retina, identify possible transport proteins and mechanisms, and prove the veracity of the photoprotection hypothesis for the macular pigments.

Artificial tear composition and promotion of recovery of the damaged corneal epithelium.

Lopez Bernal D, Ubels JL. Department of Ophthalmology, Medical College of Wisconsin, Milwaukee.

Cornea 1993 Mar;12(2):115-20

In severe dry eye syndromes the corneal epithelium is compromised with development of punctate erosions and increased permeability. In the present study the ability of artificial tear solutions to promote recovery of the corneal epithelial barrier was determined by measurement of corneal uptake of 5,6 carboxyfluorescein (CF). Corneas of anesthetized rabbits were exposed to 0.01% benzalkonium for 5 min to increase epithelial permeability. The cornea was then exposed to an artificial tear solution for 1.5 h followed by measurement of CF uptake. During exposure to three commercial isotonic, nonpreserved solutions and a solution preserved with polyquaternium-1, CF uptake decreased significantly but did not return to control. No recovery of the epithelial barrier occurred during exposure of corneas to nonpreserved hypotonic solutions. During exposure to an experimental tear solution with an electrolyte composition similar to human tears, buffered with bicarbonate, CF uptake returned to control levels. Bicarbonate is an essential component of this solution because the same formula buffered with borate or without buffer was ineffective in promoting recovery of the damaged corneal epithelium.

Changes in choriocapillaris and retinal pigment epithelium in age-related macular degeneration.

Lutty G, Grunwald J, Majji AB, Uyama M, Yoneya S. Wilmer Eye Institute, Baltimore, MD 21287-9115, USA. glutty@jhmi.edu

Mol Vis 1999 Nov 3;5:35

Retinal pigment epithelial cells (RPE) and the choriocapillaris are on opposite sides of Bruch's membrane and control transport in and out of the retina. In age-related macular degeneration (AMD), they may also be responsible for deposition of material in and on Bruch's membrane and the formation or regression of choroidal neovascularization (CNV). Indocyanine green (ICG) angiography can be used to visualize the choroidal vasculature and CNV. Filling of the choriocapillaris with ICG was delayed in subjects older than 50 years of age, and areas of hypofluorescence were observed in maculas of AMD subjects, often associated with CNV. Laser Doppler flowmetry of the choriocapillaris in the macula demonstrated that choroidal blood flow and volume are reduced in subjects older than 46 years of age and further decreased in subjects with AMD. The human choriocapillaris can be histologically studied in two dimensions by incubating the tissue for alkaline phosphatase activity, flat-embedding it in transparent polymer and sectioning it. Using this technique, choriocapillaris dropout was found to be associated with deposition of material in Bruch's membrane in diabetic subjects. When RPE are removed from Bruch's membrane, the choriocapillaris degenerates; the regeneration of choriocapillaris can be blocked by Genistein, a tyrosine kinase inhibitor. Finally, RPE cells may produce substances that both stimulate the formation and regression of CNV in animal models. These studies suggest that there may be a reduction in choriocapillaris flow in AMD, and this loss of choriocapillaris can be associated with the Bruch's membrane deposits that are hallmarks of AMD. Furthermore, RPE may stimulate the formation and regression of CNV and RPE loss can result in loss of choriocapillaris.

Effects of ginkgo-biloba on the micro-vessels of bulbar conjunctiva.

Piovella, C.

Minerva Med. 1973 Nov 7; 64(79, Suppl.): 4179-86 (in Italian).

No abstract available

Lutein and zeaxanthin concentrations in rod outer segment membranes from perifoveal and peripheral human retina.

Rapp LM, Maple SS, Choi JH. Cullen Eye Institute, Department of Ophthalmology, Baylor College of Medicine, Houston, Texas 77030, USA. lrapp@bcm.tmc.edu

Invest Ophthalmol Vis Sci 2000 Apr;41(5):1200-9

PURPOSE: In addition to acting as an optical filter, macular (carotenoid) pigment has been hypothesized to function as an antioxidant in the human retina by inhibiting the peroxidation of long-chain polyunsaturated fatty acids. However, at its location of highest density in the inner (prereceptoral) layers of the foveal retina, a specific requirement for antioxidant protection would not be predicted. The purpose of this study was to determine whether lutein and zeaxanthin, the major carotenoids comprising the macular pigment, are present in rod outer segment (ROS) membranes where the concentration of long-chain polyunsaturated fatty acids, and susceptibility to oxidation, is highest.

METHODS: Retinas from human donor eyes were dissected to obtain two regions: an annular ring of 1.5- to 4-mm eccentricity representing the area centralis excluding the fovea (perifoveal retina) and the remaining retina outside this region (peripheral retina). ROS and residual (ROS-depleted) retinal membranes were isolated from these regions by differential centrifugation and their purity checked by polyacrylamide gel electrophoresis and fatty acid analysis. Lutein and zeaxanthin were analyzed by high-performance liquid chromatography and their concentrations expressed relative to membrane protein. Preparation of membranes and analysis of carotenoids were performed in parallel on bovine retinas for comparison to a nonprimate species. Carotenoid concentrations were also determined for retinal pigment epithelium harvested from human eyes.

RESULTS: ROS membranes prepared from perifoveal and peripheral regions of human retina were found to be of high purity as indicated by the presence of a dense opsin band on protein gels. Fatty acid analysis of human ROS membranes showed a characteristic enrichment of docosahexaenoic acid relative to residual membranes. Membranes prepared from bovine retinas had protein profiles and fatty acid composition similar to those from human retinas. Carotenoid analysis showed that lutein and zeaxanthin were present in ROS and residual human retinal membranes. The combined concentration of lutein plus zeaxanthin was 70% higher in human ROS than in residual membranes. Lutein plus zeaxanthin in human ROS membranes was 2.7 times more concentrated in the perifoveal than the peripheral retinal region. Lutein and zeaxanthin were consistently detected in human retinal pigment epithelium at relatively low concentrations.

CONCLUSIONS: The presence of lutein and zeaxanthin in human ROS membranes raises the possibility that they function as antioxidants in this cell compartment. The finding of a higher concentration of these carotenoids in ROS of the perifoveal retina lends support to their proposed protective role in age-related macular degeneration.

Multicenter ophthalmic and nutritional age-related macular degeneration study--part 2: antioxidant intervention and conclusions.

Richer S. Eye Clinic 112e, DVA Medical Center, North Chicago, IL 60064, USA.

J Am Optom Assoc 1996 Jan;67(1):30-49

BACKGROUND: The experimental design, subjects, procedures and baseline data for the prospective double blind dry ARMD-antioxidant intervention study have been described in Part 1.

METHODS: At eight DVA medical centers, 32 patients (group one) were assigned a placebo and 39 patients (group two) a "broad spectrum" antioxidant capsule. Data was collected in five areas: demographic; ophthalmic; dietary analysis of daily food intake; serum analysis; and adverse gastrointestinal symptoms. Data was serially acquired at baseline, 6 months, 12 months and 18 months, and was analyzed by univariate repeated factors ANOVA, p = 0.05.

RESULTS: Group two (antioxidant po BID) maintained their distance LogMAR visual acuity (p = 0.03), while there was a trend toward both stabilized near M print (p = 0.07) and 6 cycle/degree contrast sensitivity (p approximately 0.10), in left eyes. However, group two (antioxidant) also had increased cortical opacification of the right lens (p = 0.04), compared to group one (placebo). Self perceived stabilization of vision was reported by subjects in group two and supported the objective data (Pearson chi square; p = 0.05).

CONCLUSIONS: A specific 14 component antioxidant capsule taken twice daily stabilized but did not improve dry ARMD over the study period of 1.5 years. The ARMD stabilized eyes had less advanced disease functionally but not by fundus appearance. Decreased intake of cardioprotective nutrients (vitamin E, zinc, magnesium, B6 and folate) in ARMD patients remained constant over the course of the trial.

[Radiotherapy and age-related macular degeneration: a review of the literature]

Schwartz LH; Schmitt T; Benchaboun M; Caputo G; Chauvaud D; Balosso J; Faivre C; Francais C; Koenig F Service de radiotherapie, hopital Saint-Louis, Paris, France.

Cancer Radiother (France) 1997, 1 (3) p208-12

Macular degeneration is a major health problem. Less than 10% of the cases can be successfully treated by laser therapy. Low dose radiation therapy (in the range of 20 Gy) appears to decrease neovascularisation. These early results need to be confirmed through a randomized trial. (38 Refs.)

Dietary fat and risk for advanced age-related macular degeneration.

Seddon JM, Rosner B, Sperduto RD, Yannuzzi L, Haller JA, Blair NP, Willett W. Epidemiology Unit, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA 02114, USA. Johanna_Seddon@meei.harvard.edu

Arch Ophthalmol 2001 Aug;119(8):1191-9

OBJECTIVE: To evaluate the relationship between intake of total and specific types of fat and risk for advanced age-related macular degeneration (AMD), the leading cause of irreversible blindness in adults. DESIGN: A multicenter eye disease case-control study.

SETTING: Five US clinical ophthalmology centers.

PATIENTS: Case subjects included 349 individuals (age range, 55-80 years) with the advanced, neovascular stage of AMD diagnosed within 1 year of their enrollment into the study who resided near a participating clinical center. Control subjects included 504 individuals without AMD but with other ocular diseases. Controls were from the same geographic areas as cases and were frequency-matched to cases by age and sex.

MAIN OUTCOME MEASURES: Relative risk for AMD according to level of fat intake, controlling for cigarette smoking and other risk factors.

RESULTS: Higher vegetable fat consumption was associated with an elevated risk for AMD. After adjusting for age, sex, education, cigarette smoking, and other risk factors, the odds ratio (OR) was 2.22 (95% confidence interval [CI], 1.32-3.74) for persons in the highest vs those in the lowest quintiles of intake (P for trend,.007). The risk for AMD was also significantly elevated for the highest vs lowest quintiles of intake of monounsaturated (OR, 1.71) and polyunsaturated (OR, 1.86) fats (Ps for trend,.03 and.03, respectively). Higher consumption of linoleic acid was also associated with a higher risk for AMD (P for trend,.02). Higher intake of omega-3 fatty acids was associated with a lower risk for AMD among individuals consuming diets low in linoleic acid, an omega-6 fatty acid (P for trend,.05; P for continuous variable,.03). Similarly, higher frequency of fish intake tended to reduce risk for AMD when the diet was low in linoleic acid (P for trend,.05). Conversely, neither omega-3 fatty acids nor fish intake were related to risk for AMD among people with high levels of linoleic acid intake.

CONCLUSION: Higher intake of specific types of fat--including vegetable, monounsaturated, and polyunsaturated fats and linoleic acid--rather than total fat intake may be associated with a greater risk for advanced AMD. Diets high in omega-3 fatty acids and fish were inversely associated with risk for AMD when intake of linoleic acid was low.

A prospective study of cigarette smoking and age-related macular degeneration in women.

Seddon JM, Willett WC, Speizer FE, Hankinson SE. Epidemiology Unit, Massachusetts Eye and Ear Infirmary, Boston, MA 02114, USA.

JAMA 1996 Oct 9;276(14):1141-6

OBJECTIVE: To evaluate the relationship between cigarette smoking and incidence of age-related macular degeneration (AMD) among women.

DESIGN: Prospective cohort study with 12 years of follow-up (1980 to 1992), in which information on smoking habits was updated every 2 years.

SETTING: Eleven states throughout the United States.

PARTICIPANTS: A total of 31 843 registered nurses enrolled in the Nurses' Health Study who were aged 50 to 59 years in 1980 and did not report a diagnosis of cancer or AMD at the beginning of the study. Additional women entered the analytic cohort as they reached 50 years of age.

MAIN OUTCOME MEASURE: Incidence of AMD with visual loss.

RESULTS: During 556 338 person-years of follow-up, 215 women were newly diagnosed as having AMD. After adjusting for other risk factors for AMD, women who currently smoked 25 or more cigarettes per day had a relative risk (RR) of AMD of 2.4 (95% confidence interval [CI], 1.4-4.0) compared with women who never smoked. Past smokers of this amount also had a 2-fold increased risk (RR=2.0; 95% CI, 1.2-3.4) relative to never smokers. Compared with current smokers, little reduction in risk was suggested even after quitting smoking for 15 or more years. Risk of AMD also increased with an increasing number of pack-years smoked (P for trend <.001); among women who smoked for 65 or more pack-years, the risk was 2.4 times the risk of never smokers (95% CI, 1.5-3.8). Analyses of dry and exudative types of AMD and other alternative definitions of AMD revealed similar results.

CONCLUSIONS: Cigarette smoking is an independent and avoidable risk factor for AMD among women. Because AMD is the most common cause of severe visual impairment among the elderly and treatment is not available or is ineffective for most patients, reducing the risk of this disease is another important reason to avoid smoking.

Dietary fat and fish intake and age-related maculopathy.

Smith W, Mitchell P, Leeder SR. National Centre for Epidemiology and Population Health, Australian National University, Australian Capital Territory. wayne.smith@anu.edu.au

Arch Ophthalmol 2000 Mar;118(3):401-4

OBJECTIVE: To assess whether dietary intake of fat or fish is associated with age-related maculopathy (ARM) prevalence.

DESIGN: Cross-sectional, urban population-based study.

PARTICIPANTS: People (N = 3654) aged 49 years or older.

MAIN OUTCOME MEASURES: Subjects with ARM were identified from masked grading of retinal photographs. A 145-itemself-administered, semiquantitative food frequency questionnaire was completed adequately by 88.8% of participants and was used to assess intakes of dietary fat and fish.

RESULTS: A higher frequency of fish consumption was associated with decreased odds of late ARM (odds ratio for frequency of consumption more than once per week compared with less than once per month, 0.5). Subjects with higher energy-adjusted intakes of cholesterol were significantly more likely to have late ARM, with an increased risk for late ARM for the highest compared with the lowest quintile of intake (odds ratio, 2.7).

CONCLUSION: The amount and type of dietary fat intake may be associated with ARM.

Continuing damage to rat retinal DNA during darkness following light exposure.

Specht S, Organisciak DT, Darrow RM, Leffak M. Department of Biochemistry and Molecular Biology, Wright State University School of Medicine, Dayton, OH 45435, USA.

Photochem Photobiol 2000 May;71(5):559-66

The damaging effects of visible light on the mammalian retina can be detected as functional, morphological or biochemical changes in the photoreceptor cells. Although previous studies have implicated short-lived reactive oxygen species in these processes, the termination of light exposure does not prevent continuing damage. To investigate the degenerative processes persisting during darkness following light treatment, rats were exposed to 24 h of intense visible light and the accumulation of DNA damage to restriction fragments containing opsin, insulin 1 or interleukin-6 genes was measured as single-strand breaks (ssb) on alkaline agarose gels. With longer dark treatments all three DNA fragments showed increasing DNA damage. Treatment of rats with the synthetic antioxidant dimethylthiourea prior to light exposure reduced the initial development of alkali-sensitive strand breaks and allowed significant repair of all three DNA fragments. The time course of double-strand DNA breaks was also examined in specific genes and repetitive DNA. Nucleosomal DNA laddering was evident immediately following the 24 h light treatment and increased during the subsequent dark period. The increase in the intensity of the DNA ladder pattern suggests a continuation of enzymatically mediated apoptotic processes triggered during light exposure. The protective effects of antioxidant suggests that the light-induced DNA degradative process includes both early oxidative reactions and enzymatic processes that continue after cessation of light exposure.

Suggested Reading Abstracts

Antioxidant status and neovascular age-related macular degeneration. Eye Disease Case-Control Study Group.

Anon. [No authors listed]

Arch Ophthalmol. 1993 Jan;111(1):104-9.

We evaluated the hypothesis that higher serum levels of micronutrients with antioxidant capabilities may be associated with a decreased risk of neovascular age-related macular degeneration by comparing serum levels of carotenoids, vitamins C and E, and selenium in 421 patients with neovascular age-related macular degeneration and 615 controls. Subjects were classified by blood level of the micronutrient (low, medium, and high). Persons with carotenoid levels in the medium and high groups, compared with those in the low group, had markedly reduced risks of neovascular age-related macular degeneration, with levels of risk reduced to one half and one third, respectively. Although no statistically significant protective effect was found for vitamin C or E or selenium individually, an antioxidant index that combined all four micronutrient measurements showed statistically significant reductions of risk with increasing levels of the index. Although these results suggest that higher blood levels of micronutrients with antioxidant potential, in particular, carotenoids, may be associated with a decreased risk of the most visually disabling form of age-related macular degeneration, it would be premature to translate these findings into nutritional recommendations.

Results of fluorescence angiography of the posterior pole of the eye.

Baurmann, H.

Ber. Dtsch. Ophthal. Gesellsch. 1975; 73: 56-9. No abstract available.

Subretinal neovascularization in senile macular degeneration.

Berkow JW.

Am J Ophthalmol. 1984 Feb;97(2):143-7.

When fluorescein angiograms from 563 patients with senile macular degeneration examined at a large community hospital during a 9.5-year period were retrospectively reviewed, 200 patients were found to have a dry atrophic type of senile macular degeneration, consisting of drusen and retinal pigment epithelial changes. Of the 363 patients with exudative senile macular degeneration, 244 had subretinal neovascular membranes. Seventy-eight membranes were less than 1 disk diameter in size. Most of the large (157 of 224) and small (44 of 78) membranes showed a predilection for the fovea. Only 13 large and six small neovascular membranes were 200 microns or more from the center of the foveal avascular zone.

Cigarette smoking and age related macular degeneration.

Chan D Illinois College of Optometry, Chicago 60616, USA.

Optom Vis Sci (United States) Jul 1998, 75 (7) p476 84

BACKGROUND: Age related macular degeneration (ARMD) is one of the leading causes of severe visual impairment among older Americans. Several hypotheses have been proposed regarding the pathogenesis of ARMD. The possible association of cigarette smoking and ARMD remains controversial.

METHODS: Studies concerning the relationship between cigarette smoking and ARMD are identified through the use of Vision Articles Online and PubMed. Articles published since 1970 are reviewed.

RESULTS: The literature reviewed strongly supports a link between smoking and ARMD.

CONCLUSIONS: The identification of smoking as a risk factor can lead to early intervention. Such intervention may lessen visual loss from this disease, which has limited medical treatment options. (92 Refs.)

Alternative therapies in exudative age related macular degeneration

Chong N.H.V.; Bird A.C. N.H.V. Chong, Professorial Unit, Institute of Ophthalmology (UCL), Moorfields Eye Hospital, City Road, London EC1V 2PD United Kingdom Br. J. Ophthalmol. 1998; 82(12): 1441-3.)

No abstract.

Age related macular degeneration : a review of experimental treatments.

Ciulla TA; Danis RP; Harris A Indiana University Macular Degeneration Clinic and Research Center, Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, USA.

Surv Ophthalmol (Netherlands) Sep Oct 1998, 43 (2) p134 46

Age related macular degeneration (AMD) is the leading cause of irreversible visual loss in the USA. Laser photocoagulation of choroidal neovascular membranes (CNVMs) in exudative AMD is currently the only well studied and widely accepted treatment modality. It is beneficial for only a small minority of patients who show well demarcated "classic" CNVMs, and it destroys normal retinal tissue, creates a scotoma, and is associated with an unacceptably high CNVM persistence and recurrence rate. Consequently, investigators have attempted to develop new modalities for treatment of CNVMs. These treatment modalities can be grouped into four major categories: photodynamic therapy; pharmacologic inhibition of CNVM formation with antiangiogenic agents; surgical intervention, including excision of subfoveal CNVMs; and radiation therapy. All of these experimental treatment modalities are directed toward destroyiing CNVMs, the end result of the exudative process, and all have limitations. The ideal treatment of the future must be based on the pathogenesis of the disease at a stage well before CNVMs develop. Investigations in nonexudative AMD are currently focusing on several major areas. Epidemiologic factors, such as genetics, sunlight, and nutrition, are being evaluated in several large studies, including the Age Related Eye Disease Study, with the possibility of ultimately limiting the risk of AMD through behavior modification. Laser treatment of drusen is being evaluated as a means of limiting the risk of CNVM formation, although mixed results have been reported in the small number of studies to date. Choroidal perfusion abnormalities have been described in AMD, and some investigators postulate that altering blood flow may limit the risk of CNVM formation. No perfusion treatment trials have been completed to date. (183 Refs.)

Low glutathione reductase and peroxidase activity in age-related macular degeneration.

Cohen SM, Olin KL, Feuer WJ, Hjelmeland L, Keen CL, Morse LS. Department of Ophthalmology, University of California, Davis, Sacramento 95816.

Br J Ophthalmol. 1994 Oct;78(10):791-4.

Age-related macular degeneration (ARMD) may result from events initiated by reactive oxygen species. Blood samples from 18 patients with ARMD and 18 similarly aged controls were analysed for activities of important antioxidants. Blood glutathione reductase activity was lower in patients with ARMD compared with controls (p = 0.035). The activities of glutathione peroxidase (p = 0.18) and erythrocyte superoxide dismutase (p = 0.29) were similar between the two groups by a Student's two sample t test. Logistic regression was used to determine which enzyme activities were associated with ARMD after adjusting for possible confounding variables: smoking history, age, multivitamin use, and cardiovascular disease. Glutathione reductase activity (p = 0.05) and glutathione peroxidase activity (p = 0.065) were significantly associated with ARMD by this analysis. The relation of glutathione reductase and glutathione peroxidase activity to ARMD merits further study.

Sun exposure and age related macular degeneration. An Australian case control study.

Darzins P; Mitchell P; Heller RF McMaster University, Division of Geriatric Medicine, Hamilton, Ontario, Canada.

Ophthalmology (United States) May 1997, 104 (5) p770 6

BACKGROUND: The notion that sun exposure is a risk factor for age related macular degeneration (AMD) is widespread, but studies have not shown this conclusively.

METHODS: To test the hypothesis that AMD cases have greater ocular sun exposure than control subjects, the authors compared 409 cases with 286 control subjects resident in Newcastle, Australia. Sensitivity to sun and glare of the participants was characterized. Sun exposure was estimated from detailed histories and was validated against sun seeking or avoidance behavior expected, given sun sensitivity and history of treatment for skin neoplasia.

RESULTS: Contrary to the authors' hypothesis, control subjects had greater median annual ocular sun exposure (865 hours) than cases (723 hours), Mann Whitney U (U) = 45704, z = 4.9, P > 0.0001. Cases had poorer tanning than did control subjects (mean 2 = 18.2, 4 df, P = 0.001) and as young adults were more sensitive to glare, odds ratio (OR), 2.5; 95% confidence intervals (CIs), 1.8 to 3.5. After stratifying by tanning ability, in the poor tanning group, the median annual sun exposure of control subjects (685 hours) exceeded that of cases (619 hours), U = 6556, z = 1.9, P = 0.06. Among people who tanned well, control subjects also had significantly greater annual sun exposure than did cases (940 vs. 770 hours), U = 16263, z = 3.7, P = 0.0002.

CONCLUSIONS: Sensitivity to glare and poor tanning ability are markers of increased AMD risk. Sun sensitivity confounds study of the postulated AMD sunlight link. Despite analyses stratified by sun sensitivity, sun exposure was greater in control subjects than in cases with AMD.

Antioxidant enzymes of the human retina: effect of age on enzyme activity of macula and periphery.

De La Paz MA, Zhang J, Fridovich I. Duke University Eye Center, DUMC, Durham, NC 27710, USA.

Curr Eye Res. 1996 Mar;15(3):273-8.

The purpose of this research was to evaluate the effect of age on protective antioxidant enzyme activity of normal fresh cadaver human retina of the macula and periphery. Antioxidant enzymes were assayed in tissue extracts generated from 5 mm trephined punches of retina obtained centered over the macula and the superior midperiphery of normal fresh human cadaver retina. Cadaver tissue was obtained from donors of a wide age range (age 7 to 85 years). The assays were performed within 6 h of enucleation and within 24 h of donor death. Antioxidant enzymes assayed included superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase. Hexokinase and glucose-6-phosphate dehydrogenase, enzymes not directly involved in protection against oxidative damage, were assayed for comparison. Enzyme specific activities were calculated for the macula and periphery using protein concentration of the extract as the denominator. Using linear regression analysis, over the age range of 25 to 75 years, superoxide dismutase activity of the periphery but not the macula tended to decline with age (p = 0.04, R2 = 0.21). Interindividual variability was high, and variability increased with age. The difference between the macular and peripheral enzyme activities for glutathione peroxidase tended to decline with increasing donor age (p = 0.025, R2 = 0.33). There was no effect of age on the specific activities of catalase, glucose-6-phosphate dehydrogenase, and glutathione reductase. The specific activity of hexokinase from the macula declined with increasing donor age (p = 0.022, R2 = 0.43). Time from death to enucleation or beginning of experiment was not a significant factor. In summary, age does not have an effect on the activity of major antioxidant enzymes of the macula in normal human retina. There is a tendency for an effect of age on peripheral superoxide dismutase activity and the difference between macular and peripheral glutathione peroxidase activity. High interindividual variability of antioxidant enzyme activity exists in humans.

Inhibition of glutathione reductase by flavonoids. A structure-activity study.

Elliott AJ, Scheiber SA, Thomas C, Pardini RS. Allie M. Lee Laboratory for Cancer Research, Department of Biochemistry, University of Nevada, Reno 89557.

Biochem Pharmacol. 1992 Oct 20;44(8):1603-8.

A structure-activity study of fourteen chemically related flavonoids was conducted to evaluate their abilities to inhibit glutathione reductase (GR). By comparing the I50 values of flavonoids from different classes possessing an identical hydroxyl configuration, we determined the following order of potency for inhibition of GR: anthocyanidin > dihydroflavonol = chalcone > flavonol > catechin. Enzyme inhibition by delphinidin chloride and myricetin was partially prevented in a N2 atmosphere which implicates a role for oxygen in the mechanism of inhibition. To determine the role of oxygen species in enzyme inhibition, GR was preincubated with either mannitol, diethylenetriaminepenta-acetic acid (DETAPAC), superoxide dismutase (SOD), catalase (CAT), or SOD and CAT prior to assays for enzyme inhibition by flavonoids. Enzyme inhibition by delphinidin chloride and myricetin was suppressed by the addition of SOD, suggesting that superoxide (O2-.) is involved. However, inhibition by quercetin and morin was not sensitive to antioxidants. To further investigate the role of O2-. in GR inhibition, a superoxide generating system was utilized in the presence and absence of flavonoid. The O2-. generating system failed to inhibit GR in the absence of flavonoid but enhanced the inhibition by myricetin, indicating that the O2-. did not directly inhibit GR but reacted directly with certain flavonoids to form a reactive intermediate which, in turn, inhibited GR. These findings suggest that the mechanism of inhibition of GR by flavonoids is complex and may have oxygen-dependent and oxygen-independent components.

Oxidative protector' enzymes in the macular retinal pigment epithelium of aging eyes and eyes with age related macular degeneration

Frank R.N. Dr. R.N. Frank, Kresge Eye Institute, Wayne State Univ. Sch. of Medicine, Detroit, MI United States

Trans. of the Am. Ophthalmol. Soc. 1998, 96/ (635 689)

No abstract.

Flavonoids, a class of natural products of high pharmacological potency.

Havsteen B.

Biochem Pharmacol. 1983 Apr 1;32(7):1141-8

A review has been presented of the biochemistry and pharmacology of a class of natural products, the flavonoids. These substances which are widely distributed in the plant kingdom and present in considerable quantities in common food products, spices and beverages have in a concentrated form (Propolis) been used since ancient times by physicians and laymen to treat a great variety of human diseases but they have yet to pass the tests of modern, controlled, clinical experimentation. An attempt has been made to present the fundamental evidence from the basic biological sciences which is required to stimulate the interest of the clinicians in this new field. The few existing reports on the careful pharmacodynamic, pharmacokinetic and clinical studies which have been made have been summarized to provide a basis for a full-scale investigation of the therapeutic potential of flavonoids.

Antioxidants and angiogenetic factor associated with age related macular degeneration (exudative type)]

Ishihara N; Yuzawa M; Tamakoshi A Department of Ophthalmology, Nihon University School of Medicine, Tokyo, Japan.

Nippon Ganka Gakkai Zasshi (Japan) Mar 1997, 101 (3) p248 51

To confirm the hypothesis that antioxidants and angiogenetic factors may be associated with the development of age related macular degeneration (exudative type), we compared serum levels of vitamins A, C, and E and carotinoid, zinc, selenium and b FGF (basic fibroblast growth factor) in 35 patients with age related macular degeneration (exudative type) with the levels in 66 controls. The average serum zinc level was significantly lower in the patient group than in the control group. Serum vitamin E alpha levels also tended to be lower. Most serum b FGF levels were below the standard value in each group. Based on the above results, we conclude that subnormal levels of zinc and vitamin E may be associated with the development of age related macular degeneration.

Oxidative effects of laser photocoagulation.

Jennings PE, MacEwen CJ, Fallon TJ, Scott N, Haining WM, Belch JJ. Department of Medicine and Ophthalmology, Ninewells Hospital and Medical School, Dundee, Scotland.

Free Radic Biol Med. 1991;11(3):327-30.

Diabetic proliferative retinopathy is a common and sight-threatening condition. Oxidative stress is an integral and possibly causative part of the pathogenesis. Although laser photocoagulation is usually a beneficial treatment it remains unclear how it works. The possibility that it induces a sudden, temporary increase in free radical activity either by direct thermal damage or by oxygen reperfusion is explored in this clinical study by measuring the oxidative status in the peripheral blood of 13 patients undergoing panretinal photocoagulation. There were significant increases at one hour in malondialdehyde-like material (MDA-LM), 8.1 (6.9-9.6) nmol/mL, to 9.1 (7.6-9.8) nmol/mL, (less than 0.005); plasma thiols (PSH), 423 (352-457) microns/L, to 444 (382-478) microns/L, (p less than 0.005) and red cell reduced glutathione (GSH), 1357 (1295-1655) microns/L, to 1480 (1305-1760) microns/L, (p less than 0.01). Diene conjugates rose over the first hour 0.55 (0.36-0.79) od/mL, to 0.58 (0.34-0.85) od/mL falling to 0.56 (0.36-0.79) od/mL at 2 h but these changes were not significant. At 2 h, MDA-LM 8.4 (6.7-9.6) nmol/mL and PSH 404 (379-462) microns/L had returned to baseline but GSH remained significantly elevated 1500 (1325-1675) microns/L, (p less than 0.005 compared to baseline). This is a new observation and in some circumstances such generation of free radicals could explain the mechanism behind the complications of photocoagulation by direct or indirect damage to vascular endothelium leading to increased vascular permeability manifest as macular oedema or choroidal effusions.

Genetic association of apolipoprotein E with age related macular degeneration.

Klaver CC; Kliffen M; van Duijn CM; Hofman A; Cruts M; Grobbee DE; van Broeckhoven C; de Jong PT Department of Epidemiology, Erasmus University Medical School, Rotterdam, The Netherlands.

Am J Hum Genet (United States) Jul 1998, 63 (1) p200 6

Age related macular degeneration (AMD) is the most common geriatric eye disorder leading to blindness and is characterized by degeneration of the neuroepithelium in the macular area of the eye. Apolipoprotein E (apoE), the major apolipoprotein of the CNS and an important regulator of cholesterol and lipid transport, appears to be associated with neurodegeneration. The apoE gene (APOE) polymorphism is a strong risk factor for various neurodegenerative diseases, and the apoE protein has been demonstrated in disease associated lesions of these disorders. Hypothesizing that variants of APOE act as a potential risk factor for AMD, we performed a genetic association study among 88 AMD cases and 901 controls derived from the population based Rotterdam Study in the Netherlands. The APOE polymorphism showed a significant association with the risk for AMD; the APOE epsilon4 allele was associated with a decreased risk (odds ratio 0.43 [95% confidence interval 0.21 0. 88]), and the epsilon2 allele was associated with a slightly increased risk of AMD (odds ratio 1.5 [95% confidence interval 0.8 2. 82]). To investigate whether apoE is directly involved in the pathogenesis of AMD, we studied apoE immunoreactivity in 15 AMD and 10 control maculae and found that apoE staining was consistently present in the disease associated deposits in AMD maculae that is, drusen and basal laminar deposit. Our results suggest that APOE is a susceptibility gene for AMD.

[Treatment of senile macular degeneration with Ginkgo biloba extract. A preliminary double-blind drug vs. placebo study] [Article in French]

Lebuisson DA, Leroy L, Rigal G.

Presse Med. 1986 Sep 25;15(31):1556-8.

Senile macular degeneration is a frequent cause of blindness for which there is no satisfactory medical treatment. A double-blind trial comparing Ginkgo biloba extract with a placebo was conducted in 10 out-patients at the Hopital Foch. Drug effectiveness was assessed on the results of fundoscopy and of measurements of visual acuity and visual field. In spite of the small population sample, a statistically significant improvement in long distance visual acuity was observed after treatment with Ginkgo biloba extract. The assumed pathogenesis of senile macular degeneration is discussed with emphasis on free oxygenated radicals.

Studies on Vaccinium myrtillus anthocyanosides. I. Vasoprotective and antiinflammatory activity.

Lietti A, Cristoni A, Picci M.

Arzneimittelforschung. 1976;26(5):829-32.

A Vaccinium myrtillus anthocyanosides preparation (equivalent to 25% of anthocyanidins) demonstrated significant vasoprotective and antioedema properties in exerimental animals. In rabbits, the skin capillary permeability increase, due to chloroform, was reduced both after i.p. (25--100 mg/kg) and oral administration (200--400 mg/kg) of anthocyanosides. Their activity was more lasting in comparison to rutin or mepyramine and this did not seem to be due to a specific antagonism towards inflammatory process mediators such as histamine or bradykinin. Experiments carried out in rats demonstrated that Vacinium myrtillus anthocyanosides were effective both in skin capillary permeability test as well as on vascular resistance of rats fed a P factor deficient diet. In the former test effective doses were in the range of 25--100 mg/kg (by oral route). In both the animal species investigated, anthocyanosides were two-fold more active when compared to the flavonoid rutin. Vaccinium myrtillus anthocyanosides by oral route inhibited carrageein paw oedema in rats showing a dose-response relationship. An antioedema activity was detected also after i.v. or topical application.

Photodynamic therapy with verteporfin for choroidal neovascularization caused by age-related macular degeneration: Results of a single treatment in a phase 1 and 2 study

Miller J.W.; Schmidt-Erfurth U.; Sickenberg M.; Pournaras C.J.; Laqua H.; Barbazetto I.; Zografos L.; Piguet B.; Donati G.; Lane A.-M.; Birngruber R.; Van den Berg H.; Strong H.A.; Manjuris U.; Gray T.; Fsadni M.; Bressler N.M.; Gragoudas E.S. Dr. J.W. Miller, Laser Research Laboratory, Retina Service, Massachusetts Eye and Ear Infirmary, 243 Charles St, Boston, MA 02114 United States AUTHOR EMAIL: jwmiller@meei.harvard.edu

Archives of Ophthalmology 1999, 117/9 (1161-1173)

Objective: To evaluate the safety and short-term visual and fluorescein angiographic effects of a single photodynamic therapy treatment with verteporfin with the use of different dosage regimens in patients with choroidal neovascularization (CNV) from age-related macular degeneration. Design: Nonrandomized, multicenter, open-label, clinical trial using 5 dosage regimens. Setting: Four ophthalmic centers in North America and Europe providing retinal care. Participants: Patients with subfoveal CNV caused by age-related macular degeneration. Methods: Standardized protocol refraction, visual acuity testing, ophthalmic examination, color photographs, and fluorescein angiograms were used to evaluate the effects of a single treatment of photodynamic therapy with verteporfin. Follow-up was planned through 3 months in 97 patients and for less than 3 months in 31 other patients. Results: The mean visual acuity change (and range of change) from baseline at the follow-up examination at week 12 after a single treatment with regimens 1 through 5 was -0.2 (-3 to +2), -0.9 (-9 to +5), -1.6 (-9 to +2), +0.4 (-8 to +7), and +0.1 (-8 to +9) lines, respectively. Only the highest light dose (150 J/cmsup 2) in regimens 2 and 3, which produced angiographic nonperfusion of neurosensory retinal vessels, caused marked vision loss. Some cessation of fluorescein leakage from CNV was achieved without loss of vision when the light dose used was less than 150 J/cmsup 2. Systemic adverse events were rare. Cessation of fluorescein leakage from CNV was noted in all regimens by 1 week after photodynamic therapy. Fluorescein leakage from at least a portion of the CNV reappeared by 4 to 12 weeks after treatment in almost all cases. Progression of classic CNV beyond the area of CNV identified before treatment was noted in 42 (51%) of the 83 eyes with classic CNV followed up for 3 months after a single treatment. Eyes in which the area of any CNV leakage at 12 weeks was less than at baseline had a significantly better visual acuity outcome (+0.8 line) than eyes in which CNV leakage progressed (-0.8 line). Conclusions: Photodynamic therapy with verteporfin achieved short-term cessation of fluorescein leakage from CNV without loss of vision or growth of classic CNV in some patients with age- related macular degeneration. Except for nonperfusion of neurosensory retinal vessels at a light dose of 150 J/cmsup 2, no other adverse events were of concern. Randomized clinical trials to investigate whether this new modality can preserve vision in patients with CNV secondary to age-related macular degeneration are justified.

Nutrition in the elderly.

Morley JE, Mooradian AD, Silver AJ, Heber D, Alfin-Slater RB. Department of Medicine, University of California School of Medicine, Los Angeles.

Ann Intern Med. 1988 Dec 1;109(11):890-904.

Nutritional modulation is one approach to successful aging. In animals, dietary restriction increases life span. Alterations in the macronutrient and micronutrient constituent of the diet can modulate gene expression. Anorexia is common in elderly persons. The results of studies in animals suggest that aging is associated with a decrease in the opioid feeding drive and an increase in the satiating effect of cholecystokinin. Unrecognized depression is a common, treatable cause of anorexia and weight loss in elderly persons. Protein synthesis decreases in elderly persons; nevertheless, nitrogen balance can be maintained in patients with fairly low intakes of protein. Carbohydrate intolerance is common and may be modulated by nutritional intervention and physical activity. The role of cholesterol in the development of heart disease in very old persons is controversial. Homebound and institutionalized elderly persons often do not expose their skin to sunlight; because the skin of older persons has a decreased ability to form vitamin D, the vitamin D status in these persons is precarious and they are at risk for osteopenia. Vitamins are often abused by elderly persons. Drug administration alters the vitamin requirements of persons. Borderline zinc state has been associated with deteriorating immune function, especially in persons who have diabetes mellitus or who abuse alcohol. Zinc administration appears to protect against the deteriorating vision associated with age-related macular degeneration. Selenium deficiency seems to be associated with an increased prevalence of cancer.

Studies on the mechanism of early onset macular degeneration in cynomolgus monkeys. II. Suppression of metallothionein synthesis in the retina in oxidative stress.

Nicolas MG, Fujiki K, Murayama K, Suzuki MT, Shindo N, Hotta Y, Iwata F, Fujimura T, Yoshikawa Y, Cho F, Kanai A. Department of Ophthalmology, Juntendo University School of Medicine, Tokyo, Japan.

Exp Eye Res. 1996 Apr;62(4):399-408.

Initial investigations done in this laboratory detected increased albumin and decreased glyceraldehyde 3-phosphate dehydrogenase concentrations in the retina of an animal model manifesting early onset macular degeneration. Both glyceraldehyde 3-phosphate dehydrogenase and albumin are markers of oxidative stress in cells. In this study, we used the same animal model to study further biochemical and physiological processes which may be involved in the pathogenesis of early onset macular degeneration in monkeys. We detected 60% lower catalase and glutathione peroxidase activities in the affected retinas suggesting lower antioxidant activities and oxidative stress. One of the consequences of oxidative stress is the production of metallothionein, a low molecular weight protein also induced by high concentrations of heavy metals such as zinc. Metallothionein was detected by RT-PCR in these monkey retinas. However initial quantitative PCR studies on this protein showed that the synthesis of metallothionein in affected retinas appears to be less than in normal controls. The affected retinas also showed a fourfold lower zinc concentration compared with the normal controls. No significant difference however, could be detected in the zinc concentrations in plasma samples. Since induction of metallothionein synthesis is mediated by transcription factors which require heavy metals such as zinc for binding to specific sites in the DNA, the lowered zinc concentration may, thus, correlate with the lowered metallothionein expression. And since metallothionein is suggested to function as a free radical scavenger, the lowered metallothionein synthesis may consequently contribute to increased peroxidation reactions in the affected retinas. It appears therefore, that oxidative stress and the decreased metallothionein synthesis may be involved in the pathogenesis of early onset macular degeneration in this animal model.

[Th clinical picture of retinal thrombosis (author's transl)] [Article in German]

Niesel P.

Klin Monatsbl Augenheilkd. 1977 Feb;170(2):186-92.

Besides the acute arterial occlusion and simple venous thrombosis, the clinical symptomatology may include signs of chronic arterial insufficiency, i.e. progressive blurring of vision, absolute visual field defects, cotton wool exudates, capillary occlusion and increased retinal circulation time. The poor visual prognosis is caused by progressive macular degeneration. In the case of acute arterial thrombosis, fragmentation of the blood column and absence of arterial pulsation are indicative of pronounced retinal ischemia. The ophthalmoscopic aspect of a visible embolus may be a hint for the prognosis of eventual recanalisation.

Moderate wine consumption is associated with decreased odds of developing age related macular degeneration in NHANES 1 [see comments]

Obisesan TO; Hirsch R; Kosoko O; Carlson L; Parrott M Department of Internal Medicine, Howard University Hospital, Washington, DC 20060, USA.

J Am Geriatr Soc (United States) Jan 1998, 46 (1) p1 7

OBJECTIVE: To determine the association between alcohol intake and the risk of developing age related macular degeneration (AMD).

DESIGN: Case control study. PARTICIPANTS: The sample consisted of 3072 adults 45 to 74 years of age with macular changes indicative of AMD who participated in a nationally representative sample of the first National Health Nutrition and Examination Survey (NHANES 1) between 1971 and 1975: (a) the ophthalmology data set and (b) the medical history questionnaire.

MAIN OUTCOME MEASURES: Alcohol intake and the risk of developing AMD were measured. AMD was determined by staff at the National Eye Institute by fundoscopy examination using standardized protocol.

RESULTS: Overall, 184 individuals (6%) had AMD. We observed a statistically significant but negative association between AMD and the type of alcohol consumed in a bivariate model (OR 0.86; 95% CI 0.73, 0.99). In the same model, age maintained a consistently strong association with AMD (OR 1.08; 95% CI 1.06 1.11; P < .001). Among the different types of alcohol consumed in NHANES 1 (beer, wine, and liquor), the effect of wine, either alone (OR 0.66; 95% CI 0.55 0.79) or in combination with beer (OR 0.66; 95% CI 0.55 0.79) or liquor (OR 0.74; 95% CI 0.63 0.86), dominated the negative association observed between AMD and alcohol type. Additionally, a statistically significant and negative association between wine and AMD was noted after adjusting for the effect of age, gender, income, history of congestive heart failure, and hypertension (OR 0.81; 95% CI 0.67 0.99).

CONCLUSION: Moderate wine consumption is associated with decreased odds of developing AMD. Health promotion and disease prevention activities directed at cardiovascular disease may help reduce the rate of AMD associated blindness among older people. The nature and pathophysiology of this association warrant further investigation.

Zinc as a treatment for age related macular degeneration

Olson R.J.; DeBry P. Dr. R.J. Olson, Department of Ophthalmology, University Utah Health Sciences Ctr., John A. Moran Eye Center, 50 North Medical Drive, Salt Lake City, UT 84124 United States

Journal of Trace Elements in Experimental Medicine 1998, 11/2 3 (137 145)

Evidence continues to increase that antioxidants are an important factor in the progress and development of age related macular degeneration. While zinc supplementation fits nicely in this thesis as a mineral co factor of vital antioxidant enzymes, the clinical evidence for oral zinc supplementation is mixed and presently inconclusive.

The evoked cortical potential in macular degeneration.

Orpin, J.A., Orpin, E., McCulloch, C.

J. Am. Geriatr. Soc. 1974 Dec; 22(12): 536-7.

Results with anthocyanosides from Vaccinium myrtillus equivalent to 25% of anthocyanidines in the treatment of haemorrhagic diathesis due to defective primary haemostasis.

Piovella, F., Almasio, P., Ricetti, M.M. et al.

Gazz. Med. Ital. 1981; 140(10): 445-9.

No abstract available.

Antioxidant enzymes in RBCs as a biological index of age related macular degeneration.

Prashar S, Pandav SS, Gupta A, Nath R. Department of Biochemistry, Postgraduate Institute of Medical Education and Research, Chandigarh, India.

Acta Ophthalmol (Copenh). 1993 Apr;71(2):214-8.

The present study was undertaken to assess the levels of antioxidant enzymes in red blood cells of subjects with age-related macular degeneration and age-matched controls. The results obtained show a significant decrease in activities of superoxide dismutase (p < 0.001) and glutathione peroxidase (p <0.001) as compared to the controls. A good correlation (r = -0.99) was alsoobserved between age and decreased activity of antioxidant enzymes in controls, and also correlated well with age-related macular degeneration. In conclusion, oxidative stress as assessed by antioxidant enzymes is more pronounced in subjects with age-related macular degeneration as compared to age-matched controls.

Atrophic macular degeneration. Rate of spread of geographic atrophy and visual loss.

Schatz H, McDonald HR. Retina Research Fund, St. Mary's Hospital and Medical Center, San Francisco, California.

Ophthalmology. 1989 Oct;96(10):1541-51.

The authors studied 50 eyes with atrophic (dry) macular degeneration (geographic atrophy of age-related macular degeneration [GAMD], in 50 consecutive patients for 2 to 6 years (average, 3.4 years). There were 35 women and 15 men ranging in age from 60 to 89 years (average, 73 years). The areas of atrophy tended to follow the disappearance or flattening of soft drusen, pigment epithelial detachment, or reticular mottling of the retinal pigment epithelium. The atrophic areas were multifocal in 20 of the 50 eyes. Atrophy of the retinal pigment epithelium was followed by atrophy of the choriocapillaris. The atrophic areas tended to expand (average rate in one direction, 139 microns per year) and cause gradual loss of central visual acuity. The rate of significant visual loss (from 20/50 or better to 20/100 or worse) was 8% of eyes per year. There was a tendency toward resistance of the spread of atrophy into the fovea. The atrophy tended to expand faster in patients under age 75 and slower in patients aged 75 and over. Subretinal neovascularization developed in ten of the 50 eyes

Radiotherapy and age related macular degeneration: a review of the literature]

Schwartz LH; Schmitt T; Benchaboun M; Caputo G; Chauvaud D; Balosso J; Faivre C; Francais C; Koenig F Service de radiotherapie, hopital Saint Louis, Paris, France.

Cancer Radiother (France) 1997, 1 (3) p208 12

Macular degeneration is a major health problem. Less than 10% of the cases can be successfully treated by laser therapy. Low dose radiation therapy (in the range of 20 Gy) appears to decrease neovascularisation. These early results need to be confirmed through a randomized trial. (38 Refs.)

Dietary carotenoids, vitamins A, C, and E, and advanced age-related macular degeneration. Eye Disease Case-Control Study Group.

Seddon JM, Ajani UA, Sperduto RD, Hiller R, Blair N, Burton TC, Farber MD, Gragoudas ES, Haller J, Miller DT, et al. Epidemiology Unit, Massachusetts Eye and Ear Infirmary, Boston 02114.

JAMA. 1994 Nov 9;272(18):1413-20.

OBJECTIVE--To evaluate the relationships between dietary intake of carotenoids and vitamins A, C, and E and the risk of neovascular age-related macular degeneration (AMD), the leading cause of irreversible blindness among adults.

DESIGN--The multicenter Eye Disease Case-Control Study. SETTING--Five ophthalmology centers in the United States. PATIENTS--A total of 356 case subjects who were diagnosed with the advanced stage of AMD within 1 year prior to their enrollment, aged 55 to 80 years, and residing near a participating clinical center. The 520 control subjects were from the same geographic areas as case subjects, had other ocular diseases, and were frequency-matched to cases according to age and sex.

MAIN OUTCOME MEASURES--The relative risk for AMD was estimated according to dietary indicators of antioxidant status, controlling for smoking and other risk factors, by using multiple logistic-regression analyses.

RESULTS--A higher dietary intake of carotenoids was associated with a lower risk for AMD. Adjusting for other risk factors for AMD, we found that those in the highest quintile of carotenoid intake had a 43% lower risk for AMD compared with those in the lowest quintile (odds ratio, 0.57; 95% confidence interval, 0.35 to 0.92; P for trend = .02). Among the specific carotenoids, lutein and zeaxanthin, which are primarily obtained from dark green, leafy vegetables, were most strongly associated with a reduced risk for AMD (P for trend = .001). Several food items rich in carotenoids were inversely associated with AMD. In particular, a higher frequency of intake of spinach or collard greens was associated with a substantially lower risk for AMD (P for trend < .001). The intake of preformed vitamin A (retinol) was not appreciably related to AMD. Neither vitamin E nor total vitamin C consumption was associated with a statistically significant reduced risk for AMD, although a possibly lower risk for AMD was suggested among those with higher intake of vitamin C, particularly from foods.

CONCLUSION--Increasing the consumption of foods rich in certain carotenoids, in particular dark green, leafy vegetables, may decrease the risk of developing advanced or exudative AMD, the most visually disabling form of macular degeneration among older people. These findings support the need for further studies of this relationship.

Hydergine-a new promise in neuro-retinal disorders.

Shukla, M.

Afro-Asian J. Ophthalmol. 1989; 8(1): 28-30.

No abstract available.

Autofluorescence characteristics of lipofuscin components in different forms of late senile macular degeneration]

Spital G; Radermacher M; Muller C; Brumm G; Lommatzsch A; Pauleikhoff D Augenabtlg. St. Franziskus Hospital, Munster.

Klin Monatsbl Augenheilkd (Germany) Jul 1998, 213 (1) p23 31

BACKGROUND: Lipofuscin is the main fluorophore of the human fundus. Because lipofuscin is the result of the accumulation of metabolic debris in pigmentepithelial cells (RPE), the autofluorescence can be interpreted as a clinical sign for the metabolic activity of the RPE. In order to get informations of RPE function in different types of late AMD, the autofluorescence patterns in patients with late AMD were analyzed.

MATERIAL AND METHOD: A prospective examination of the fundus autofluorescence of 64 eyes of 52 patients with different types of late AMD was performed using a confocal scanning laser opthalmoscope. The autofluorescence images were categorized in respect to the type of late AMD according to the opthalmoscopic and fluoresceine angiographic findings.

RESULTS: Reduced autofluorescence was found in the centre of occult (78.6%) and classic (100%) choroidal neovascularisations (NV) as well as in the occult NV of RPE detachments. A loss of autofluorescence was related to the RPE free area of RPE tears (100%) and to RPE atrophy (88.9%) with sometimes increased autofluorescence at the rim. Increased autofluorescence could be seen at the surface of RPE detachments (71.4%), in the area of the shrink age of RPE in RPE tears (100%) as well as at RPE proliferations in small occult NV (100%). Disciforme scars showed variable patterns of autofluorescence.

CONCLUSION: The autofluorescence of the RPE can be analyzed clinically with the described method. Different patterns of autofluorescence could be revealed in different types of late AMD. Increased autofluorescence was found in lesions with proliferative or phagocytotic metabolic activity of the RPE like RPE detachments, shrinked RPE in RPE tears or occult NV with RPE proliferations. The reduced autofluorescence in occult or classical choroidal NV can be interpreted as a sign of decompensation of the RPE and was also seen in areas with RPE loss.

Age related macular degeneration. Can we stem this worldwide public health crisis?

Starr CE; Guyer DR; Yannuzzi LA Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, USA.

Postgrad Med (United States) May 1998, 103 (5) p153 6, 161 4

Age related macular degeneration, the leading cause of legal blindness in people over age 60 worldwide, represents a public health crisis that deserves the attention and understanding of all physicians. The dry form of the disease is more common than the wet, but the wet form causes the most severe vision loss. Other than vision aids (e.g., glasses, magnifiers), no treatments or preventive measures are currently available for patients with dry macular degeneration, and laser photocoagulation with fluorescein angiography is the only clinically proven therapy for neovascular disease. Indocyanine green angiography is a promising new imaging tool that may improve detection of patients likely to benefit from laser therapy. Until better diagnostic and treatment options are available, early screening and patient education offer the best hope for reducing the widespread devastation caused by this disease. (32 Refs.)

The development of neovascularization of senile disciform macular degeneration.

Teeters, V.W., Bird, A.C.

Am. J. Ophthalmol. 1973 Jul; 76(1): 1-18.

No abstract available.

Treatment of macular degeneration, according to Bangerter.

Teichmann KD King Khaled Eye Specialist Hospital P.O. Box Riyadh 7191, Riyadh 11 462 Kingdom of Saudi Arabia ++966 1/482 1234 ++966 1/482 1908.

Eur J Med Res (Germany) Oct 30 1997, 2 (10) p445 54

Age related macular degeneration (AMD) is a common cause of visual loss among elderly patients. Although some risk factors have been determined, the ultimate cause of the disease is not known. For a long time, therapeutic nihilism has been the rule among ophthalmologists confronted with such patients. Bangerter has not shared this attitude, especially since the time that he incidentally discovered, more than 40 years ago, the beneficial effects of radiotherapy, in discouraging the growth of new vessels at the posterior pole of the eye. A variety of approaches are combined and used by Bangerter in the treatment of the different types of AMD, including retrobulbar injections of either vasodilating medications (in the dry or atrophic type) or corticosteroids (in the wet or exudative type), general medical measures aimed at improving metabolic and vascular functions such as supplementation with trace elements, antioxidants, and vitamins; ozone therapy; advice to increase physical fitness, improve nutrition, and abstain from smoking; and protection from excessive light exposure. Being convinced of the usefulness of his type of combination treatment, he has always rejected undertaking controlled clinical trials, of only single aspects of the therapy, as unethical and invalid. For this reason, scientific journals have not proven cooperative in several attempts at publishing his results, as collected in retrospective surveys. Recently, however, some of the several approaches combined by Bangerter in treating AMD have been pronounced effective by other investigators. We present here an overview of his treatment approaches, as few people are aware of them, to clear up misconceptions and to set records straight. (59 Refs.)

Evidence by in vivo and in vitro studies that binding of pycnogenols to elastin affects its rate of degradation by elastases.

Tixier JM, Godeau G, Robert AM, Hornebeck W.

Biochem Pharmacol. 1984 Dec 15;33(24):3933-9.

Procyanidol oligomers and (+) catechin bound to insoluble elastin markedly affect its rate of degradation by elastases. Insoluble elastin pretreated with procyanidol oligomers (PCO) was resistant to the hydrolysis induced by both porcine pancreatic and human leukocyte elastases. The quantitative adsorption of pancreatic elastase was similar on either untreated or PCO-treated elastin suggesting that the binding of this compound to elastin increases the non-productive catalytic sites of elastase molecules. (+) Catechin-insoluble elastin complexes were partially resistant to the degradation induced by human leukocyte elastase but were hydrolysed at the same rate as untreated samples by a constant amount of pancreatic elastase. In addition, the coacervation profile of kappa-elastin peptides as a function of temperature is greatly modified in presence of these flavonoids. We conclusively evidenced that PCOs bind to skin elastic fibres when injected intradermally into young rabbits. As a result, these elastic fibres were found more resistant to the hydrolytic action of porcine pancreatic elastase when injected to the same site. These in vivo studies further emphasized the potential effect of these compounds in preventing elastin degradation by elastase(s) as occurred in inflammatory processes.

Dynamics of accumulation and degradation of lipofuscin in retinal pigment epithelium in senile macular degeneration]

von Ruckmann A; Schmidt KG; Fitzke FW; Bird AC; Jacobi KW Institute of Ophthalmology, Universitats Augenklinik, Giessen.

Klin Monatsbl Augenheilkd (Germany) Jul 1998, 213 (1) p32 7

BACKGROUND: It is thought that lipofuscin plays a central role in the pathogenesis of age related macular degeneration (AMD). The lack of histopathological material has been a severe limitation in our knowledge on lipofuscin in this disease. A new technique has been developed that allows in vivo imaging of fundus autofluorescence derived from lipofuscin in the retinal pigment epithelium (RPE) using a confocal Laser Scanning Ophthalmoscope (LSO). We studied the dynamics of lipofuscin accumulation and degradation in patients with AMD.

MATERIALS AND METHODS: Serial examinations of the spatial distribution of fundus autofluorescence were performed in 148 eyes of 74 patients with AMD using a LSO over a period of 1 3.5 years.

RESULTS: Fundus autofluorescence changed over time in almost all eyes studied. Areas of increased autofluorescence occurred progressively during follow up in eyes with drusen and hyperpigmentation. The size of pathologic autofluorescence increased over time in almost all eyes with geographic atrophy, subretinal neovascularisations and disciform scars. Irregular autofluorescence was seen over most subretinal neovascularisations. Autofluorescence intensity decreased in old subretinal neovascularisations and disciform scars over time.

CONCLUSIONS: Changes of the distribution of autofluorescence occur in eyes with AMD over time. Fundus autofluorescence imaging allows in vivo analysis of the dynamics of accumulation and degradation of lipofuscin in the RPE in eyes with AMD and documentation of metabolic activity of the RPE.

Cystoid macular degeneration in experimental branch retinal vein occlusion.

Wallow IH, Danis RP, Bindley C, Neider M. Department of Ophthalmology, University of Wisconsin School of Medicine, Madison.

Ophthalmology. 1988 Oct;95(10):1371-9.

Macular edema and collateral vessels were examined clinically and histopathologically up to 48 months after branch retinal vein occlusion in six eyes of five cynomolgus monkeys. In all six, central macular swelling and fluorescein leakage from the retinal vasculature were confined to the acute stage. However, histopathologically, at the chronic stage, only two maculas were completely recovered and unremarkable, whereas the other four showed variable degrees of cystoid degeneration and photoreceptor cell loss. In the two recovered maculas, six to eight normal-sized capillaries separated the fovea from the nearest cluster of capillary collaterals. In three maculas with cystic degeneration, collaterals incorporated the circumfoveal capillaries. In the fourth macula with cystic degeneration, collaterals were separated from the center by two normal-sized capillaries but were also associated with large areas of capillary nonperfusion partially due to occlusion of the macular arteriole.

Study of aging macular degeneration in China.

Wu LH. Zhongshan Ophthalmic Center, Sun Yat-sen University of Medical Sciences, Guangzhou, China.

Jpn J Ophthalmol. 1987;31(3):349-67.

Studies of the epidemiology, pathogenetic factors and visual function of aging macular degeneration (AMD) show that it has become an ocular disease worth noticing in China. Although most AMD cases were of the dry type and the patients had rather good visual acuity, various determinations of visual function showed different degrees of impairment. Controlling light exposure and improving trace metal metabolism may be helpful for early prevention and treatment of AMD. It will also be an important factor in the prevention of blindness in Asian nations.

Delayed macular choriocapillary circulation in age-related macular degeneration.

Zhao J, Frambach DA, Lee PP, Lee M, Lopez PF. Doheny Eye Institute, University of Southern California School of Medicine, Los Angeles 90033, USA.

Int Ophthalmol. 1995;19(1):1-12.

PURPOSE. To investigate the macular choriocapillary circulation (MCC) in eyes with age-related macular degeneration (ARMD) and to correlate these findings with the associated clinical and angiographic drusen characteristics.

METHODS. Scanning laser ophthalmoscope fluorescein videoangiography was performed on 34 eyes with age-related macular degeneration and eight age-matched normal volunteers. Drusen characteristics were assessed using the Wisconsin age-related maculopathy grading scale.

RESULTS. A delayed macular choriocapillary circulation (DMCC) was defined as a macular choriocapillary filling time greater than 3 standard deviations from the normal mean (greater than 5 seconds). Nine (26%) of the 34 eyes with ARMD were found to have a DMCC. After age adjustment, eyes with DMCC were more likely to have geographic atrophy of the retinal pigment epithelium (p = 0.003) or choroidal neovascularization p = 0.07) than were eyes with a normal MCC. Regional differences in choriocapillary filling times were present in the eyes with a DMCC, including nasal-to-temporal, central-to-peripheral, and inferior-to-superior gradients of progressively less choriocapillary filling delay. The DMCC correlated with the location, number, size, confluence, and fluorescein staining characteristics of the associated drusen.

CONCLUSION. DMCC occurs in some eyes with ARMD. This finding may not only assist in defining eyes at risk for progressive disease but may also help to elucidate the pathogenesis of age-related macular degeneration.