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Omega-3 (n-3) polyunsaturated fatty acids (PUFAs), particularly docosahexaenoic acid (DHA), are required for the structure and function of the retina. They could also help to prevent or delay the development of retinopathies. Given the accumulating evidence showing the role of gut microbiota in regulating retinal physiology and host lipid metabolism, we evaluated the potential of long-term dietary supplementation with the Gram-positive bacterium Lacticaseibacillus helveticus strain VEL12193 to modulate the retinal n-3 PUFA content. A set of complementary approaches was used to study the impact of such a supplementation on the gut microbiota and host lipid/fatty acid (FA) metabolism. L. helveticus-supplementation was associated with a decrease in retinal saturated FAs (SFAs) and monounsaturated FAs (MUFAs) as well as an increase in retinal n-3 and omega-6 (n-6) PUFAs. Interestingly, supplementation with L. helveticus enriched the retina in C22:5n-3 (docosapentaenoic acid, DPA), C22:6n-3 (DHA), C18:2n-6 (linoleic acid, LA) and C20:3n-6 (dihomo gamma-linolenic acid, DGLA). Long-term consumption of L. helveticus also modulated gut microbiota composition and some changes in OTUs abundance correlated with the retinal FA content. This study provides a proof of concept that targeting the gut microbiota could be an effective strategy to modulate the retinal FA content, including that of protective n-3 PUFAs, thus opening paths for the design of novel preventive and/or therapeutical strategies for retinopathies.

To evaluate the proportion, baseline predictors, and outcomes of neovascular age-related macular degeneration (nAMD) patients treated with a high burden of vascular endothelial growth factor (VEGF) inhibitor intravitreal injections (IVT) at two years in routine clinical practice. European retrospective data analysis from a prospectively designed observational outcomes registry: the Fight Retinal Blindness! (FRB!) Project. Treatment-naïve eyes (one eye per patient) initiating VEGF inhibitors IVT from January 2017 to March 2020 with 24 months of follow-up, a minimum of 3 injections, and no gap between visits exceeding 365 days were tracked in the registry. We analyzed three treatment burden (TB) groups defined by the mean interval of the three closest injections to the 24-month visit: (1) those with a high TB had injection interval ≤ 42 days, (2) those with a low TB had injection interval between >42 and

Purpose: Age-related maculopathy susceptibility 2 (ARMS2) is considered the most enigmatic of the genes for age-related macular degeneration (AMD). We investigated the phenotypic course and spectrum of AMD for the risk haplotype at the ARMS2 and high-temperature requirement A serine peptidase 1 (HTRA1) locus in a large European consortium. Design: Pooled analysis of 4 case-control and 6 cohort studies. Participants: Individuals (N = 17 204) aged 55 years or older participating in the European Eye Epidemiology consortium. Methods: Age-related macular degeneration features and macular thickness were determined on multimodal images; data on genetics and phenotype were harmonized. Risks of AMD features for rs3750486 genotypes at the ARMS2/HTRA1 locus were determined by logistic regression and were compared with a genetic risk score (GRS) of 19 variants at the complement pathway. Lifetime risks were estimated with Kaplan–Meier analyses in population-based cohorts. Main Outcome Measures: Age-related macular degeneration features and stage. Results: Of 2068 individuals with late AMD, 64.7% carried the ARMS2/HTRA1 risk allele. For homozygous carriers, the odds ratio (OR) of geographic atrophy was 8.6 (95% confidence interval [CI], 6.5–11.4), of choroidal neovascularization (CNV) was 11.2 (95% CI, 9.4–13.3), and of mixed late AMD was 12.2 (95% CI, 7.3–20.6). Cumulative lifetime risk of late AMD ranged from 4.4% for carriers of the nonrisk genotype to 9.4% and 26.8% for heterozygous and homozygous carriers. The latter received the diagnosis of late AMD 9.6 years (95% CI, 8.0–11.2) earlier than carriers of the nonrisk genotype. The risk haplotype was not associated with hard or soft drusen < 125 μm (OR, 1.2; 95% CI, 0.9–1.7), but risks increased significantly for soft drusen ≥ 125 μm (OR, 2.1; 95% CI, 1.5–3.0), up to an OR of 7.2 (95% CI, 3.8–13.8) for reticular pseudodrusen. Compared with persons with a high GRS for complement, homozygous carriers of ARMS2/HTRA1 showed a higher risk of CNV (OR, 4.1; 95% CI, 3.2–5.4); risks of other characteristics were not different. Conclusions: Carriers of the risk haplotype at ARMS2/HTRA1 have a particularly high risk of late AMD at a relatively early age. Data suggest that risk variants at ARMS2/HTRA1 act as a strong catalyst of progression once early signs are present. The phenotypic spectrum resembles that of complement genes, only with higher risks of CNV.

Purpose : Changes in lipid metabolism, chronic inflammation and increased oxidative stress have been discussed as patho-etiogenetic drivers in age-related macular degeneration (AMD). Systemic medication, such as lipid-lowering drugs (LLD) and anti-diabetic drugs, affect these pathways and may therefore also play a role in AMD pathogenesis. We aimed to investigate associations of commonly used systemic drugs with AMD prevalence in the European population.Methods : We included 38,694 adults from 14 population-based studies from the European Eye Epidemiology (E3) consortium. We performed multivariable logistic regression modelling to examine medication use association with prevalence of AMD as well as late AMD. Analyses were carried out separately by study and results pooled using random effects meta-analysis. We conducted these analyses separately for LLD, anti-diabetic drugs, non-steroidal anti-inflammatory drugs (NSAID), and L-Dopa.Results : Between studies, mean age ranged from 61.5 ± 7.1 to 82.6 ± 3.8 years and prevalence ranged from 12.1% to 64.5% and from 0.5% to 35.5% for any and any late AMD, respectively. In the meta-analysis of our multivariable models, LLD and anti-diabetic drugs were associated with lower AMD prevalence (OR 0.85, 95% confidence interval (CI)=0.79 - 0.91 and OR 0.78, 95% CI=0.66 - 0.91). We found no association with late AMD or with any other medication.Conclusions : Our study shows an association of LLD and anti-diabetic drug use with lower AMD prevalence across multiple European cohorts. Our findings support the importance of metabolic processes in the complex etiology of AMD.

Purpose : To investigate the association of common systemic medication use with intraocular pressure and glaucoma prevalence in the European population.Methods : We examined associations of systemic medication use with intraocular pressure and glaucoma prevalence in a meta-analysis of multiple cohort studies of the European Eye Epidemiology (E3) consortium. IOP measurement method and glaucoma ascertainment were according to individual study protocols. Multivariable regression (linear for IOP and logistic for glaucoma prevalence) was carried out in each study and results pooled using random effects meta-analysis. Age, sex, body-mass index and diabetes were included as co-variables. Associations of antidiabetic medications were evaluated only in diabetic subjects.Results : A total of 46,845 participants from 11 population-based studies from the E3-consortium were included. In the meta-analysis of our fully-adjusted multivariable models, beta-blocker usage was associated with a lower IOP (all beta-blockers: Beta=-0.33 mmHg, 95% confidence interval (CI)=-0.58 to -0.08; non-selective betablockers: Beta=-0.56, 95% CI=-0.92 to -0.21; selective betablockers: Beta= -0.40, 95% CI=-0.64 to -0.16). In the meta-analysis of our fully-adjusted multivariable models, usage of calcium-channel blockers was positively associated with a higher glaucoma prevalence (all calcium-channel blockers: OR=1.25, 95% CI=1.05 to 1.50; selective calcium-channel blockers with mainly vascular effects: OR=1.27, 95% CI=1.05 to 1.53; selective calcium-channel blockers with direct cardiac effects: OR=1.54, 95% CI=1.07 to 2.21). Usage of RAS-inhibitors, diuretics, alpha-agonists, statins, fibrates, non-selective monoamine reuptake inhibitors, selective serotonin reuptake inhibitors, and antidiabetic medications was not associated with IOP or glaucoma.Conclusions : Our study supports and quantifies the known IOP-lowering effect of systemic beta-blockers, but there was no evidence of an IOP-lowering effect of other commonly used systemic medications. The usage of calcium-channel blockers (both with vascular and direct cardiac effects) was associated with a higher prevalence of glaucoma but not with higher IOP. Further studies are required to probe whether this harmful association of calcium-channel blockers with glaucoma is causal.

International audience; PURPOSE: Age-related macular degeneration(AMD) is a common multifactorial disease in elderly with a prominent genetic basis. Many risk variants have been identified, but the interpretation is still challenging. We investigated the genetic distribution of AMD-associated risk variants in a large European consortium, calculated attributable, and pathway-specific genetic risks, and assessed the influence of lifestyle on genetic outcomes. DESIGN: Pooled analysis of cross-sectional data from the E3 consortium. PARTICIPANTS: 17.174 individuals aged 45+ participating in 6 population-based cohort studies, 2 clinic based studies, 1 case-control study. METHODS: AMD was diagnosed and graded based on fundus photographs. Data on genetics, lifestyle, and diet were harmonized and completed where necessary. Minor allele frequencies and population attributable fraction (PAF) were calculated per single nucleotide polymorphism (SNP). A total genetic risk score (GRS) and pathway-specific risk scores (complement, lipid, extra-cellular matrix, other) were constructed based on the dosage of SNPs and conditional beta's; a lifestyle score was constructed based on smoking and dietary intake. RESULTS: The risk variants with the largest difference between late AMD cases and controls, and the highest PAFs were located in ARMS2 (rs3750846) and CHF (rs570618 and rs10922109). Both risk increasing and protective variants had the highest PAFs. Combining all genetic variants, the total genetic risk score ranged from -3.50 to 4.63, was normally distributed and increased with AMD severity. Of the late AMD cases, 1581/1777 (89%) had a positive total GRS. The complement pathway and ARMS2 were by far the most prominent genetic pathways contributing to late AMD (positive GRS 90% of late cases), but risk in three pathways was most frequent (35% of late cases). Lifestyle was a strong determinant of the outcome in each genetic risk category; unfavorable lifestyle increased the risk of late AMD at least twofold. CONCLUSIONS: Genetic risk variants contribute to late AMD in the majority of cases. However, lifestyle factors have a strong influence on the outcome of genetic risk, and should be a strong focus in patient management. Genetic risks in ARMS2 and the complement pathway are present in the majority of late AMD, but are mostly combined with risks in other pathways.

Macular oedema corresponds to an increase in macular thickness most often associated with a rupture of the hematoretinal barriers. Diagnosis is based on the notion of reduced vision, but above all on multimodal imaging in which optical coherence tomography (OCT) plays an essential role both for the initial diagnosis and for follow-up. The mechanisms involved in the occurrence of macular oedema are primarily vascular endothelial growth factor (VEGF) and cytokines regardless of the aetiology of the oedema. Treatment often involves a combination of local treatment - primarily intravitreal injections of anti-VEGF or corticosteroids - and, in certain situations, such as diabetes or uveitis, general treatment. The principle of treatment is to try to treat the oedema while the tissue damage is not too severe. The analysis of the aetiology defines the therapeutic modalities. Certain investigations may be indicated when the presentations or the evolution under treatment remain atypical., L'œdème maculaire correspond à une augmentation de l'épaisseur maculaire le plus souvent associé à une rupture des barrières hématorétiniennes. Le diagnostic repose sur la notion de baisse de vision, mais surtout sur l'imagerie multimodale dans laquelle la tomographie par cohérence optique (OCT) joue un rôle essentiel tant pour le diagnostic initial que pour le suivi. Les mécanismes impliqués dans la survenue d'un œdème maculaire sont avant tout le vascular endothelial growth factor (VEGF) et les cytokines quelle que soit l'étiologie de l'œdème. Le traitement associe souvent un traitement local - avant tout par injection intravitréenne d'anti-VEGF ou de corticoïdes - et, pour certaines situations, comme le diabète ou les uvéites, un traitement général. Le principe du traitement est d'essayer de traiter l'œdème alors que les lésions tissulaires ne sont pas trop avancées. L'analyse de l'étiologie définit les modalités thérapeutiques. Certaines explorations peuvent être indiquées lorsque les présentations ou l'évolution sous traitement restent atypiques.

International audience; Purpose : Although rare, endophthalmitis is a severe complication of ophthalmological procedures. The incidence of endophthalmitis following cataract, glaucoma, vitreoretinal surgeries, and intravitreal injections has previously been described in large-scale studies, but no data is available on the proportion of causative procedures. We aimed to describe longitudinally the causes of endophthalmitis at a national scale using the French medico-administrative database.Methods : The SNIIRAM (French national inter-scheme insurance database) collects all data of medical expenditures and procedures performed in France. We extracted acute endophthalmitis occurring 42 days after an ophthalmological procedure, by means of hospital discharge code (CIM10 H440, H441) and procedures codes from 2009 to 2018.Results : From 2009 to 2018, 7 776 acute endophthalmitis followed ophthalmological procedures, in 7 754 patients. Age at diagnosis was 71.7 ± 12.9 years) and 51.02% of the patients were women. Most endophthalmitis were caused by non-combined cataract surgery (4 957 cases, 63.75%), followed by IVTs (1 392, 17.90%), vitreoretinal surgery (761, 9.79%), anterior segment surgery (226, 2.91%), combined cataract and vitreoretinal surgery (154, 1.98%), cornea surgery (131, 1.68%), glaucoma surgery (84, 1.08%). The frequency of causative procedures remained stable over the years for all procedures except for cataract surgery which decreased from 2009 (763, 79.98% of the year’s etiologies) to 2018 (432, 51.92%) with a rapid decrease in 2012, and for IVT which increased in the same time period (from 70, 7.34% to 258, 31.01%). Patients with acute endophthalmitis following IVTs were the oldest (75.2 ± 12.3 years old), Endophthalmitis following Intravitreal procedures, IVTs, and vitreoretinal surgeries occurred sooner than after other procedures (median (IQR); 4.0 days (3.0-7.0) and 4.0 (2.0-8.0), respectively) versus 6.0 days (4.0-11.0) days in cataract surgery.Conclusions : We observe that in more than 1.3 million ophthalmological procedures per year in France, the occurrence of acute endophthalmitis is low. This data shows a shift in causative factors with a decrease of endophthalmitis following cataract surgery and an increasing number after IVT.

International audience; Purpose : To characterize clinically and genetically two families with autosomal dominant retinitis pigmentosa (adRP) with new causative mutations in PRPF6, a gene described to be associated with this condition in a single study.Methods : A large adRP and sporadic RP cohort was screened for mutations using targeted next-generation sequencing. Clinical investigations included visual acuity and visual field testing, fundus examination, high-resolution spectral-domain optical coherence tomography (OCT), fundus autofluorescence imaging, full-fields and multifocal electroretinogram (ERG) recording. Cellular localization of GFP-tagged wild-type or mutated PRPF6 in HEK293 transfected cells was observed by confocal microscopy.Results : Two heterozygous mutations c.680C>T (p.Thr227Met) and c.514C>T (p.Arg172Trp) in PRPF6 were identified in an adRP family and in a sporadic RP patient, respectively. Both variants segregated with the disease phenotype and were predicted to be pathogenic. An asymptomatic heterozygous carrier of the p.Arg172Trp mutation was also identified. In HEK293 transfected cells, an abnormal accumulation of the two mutated GFP-PRPF6, but not wild-type, within Cajal bodies was observed.Conclusions : We identified two novel causative mutations in PRPF6, responsible for autosomal dominant retinitis pigmentosa with variation of penetrance. Presence of asymptomatic carriers is common among patients with adRP, especially when the cause of the disease is due to a mutation in splicing factors’ genes. The two mutations identified lead to a mislocalization of the PRPF6 protein within the nucleus, which could indicate a possible alteration in the assembly or recycling of the tri-snRNP complex of the spliceosome.

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International audience

International audience

La rétinopathie diabétique (RD) est responsable de lésions microvasculaires et d’une dysfonction rétinienne d’évolution progressive. Elle est secondaire à l’exposition chronique à l’hyperglycémie et à d’autres facteurs de risque, comme l’hypertension artérielle, qui entraînent des cascades de changements biochimiques et physiologiques. Elle peut être responsable de complications cécitantes telles que l’hémorragie du vitré, le décollement de rétine tractionnel ou le glaucome néovasculaire. Afin qu’elle n’évolue vers de telles pathologies, il est important de la stabiliser par l’équilibration des facteurs de risque systémiques (optimisation glycémique et tensionnelle), parfois par la réalisation d’une photocoagulation panrétinienne (PPR) et/ou, plus récemment, par des injections d’anti-VEGF (Vascular Endothelial Growth Factor).

Les télangiectasies maculaires de type 1 (MacTel 1) appartiennent au groupe plus large des télangiectasies maculaires. Leur diagnostic clinique se fait sur un aspect de dilatations anévrysmales de petite taille et d’ectasies paracentrales. Le patient peut présenter une baisse de vision avec un aspect d’oedème maculaire. À ce titre, les télangiectasies maculaires appartiennent aux causes d’oedème maculaire d’origine vasculaire. Le plus souvent ces télangiectasies surviennent dans un contexte de trouble de l’angiogenèse comme on le constate dans le diabète, les occlusions veineuses ou les vascularites… Elles sont alors qualifiées de secondaires. L’examen clinique confirme souvent l’existence d’une rétinopathie diabétique ou le contexte d’une occlusion veinulaire. Dans des cas limités, les télangiectasies maculaires ne sont pas liées aux causes précédentes ; elles sont alors idiopathiques et dénommées MacTel 1. Toutefois, ces MacTel 1 sont souvent associées à une atteinte périphérique de type maladie de Coats. Il est donc assez probable qu’elles soient juste une forme centrale du cadre nosologique plus large de la maladie de Coats. Le diagnostic de cette dernière est souvent fait chez l’enfant lorsque l’exsudation atteint le pole postérieur et entraîne une baisse de vision alors que le diagnostic de MacTel 1 est porté chez l’adulte d’âge moyen [1]. Il est toutefois assez fréquent de trouver des signes périphériques plus ou moins prononcés, de type dilatations vasculaires et réaction exsudative périphérique jusqu’alors méconnues. Ces 2 affections partagent donc les mêmes caractéristiques : elles touchent avant tout l’homme et sont en majorité unilatérale [2]. Cette affection rare n’est actuellement associée à aucun terrain génétique. Toutefois ces affections appartiennent probablement à un spectre d’anomalies génétiques regroupées sous l’appellation « hypovasculopathies rétiniennes » qui s’accompagnent d’anomalies de l’angiogenèse rétinienne.

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La dégénérescence maculaire liée à l’âge (DMLA) est actuellement la première cause de handicap visuel dans les pays développés chez les plus de 50 ans. Elle touche en effet environ 8% de la population française et plus de 25% des plus de 75 ans. La constatation d’une insuffisance de traitement lors d’un régime « réactif » a poussé les cliniciens à proposer d’autres types de régimes. Le « Treat and Extend » (T&E) est né de la volonté d’adapter les intervalles de retraitement des patients pour une prise en charge plus personnalisée.

International audience; Glaucoma is a neurodegenerative pathology characterized by retinal ganglion cell death. Cholesterol homeostasis disruption has been implicated in several neurodegenerative diseases such as Alzheimer and Huntington. However, its specific role in the retina and association with glaucoma remain unclear. The aim of this study was to characterize the modifications of cholesterol metabolism occurring during an experimental model of glaucoma in rats. Eight-weeks old male rats were subjected to laser photocoagulation of episcleral veins, limbus and trabecular meshwork to elevate intraocular pressure. At a short (3 days) and a long (2 months) time period post-laser, the retinal levels of sterols and oxysterols were measured by gas chromatography. The expression of various genes implicated in cholesterol metabolism was assayed by RT-qPCR. Statistical significance was calculated using the paired Wilcoxon test (n=8). At 3 days post-laser, the levels of cholesterol precursors, desmosterol and lathosterol, were strongly increased (x1.6 between laser-treated and contralateral retinas, p=0.008 and x3, p=0.02, respectively) while cholesterol levels were slightly increased (x 1.3, p=0.008). We did not detect any change in the levels of 24S-hydroxycholesterol, a major elimination form of cholesterol in retinal ganglion cells. On the contrary, the expression of ABCA1, a transporter regulating cholesterol efflux, as well as LXR, a transcription factor activating hypocholesterolemic pathways, was increased. The expression of LDL receptor, regulating cholesterol uptake, as well as SREBP2, a transcription factor activating hypercholesterolemic pathways, was decreased. At 2 months post-laser, cholesterol precursor levels were decreased. Interestingly, we also measured a significant increase in the expression of CYP27A1 (x1.8, p=0.02), an enzyme implicated in cholesterol efflux and in the levels of its product 27-hydroxycholesterol (x1.6, p=0.02). Our observations suggest that cholesterol metabolism disturbances are associated with glaucoma. Indeed, hypocholesterolemic mechanisms are induced in the rat glaucoma model in order to counteract the activation of cholesterol biosynthetic pathways consecutive to intraocular pressure elevation. Moreover, our results suggest that CYP27A1 might play an important role in the regulation of cholesterol metabolism in the retina.

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International audience

L’identification à l’examen clinique de petites dilatations anévrismales et d’ectasies paracentrales fait évoquer le diagnostic de télangiectasies maculaires. Celles-ci sont le plus souvent secondaires à une pathologie, notamment au diabète, aux occlusions veineuses, aux vascularites, à un néovaisseau choroïdien de type 3, etc. Le contexte et le reste de l’examen identifieront généralement l’affection primitive. Les télangiectasies maculaires de type 1 (MacTel 1) sont idiopathiques sans cause retrouvée. Ce sont des affections rares, en grande majorité unilatérales, touchant préférentiellement l’homme d’âge moyen (1).