Hyperreflective ganglion cell layer band in a large cohort of non-syndromic retinitis pigmentosa: Frequency and clinical correlations.

PURPOSE: Recently, an 'hyperreflective ganglion cell layer band' (HGB) has been described on spectral-domain optical coherence tomography (SD-OCT) in a subset of patients with retinitis pigmentosa (RP). This study aims to validate and describe the frequency of HGB in a large cohort of Portuguese patients with RP. METHODS: This single-centre, cross-sectional cohort study included consecutive patients with a genetic diagnosis of RP. SD-OCT images were reviewed to identify the presence of the HGB and other retinal comorbidities. The HGB was defined as a continuous hyperreflective band within the thickness of the ganglion cell layer (GCL). We built mixed-effects regression models, accounting for inter-eye correlations, to investigate features predictive of visual acuity. Subsequently, a reduced model was fitted. RESULTS: A total of 398 eyes from 201 patients were included. HGB was identified in 69 (17.3%) eyes from 39 (19.4%) patients. Patients presenting with the HGB were significantly younger at diagnosis and at symptom onset. Median BCVA [ETDRS (IQR)] was 65 (29) letters in eyes with the HGB and 70 (21) letters in eyes without HGB (p < 0.001). In both the full and reduced mixed-effects models, the presence of HGB and macular hole (MH) was significantly associated with worse BCVA. CONCLUSIONS: This study validates the recent description of HGB within the GCL in a subset of patients with RP. Eyes with HGB demonstrated significantly worse BCVA compared to those without HGB, suggesting that the presence of HGB may serve as an SD-OCT biomarker of worse visual prognosis in these patients.

Expanding the mutational and phenotypical spectrum of FHONDA syndrome.

Foveal hypoplasia, optic nerve decussation, and anterior segment dysgenesis (FHONDA) is a rare recessively inherited syndrome first described in 2013. FHONDA is associated with biallelic disease-causing variants in the SLC38A8 gene, which has a strong expression in the photoreceptor layer. To date, 60 different disease-causing variants in the SLC38A8 gene have been described. In this cross-sectional case series, we included three unrelated female patients with FHONDA syndrome who presented with congenital nystagmus and decreased visual acuity from infancy. Best-corrected visual acuity was 20/100 OD and 20/60 OS for Patient 1 (P1) (72 years old); light perception OD and hand motion OS for Patient 2 (P2) (66 years old); and 20/100 OD and 20/100 OS for Patient 3 (P3) (25 years old). While normal retinal pigmentation was seen on P1 and P3, P2 presented retinal features of retinitis pigmentosa, including a pale optic nerve head, vessel thinning, and 360° dense bone spicule hyperpigmentation OU. Spectral-domain optical coherence tomography revealed grade 4 foveal hypoplasia in all patients. In P1 and P2, the novel class IV c.388 + 1G > T p.? variant in SLC38A8 was present in homozygosity; while P3 harboured the novel c.214G > C p.(Gly72Arg) variant in homozygosity, classified as class III. Thus, we expand the mutational spectrum of FHONDA by reporting two novel variants. In addition, we describe features of retinitis pigmentosa for the first time in a patient with biallelic homozygous SLC38A8 variants, thus broadening our understanding of the clinical phenotype associated with this rare syndrome.

EFFICACY AND SAFETY OF THE PROPOSED BIOSIMILAR AFLIBERCEPT, SDZ-AFL, IN PATIENTS WITH NEOVASCULAR AGE-RELATED MACULAR DEGENERATION: 52-Week Results From the Phase 3 Mylight Study.

PURPOSE: The Phase 3 Mylight study was designed to confirm clinical equivalence of proposed biosimilar aflibercept (SOK583A1; Sandoz [proposed biosimilar aflibercept, SDZ-AFL]) to its reference biologic (Eylea; Regeneron Pharmaceuticals, Inc; Bayer AG [reference aflibercept, Ref-AFL]). METHOD: Mylight was a prospective, double-masked, 2-arm, parallel Phase 3 study. Participants with neovascular age-related macular degeneration were randomized 1:1 to receive eight injections of SDZ-AFL (n = 244) or Ref-AFL (n = 240) over 48 weeks. The primary endpoint was mean change in best-corrected visual acuity score from baseline to Week 8. Secondary endpoints included anatomical outcomes, best-corrected visual acuity at Weeks 24 and 52, safety, and pharmacokinetics. RESULTS: Similarity in mean change in best-corrected visual acuity score was established between SDZ-AFL (n = 235) and Ref-AFL (n = 226) at Week 8 (difference: -0.3 [90% CI, -1.5 to 1.0]) and Week 52. No clinically meaningful differences occurred between groups in anatomical outcomes. Safety profiles were similar, with comparable incidences of treatment-related adverse events (SDZ-AFL: 2.5%; Ref-AFL: 2.9%). The incidence of anti-drug antibodies was similar between groups. Systemic free aflibercept concentrations 24 hours postdose were low and comparable between SDZ-AFL and Ref-AFL. CONCLUSION: Proposed biosimilar aflibercept matched reference aflibercept in efficacy, safety, and pharmacokinetics in participants with neovascular age-related macular degeneration. Therefore, this Phase 3 study confirmed biosimilarity of SDZ-AFL to Ref-AFL.

Informing Endpoints for Clinical Trials of Geographic Atrophy.

Geographic atrophy (GA), the non-neovascular advanced form of age-related macular degeneration, remains an important disease area in which treatment needs are currently unmet. Recent clinical trials using drugs that target the complement pathway have shown modest yet consistent reductions in GA expansion but without commensurate changes in measures of visual function. In this review, we summarize information from the wide range of studies describing the characteristics of GA morphology and enumerate the factors influencing the growth rates of lesions and the directionality of expansion. In addition, we review the relationship between GA growth and the various measures of vision that reflect changes in function. We consider the reasons for the discordance between the anatomical and functional endpoints in current use and discuss methods to align these key outcomes.

ANO2 Genetic Variants and Anti-VEGF Treatment Response in Neovascular AMD: A Pharmacogenetic Substudy of VIEW 1 and VIEW 2.

Purpose: This analysis investigated potential associations between gene variants and clinical end points in the VIEW 1 and 2 randomized clinical trials of intravitreal aflibercept and ranibizumab in neovascular age-related macular degeneration (AMD). Methods: A genome-wide association analysis was conducted in a subgroup of patients from VIEW 1 and 2 consenting to the optional pharmacogenetic analysis. Results: Data were pooled from 780 samples from patients representative of the overall VIEW 1 and 2 populations. After Bonferroni correction for multiplicity and statistical adjustment for baseline risk factors, no significant associations were found between previously identified prognostic AMD gene variants and treatment response according to key prespecified VIEW 1 and 2 end points. Genome-wide, there were no significant genetic associations in patients experiencing gains of ≥15 Early Treatment of Diabetic Retinopathy Study letters after 1 or 2 years of treatment. A cluster of variants in ANO2 (encoding anoctamin 2, a calcium-activated chloride channel expressed on photoreceptor cells) on chromosome 12 reached the level of significance for loss of ≥5 letters after 1 year of treatment (P < 5 × 10-8), with the ANO2 rs2110166 SNP demonstrating highly significant association (P = 1.99 × 10-8). Carriers of the ANO2 rs2110166 TT genotype showed a robust increase in visual acuity versus baseline compared with a small decrease in those with the TC genotype. Conclusions: None of the potential prognostic candidate genes were associated with the clinical end points for treated patients. Preliminary analyses suggest an association of ANO2 with retinal function, with a potential impact on vision of approximately one line over at least the first year. Further investigation of the function of ANO2 in retinal pathophysiology is merited.

Exploring self-reported visual function and vision-related anxiety in patients with RPGR-associated retinal degeneration.

Variants in the retinitis pigmentosa GTPase regulator (RPGR) gene are responsible for the majority of X-linked retinitis pigmentosa cases, which not only affects male patients but also some heterozygous females. Vision-related disability and anxiety of patients with RPGR-associated retinal degeneration have never been explored before. This study aimed to evaluate self-reported visual function and vision-related anxiety in a Portuguese cohort of male and female patients with RPGR-associated retinal degeneration using two validated patient-reported outcome measures. Cross-sectional data of thirty-two genetically-tested patients was examined, including scores of the Michigan retinal degeneration questionnaire (MRDQ) and Michigan vision-related anxiety questionnaire. Patients were classified according to retinal phenotypes in males (M), females with male phenotype (FM), and females with radial or focal pattern. Both M and FM revealed higher rod-function and cone-function anxiety scores (p < 0.017). Most MRDQ disability scores were higher in M and FM (p < 0.004). Overall, positive correlations (p < 0.004) were found between every MRDQ domain and both anxiety scores. In RPGR-associated retinal degeneration, males and females with male phenotype show similar levels of increased vision-related anxiety and disability. Every MRDQ visual function domain showed a strong correlation with anxiety scores.

Unveiling Statins and Genetics in Age-Related Macular Degeneration: The Coimbra Eye Study-Report 9.

Purpose: To assess the association of age-related macular degeneration (AMD) progression and statins, connected with AMD genetic risk, and if there is an interplay between statins and genetics. Methods: In this analysis, 682 subjects made two visits (6.5-year follow-up) of the Coimbra Eye Study. Subjects who started taking statins at any time point between the two visits were considered. Progressors were defined as not having AMD at baseline and having any AMD at follow-up. Genetic risk scores (GRSs) were calculated individually with 52 independent variants associated with AMD. Time to progression was estimated using unadjusted Kaplan-Meier curves. An extended Cox model was used for the association between statins and GRS with the risk for AMD progression. Multiplicative and additive interactions were assessed. Results: Median survival time was 7.50 years for subjects not taking statins and 7.62 for subjects taking statins (P < 0.001). Statin intake reduced the risk for progression to AMD in 48%, adjusting for age, sex, body mass index, smoking, and diabetes (model 1) and GRS (model 2). The combined effects of not taking statins and having high GRS increased the progression risk fourfold compared to taking statins and having low GRS (hazard ratio [HR] = 4.25; 95% confidence interval [CI], 1.62-11.16; P = 0.003). For subjects not taking statins, an increased risk of progression was found for those subjects with high GRS compared to subjects with low GRS (HR = 1.80; 95% CI, 1.13-2.85; P = 0.013). No statistically significant multiplicative or additive interactions were found. Conclusions: Statins seem to be protective against AMD progression, and genetics may play a role in treatment response.

Metabolomic-derived endotypes of age-related macular degeneration (AMD): a step towards identification of disease subgroups.

Age-related macular degeneration (AMD) is a leading cause of blindness worldwide, with a complex pathophysiology and phenotypic diversity. Here, we apply Similarity Network Fusion (SNF) to cluster AMD patients into putative metabolomics-derived endotypes. Using a discovery cohort of 163 AMD patients from Boston, US, and a validation cohort of 214 patients from Coimbra, Portugal, we identified four distinct metabolomics-derived endotypes with varying retinal structural and functional characteristics, confirmed across both cohorts. Patients clustered into Endotype 1 exhibited a milder form of AMD and were characterized by low levels of amino acids in specific metabolic pathways. Meanwhile, patients clustered into both Endotype 3 and 4 were associated with more severe AMD and exhibited low levels of fatty acid metabolites and elevated levels of sphingomyelins and fatty acid metabolites, respectively. These preliminary findings indicate that metabolomics-derived endotyping may offer a refined strategy for categorizing AMD patients based on their specific pathophysiological underpinnings, rather than relying solely on traditional observational clinical indicators.

Age-Related Macular Degeneration and Extramacular Drusen: Genetic Associations in the Coimbra Eye Study.

Purpose: To explore the association between the genetics of age-related macular degeneration (AMD) and extramacular drusen (EMD) in patients with and without AMD. Methods: We included 1753 eyes (912 subjects) with phenotypic characterization regarding AMD and EMD. Genetic sequencing and the genetic risk score (GRS) for AMD were performed according to the EYE-RISK consortium methodology. To test for differences in the GRS from EMD cases, AMD cases, and controls, a clustered Wilcoxon rank-sum test was used. The association of AMD, EMD, and the GRS was evaluated using logistic regression models adjusted for age and sex. Individual associations of common risk variants for AMD with EMD were explored. Results: EMD were found in 755 eyes: 252 (14.4%) with AMD and 503 (28.7%) without. In total, 122 eyes (7.0%) had only AMD, and 876 (50.0%) were controls. EMD were strongly associated with AMD (odds ratio [OR], 3.333; 95% confidence interval [CI], 2.356-4.623; P < 0.001). The GRS was associated with an increased risk of AMD (OR, 1.416; 95% CI, 1.218-1.646; P < 0.001) but not with EMD. Individually, the common risk variants ARMS2 rs10490924 (P = 0.042), C3 rs2230199 (P = 0.042), and CETP rs5817082 (P = 0.042) were associated with EMD, after adjustment for AMD, sex, and age. Conclusions: We found a strong association between EMD and AMD, suggesting a common pathogenesis. The GRS for AMD was not associated with EMD, but a partially overlapping genetic basis was suggested when assessing individual risk variants. We propose that EMD per se do not represent an increase in the global genetic risk for AMD.

Prognostic impact of hyperreflective foci in nonsyndromic retinitis pigmentosa.

PURPOSE: To evaluate the prognostic impact of hyperreflective foci (HRF) on spectral-domain optical coherence tomography (SD-OCT) in nonsyndromic retinitis pigmentosa (RP). METHODS: Retrospective, single-center cohort study including genetically-tested RP patients with a minimum follow-up of 24 months. Clinical data including demographics, genetic results and best-corrected visual acuity (BCVA) at baseline and follow-up were collected. Horizontal and vertical SD-OCT scans were analyzed by 2 independent graders. Outer nuclear layer (ONL) thickness and ellipsoid zone (EZ) width were manually measured in horizontal and vertical scans. HRF were classified according to location: outer retinal layers within the central 3mm (central-HRF), outer retinal layers beyond the central 3mm (perifoveal-HRF), and choroid (choroidal-HRF). Central macular thickness (CMT), central point thickness (CPT) and choroidal thickness (CT) at baseline and follow-up were also recorded. RESULTS: A total of 175 eyes from 94 RP patients (47.9% female, mean age 50.7±15.5 years) were included, with a mean follow-up of 29.24±7.17 months. Mean ETDRS (early treatment diabetic retinopathy study) BCVA decreased from 61.09±23.54 to 56.09±26.65 (p=0.082). At baseline, 72 eyes (41.1%) showed central-HRF, 110 eyes (62.9%) had perifoveal-HRF and 149 eyes (85.1%) exhibited choroidal-HRF. Central-HRF and perifoveal-HRF were associated with worse final BCVA, as well as greater BCVA deterioration (all p<0.0029). Only central-HRF were associated with a worse final CMT (p<0.001). Shorter EZ widths were associated with all types of HRF (p<0.05). Perifoveal and choroidal-HRF predicted smaller final EZ areas (p<0.01). CONCLUSION: HRF are highly prevalent in RP patients and appear to have a negative prognostic impact in visual function and EZ area.

Mutational spectrum and deep phenotyping in Pseudoxanthoma Elasticum: Findings from a Portuguese cohort.

INTRODUCTION: Pseudoxanthoma Elasticum (PXE) is a rare autosomal recessive disorder originated by disease-causing variants in ABCC6 gene. The purpose of this study was to characterize the genetic landscape, phenotypic spectrum and genotype-phenotype correlations in a Portuguese cohort of PXE patients. METHODS: Multicentric cross-sectional study conducted in patients with a clinical and genetic diagnosis of PXE. Patients were identified using the IRD-PT registry (www.retina.com.pt). Genotypes were classified into 3 groups: (1) two truncating variants, (2) two non-truncating variants, or (3) mixed variants. Deep phenotyping comprised a comprehensive ophthalmologic and systemic evaluation using the updated Phenodex Score (PS). RESULTS: Twenty-seven patients (23 families) were included. Sixteen different ABCC6 variants were identified, 7 of which are novel. The most prevalent variant was the nonsense variant c.3421C > T p.(Arg1141*) with an allele frequency of 18.5%. All patients exhibited ocular manifestations. Cutaneous manifestations were present in most patients (88.9%, n = 24/27). A PS score > E2 was strongly associated with worse visual acuity (B = -29.02; p = 0.001). No association was found between genotypic groups and cutaneous, vascular or cardiac manifestations. CONCLUSIONS: This study describes the genetic spectrum of patients with PXE for the first time in a Portuguese cohort. A total of 16 different variants in ABCC6 were found (7 of which are novel), thus highlighting the genotypic heterogeneity associated with this condition and expanding its mutational spectrum. Still, no major genotype-phenotype associations could be established.

Imaging characterization of the fellow eye in patients with unilateral polypoidal choroidal vasculopathy.

INTRODUCTION: New insights on polypoidal choroidal vasculopathy (PCV) have shed light regarding its pathophysiology and associations. However, PCV characterization is still incomplete in Caucasians, which is due to presumed lower prevalence in this population. Features typically associated with AMD such as drusen, retinal pigmentary changes or atrophy are seen in PCV, as precursors and in the fellow eye. Pachychoroid spectrum, predisposing to PCV, also presents with chronic changes in the retinal pigment epithelium (RPE), such as drusen-like deposits (DLD), and in the choroid. The purpose of this study is to perform a multimodal imaging characterization of unaffected fellow eyes in a sample of Caucasian patients with unilateral PCV. METHODS: Multicenter retrospective cohort study with a sample of 55 unaffected fellow eyes from patients diagnosed with unilateral PCV confirmed by indocyanine green angiography. The sample was characterized in the baseline by color fundus photography, spectral domain optical coherence tomography (SD-OCT), fluorescein angiography and indocyanine green angiography. Morphological characteristics of both the retina and the choroid were evaluated. The SD-OCT of the last follow-up visit was also evaluated in order to exclude evolution to PCV or choroidal neovascularization. All images captured underwent evaluation by two independent graders. Informed consent was obtained from all participants. RESULTS: Fifty-five patients (median age, 74 ± 15 years) were included. After 15.5 ± 6.4 months of follow-up, only one developed disease (1.9%). Soft and/or hard drusen were present in 60% and pachydrusen in 23.6%. Pachychoroid signs were present in 47.2%, the double-layer sign in 36.4%, disruption of the RPE changes in 16.4% and RPE atrophy in 10.9%. ICGA revealed choroidal vascular dilation in 63.6% and punctiform hyperfluorescence in 52.7%. Branching vascular networks were identified in only 1.9% of cases. CONCLUSION: The identification of pachychoroid signs in the OCT and ICGA were present in over half of the cases and the presence of the double-layer sign in more than a third provide crucial insights for enhanced characterization of this pathology and deeper understanding of its pathogenesis. These findings contribute significantly to the current knowledge, offering valuable markers to discern various phases of the pathology's progression.

Intravitreal Aflibercept for Neovascular Age-Related Macular Degeneration Beyond One Year of Treatment: AZURE, a Randomized Trial of Treat-and-Extend vs. Fixed Dosing.

INTRODUCTION: AZURE was a 76-week, randomized, open-label, parallel-group, phase IIIb noninferiority study comparing the efficacy and safety of intravitreal aflibercept (IVT-AFL) in a treat-and-extend (T&E) regimen with fixed dosing in patients with neovascular age-related macular degeneration (nAMD) previously receiving IVT-AFL for ≥ 1 year. METHODS: Patients were aged ≥ 51 years and had completed ≥ 1 year of IVT-AFL treatment prior to enrollment (IVT-AFL once per month [- 1 or + 2 weeks] for 3 months followed by IVT-AFL every 2 months [6-12 weeks]). Patients were randomly assigned (1:1) to receive IVT-AFL 2 mg in either a T&E (minimum treatment interval of 8 weeks with no upper limit, adjusted according to functional and anatomic outcomes, as assessed by the investigator; n = 168), or a fixed dosing regimen (treatment every 8 weeks [± 3 days]; n = 168). The primary endpoint was best-corrected visual acuity (BCVA) change from baseline to week (W) 52. The key secondary endpoint was the proportion of patients maintaining vision (< 15-letter loss) at W52. RESULTS: The full analysis set comprised 332 patients (T&E: n = 165; fixed dosing: n = 167). Mean BCVA change (baseline to W52) was - 0.3 ± 7.5 vs. - 0.5 ± 8.4 letters (T&E vs. fixed dosing; least-squares mean difference [95% CI]: 0.22 [- 1.51 to 1.96] letters; P < 0.0001 for noninferiority test [5-letter margin]). From baseline to W52, 95.2% (T&E) and 94.0% (fixed dosing) of patients maintained vision. Mean central subfield thickness change from baseline to W52 was - 24 ± 55 (T&E) and - 33 ± 47 (fixed dosing) µm. Last treatment interval to W76 was ≥ 12 weeks for 37.0% of T&E patients. No new safety signals were identified. CONCLUSION: IVT-AFL T&E can achieve similar functional and anatomic outcomes to fixed dosing every 8 weeks over 52 weeks in patients with nAMD who have completed ≥ 1 year of treatment, while reducing treatment burden. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02540954.

Genetic profile of syndromic retinitis pigmentosa in Portugal.

PURPOSE: Retinitis pigmentosa (RP) comprises a genetically and clinically heterogeneous group of inherited retinal degenerations, where 20-30% of patients exhibit extra-ocular manifestations (syndromic RP). Understanding the genetic profile of RP has important implications for disease prognosis and genetic counseling. This study aimed to characterize the genetic profile of syndromic RP in Portugal. METHODS: Multicenter, retrospective cohort study. Six Portuguese healthcare providers identified patients with a clinical diagnosis of syndromic RP and available genetic testing results. All patients had been previously subjected to a detailed ophthalmologic examination and clinically oriented genetic testing. Genetic variants were classified according to the American College of Medical Genetics and Genomics; only likely pathogenic or pathogenic variants were considered relevant for disease etiology. RESULTS: One hundred and twenty-two patients (53.3% males) from 100 families were included. Usher syndrome was the most frequent diagnosis (62.0%), followed by Bardet-Biedl (19.0%) and Senior-Løken syndromes (7.0%). Deleterious variants were identified in 86/100 families for a diagnostic yield of 86.0% (87.1% for Usher and 94.7% for Bardet-Biedl). A total of 81 genetic variants were identified in 25 different genes, 22 of which are novel. USH2A and MYO7A were responsible for most type II and type I Usher syndrome cases, respectively. BBS1 variants were the cause of Bardet-Biedl syndrome in 52.6% of families. Best-corrected visual acuity (BCVA) records were available at baseline and last visit for 99 patients (198 eyes), with a median follow-up of 62.0 months. The mean BCVA was 56.5 ETDRS letters at baseline (Snellen equivalent ~ 20/80), declining to 44.9 ETDRS letters (Snellen equivalent ~ 20/125) at the last available follow-up (p < 0.001). CONCLUSION: This is the first multicenter study depicting the genetic profile of syndromic RP in Portugal, thus contributing toward a better understanding of this heterogeneous disease group. Usher and Bardet-Biedl syndromes were found to be the most common types of syndromic RP in this large Portuguese cohort. A high diagnostic yield was obtained, highlighting current genetic testing capabilities in providing a molecular diagnosis to most affected individuals. This has major implications in determining disease-related prognosis and providing targeted genetic counseling for syndromic RP patients in Portugal.

Plasma Metabolites Associated with OCT Features of Age-Related Macular Degeneration.

Purpose: The most widely used classifications of age-related macular degeneration (AMD) and its severity stages still rely on color fundus photographs (CFPs). However, AMD has a wide phenotypic variability that remains poorly understood and is better characterized by OCT. We and others have shown that patients with AMD have a distinct plasma metabolomic profile compared with controls. However, all studies to date have been performed solely based on CFP classifications. This study aimed to assess if plasma metabolomic profiles are associated with OCT features commonly seen in AMD. Design: Prospectively designed, cross-sectional study. Participants: Subjects with a diagnosis of AMD and a control group (> 50 years old) from Boston, United States, and Coimbra, Portugal. Methods: All participants were imaged with CFP, used for AMD staging (Age-Related Eye Disease Study 2 classification scheme), and with spectral domain OCT (Spectralis, Heidelberg). OCT images were graded by 2 independent graders for the presence of characteristic AMD features, according to a predefined protocol. Fasting blood samples were collected for metabolomic profiling (using nontargeted high-resolution mass spectrometry by Metabolon Inc). Analyses were conducted using logistic regression models including the worst eye of each patient (AREDS2 classification) and adjusting for confounding factors. Each cohort (United States and Portugal) was analyzed separately and then results were combined by meta-analyses. False discovery rate (FDR) was used to account for multiple comparisons. Main Outcome Measures: Plasma metabolite levels associated with OCT features. Results: We included data on 468 patients, 374 with AMD and 94 controls, and on 725 named endogenous metabolites. Meta-analysis identified significant associations (FDR < 0.05) between plasma metabolites and 3 OCT features: hyperreflective foci (6), atrophy (6), and ellipsoid zone disruption (3). Most associations were seen with amino acids, and all but 1 metabolite presented specific associations with the OCT features assessed. Conclusions: To our knowledge, we show for the first time that plasma metabolites have associations with specific OCT features seen in AMD. Our results support that the wide spectrum of presentations of AMD likely include different pathophysiologic mechanisms by identifying specific pathways associated with each OCT feature. Financial Disclosures: Proprietary or commercial disclosure may be found after the references.

ILUVIEN® in diabetic macular edema that persists or recurs despite treatment: Results from the Retina.pt® RIVER audit.

PURPOSE: Persistent diabetic macular edema (DME) remains a problem in clinical practice, with many patients having a suboptimal response to the standard of care (SOC). Evidence supports the long-term efficacy of intravitreal fluocinolone acetonide (FAc) implant (ILUVIEN®) in patients that have responded sub-optimally, although there is still scarce data from real-world Portuguese practices. We aimed to monitor the current SOC in selected Portuguese practices prior to FAc implantation and then assess the long-term effectiveness and safety of the FAc implant. SETTINGS: The study included patient data from five Portuguese public hospitals. DESIGN: This was a non-interventional, multicenter audit of data collected from Retina.pt registry from patients with persistent or recurrent DME despite treatment. METHODS: Outcome measures included changes in best-corrected visual acuity (BCVA), central macular thickness (CMT), and intraocular pressure (IOP). Results were compared at regular times over 36 months. RESULTS: This study included 222 eyes from 152 patients. A significant decrease in BCVA (P < 0.001) and a significant increase in CMT (P = 0.013) were observed prior to FAc. A significant increase in BCVA was registered at 6 months after FAc implant administration (P < 0.001), which was maintained during follow-up. No relevant changes in IOP were observed. Treatment burden was reduced as a result of treatment with FAc (P < 0.001 for anti-VEGF, corticosteroids, or both treatments) in the full population. CONCLUSIONS: In Portuguese practice, data showed that pre-FAc implantation, some patients did not respond to SOC treatment and/or they were undertreated. Following FAc implant administration, there were rapid, sustained, long-term visual and anatomical improvements, and a marked reduction in treatment burden.

Interaction between genetics and the adherence to the Mediterranean diet: the risk for age-related macular degeneration. Coimbra Eye Study Report 8.

BACKGROUND: Age-related macular degeneration (AMD) is a multifactorial degenerative disease of the macula. Different factors, environmental, genetic and lifestyle, contribute to its onset and progression. However, how they interconnect to promote the disease, or its progression, is still unclear. With this work, we aim to assess the interaction of the genetic risk for AMD and the adherence to the Mediterranean diet in the Coimbra Eye Study. METHODS: Enrolled subjects (n = 612) underwent ophthalmological exams and answered a food questionnaire. Adherence to the Mediterranean diet was assessed with mediSCORE. An overall value was calculated for each participant, ranging from 0 to 9, using the sum of 9 food groups, and a cut off value of ≥ 6 was considered high adherence. Rotterdam Classification was used for grading. Participants' genotyping was performed in collaboration with The European Eye Epidemiology Consortium. The genetic risk score (GRS) was calculated for each participant considering the number of alleles at each variant and their effect size. Interaction was assessed with additive and multiplicative models, adjusted for age, sex, physical exercise, and smoking. RESULTS: The AMD risk was reduced by 60% in subjects with high adherence to the Mediterranean diet compared to subjects with low adherence to the Mediterranean diet. Combined effects of having low adherence to the Mediterranean diet and high GRS led to almost a 5-fold increase in the risk for AMD, compared to low GRS and high adherence to the Mediterranean diet. The multiplicative scale suggested a multiplicative interaction, although not statistically significant [odds ratio (OR) = 1.111, 95% CI 0.346-3.569, P = 0.859]. The additive model showed a causal positive effect of the interaction of GRS and adherence to the Mediterranean diet: relative excess risk due to interaction (RERI) = 150.9%, (95% CI: - 0.414 to 3.432, P = 0.062), attributable proportion due to interaction (AP) = 0.326 (95% CI: - 0.074 to 0.726, P = 0.055) and synergy index (SI) = 1.713 (95% CI: 0.098-3.329, P = 0.019). High GRS people benefited from adhering to the Mediterranean diet with a 60% risk reduction. For low-GRS subjects, a risk reduction was also seen, but not significantly. CONCLUSIONS: Genetics and Mediterranean diet interact to protect against AMD, proving there is an interplay between genetics and environmental factors. TRIAL REGISTRATION: The AMD Incidence (NCT02748824) and Lifestyle and Food Habits Questionnaire in the Portuguese Population Aged 55 or More (NCT01715870) studies are registered at www. CLINICALTRIALS: gov . Five-year Incidence of Age-related Macular Degeneration in the Central Region of Portugal (AMD IncidencePT); NCT02748824: date of registration: 22/04/16. Lifestyle and Food Habits Questionnaire in the Portuguese Population Aged 55 or More; NCT01715870: date of registration: 29/10/12.

Integrating genetics and metabolomics from multi-ethnic and multi-fluid data reveals putative mechanisms for age-related macular degeneration.

Age-related macular degeneration (AMD) is a leading cause of blindness in older adults. Investigating shared genetic components between metabolites and AMD can enhance our understanding of its pathogenesis. We conduct metabolite genome-wide association studies (mGWASs) using multi-ethnic genetic and metabolomic data from up to 28,000 participants. With bidirectional Mendelian randomization analysis involving 16,144 advanced AMD cases and 17,832 controls, we identify 108 putatively causal relationships between plasma metabolites and advanced AMD. These metabolites are enriched in glycerophospholipid metabolism, lysophospholipid, triradylcglycerol, and long chain polyunsaturated fatty acid pathways. Bayesian genetic colocalization analysis and a customized metabolome-wide association approach prioritize putative causal AMD-associated metabolites. We find limited evidence linking urine metabolites to AMD risk. Our study emphasizes the contribution of plasma metabolites, particularly lipid-related pathways and genes, to AMD risk and uncovers numerous putative causal associations between metabolites and AMD risk.

Mutational Spectrum, Ocular and Olfactory Phenotypes of CNGB1-Related RP-Olfactory Dysfunction Syndrome in a Multiethnic Cohort.

CNGB1 gene mutations are a well-known cause of autosomal recessive retinitis pigmentosa (RP), which was recently associated with olfactory dysfunction. The purpose of this study was to report the molecular spectrum and the ocular and olfactory phenotypes of a multiethnic cohort with CNGB1-associated RP. A cross-sectional case series was conducted at two ophthalmic genetics referral centers. Consecutive patients with molecularly confirmed CNGB1-related RP were included. All patients underwent a complete ophthalmological examination complemented by psychophysical olfactory evaluation. Fifteen patients (10 families: 8 Portuguese, 1 French, and 1 Turkish), mean aged 57.13 ± 15.37 years old (yo), were enrolled. Seven disease-causing variants were identified, two of which are reported for the first time: c.2565_2566del and c.2285G > T. Although 11/15 patients reported onset of nyctalopia before age 10, diagnosis was only established after 30 yo in 9/15. Despite widespread retinal degeneration being present in 14/15 probands, a relatively preserved visual acuity was observed throughout follow-up. Olfactory function was preserved in only 4/15 patients, all of whom carried at least one missense variant. Our study supports previous reports of an autosomal recessive RP-olfactory dysfunction syndrome in association with certain disease-causing variants in the CNGB1 gene and expands the mutational spectrum of CNGB1-related disease by reporting two novel variants.

Self-reported visual function and psychosocial impact of visual loss in EYS-associated retinal degeneration in a Portuguese population.

PURPOSE: To evaluate self-reported visual function and the psychosocial impact of visual loss EYS-associated retinal degeneration (EYS-RD) using two patient-reported outcome (PRO) measures: Michigan Retinal Degeneration Questionnaire (MRDQ) and Michigan Vision-related Anxiety Questionnaire (MVAQ). METHODS: Cross-sectional, single-center study conducted at a tertiary care hospital in Portugal. Patients with biallelic EYS variants were invited to participate. Clinical data including demographics, ETDRS best-corrected visual acuity (BCVA) in the better-seeing eye and genetic testing results were collected. Interviews were carried out during clinic visits or by phone between November 2021 and February 2022. A blind grader used horizontal and vertical spectral domain optical coherence tomography (SD-OCT) scans to manually measure ellipsoid zone (EZ) width in the nasal, temporal, superior and inferior macular quadrants to calculate the EZ area. RESULTS: Forty-nine patients (53.1% males; mean age 53 ± 14 years) were included. A positive correlation (p < .05) was found between age and most MRDQ domain scores (central vision, color vision, contrast sensitivity, scotopic function, photopic peripheral vision and mesopic peripheral vision). A negative correlation was found between both BCVA and EZ area across all MRDQ domains. In MVAQ, SD-OCT EZ area negatively correlated with both rod function and cone function-related anxiety. Neither age, BCVA or gender correlated with MVAQ domains. CONCLUSIONS: This study provides strong evidence supporting a correlation between PRO measures and both functional and structural clinician-reported outcomes. The use of MRDQ and MVAQ adds a new dimension to our understanding of EYS-RD and establishes both PRO measures as important disease outcome measures.