Geographic Atrophy and micronutritional supplements: A complex relationship.

In 2019, the Age-Related Eye Disease Study (AREDS) remains the basis for micronutritional supplement guidelines aiming to slow the progression of Age-Related Macular Degeneration (AMD) and reduce the risk of neovascularization. However, for Geographic Atrophy (GA) patients specifically, there seem to be more arguments for prescribing micronutritional supplements for the prevention of neovascular complications than to slow the progression of the atrophy. The AREDS report 8 showed a significant decrease in AMD progression over a five-year follow-up associated with a formulation containing antioxidants and zinc. It is noteworthy that the protective effect that was demonstrated was mainly related to the risk of a neovascularization and that the AREDS did not really demonstrate a protective effect that would slow the progression of GA. The 2013 AREDS II results have led to a change in the AREDS formulation. Nevertheless, the replacement of beta-carotene by lutein and zeaxanthine and the addition of Omega-3 did not add any further evidence for a protective effect on GA. Furthermore, the AREDS study used color photographs rather than fundus autofluorescence or OCT to assess the presence or the evolution of patches of atrophy. Over the last 10 years, it has been shown that OCT is far more accurate than color photographs to measure the size of the atrophic areas and to evaluate the extent of alterations in the chorioretinal layers. While lack of evidence of a protective effect of the AREDS formulation for GA is not a proof of the absence of effect, many publications seem to have taken the results of the AREDS in such a global way that the lack of evidence concerning GA seems to have been ignored. Micronutrition supplements are well prescribed for AMD patients, and the key factor for adherence is explanation to the patient. So far, it appears worth explaining to GA patients that prescription of the AREDS formulation is mainly aimed at reducing the risk of neovascularization.

[Nutrition and age-related macular degeneration]. / Nutrition et dégénérescence maculaire liée à l'âge.

Age-related macular degeneration is a growing burden disease with a high prevalence in elderly: it is the first cause of blindness in developped countries. It is a multifactorial disease with genetic factors and nutritional factors. Carotenoids, lutein and zeaxanthin are components of macular pigment and they have a filter role for blue light and an antioxidant role. Other nutritional factors might play a role as antioxidants: zinc, selenium, vitamin E, vitamin C… which lead to the ARED Study. It is the only one study with proven positive effects on the disease progression (stages 3 and 4). A high glycemic index increases oxidative stress. Long chain omega-3 polyunsaturated fatty acids have a protective effect. Available data are presented and discussed. These are new preventive issues.

[Some notions about possible harmlessness and/or toxicity of the antioxidant micronutriments]. / Quelques notions sur l'innocuité et la toxicité éventuelles des supplémentations en micronutriments antioxydants.

Report # 8 of the Age Related Eye Disease Study (AREDS) showed the interest of a cocktail of antioxidant micronutrients for the uni- or bilateral intermediate forms and the unilateral evolved forms of Age related Macular Degeneration. This use of supranutritional amounts aiming at obtaining a therapeutic effect corresponds to the concept of "neutraceuticals" which can be opposed to the concept of nutritional amounts. Although the AREDS was carried out under strict conditions, the evolution of knowledge in micronutrition since its design has led to some criticism of both the amounts of the micronutrients and the composition of the formulation. For example several authors pointed out that beta-carotene used at 3 fold the daily recommendations could have harmful effects, especially among smokers or former smokers. Other authors pointed out that vitamin E, at amounts corresponding to 40 to 60 fold the amounts recommended could be correlated with a lethal risk. We develop here some notions about safety and/or harmlessness of the antioxidant micronutrients.

[Hypothesis on the role of nutritional factors in ocular hypertension and glaucoma]. / Hypothèses sur le rôle des facteurs nutritionnels au cours des hypertonies oculaires et du glaucome.

Recent notions in connection with oxidative stress and the fat balance of long chain polyunsaturated fatty acids (PUFA) families have brought new insight to a probable role of nutritional factors in glaucoma and intraocular hypertony. The modifications of the extracellular matrix of the trabecula could be influenced by oxidative stress. On the one hand, collagen apoptosis and remodeling (associated with an increase in intraocular pressure) are mainly influenced by hydrosoluble antioxidants such as glutathione. On the other hand, elastin apoptosis and remodeling (correlated with the occurrence of optic atrophy) are particularly influenced by liposoluble antioxidants such as vitamin E. In addition, the dietary ratio of omega3/omega6PUFA intake could influence the balance of intraocular pressure. Omega-3 PUFA could influence cyclooxygenase competition. A diet with increased omega-3 and decreased omega-6 could thus favor an increase in intraocular pressure reducing synthesis of PG-F2, leading to a decrease in uveoscleral outflow. The true importance of these factors has not yet been solidly determined and studies are in progress to clarify the real implication of these nutritional factors.

[Nutrition and age-related macular degeneration]. / Nutrition et dégénérescence maculaire liée à l'âge.

The nutritional factors involved in the pathogenesis of age-related macular degeneration (AMD) include antioxidants or antioxidant cofactors: vitamins A, C, etc.; zinc, etc.; anti-free-radicals such as beta-carotene and carotenoids, including lutein and zeaxanthin; micronutrients protecting from blue light such as lutein and zeaxanthin; and finally components of the membranes of the photoreceptors docosahexaenoic acid (DHA). These nutritional factors are closely related to environmental risk factors such as smoking and chronic blue light exposure. Although the experimental and epidemiological data are concordant and coherent, the protective role of these micronutrients is not clearly established, mainly because there are very few clinical studies. However, a first observation study showed positive effects at stages 3 and 4 of AMD. Report #8 of the Age-Related Eye Disease Study (AREDS) provides important results for preventing complications of AMD (secondary prevention), and the cocktail of micronutrients proposed even encourages complementary studies on, for example, lutein and zeaxanthin instead of beta-carotene. The outcome of observation studies including a supplementation of long-chain polyunsaturated fatty acids (PUFA) of the omega-3 family (DHA) is also important, as it addresses primary prevention of the disease. A supplementation of omega-3 PUFAs could be proposed to certain subjects at risk for AMD for primary prevention and a supplementation with an antioxidant cocktail of micronutrients could be proposed to patients presenting AMD at stages 3 or 4 or to subjects with a nutritional imbalance. These conceivable supplementations are compatible with simple dietary advice. The supplements currently proposed could be optimized to increase their advantages. New research and new clinical studies are necessary to definitively validate these formulations in order to grant them an authentic drug status.

[Transpupillary thermotherapy and age-related macular degeneration]. / Thermothérapie transpupillaire et dégénérescence maculaire liée à l'âge.

Transpupillary thermotherapy (TTT) has been proposed over the last a few years for the treatment of subfoveal occult choroidal neovessels resulting from age-related degeneration (AMD) when they are symptomatic and associated with exudation. Several pilot studies have shown how this technique can decrease or slow down the progression of exudation related to choroidal neovessels. Based on these pilot studies, a randomized study (TTT4CNV) is in progress to evaluate the efficacy of TTT. While the inclusion of the patients in this study has come to an end, the therapeutic context of AMD has recently been changed with a permit to market Visudyn for photodynamic therapy (PDT) for some types of subfoveal occult choroidal neovessels. Moreover, the clinical studies in progress on photodynamic therapy and antiangiogenic drugs now make it possible to consider combined treatments possibly including TTT. This paper aims to provide a report on the current place and potential of TTT within the therapeutics available or soon available for subfoveal occult choroidal neovessels of AMD.

Heat shock protein hyperexpression on chorioretinal layers after transpupillary thermotherapy.

PURPOSE: To assess a biological effect induced by temperature elevation during transpupillary thermotherapy (TTT). METHODS: Six pigmented rabbits were anesthetized, and TTT was performed on the right eye using an 810-nm diode laser installed on a slit lamp (spot size, 1.3 mm; duration, 60 seconds; power, 92-150 mW). A series of laser pulses were aimed at the posterior pole of the retina. The left eyes were used as the control. Twenty-four hours after laser irradiation, a histologic study was performed on the chorioretinal layers. Tissue samples were fixed in formalin and embedded in paraffin. A monoclonal antibody was used to detect heat shock protein (Hsp)70 immunoreactivity, followed by a biotinylated goat anti-mouse antibody, revealed by the avidin-biotin complex and the 3-amino-9-ethyl-carbazole (AEC) chromogen. Retinal structures were further identified by hematoxylin erythrosin saffron (HES) coloration. RESULTS: The photocoagulation threshold was found to be at the 150-mW laser power. Under this threshold, Hsp70 immunostaining was the strongest at the 127-mW power, with staining of some choroidal cells, including capillary endothelial cells. No Hsp70 immunoreactivity was observed on the retina. At the 107-mW power, Hsp70 reactivity was observed only in occasional choroidal cells. At the 98-mW power, only mild, diffuse Hsp70 immunoreactivity was observed in the choroid. At the 92-mW power, as in nonirradiated eyes, no Hsp70 immunoreactivity was detected. CONCLUSIONS: Subthreshold transpupillary 810-nm laser irradiation induces choroidal Hsp hyperexpression. This confirms that choroidal Hsp hyperexpression can be induced during TTT, as has been recently hypothesized by several investigators.

[Choroidal heat shock overexpression in transpupillary thermotherapy: preliminary results]. / Hyperexpression choroïdienne de Heat Shock Proteins au cours de la thermothérapie transpupillaire: résultats préliminaires.

PURPOSE: To assess retinochoroidal overexpression of heat shock proteins (HSP-70) induced by a transpupillary laser irradiation below the photocoagulation threshold. METHODS: Four pigmented rabbits were anesthetized and TTT was performed on the right eye using a 810nm diode laser (Iridis, Quantel-Medical, France) adapted on slit lamp (spot size: 1.3 mm, duration: 60 seconds; power 92-150 mW). Series of laser impacts were aimed at the posterior pole of the retina. Left eyes were used as control. Twenty-four hours after laser irradiation, a histological study was done on chorioretinal layers. Tissue samples were fixed in formalin and embedded in paraffin. A monoclonal antibody was used to detect HSP-70 immunoreactivity (mouse IgGl, SPA-810, Stress Gen, Canada), followed by a biotinylated goat antimouse antibody (Dako, Denmark), revealed by the avidin-biotin complex (Vectastain kit, Vector, USA) and the AEC chromogen. Retinal structures were further identified by HES coloration. RESULTS: The photocoagulation threshold was obtained for laser power at 150 mW. Under this threshold, HSP-70 immunostaining was the strongest for power 127 mW with a staining of some choroidal cells, including capillary endothelial cells. No HSP-70 immunoreactivity was observed on the retina. For the laser power 107 mW, HSP-70 reactivity was observed only in occasional choroidal cells. For the laser power 92 mW, as for nonirradiated eyes, no HSP-70 immunoreactivity was detected. CONCLUSIONS: Transpupillary 810 nm laser irradiation under the photocoagulation threshold induces choroidal HSP overexpression. This study concludes that choroidal HSP overexpression can be induced during TTT.