Recessive MECR pathogenic variants cause an LHON-like optic neuropathy.

BACKGROUND: Leber's hereditary optic neuropathy (LHON) is a mitochondrial disorder characterised by complex I defect leading to sudden degeneration of retinal ganglion cells. Although typically associated with pathogenic variants in mitochondrial DNA, LHON was recently described in patients carrying biallelic variants in nuclear genes DNAJC30, NDUFS2 and MCAT. MCAT is part of mitochondrial fatty acid synthesis (mtFAS), as also MECR, the mitochondrial trans-2-enoyl-CoA reductase. MECR mutations lead to a recessive childhood-onset syndromic disorder with dystonia, optic atrophy and basal ganglia abnormalities. METHODS: We studied through whole exome sequencing two sisters affected by sudden and painless visual loss at young age, with partial recovery and persistent central scotoma. We modelled the candidate variant in yeast and studied mitochondrial dysfunction in yeast and fibroblasts. We tested protein lipoylation and cell response to oxidative stress in yeast. RESULTS: Both sisters carried a homozygous pathogenic variant in MECR (p.Arg258Trp). In yeast, the MECR-R258W mutant showed an impaired oxidative growth, 30% reduction in oxygen consumption rate and 80% decrease in protein levels, pointing to structure destabilisation. Fibroblasts confirmed the reduced amount of MECR protein, but failed to reproduce the OXPHOS defect. Respiratory complexes assembly was normal. Finally, the yeast mutant lacked lipoylation of key metabolic enzymes and was more sensitive to H2O2 treatment. Lipoic Acid supplementation partially rescued the growth defect. CONCLUSION: We report the first family with homozygous MECR variant causing an LHON-like optic neuropathy, which pairs the recent MCAT findings, reinforcing the impairment of mtFAS as novel pathogenic mechanism in LHON.

OCT risk factors for 2-year foveal involvement in non-treated eyes with extrafoveal geographic atrophy and AMD.

PURPOSE: To assess the relationship of optical coherence tomography (OCT) findings and progression to foveal atrophy in a cohort of eyes with extrafoveal geographic atrophy (GA) and age-related macular degeneration (AMD) at inclusion. METHODS: We retrospectively analyzed 45 participants (45 eyes) with extrafoveal GA at baseline and with 2 years of regular follow-ups. Several OCT qualitative features (i.e., presence of foveal flat pigment epithelium detachment with a thin double layer sign [DLS] and reticular pseudodrusen, GA focality) and quantitative measurements (outer retinal layer thickness, retinal pigment epithelium [RPE] to Bruch's membrane [BM] volume, minimum distance from the central foveal circle, and untransformed GA lesion size area) were assessed at baseline. Logistic regression analyses were carried out to identify independent significant predictors and compute odds ratios (ORs) for the risk of the development of atrophy. RESULTS: At month 24, 26 eyes (57.8%) developed atrophy in the foveal central circle, while 11 eyes (24.4%) developed atrophy in the foveal central point. Significant independent predictive features for the development of atrophy in the foveal central circle included foveal outer retinal thickness (OR, 0.867; p = 0.015), minimum distance from the foveal central circle (OR, 0.992; p = 0.022), and foveal thin DLS (OR, 0.044; p = 0.036). The only independent predictive feature for the development of atrophy in the foveal central point was the presence of foveal thin DLS (OR, 0.138; p = 0.017). CONCLUSIONS: We identified OCT risk factors for 2-year foveal atrophy in eyes with untreated extrafoveal GA at baseline.

Structural OCT and OCT angiography biomarkers associated with the development and progression of geographic atrophy in AMD.

BACKGROUND: Geographic atrophy (GA) is an advanced, irreversible, and progressive form of age-related macular degeneration (AMD). Structural optical coherence tomography (OCT) and OCT angiography (OCTA) have been largely used to characterize this stage of AMD and, more importantly, to define biomarkers associated with the development and progression of GA in AMD. METHODS: Articles pertaining to OCT and OCTA biomarkers related to the development and progression of GA with relevant key words were used to search in PubMed, Researchgate, and Google Scholar. The articles were selected based on their relevance, reliability, publication year, published journal, and accessibility. RESULTS: Previous reports have highlighted various OCT and OCTA biomarkers linked to the onset and advancement of GA. These biomarkers encompass characteristics such as the size, volume, and subtype of drusen, the presence of hyperreflective foci, basal laminar deposits, incomplete retinal pigment epithelium and outer retinal atrophy (iRORA), persistent choroidal hypertransmission defects, and the existence of subretinal drusenoid deposits (also referred to as reticular pseudodrusen). Moreover, biomarkers associated with the progression of GA include thinning of the outer retina, photoreceptor degradation, the distance between retinal pigment epithelium and Bruch's membrane, and choriocapillaris loss. CONCLUSION: The advent of novel treatment strategies for GA underscores the heightened need for prompt diagnosis and precise monitoring of individuals with this condition. The utilization of structural OCT and OCTA becomes essential for identifying distinct biomarkers associated with the initiation and progression of GA.

Long-term predictors of anti-VEGF treatment response in patients with neovascularization secondary to CSCR: a longitudinal study.

PURPOSE: To identify the baseline predictors of anti-VEGF treatment response at 3 years in patients affected by choroidal neovascularization (CNV) secondary to central serous chorioretinopathy (CSCR). METHODS: In this retrospective longitudinal study, medical records of patients diagnosed with CNV secondary to CSCR and treated using anti-VEGF injections between April 2015 and May 2020 were reviewed. The potential qualitative and quantitative predictors of treatment response were identified or measured based on the multimodal imaging examination available for each patient at the baseline, including structural OCT, fluorescein angiography (FA), indocyanine green angiography (ICGA), and OCT-angiography (OCT-A). Univariate and multivariate analyses were performed. RESULTS: Twenty-nine eyes from 29 patients affected by CNV complicating CSCR were included in the study. At the end of the 3-year follow-up, the mean BCVA was 20/50 Snellen equivalent (0.38 ± 0.36 LogMAR), and no significant difference with baseline BCVA (0.37 ± 0.29 LogMAR) was found (p = 0.9). Twenty out of 29 eyes (69%) had active lesions at the end of the follow-up. At multivariate analysis, none of the included features was independently associated with the 3-year BCVA outcome. Pigment epithelium detachment (PED) height (ß = 0.017, p = 0.028) and outer limiting membrane (OLM) preservation at the fovea (ß = -5.637, p = 0.026) were independently associated with the CNV activity at 3 years. CONCLUSION: PED height and OLM obliteration at the fovea might be considered baseline predictors of lesion activity at 3-year follow-up in patients with CNV secondary to CSCR treated with anti-VEGF therapy.

Peripapillary hyperreflective ovoid mass-like structures (PHOMS) in patients with acute Leber's hereditary optic neuropathy.

PURPOSE: Peripapillary hyperreflective ovoid mass-like structures (PHOMS) represent an optical coherence tomography (OCT) finding that has been characterized in different forms of pseudopapilledema. The aim of this study was to investigate the prevalence of PHOMS in patients affected by acute LHON using structural OCT, and to provide a detailed description of these findings. METHODS: Patients with a clinical and molecularly confirmed diagnosis of acute LHON (visual loss having occurred less than 6 months) were enrolled from the neuro-ophthalmology clinic at San Raffaele Scientific Institute. Patients had a complete ophthalmologic evaluation, including imaging with structural OCT. RESULTS: Our analysis included 16 patients (21 eyes-8 males and 8 females) with acute LHON. Structural OCT exhibited PHOMS in 12 eyes from 9 patients with a prevalence rate of 57.1%. In a subsequent topographical assessment in the peripapillary area, the most common location of PHOMS was the temporal region (12 out of 12 eyes), while the nasal region was affected in 2 eyes (16.7%). Considering the 12 eyes with PHOMS, mean ± SD temporal peripapillary RNFL thickness was 87.5 ± 28.4 microns. The temporal peripapillary RNFL thickness was significantly lower in eyes without PHOMS (63.7 ± 32.2 microns; P = 0.40). At the 12-month follow-up visit, PHOMS disappeared in 10 out of 12 eyes. CONCLUSIONS: Acute LHON eyes have PHOMS which are mainly confined to the temporal peripapillary sector. PHOMS may represent swelled retinal fibers that have herniated or are in stasis.

INTERSESSION REPEATABILITY OF READING PERFORMANCE MEASURES IN PATIENTS WITH NEOVASCULAR AGE-RELATED MACULAR DEGENERATION.

PURPOSE: To assess the intersession repeatability of reading performance measures in patients with previously treated neovascular age-related macular degeneration and good best-corrected visual acuity (≥20/40 Snellen). METHODS: Ninety-one patients (91 eyes) with a diagnosis of previously treated neovascular age-related macular degeneration and good best-corrected visual acuity (≥20/40 Snellen) were prospectively enrolled. Reading performance metrics were assessed using Radner charts, and these measurements were repeated after 7 days to obtain the intersession repeatability. To test repeatability, we calculated the intraclass correlation coefficient, the 95% coefficient of repeatability, and the coefficient of variation for each reading parameter: 1) reading acuity (RA-LogRAD); 2) maximal reading speed-words per minute; 3) RA score (RA score-LogRAD); and 4) critical print size-LogRAD. RESULTS: Mean ± standard deviation best-corrected visual acuity was 0.13 ± 0.01 logMAR [range: 0.00-0.30 logMAR]. The intraclass correlation coefficient values indicated a good reliability for all the analyzed metrics (0.901 for RA; 0.859 for max reading speed; 0.906 for RA score; and 0.868 for critical print size). The coefficient of repeatability was 0.2 LogRAD for RA, 63.2 words per minute for max reading speed, 0.2 LogRAD for RA score, and 0.2 LogRAD for critical print size. Coefficient of variation was 5.5% for RA, 8.9% for max reading speed, 5.8% for RA score, and 6.9% for critical print size. CONCLUSION: Reading performance metrics are characterized by good values of intersession repeatability in patients with neovascular age-related macular degeneration with good best-corrected visual acuity. Our findings may grant the employment of such measures in trials assessing the visual outcome in these patients.

NONEXUDATIVE INTRARETINAL FLUID IN INTERMEDIATE AGE-RELATED MACULAR DEGENERATION.

BACKGROUND: To describe the occurrence of nonexudative intraretinal fluid (IRF) in intermediate age-related macular degeneration. METHODS: A retrospective study was designed to include consecutive cases with intermediate age-related macular degeneration associated with IRF. A multimodal imaging approach was used to confirm diagnosis of IRF in intermediate age-related macular degeneration. Multimodal imaging included color fundus photograph, fundus autofluorescence, fluorescein angiography, indocyanine green angiography, optical coherence tomography, and optical coherence tomography angiography. RESULTS: Ten eyes of 10 patients (2 male and 8 female patients, ages 68-80 years) showing IRF in intermediate age-related macular degeneration were included in the study. The mean best-corrected visual acuity was 20/40 Snellen equivalent. Multimodal imaging including fluorescein angiography/indocyanine green angiography and optical coherence tomography demonstrated the absence of macular neovascularization in all cases; optical coherence tomography-angiography did not detect any abnormal flow signal associated with IRF. Seven of 10 patients developed IRF in correspondence of pigment epithelium detachment. Three of 10 patients presented IRF in correspondence of an area of nascent geographic atrophy. CONCLUSION: Nonexudative intraretinal fluid in intermediate age-related macular degeneration is a novel, distinctive feature that is characterized by the presence of IRF with no evidence of macular neovascular lesions. The authors described different phenotypes of IRF in intermediate age-related macular degeneration. The definite diagnosis of this condition requires further studies with thorough application of multimodal imaging.

PHENOTYPIC CHARACTERIZATION OF PREDICTORS FOR DEVELOPMENT AND PROGRESSION OF GEOGRAPHIC ATROPHY USING OPTICAL COHERENCE TOMOGRAPHY.

PURPOSE: To evaluate the impact of optical coherence tomography phenotypes preceding atrophy related to age-related macular degeneration on the progression of atrophic lesions. METHODS: In this observational retrospective cohort study, a total of 70 eyes of 60 consecutive patients with intermediate age-related macular degeneration with a minimum follow-up of 24 months were included. The atrophy was quantified using fundus autofluorescence, also considering the directionality of atrophy as centrifugal and centripetal progression rates. The main outcome measures were geographic atrophy (GA) progression rate (mm 2 /year) and square root transformation of GA (mm 2 /year). RESULTS: The best-fit model for GA (odds ratio: 1.81, P < 0.001) and square root transformation of GA (odds ratio: 1.36, P < 0.001) areas revealed that the main baseline predictor was the presence of a retinal pigment epithelium-basal lamina-Bruch membrane splitting. Large drusen at baseline appeared protective for the GA area lesion expansion over time (odds ratio: 0.52, P < 0.001) when considered with other confounders. CONCLUSION: A thin retinal pigment epithelium-basal lamina-Bruch membrane splitting without evidence of neovascularization on optical coherence tomography angiography likely represents an optical coherence tomography signature for late basal laminar deposits. Identifying this phenotype can help identify individuals with a higher risk of rapid progression and atrophy expansion.

Deep Learning in Neovascular Age-Related Macular Degeneration.

Background and objectives: Age-related macular degeneration (AMD) is a complex and multifactorial condition that can lead to permanent vision loss once it progresses to the neovascular exudative stage. This review aims to summarize the use of deep learning in neovascular AMD. Materials and Methods: Pubmed search. Results: Deep learning has demonstrated effectiveness in analyzing structural OCT images in patients with neovascular AMD. This review outlines the role of deep learning in identifying and measuring biomarkers linked to an elevated risk of transitioning to the neovascular form of AMD. Additionally, deep learning techniques can quantify critical OCT features associated with neovascular AMD, which have prognostic implications for these patients. Incorporating deep learning into the assessment of neovascular AMD eyes holds promise for enhancing clinical management strategies for affected individuals. Conclusion: Several studies have demonstrated effectiveness of deep learning in assessing neovascular AMD patients and this has a promising role in the assessment of these patients.

Comparison of peripheral extension, acquisition time, and image chromaticity of Optos, Clarus, and EIDON systems.

PURPOSE: To evaluate differences in acquisition time, peripheral extension, and chromaticity between 3 different commercialized ultra-wide-field (UWF) fundus cameras. METHODS: Patients were prospectively enrolled from 07/2021 to 11/2021. Patients underwent fundus photography with the following scanning protocols: (1) single shot with Silverstone (Optos, California), two-shot montage with Clarus 500 (Carl Zeiss, Dublin, CA), and three-shot montage with iCare EIDON FA with UWF module (CenterVue Spa, a company of iCare Finland Oy; Vantaa, Finland). Acquisition time was calculated as the interval between the beginning and the end of the acquisition. Peripheral extension was quantified as the average ratio between the total retinal pixel area and the optic nerve head (ONH) pixel area. The average chromaticity of all pixels in the red-green-blue (RGB) space was calculated. RESULTS: Twenty-three eyes of 13 prospectively enrolled healthy controls were included in the study. Optos Silverstone had a higher total retina area/ONH area ratio (509.1 [480.9;559.3]) compared to Zeiss Clarus (442.0 [431.9;510.5], p = 0.02) and iCare EIDON (369.7 [345.3;387.8], p < 0.0001). Silverstone demonstrated the shortest acquisition time (median [interquartile range]: 32 [20;58.5] s) compared to Zeiss Clarus (42 [28.5;53.5] s, p = 0.6733) and iCare EIDON (72 [68.5;78] s, p = 0.0003). iCare EIDON demonstrated the lowest variability of acquisition time (9.5 s), compared to Zeiss Clarus (25 s) and Optos Silverstone (38.5 s). A statistically significant difference was found in the RGB distribution between each of the 3 devices (p < 0.001). iCare EIDON demonstrated an average barycenter position (RGB = [0.412, 0.314, 0.275]) that represented the best color balance of the image. Zeiss Clarus had a noticeable red shift at the expense of the blue and green channels (RGB = [0.515, 0.294, 0.191]). Optos Silverstone showed an absence of the blue channel (RGB = [0.621, 0.372, 0.007]) which results in a distortion of the color of the image. CONCLUSION: Optos Silverstone and Zeiss Clarus required less time than iCare EIDON to acquire a comparable size image and captured larger areas of the retina than iCare EIDON. iCare EIDON provided more color-balanced retinal images with greater richness of color content than the other two devices.

Individual vs. combined imaging modalities for diagnosing neovascular central serous chorioretinopathy.

PURPOSE: To assess the diagnostic accuracy of individual and combined imaging modalities compared with multimodal imaging for the detection of choroidal neovascularization (CNV) in central serous chorioretinopathy (CSC). METHODS: We analyzed patients with CSC with and without CNV who had indocyanine green angiography (ICGA), structural optical coherence tomography (OCT), and OCT angiography (OCTA) obtained on the same day. The presence of CNV was determined using multimodal imaging by a senior retina specialist (i.e., diagnostic reference). Individual and combined (i.e., ICGA + structural OCT) imaging modalities were then graded by two expert readers for the presence of CNV. Sensitivity, specificity, positive (PPV), and negative (NPV) predictive values were computed for individual and combined imaging modalities relative to the diagnostic reference. RESULTS: CNV was detected in 17 eyes in 17 out of 33 CSC patients according to the reference standard. Using ICGA, the identification of CNV had a sensitivity of 66.7%, specificity of 66.7%, PPV of 70.6%, and NPV of 62.5%. Structural OCT had the following diagnostic accuracy values: 83.3% of sensitivity, 53.3% of specificity, 68.1% of PPV, and 72.7% of NPV. Using OCTA, CNV was graded to be present with a sensitivity of 77.8%, specificity of 86.7%, PPV of 87.5%, and NPV of 76.5%. The combination of ICGA and structural OCT granted the identification of CNV with a sensitivity of 83.3%, specificity of 86.7%, PPV of 88.2%, and NPV of 81.3%. CONCLUSIONS: OCTA has an elevated diagnostic accuracy in identifying CSC-associated CNV, though a combination of ICGA and structural OCT has a comparable diagnostic efficiency.

INVERTED INTERNAL LIMITING MEMBRANE FLAP FOR SMALL-SIZED (<250 µ m) FULL-THICKNESS MACULAR HOLE : Anatomical and Functional Outcome.

PURPOSE: To compare the anatomical and functional outcome of small (<250 µ m) and medium (250-400 µ m) full-thickness macular holes (FTMHs) treated with internal limiting membrane (ILM) inverted flap (IF) or with the standard technique. METHODS: Retrospective longitudinal analysis of successfully operated eyes with small or intermediate FTMH. Outcome measures were best-corrected visual acuity (BCVA), microperimetric sensitivity (with fixation stability), and restoration of the external limiting membrane (ELM) and ellipsoid zone (EZ) at 6 months. RESULTS: Fifty small and 50 intermediate eyes with FTMH were included, half of each group (25) treated with the standard technique, half with IF. BCVA increased in every subgroup, similarly within the same stage regardless the technique. Small FTMH treated with IF disclosed inferior foveal sensitivity at 6 months (20.79 ± 0.48 dB) compared with the standard technique (21.51 ± 0.79 dB; P = 0.0035). At 1 month, inferior rates of ELM (24%) and EZ (24%) restoration were also found, compared with the standard technique (56% ELM P = 0.0420; 64% EZ P = 0.0095). At 6 months, ELM and EZ were similarly restored. CONCLUSION: The surgical repair of small FMTH with ILM IF seem to delay the foveal structural repair and to gain an inferior foveal sensitivity compared to the standard technique.

PUNCTATE INNER PACHYCHOROIDOPATHY: Demographic and Clinical Features of Inner Choroidal Inflammation in Eyes with Pachychoroid Disease.

PURPOSE: To perform an unsupervised machine learning clustering of patients with punctate inner choroidopathy (PIC) and provide new insights into the significance of pachychoroid disease features in PIC eyes. METHODS: Retrospective multicenter study, including 102 eyes from 82 patients diagnosed with PIC. Demographics, clinical data, and multimodal imaging, including fundus photography, optical coherence tomography, and indocyanine green angiography, were collected. Clusters of eyes were identified, and multilevel logistic regression analysis was performed to compare between-group differences. RESULTS: Using 17 clinical features, two distinct clusters of patients with PIC were identified. Cluster 1 patients were characterized by older age, high myopia, myopic maculopathy features, thin choroids, multiple lesions, and a higher likelihood of developing patchy chorioretinal atrophy. Cluster 2 consisted of younger age, emmetropia or low myopia, thick choroids, choroidal vascular hyperpermeability on late-phase indocyanine green angiography, and high prevalence of focal choroidal excavation. These features exhibited significant differences ( P < 0.05) between the two clusters. CONCLUSION: While PIC typically affects young myopic female patients with thin choroids, a subset of patients with PIC exhibits features associated with pachychoroid disease. Considering the potential influence of choroidal venous insufficiency on PIC manifestations and secondary complications, we propose the term "punctate inner pachychoroidopathy" to characterize this distinct subtype of PIC.

PREVALENCE AND MORPHOLOGIC BIOMARKERS OF METAMORPHOPSIA IN EYES WITH "RESOLVED" CHRONIC CENTRAL SEROUS CHORIORETINOPATHY.

PURPOSE: To assess relationships between demographics, clinical characteristics, and optical coherence tomography characteristics with persistence of metamorphopsia after resolution of subretinal fluid in eyes with chronic central serous chorioretinopathy. METHODS: One-hundred participants with "resolved" (absence of subretinal fluid) chronic central serous chorioretinopathy were retrospectively analyzed. Patients underwent a complete ophthalmologic evaluation, including assessment of the presence of metamorphopsia. At the study visit, optical coherence tomography scans were reviewed for qualitative and quantitative features. RESULTS: Sixty-six of 100 patients (66.0%) complained of metamorphopsia. Both the foveal and parafoveal ganglion cell complex thicknesses were thinner in central serous chorioretinopathy eyes with metamorphopsia (35.1 ± 10.6 µ m and 82.0 ± 18.1 µ m vs. 40.7 ± 11.8 µ m and 93.1 ± 13.5 µ m, P = 0.030 and P < 0.0001). In the foveal region, the outer plexiform layer and outer nuclear layer thicknesses were thinner in patients with metamorphopsia (24.6 ± 8.5 µ m and 63.1 ± 20.9 µ m vs. 29.1 ± 8.7 and 76.2 ± 18.2 µ m, P = 0.016 and P = 0.005). The ellipsoid zone band was more frequently discontinued in eyes with metamorphopsia (56.1% vs. 35.3%, P = 0.039). Multivariate stepwise linear regression analysis demonstrated that the strongest associations with the presence of metamorphopsia were with parafoveal ganglion cell complex thickness ( P = 0.004), foveal outer nuclear layer thickness ( P = 0.010), and number of previous recurrences of subretinal fluid accumulation ( P = 0.017). The time interval from the last subretinal fluid resolution was not associated with the presence of metamorphopsia. CONCLUSION: In "resolved" central serous chorioretinopathy, clinical aspects (i.e., number of previous recurrences) and structural changes (i.e., ganglion cell complex and outer nuclear layer thinning) are associated with metamorphopsia after subretinal fluid resolution.

FUNDUS AUTOFLUORESCENCE IN EXTENSIVE MACULAR ATROPHY WITH PSEUDODRUSEN AND DIFFUSE TRICKLING GEOGRAPHIC ATROPHY.

PURPOSE: To establish whether extensive macular atrophy with pseudodrusen (EMAP) can be distinguished from the diffuse-trickling phenotype of geographic atrophy (DTGA) secondary to age-related macular degeneration on the basis of its features on blue-light autofluorescence. METHODS: The authors reviewed our prospectively maintained database to enroll patients with a diagnosis of EMAP, DTGA, and non-DTGA with a minimum follow-up of 1 year. Atrophic areas and growth rates were measured on blue-light autofluorescence images, using the Heidelberg Region Finder tool. Circularity and roundness were chosen as atrophy shape descriptors, extracted using ImageJ, and compared between disease groups. RESULTS: A total of 28 EMAP, 27 DTGA, and 30 non-DTGA eyes were included in the analysis. The median follow-up time was around 3.5 years. Extensive macular atrophy with pseudodrusen was characterized by an irregular and elongated shape (low circularity and low roundness) and associated with a fast atrophy growth rate (3.6 mm 2 /year), compared with non-DTGA. However, these parameters were not significantly different between EMAP and DTGA. CONCLUSION: Our study found that EMAP and DTGA cannot be effectively differentiated on fundus autofluorescence. In both diseases, the macular atrophic area has a major vertical axis, fringed borders, and fast progression.

RISK FACTORS OF VISION LOSS AND MULTIPLE RECURRENCES IN MYOPIC MACULAR NEOVASCULARIZATION.

PURPOSE: To investigate the factors associated with maximum visual improvement (peak vision) gain and the risk factors of peak vision loss and multiple recurrences in myopic macular neovascularization undergoing antivascular endothelial growth factor therapy. METHODS: Retrospective study of 310 eyes with active myopic macular neovascularization and median follow-up of 3.5 years. We defined peak vision gain as the maximum best-corrected visual acuity value reached under treatment and peak vision loss as best-corrected visual acuity never scoring as peak vision. We used multiple-event Prentice, Williams, and Peterson models to compute recurrences' incidence and Cox regression to identify risk factors for peak vision gain, peak vision loss, and multiple recurrences. RESULTS: Eyes with worse baseline best-corrected visual acuity {hazard ratio (HR) = 2.59 (95% confidence interval [CI]: 1.63-4.11) for 0.1 logMAR increase, P < 0.001} had higher chance to achieve peak vision. Peak vision was lost in 162 eyes (52%). Older age (HR = 1.22 [95% CI: 1.02-1.43] for 10-year increase, P = 0.02) and recurrences (HR = 1.10 [95% CI: 1.01-1.22] for event, P = 0.04) predicted nonsustained peak vision. Older age (HR = 1.13 [95% CI: 1.04-1.27] for 10-year increase, P = 0.006), larger myopic macular neovascularization (HR = 1.06 [95% CI: 1.01-1.13] for 1-mm 2 increase, P = 0.04), and juxtafoveal location (HR = 1.88 [95% CI: 1.28-2.77] vs. extrafoveal, P = 0.001) predicted multiple recurrences. CONCLUSION: Myopic macular neovascularization eyes lose vision mainly because of multiple recurrences. Patients at risk for recurrences should undergo more attentive monitoring to avoid vision loss.

HYPERREFLECTIVE BAND IN THE GANGLION CELL LAYER IN RETINITIS PIGMENTOSA.

PURPOSE: To describe a sign that takes the form of a continuous hyperreflective band within the thickness of the ganglion cell layer (GCL), thus dubbed the "hyperreflective ganglion cell layer band" (HGB), which the authors detected in a fraction of patients affected by retinitis pigmentosa (RP). METHODS: Retrospective, cross-sectional, observational study. Optical coherence tomography (OCT) images of patients with RP examined between May 2015 and June 2021 were retrospectively reviewed for the presence of HGB, epiretinal membrane (ERM), macular hole, and cystoid macular edema (CME). The ellipsoid zone (EZ) width was also measured. A subgroup of patients underwent microperimetry in the central 2°, 4°, and 10°. RESULTS: One hundred and fifty-four eyes from 77 subjects were included in the study. The HGB was present in 39 (25.3%) eyes with RP. Mean best-corrected visual acuity (BCVA) was 0.39 ± 0.05 logMAR (approximately 20/50 Snellen equivalent) and 0.18 ± 0.03 logMAR (approximately 20/32 Snellen equivalent) in eyes with and without HGB, respectively ( P < 0.001). The two groups did not differ regarding EZ width; mean 2°, 4°, and 10° retinal sensitivity; and prevalence of CME, ERM, and macular hole. The multivariable analysis showed the presence of HGB to be a predictor of poorer BCVA ( P < 0.001). CONCLUSION: HGB is an OCT finding detectable in approximately a quarter of eyes with RP and is associated with a poorer visual function. In the discussion, the authors speculate about possible morphogenetic scenarios to explain this observation.

ARTIFICIAL INTELLIGENCE'S ROLE IN DIFFERENTIATING THE ORIGIN FOR SUBRETINAL BLEEDING IN PATHOLOGIC MYOPIA.

PURPOSE: To identify salient imaging features to support human-based differential diagnosis between subretinal hemorrhage (SH) due to choroidal neovascularization (CNV) onset and SH without CNV (simple bleeding [SB]) in pathologic myopia eyes using a machine learning (ML)-based step-wise approach. METHODS: Four different methods for feature extraction were applied: GradCAM visualization, reverse engineering, image processing, and human graders' measurements. GradCAM was performed on a deep learning model derived from Inception-ResNet-v2 trained with OCT B-scan images. Reverse engineering consisted of merging U-Net architecture with a deconvolutional network. Image processing consisted of the application of a local adaptive threshold. Available OCT B-scan images were divided in two groups: the first group was classified by graders before knowing the results of feature extraction and the second (different images) was classified after familiarization with the results of feature extraction. RESULTS: Forty-seven and 37 eyes were included in the CNV group and the simple bleeding group, respectively. Choroidal neovascularization eyes showed higher baseline central macular thickness ( P = 0.036). Image processing evidenced in CNV eyes an inhomogeneity of the subretinal material and an interruption of the Bruch membrane at the margins of the SH area. Graders' classification performance improved from an accuracy of 76.9% without guidance to 83.3% with the guidance of the three methods ( P  = 0.02). Deep learning accuracy in the task was 86.0%. CONCLUSION: Artificial intelligence helps identifying imaging biomarkers suggestive of CNV in the context of SH in myopia, improving human ability to perform differential diagnosis on unprocessed baseline OCT B-scan images. Deep learning can accurately distinguish between the two causes of SH.

Associations and Prognostic Significance of Fluctuations in Diabetic Retinopathy Severity in Eyes Treated for Diabetic Macular Edema.

INTRODUCTION: The aim of our study was to investigate factors associated with diabetic retinopathy (DR) severity fluctuations in patients undergoing intravitreal injections for diabetic macular edema and to explore risk factors for proliferative DR (PDR). METHODS: We graded ultra-widefield fundus photography imaging at each visit using the Early Treatment Diabetic Retinopathy Study Severity Scale (DRSS). We calculated the deviation from the mode (DM) of DRSS values as a proxy of DR severity fluctuations, and we analyzed its clinical associations with linear models. We computed risk factors for PDR with Cox hazard models. We included the DRSS area-under-the-curve (AUC) of DRSS scores as a covariate in all analyses. RESULTS: We included 111 eyes with a median follow-up of 44 months. Higher DRSS-AUC values (ß = +0.03 DRSS DM for unitary DRSS/month increase, p = 0.01) and a higher number of anti-VEGF injections (ß = +0.07 DRSS DM for injection, p = 0.045) were associated with wider DR severity fluctuations. Higher DRSS-AUC values (HR = 1.45 for unitary DRSS/month increase, p = 0.001) and wider DR severity fluctuations (HR = 22.35 4th quartile vs. 1st-3rd quartile of DRSS DM, p = 0.01) were risk factors for PDR. CONCLUSION: Patients with larger DR variability in response to intravitreal injections may be at higher risk of DR progression. We advocate attentive follow-up in these patients to recognize PDR early.

Real-Life Experience and Predictors of Visual Outcomes with Intravitreal Brolucizumab Switch for Treatment of Neovascular Age-Related Macular Degeneration.

INTRODUCTION: To analyze visual and anatomical outcomes after switch to intravitreal brolucizumab therapy in eyes affected by neovascular age-related macular degeneration (nAMD) previously treated with other intravitreal anti-vascular endothelial growth factor (anti-VEGF) agents. METHODS: Retrospective study of eyes with nAMD that underwent intravitreal brolucizumab at San Raffaele Hospital (Milan, Italy) or San Rocco Clinical Institute (Ome, Italy) between January 2021 and July 2022. All study eyes had persistent residual retinal fluid after receiving at least 3 intravitreal injections of other anti-VEGF agents prior to switch to brolucizumab. RESULTS: Among 66 eyes from 60 patients (35 males; mean age 76.5 ± 7.4 years) with nAMD, 43 (65.2%) eyes received a complete loading dose of 3 brolucizumab injections, while 15 (22.7%) and 8 (12.1%) eyes were treated with 2 or 1 brolucizumab injections, respectively. The average number of brolucizumab injections was 2.5 during 4.0 ± 2.0 months (mean interval between two injections of 51.2 days). Lower letter gains (<5 letter improvement from baseline) were found in eyes that did not complete a loading dose, after a greater number of previous anti-VEGF injections, after a longer duration of disease, and in eyes with a greater rate of macular atrophy at baseline. No serious ocular or systemic adverse events were found after switch to brolucizumab. CONCLUSION: nAMD eyes with persistent residual retinal fluid despite frequent anti-VEGF treatment can still gain functional and anatomical improvements after switch to brolucizumab therapy. Despite a relevant heterogeneity in patients' response to brolucizumab, we identified potential biomarkers for functional and anatomical improvement.