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The present study aimed to investigate ocular findings in hereditary transthyretin amyloidosis (ATTRv) pre-symptomatic carriers. Fourteen ATTRv pre-symptomatic carriers, who are patients with positive genetic testing but without signs or symptoms of the disease, were retrospectively evaluated. Retinal morphology was assessed using optical coherence tomography (OCT) and OCT-angiography. Retinal function was evaluated using cone b-wave and photopic negative response (PhNR). Pupillometry and in vivo corneal confocal microscopy (IVCM) were performed. ATTRv pre-symptomatic carriers presented a significantly reduced central macular thickness (CMT) (p = 0.01) and outer nuclear layer (ONL) thickness (p = 0.01) in comparison to normal controls. No differences were found when analyzing sub-foveal choroidal thickness, retinal nerve fiber layer and ganglion cell complex. In comparison to healthy controls, pre-symptomatic carriers presented an attenuated superficial retinal vascular network and a significantly augmented PhNR amplitude (p = 0.01). However, PhNR implicit times, B-wave amplitude and B-wave peak time did not show significant differences in comparison to controls. No differences were found for pupillometric values. All the examined eyes presented alterations in the IVCM. Preclinical ocular structural and functional abnormalities can be found in ATTRv pre-symptomatic carriers. Thus, an extensive ophthalmological evaluation should be included at the baseline visit and during follow-up. Considering the availability of new drugs potentially able to prevent or delay disease progression, the identification of new disease biomarkers appears to be particularly promising.

Facioscapulohumeral muscular dystrophy (FSHD) is a slowly progressive muscular dystrophy with a wide range of manifestations including retinal vasculopathy. This study aimed to analyse retinal vascular involvement in FSHD patients using fundus photographs and optical coherence tomography-angiography (OCT-A) scans, evaluated through artificial intelligence (AI). Thirty-three patients with a diagnosis of FSHD (mean age 50.4 +/- 17.4 years) were retrospectively evaluated and neurological and ophthalmological data were collected. Increased tortuosity of the retinal arteries was qualitatively observed in 77% of the included eyes. The tortuosity index (TI), vessel density (VD), and foveal avascular zone (FAZ) area were calculated by processing OCT-A images through AI. The TI of the superficial capillary plexus (SCP) was increased (p < 0.001), while the TI of the deep capillary plexus (DCP) was decreased in FSHD patients in comparison to controls (p = 0.05). VD scores for both the SCP and the DCP results increased in FSHD patients (p = 0.0001 and p = 0.0004, respectively). With increasing age, VD and the total number of vascular branches showed a decrease (p = 0.008 and p < 0.001, respectively) in the SCP. A moderate correlation between VD and EcoRI fragment length was identified as well (r = 0.35, p = 0.048). For the DCP, a decreased FAZ area was found in FSHD patients in comparison to controls (t (53) = -6.89, p = 0.01). A better understanding of retinal vasculopathy through OCT-A can support some hypotheses on the disease pathogenesis and provide quantitative parameters potentially useful as disease biomarkers. In addition, our study validated the application of a complex toolchain of AI using both ImageJ and Matlab to OCT-A angiograms.

Background. Eyes shut homolog (EYS) gene mutations are estimated to affect at least 5% of patients with autosomal recessive retinitis pigmentosa. Since there is no mammalian model of human EYS disease, it is important to investigate its age-related changes and the degree of central retinal impairment. Methods. A cohort of EYS patients was studied. They underwent full ophthalmic examination as well as assessment of retinal function and structure, by full-field and focal electroretinograms (ERGs) and spectral domain optical coherence tomography (OCT), respectively. The disease severity stage was determined by the RP stage scoring system (RP-SSS). Central retina atrophy (CRA) was estimated from the automatically calculated area of the sub-retinal pigment epithelium (RPE) illumination (SRI). Results. The RP-SSS was positively correlated with age, showing an advanced severity score (>= 8) at an age of 45 and a disease duration of 15 years. The RP-SSS was positively correlated with the CRA area. LogMAR visual acuity and ellipsoid zone width, but not ERG, were correlated with CRA. Conclusions. In EYS-related disease, the RP-SSS showed advanced severity at a relative early age and was correlated with the central area of the RPE/photoreceptor atrophy. These correlations may be relevant in view of therapeutic interventions aimed at rescuing rods and cones in EYS-retinopathy.

In spite of its variety of biological activities, the clinical exploitation of human NGF (hNGF) is currently limited to ocular pathologies. It is therefore interesting to test the effects of hNGF in preclinical models that may predict their efficacy and safety in the clinical setting of ocular disorders and compare the effects of hNGF with those of its analogs. We used a human retinal pigment cell line, ARPE-19 cells, to investigate the effects of hNGF and its analogs, mouse NGF (mNGF) and painless NGF (pNGF), on cell viability under basal conditions and after exposure to oxidative stimuli, i.e., hydrogen peroxide (H2O2) and ultraviolet (UV)-A rays. The effects of hNGF and pNGF were also tested on the gene expression and protein synthesis of the two NGF receptor subtypes, p75 neurotrophic receptors (p75(NTR)) and tyrosine kinase A (TrkA) receptors. We drew the following conclusions: (i) the exposure of ARPE-19 cells to H2O2 or UV-A causes a dose-dependent decrease in the number of viable cells; (ii) under baseline conditions, hNGF, but not pNGF, causes a concentration-dependent decrease in cell viability in the range of doses 1-100 ng/mL; (iii) hNGF, but not pNGF, significantly potentiates the toxic effects of H2O2 or of UV-A on ARPE-19 cells in the range of doses 1-100 ng/mL, while mNGF at the same doses presents an intermediate behavior; (iv) 100 ng/mL of hNGF triggers an increase in p75(NTR) expression in H2O2-treated ARPE-19 cells, while pNGF at the same dose does not; (v) pNGF, but not hNGF (both given at 100 ng/mL), increases the total cell fluorescence intensity for TrkA receptors in H2O2-treated ARPE-19 cells. The present findings suggest a vicious positive feedback loop through which NGF-mediated upregulation of p75(NTR) contributes to worsening the toxic effects of oxidative damage in the human retinal epithelial cell line ARPE-19. Looking at the possible clinical relevance of these findings, one can postulate that pNGF might show a better benefit/risk rat

The long-term effect of intravitreal Fluocinolone acetonide (FAc) on retinal morphology and function in diabetic macular edema (DME) was investigated. Seventeen eyes of twelve consecutive DME patients, treated by intravitreal FAc, were retrospectively evaluated. Retinal morphology was assessed with central macular thickness (CMT). Retinal function was assessed by best-corrected visual acuity (BCVA) and cone b-wave and photopic negative response (PhNR). The main outcome was a mean change in CMT at month 24. The secondary outcomes were changes in cone b-wave and PhNR at month 24. The incidence of adverse events was also recorded. Mean CMT decreased from 406.52 mu m (+/- 138.74) at baseline to 310 mu m (+/- 130.39) at 24 months (p = 0.008). No significant changes in the other parameters were found. At baseline, BCVA and PhNR amplitude were negatively correlated (r = -0.55) with CMT. At the end of follow-up, the change in CMT was negatively correlated with baseline CMT (r = -0.53, p = 0.03) and positively correlated with baseline PhNR amplitude (r = 0.58, p < 0.01). A significant, long-term reduction in CMT was observed in DME patients after FAc implant. The anti-edema effect tended to be stronger in patients with the poorest baseline retinal morphology (CMT) and function (PhNR). Structure/function correlations might help to characterize the patients who may benefit from this treatment.

PURPOSE. To investigate the course of inherited retinal degenerations (IRD) due to mutations in the RPE65 gene. METHODS. This longitudinal multicentric retrospective chart-review study was designed to collect best corrected visual acuity (BCVA), Goldman visual field, optical coherence tomography (OCT), and electroretinography (ERG) measurements. The data, including imaging, were collected using an electronic clinical research form and were reviewed at a single center to improve consistency. RESULTS. From an overall cohort of 60 Italian patients with RPE65-associated IRD, 43 patients (mean age, 27.8 ± 19.7 years) were included and showed a mean BCVA of 2.0 ± 1.0 logMAR. Time-to-event analysis revealed a median age of 33.8 years and 41.4 years to reach low vision and blindness based on BCVA, respectively. ERG (available for 34 patients) showed undetectable responses in most patients (26; 76.5%). OCT (available for 31 patients) revealed epiretinal membranes in five patients (16.1%). Central foveal thickness significantly decreased with age at a mean annual rate of −0.6%/y (P = 0.044). We identified 43 different variants in the RPE65 gene in the entire cohort. Nine variants were novel. Finally, to assess genotype-phenotype correlations, patients were stratified according to the number of RPE65 loss-of-function (LoF) alleles. Patients without LoF variants showed significantly (P < 0.05) better BCVA compared to patients with one or two LoF alleles. CONCLUSIONS. We described the natural course of RPE65-associated IRD in an Italian cohort showing for the first time a specific genotype-phenotype association. Our findings can contribute to a better management of RPE65-associated IRD patients.

Figure Legend In the original publication [1], there was a mistake in the legend for Figure 8. Values for C1 and C2 were inverted. The correct legend appears below. Figure 8 legend becomes: Clustering analysis from Inception V3 deep learning features based on combined superficial and deep OCT-As. The mean 1-year BVCA for C1 and C2 was 66.67 and 49.1, respectively, with a t-test p-value equal to 0.005. Text Correction There was an error in the original publication. Values for C1 and C2 were inverted. A correction has been made to Abstract, sentence: best-corrected visual acuity (BCVA) C1 = 49.10 (18.60 SD) and BCVA C2 = 66.67 (16.00 SD, p = 0.005) The sentence becomes: best-corrected visual acuity (BCVA) C1 = 66.67 (16.00 SD) and BCVA C2 = 49.10 (18.60 SD, p = 0.005). A correction has been made to Results, Paragraph 9, sentence: In this configuration, the mean of letters for C1 and C2 was 49.1 and 66.67, respectively, with a t-test p-value equal to 0.005 (Figure 8) The sentence becomes: In this configuration, the mean of letters for C1 and C2 was 66.67 and 49.1, respectively, with a t-test p-value equal to 0.005 (Figure 8). Error in Table In the original publication, there was a mistake in Table 2 as published. Values for C1 and C2 were inverted. The corrected Table 2 appears below.

Environmental pollution, inadequate eating habits and unhealthy lifestyles have led to a tremendous increase in ocular diseases worldwide. Given the costly treatments that are currently available for the most common and threatening eye diseases (such as cataract, dry eye disorder, or diabetic retinopathy), curing these diseases or preventing refractive errors by taking nutraceuticals and natural compounds that are present in our daily diet is a very valuable intervention. The eyes are the most important part of our visual system and require micronutrients such as vitamins, carotenoids, trace metals, and omega-3 fatty acids in order to function properly and to protect themselves against light-induced and age-mediated degenerative disorders. The Mediterranean Diet (MedDiet) has been in the limelight since the 1980s because of the several health benefits it provides, including eye health. MedDiet is characterized by the consumption of small amounts of red meat, while emphasizing the intake of fish, eggs, nuts, legumes, citrus fruits, green vegetables, olives and their derivatives, especially olive oil, and dairy products in a proportionate manner, in order to achieve the maximum health benefits. The antioxidant, anti-inflammatory, and neuroprotective properties of these foods – both when used as an ingredient in the dietary regime or as a source of nutritional supplements – have shown promising results in the management of chronic degenerative ocular diseases, both in animal models and in human subjects. In this chapter, we will focus on the importance of MedDiet and natural compounds for the visual system and its role in slowing down age-related ocular degeneration.

Purpose: To evaluate the correlation between functional visual acuity and focal electroretinograms (fERGs) and morphological abnormalities in the retinal pigment epithelium and outer retinal atrophy (RORA) assessed by subretinal illumination (SRI) parameter at optical coherence tomography (OCT) examinations as signs of early disease in early and intermediate non-exudative age-related macular degeneration (ne-AMD). Methods: One hundred forty-one eyes of 74 patients were retrospectively evaluated. A subgroup of patients (34/74) had a follow-up of at least 1 year. The study included both cross-sectional and longitudinal analyses. All eyes were assessed by OCT to measure the macular outer nuclear layer thickness, extent of ellipsoid zone interruption, absence or presence of drusen/reticular pseudodrusen in the foveal and perifoveal fields, and the SRI area closest to the fovea. Additionally, fERGs were performed. Results: In the cross-sectional analysis, visual acuity and fERG amplitude were correlated (P < 0.01) with the SRI area. The fERG amplitude was correlated (P < 0.01) with the extent of ellipsoid zone interruption and tended to be lower in reticular pseudodrusen compared with drusen. In the longitudinal analysis, fERG amplitudes and outer retinal thickness tended to decrease on average by 15% and 18%, respectively, after 1 year of follow-up. The baseline RORA area, but not fERG amplitude or visual acuity, significantly predicted with 77% accuracy (P < 0.01) morphological deterioration, which was determined by an increase in the RORA area after 1 year. Conclusions: Functional visual acuity and its morphological correlations can be assessed in early and intermediate ne-AMD eyes. SRI, as a result of RORA, is a potential predictor of ne-AMD progression in a short-term follow-up. Translational Relevance: SRI assessment, an objective method to measure RORA, is a potential biomarker for non-exudative AMD progression.