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Background: To analyze the concentration of aqueous humor (AH) cytokines in eyes with idiopathic epiretinal membrane (iERM) and to investigate their potential correlation with disease severity. Methods: Retrospective cross-sectional case-control institutional study. A total of 16 eyes of 16 iERM patients and 14 eyes of 14 age-matched healthy controls were enrolled. AH samples were analyzed for various biomarkers using a glass-chip protein array. Cytokines associated with inflammation, fibrosis, angiogenesis, and glial signal transduction were quantified. Results: Significant differences in cytokine concentration were observed between the iERM group and controls, with 19 cytokines elevated in the iERM group (among them IL-6, IL-8, PDGF-AB, PDGF-BB, TGFB-1, TGFB-2, TGFB-3, VEGF A, VEGF C, VEGF D, p < 0,05, 95% confidence interval). Correlation analysis revealed associations between cytokine levels and iERM severity. Notably, stages 2, 3, and 4 of iERM demonstrated increased levels of various biomarkers. Conclusions: This study provides insights into the complex molecular interactions underlying iERM pathogenesis, describing a correlation between neuroinflammation and iERM severity. [ABSTRACT FROM AUTHOR]

This study aimed to assess outer retinal layer (ORL), retinal pigment epithelium (RPE), choroid (Ch) and choriocapillaris (CC) modifications in adolescents with long-lasting (>10 years) type 1 diabetes (T1D) without (noDR) or with diabetic retinopathy (DR). ORL and RPE thickness were measured at optical coherence tomography (OCT) macular scans. Vascular parameters of Ch and CC were quantified after elaboration of macular OCT-angiography (OCTA) images. Insulin dose and auxological and metabolic parameters were correlated with OCT and OCTA findings in patients. ORL thickness was higher in DR eyes than in noDR and healthy controls (HC), and RPE thickness was higher in noDR and DR eyes than in HC, with statistical significance for some sectors in noDR versus HC. No OCTA parameters of CC and Ch differed among groups, and no significant correlation was observed with auxological and metabolic parameters. In conclusion, ORL and RPE were both increased in adolescents with long-lasting T1D. Such changes were not associated with insulin dose and glycemia control, nor to any choroid or choriocapillaris flow change clinically detectable at OCTA, and they could be potential imaging biomarkers of disease progression. [ABSTRACT FROM AUTHOR]

The disorganization of retinal inner layers (DRIL) is an optical coherence tomography (OCT) biomarker strictly associated with visual outcomes in patients with diabetic macular edema (DME) whose pathophysiology is still unclear. The aim of this study was to characterize in vivo, using retinal imaging and liquid biopsy, DRIL in eyes with DME. This was an observational cross-sectional study. Patients affected by center-involved DME were enrolled. All patients underwent spectral domain optical coherence tomography (SD-OCT) and proteomic analysis of aqueous humor (AH). The presence of DRIL at OCT was analyzed by two masked retinal experts. Fifty-seven biochemical biomarkers were analyzed from AH samples. Nineteen eyes of nineteen DME patients were enrolled. DRIL was present in 10 patients (52.63%). No statistically significant difference was found between DME eyes with and without DRIL, considering the AH concentration of all the analyzed biomarkers except for glial fibrillary acidic protein (GFAP), a biomarker of Müller cells dysfunction (p = 0.02). In conclusion, DRIL, in DME eyes, seems to strictly depend on a major dysfunction of Müller cells, explaining its role not only as imaging biomarker, but also as visual function Müller cells-related parameter. [ABSTRACT FROM AUTHOR]

Artificial intelligence (AI) and deep learning (DL)-based systems have gained wide interest in macular disorders, including diabetic macular edema (DME). This paper aims to validate an AI algorithm for identifying and quantifying different major optical coherence tomography (OCT) biomarkers in DME eyes by comparing the algorithm to human expert manual examination. Intraretinal (IRF) and subretinal fluid (SRF) detection and volumes, external limiting-membrane (ELM) and ellipsoid zone (EZ) integrity, and hyperreflective retina foci (HRF) quantification were analyzed. Three-hundred three DME eyes were included. The mean central subfield thickness was 386.5 ± 130.2 µm. IRF was present in all eyes and confirmed by AI software. The agreement (kappa value) (95% confidence interval) for SRF presence and ELM and EZ interruption were 0.831 (0.738–0.924), 0.934 (0.886–0.982), and 0.936 (0.894–0.977), respectively. The accuracy of the automatic quantification of IRF, SRF, ELM, and EZ ranged between 94.7% and 95.7%, while accuracy of quality parameters ranged between 99.0% (OCT layer segmentation) and 100.0% (fovea centering). The Intraclass Correlation Coefficient between clinical and automated HRF count was excellent (0.97). This AI algorithm provides a reliable and reproducible assessment of the most relevant OCT biomarkers in DME. It may allow clinicians to routinely identify and quantify these parameters, offering an objective way of diagnosing and following DME eyes. [ABSTRACT FROM AUTHOR]

Distal symmetric polyneuropathy (DPN), particularly chronic sensorimotor DPN, represents one of the most frequent complications of diabetes, affecting 50% of diabetic patients and causing an enormous financial burden. Whilst diagnostic methods exist to detect and monitor this condition, they have significant limitations, mainly due to their high subjectivity, invasiveness, and non-repeatability. Corneal confocal microscopy (CCM) is an in vivo, non-invasive, and reproducible diagnostic technique for the study of all corneal layers including the sub-basal nerve plexus, which represents part of the peripheral nervous system. We reviewed the current literature on the use of CCM as an instrument in the assessment of diabetic patients, particularly focusing on its role in the study of sub-basal nerve plexus alterations as a marker of DPN. CCM has been demonstrated to be a valid in vivo tool to detect early sub-basal nerve plexus damage in adult and pediatric diabetic patients, correlating with the severity of DPN. Despite its great potential, CCM has still limited application in daily clinical practice, and more efforts still need to be made to allow the dissemination of this technique among doctors taking care of diabetic patients. [ABSTRACT FROM AUTHOR]

Purpose: von Hippel-Lindau (VHL) disease is caused by a mutation of the VHL gene and characterized by the development of retinal hemangioblastomas (RH). Current pathophysiologic mechanisms of RH development and progression are still insufficient to predict RH behavior. VHL gene is involved in the cellular response to hypoxia and in many intracellular signaling pathways expressed both in angiogenesis and inflammation. Optical coherence tomography (OCT) allows to identify hyper-reflective retinal foci (HRF) known as aggregates of activated microglial cells as possible in vivo biomarker of local inflammation. The aim of the present study was to investigate the presence of HRF in patients with genetically confirmed VHL disease. Methods: In this cross-sectional study, patients with VHL underwent complete ophthalmological examination and OCT with HRA + OCT Spectralis. HRF were manually identified and calculated in inner (IR), outer (OR) and full retina. Age-matched healthy subjects were enrolled as controls. Results: 113 eyes of 63 VHL patients and 56 eyes of 28 healthy subjects were evaluated. HRF number was significantly higher in VHL than in controls in IR (28.06 ± 7.50 vs 25.25 ± 6.64, p = 0.042). No difference was observed in OR and in full retina (OR: 7.73 ± 2.59 vs 7.95 ± 2.51, p = 0.599; full retina: 35.79 ± 8.77 vs 33.20 ± 7.47, p = 0.093). Conclusion: The increase of HRF, which mirror retinal microglial activation, characterizes VHL eyes. The role of activated microglia in the retina of VHL eyes needs to be better investigated, mainly considering local VHL disease manifestations. [ABSTRACT FROM AUTHOR]

The purpose of this study was to evaluate retinal changes in adolescents with childhood-onset, long-lasting type 1 diabetes mellitus (T1D). Patients and healthy controls (HC) underwent optical coherence tomography (OCT) and OCT-angiography (OCTA). Individual macular layers, peripapillary retinal nerve fiber layer (pRNFL), and vascular parameters (vessel area density (VAD), vessel length fraction (VLF) and vessel diameter index (VDI)) of macular superficial vascular (SVP), intermediate (ICP), deep (DCP) and radial peripapillary capillary plexuses (RPCP) were quantified. Thirty-nine patients (5 with (DR group) and 34 without (noDR group) diabetic retinopathy) and 20 HC were enrolled. The pRNFL and ganglion cell layer (GCL) were thicker in noDR compared to HC and DR, reaching statistically significant values versus HC for some sectors. At the macular level, VAD and VLF were reduced in DR versus HC in all plexuses, and versus noDR in SVP (p < 0.005 for all). At the RPCP level, VAD and VDI were increased in noDR versus HC, significantly for VDI (p = 0.0067). Glycemic indices correlated to retinal parameters. In conclusion, in T1D adolescents, retinal capillary and neuronal changes are present after long-lasting disease, even in the absence of clinical DR. These changes modify when clinical retinopathy develops. The precocious identification of specific OCT and OCTA changes may be a hallmark of subsequent overt retinopathy. [ABSTRACT FROM AUTHOR]

The aim of the study was to validate the performance of the Optomed Aurora® handheld fundus camera in diabetic retinopathy (DR) screening. Patients who were affected by diabetes mellitus and referred to the local DR screening service underwent fundus photography using a standard table-top fundus camera and the Optomed Aurora® handheld fundus camera. All photos were taken by a single, previously unexperienced operator. Among 423 enrolled eyes, we found a prevalence of 3.55% and 3.31% referable cases with the Aurora® and with the standard table-top fundus camera, respectively. The Aurora® obtained a sensitivity of 96.9% and a specificity of 94.8% in recognizing the presence of any degree of DR, a sensitivity of 100% and a specificity of 99.8% for any degree of diabetic maculopathy (DM) and a sensitivity of 100% and specificity of 99.8% for referable cases. The overall concordance coefficient k (95% CI) was 0.889 (0.828–0.949) and 0.831 (0.658–1.004) with linear weighting for DR and DM, respectively. The presence of hypertensive retinopathy (HR) was recognized by the Aurora® with a sensitivity and specificity of 100%. The Optomed Aurora® handheld fundus camera proved to be effective in recognizing referable cases in a real-life DR screening setting. It showed comparable results to a standard table-top fundus camera in DR, DM and HR detection and grading. The Aurora® can be integrated into telemedicine solutions and artificial intelligence services which, in addition to its portability and ease of use, make it particularly suitable for DR screening. [ABSTRACT FROM AUTHOR]

A large spectrum of neurological manifestations has been associated with coronavirus disease 2019 (COVID-19), and recently, the involvement of small fibers has been suggested. This study aims to investigate the involvement of small peripheral nervous fibers in recovered COVID-19 patients using in-vivo corneal confocal microscopy (CCM). Patients recovered from COVID-19 and a control group of healthy subjects underwent in-vivo CCM. Corneal nerve fiber density (CNFD), corneal nerve branch density (CNBD), corneal nerve fiber length (CNFL), corneal nerve fiber total branch density (CTBD), corneal nerve fiber area (CNFA), corneal nerve fiber width (CNFW), fiber tortuosity (FT), number of beadings (NBe), and dendritic cells (DC) density were quantified. We enrolled 302 eyes of 151 patients. CNBD and FT were significantly higher (p = 0.0131, p < 0.0001), whereas CNFW and NBe were significantly lower (p = 0.0056, p = 0.0045) in the COVID-19 group compared to controls. Only CNBD and FT resulted significantly correlated to antiviral drugs (increased) and corticosteroids (decreased). No significant relationship with disease severity parameters was found. COVID-19 may induce peripheral neuropathy in small fibers even months after recovery, regardless of systemic conditions and therapy, and CCM may be a useful tool to identify and monitor these morphological changes. [ABSTRACT FROM AUTHOR]

Simple Summary: Choroidal abnormalities (CAs) have recently been introduced as one of the criteria for the diagnosis of neurofibromatosis type 1 (NF1). The aim of the present study was to assess the natural history of CAs in a large pediatric population affected by NF1, evaluating, on a long-term follow-up, CAs progression both in number and dimensions. To avoid bias due to the growing process of the eye, the CAs dimensions were normalized for the optic disc size. Our study demonstrated, in 99 eyes of 53 pediatric patients, an increase in the number, area and perimeter of CAs. The present study thus provides evidence that, in NF1 pediatric patients, CAs change with time, increasing both in number and dimensions, independently from the physiological growth of the eye. While the increase of the CAs number occurs particularly at an earlier age, the increase in the CAs dimensions is a slow process that remains constant during childhood. The purpose of this study was to assess the long-term natural history of choroidal abnormalities (CAs) in a large pediatric neurofibromatosis type 1 (NF1) population, quantifying their progression in number and dimensions. Pediatric patients (<16 years old) affected by NF1 with a minimum follow-up of 3 years with at least one CA in one eye were consecutively recruited. Near-infrared (NIR) imaging was performed to identify CAs, which were quantified in number and size. The CAs area and perimeter were normalized for the optic disc dimensions to avoid possible bias related to the growing process of the eye. Ninety-nine eyes of 53 patients were evaluated. The CAs number, area and perimeter significantly increased during follow-up (p < 0.0001 for each parameter). The patient age at baseline was inversely correlated with the CAs number over time (coefficient = −0.1313, p = 0.0068), while no correlation was found between the patient age and CAs progression in size. In conclusion, we provide evidence that, in NF1 pediatric patients, CAs change over time, increasing both in number and dimensions, independently from the physiological growth of the eye. While the increase of the CAs number occurs particularly at an earlier age, the increase in the CAs dimensions is a slow process that remains constant during childhood. [ABSTRACT FROM AUTHOR]

This study aimed to prospectively evaluate, on a long-term basis, corneal side effects secondary to compassionate administration of epidermal growth factor receptor (EGFR) inhibitor depatuxizumab mafodotin (ABT-414) in patients affected by EGFR-amplified recurrent glioblastoma. Fifteen patients with a median follow-up of 4.3 months after treatment discontinuation were enrolled. Each patient underwent full ophthalmologic examination including in vivo corneal confocal microscopy (CCM). No CTCAE grade 4 toxicity and four (27%) grade 3 toxicities were documented during treatment. Ocular symptoms (blurred vision, eye pain, photophobia) were experienced by all patients, reaching maximal severity after the second ABT-414 infusion, with persistence until treatment discontinuation. During treatment, CCM documented specific changes in the corneal epithelium and in the sub-basal nerve plexus layer fibers of all eyes. The median time of symptoms resolution after treatment discontinuation ranged from 38 days (eye pain) to 53 days (photophobia). The median time of signs resolution ranges from 14 days (corneal ulcer) to 38 days (superficial punctate epitheliopathy, corneal stroma edema and intraepithelial cysts). ABT-414 corneal side effects are detectable in all treated patients. Related symptoms are gradually experienced by all patients during treatment and although reversible, they are characterized by a relative prolonged persistence after treatment discontinuation. [ABSTRACT FROM AUTHOR]

This study aims to evaluate if a disease thickness cut-off of 5 mm can be considered the best choice to select gamma emitter sources, as 125I, for the treatment of uveal melanomas. METHODS The records of patients affected by primary uveal melanoma and treated in our institutional IOC (Interventional Oncology Center) from December 2006 to December 2016 were retrospectively reviewed. Only patients with a disease thickness between 4 mm and 6 mm treated with 106Ru or 125I plaque were considered for this analysis. RESULTS Between December 2006 and December 2016, 107 patients (107 eyes) with UM received brachytherapy treatment with tumor thickness between 4 and 6 mm. Nine patients developed local recurrence while seven patients had distant metastases. No statistically significant difference (p=0.36) was observed between the two groups (125I versus 106Ru) concerning DFS. Five patients treated with 125I (19.2%) experienced radiation maculopathy; this finding is noteworthy because this toxicity was experienced by 21 patients treated with 106Ru (25.9%). CONCLUSION In this study, we report that the use of 125I seeds for UM with a thickness between 5 mm and 6 mm is not associated with a statistically significant increased risk of radiation maculopathy. It is desirable that further multicentric investigations may help to confirm the results of our study. [ABSTRACT FROM AUTHOR]

Simple Summary: The in vivo optical coherence tomography analysis of the biomarkers of retinal microglia and macroglia in Von Hippel–Lindau disease represents an innovative field of research. The different behavior of these glial cells in Von Hippel–Lindau patients provides new data regarding the pathophysiology of retinal hemangioblastoma, the most common ocular manifestation of this hereditary disorder. Moreover, these biomarkers show a different behavior in Von Hippel–Lindau patients in relation to the presence or absence of retinal hemangioblastoma. Therefore, we can hypothesize that retinal hemangioblastoma is mainly due to the activation of macroglia by previously activated microglial cells. Background: Von Hippel–Lindau (VHL) disease is a neoplastic syndrome caused by a mutation of the VHL tumor suppressor gene. Retinal hemangioblastoma (RH) is a vascularized tumor and represents the most common ocular manifestation of this disease. At the retinal level, VHL protein is able to regulate tumor growth, angiogenic factors, and neuroinflammation, probably stimulating retinal glial cells. The aim of the present study was to analyze in vivo the optical coherence tomography (OCT) biomarkers of retinal macroglia and microglia in a cohort of VHL patients. Methods: The mean thicknesses of macular retinal nerve fiber layer (mRNFL), ganglion cell layer (GCL), and peripapillary retinal nerve fiber layer (pRNFL) were measured with OCT as biomarkers of retinal macroglia. OCT images were also analyzed to detect and quantify hyperreflective retinal foci (HRF), a biomarker of retinal activated microglia. Results: 61 eyes of 61 VHL patients (22 eyes (36.07%) with peripheral RH and 39 eyes (63.93%) without RH) and 28 eyes of 28 controls were evaluated. pRNFL was thinner in VHL patients (p < 0.05) and in VHL without RH (p < 0.01) compared to controls, and thicker in VHL patients with RH than in those without RH (p < 0.05). The thickness of mRNFL (p < 0.0001) and GCL (p < 0.05) was reduced in VHL patients and in VHL without RH compared to controls, whereas mRNFL (p < 0.0001) and GCL (p < 0.05) were increased in VHL patients with RH compared to those without RH. HRF were significantly higher in number in VHL patients and in VHL without RH, than in controls, and significantly lower (p < 0.05) in the eyes of VHL patients with RH, than in those without RH. Conclusions: The OCT analysis, which detects and allows to quantify the biomarkers of retinal microglia (HRF) and macroglia (pRNFL, mRNFL and GCL), showed a different behavior of these two retinal glial cells populations in VHL patients, related to the presence or absence of peripheral RH. These data allow to hypothesize a novel pathophysiologic pathway of retinal hemangioblastoma in VHL disease. [ABSTRACT FROM AUTHOR]

Purpose. To evaluate the presence of hyper reflective spots (HRS) in diabetic patients without clinically detectable retinopathy (no DR) or with non proliferative mild to moderate retinopathy (DR) without macular edema, and compare the results to controls. Methods. 36 subjects were enrolled: 12 with no DR, 12 with DR, and 12 normal subjects who served as controls. All studied subjects underwent full ophthalmologic examination and spectral domain optical coherence tomography (SD-OCT). SD-OCT images were analyzed to measure and localize HRS. Each image was analyzed by two independent, masked examiners. Results. The number of HRS was significantly higher in both diabetics without and with retinopathy versus controls (P < 0.05) and in diabetics with retinopathy versus diabetics without retinopathy (P < 0.05). The HRS were mainly located in the inner retina layers (inner limiting membrane, ganglion cell layer, and inner nuclear layer). The intra observer and interobserver agreement was almost perfect (k > 0.9). Conclusions. SD-OCT hyperreflective spots are present in diabetic eyes even when clinical retinopathy is undetectable. Their number increases with progressing retinopathy. Initially, HRS are mainly located in the inner retina, where the resident microglia is present. With progressing retinopathy, HRS reach the outer retinal layer. HRS may represent a surrogate of microglial activation in diabetic retina. [ABSTRACT FROM AUTHOR]

This study aimed to prospectively evaluate the association between the appearance and evolution of retinopathy of prematurity (ROP) and selected blood parameters, focusing on platelets count. In total, 157 preterm consecutive babies screened for ROP were included and classified in: ROP necessitating treatment (group ROP1), ROP regressed without therapy (group ROP2) and no ROP (group no-ROP), divided in two phases for each group depending on gestational age. Blood parameters were weekly gathered and referred to postmenstrual age, ROP severity and phase. Platelet count mean values were statistically lower (p < 0.001) during both phases in ROP1 group (179 × 109/L vs. 213 × 109/L in phase 1 and 2, respectively) vs. other groups (ROP2: 286 × 109/L vs. 293 × 109/L; no ROP: 295 × 109/L vs. 313 × 109/L). Platelet count at birth <181 × 109 was statistically associated with Type 1 ROP development and evolution (sensibility = 76.47%, 95% confidence interval 60.0–87.6; specificity = 66.12%, 95% confidence interval 57.3–73.9). In ROP 1 group, a platelets count mean value "spike" (392.6 × 109/L) was documented at 36 weeks of corrected gestational age, preceding the need for treatment performed at a median of 38.1 ± 3.2 weeks. Early birth thrombocytopenia is confirmed as a biomarker of development and progression of ROP requiring treatment. The increase of platelets count at 35–37 weeks of corrected gestational age can be considered a possible clinical biomarker anticipating Type 1 ROP progression in preterm infants. [ABSTRACT FROM AUTHOR]

To analyze the early microvascular retinal changes and oscillatory potentials alterations secondary to diabetic retinal damage, 44 eyes of 22 diabetic patients without and with mild diabetic retinopathy (DR) and 18 eyes of 9 healthy controls were examined. All subjects underwent spectral domain optical coherence tomography (SD-OCT), OCT angiography (OCTA), and electroretinography of oscillatory potentials (OPs). At OCTA, vessel area density (VAD), vessel length fraction (VLF), and fractal dimension (FD) were significantly reduced in the superficial vascular plexus (SVP), VLF and FD in the intermediate capillary plexus (ICP), and FD in the deep capillary plexus (DCP) in the diabetic group compared to the control group. The amplitude (A) of OP2, OP3, OP4 and the sum of OPs were significantly reduced in the diabetic group versus the controls, and the last two parameters were reduced also in patients without DR versus the controls. Moreover, in the diabetic group, a significant direct correlation was found between the A of OP1, OP2, OP3 and sOP and the VLF and FD in the SVP, while a statistically significant inverse correlation was found between the A of OP3 and OP4 and the VDI in the ICP and DCP. The reduced oscillatory potentials suggest a precocious involvement of amacrine cells in diabetic eyes, independently of DR presence, and their correlation with vascular parameters underlines the relevance of the crosstalk between these cells and vascular components in the pathophysiology of this chronic disease. [ABSTRACT FROM AUTHOR]

Subthreshold micropulse laser treatment has become a recognized option in the therapeutic approach to diabetic macular edema. However, some yet undefined elements pertaining to its mechanism of action and most effective treatment method still limit its clinical diffusion. We reviewed the current literature on subthreshold micropulse laser treatment, particularly focusing on its effects on the modulation of retinal neuroinflammation. Subthreshold micropulse laser treatment seems to determine a long-term normalization of specific retinal neuroinflammatory metabolic pathways, contributing to the restoration of retinal homeostasis and the curtailing of local inflammatory processes. Optimized and standardized parameters ensure effective and safe treatment. [ABSTRACT FROM AUTHOR]

The aim of this study was to evaluate the long-term efficacy and safety of 577-nm subthreshold micropulse laser (SMPL) treatment in a large population of patients affected by mild diabetic macular edema (DME) in a real-life setting. We retrospectively evaluated 134 eyes affected by previously untreated center-involving mild DME, and treated with 577-nm SMPL, using fixed parameters. Retreatment was performed at 3 months, in case of persistent retinal thickening. Optical coherence tomography (OCT), along with short and near-infrared fundus autofluorescence, were used to confirm long-term safety. At the end of at least one year follow-up, a significant improvement in visual acuity was documented, compared to baseline (77.3 ± 4.5 and 79.4 ± 4.4 ETDRS score at baseline and at final follow-up, respectively), as well as a reduction in the mean retinal thickness of the thickest ETDRS macular sector at baseline. A reduction in the central retinal thickness and the mean thickness of the nine ETDRS sectors was also found, without reaching statistical significance. No patients required intravitreal injections. No adverse effects were detected. This study suggests that 577-nm SMPL is a safe and repeatable treatment for mild DME that may be applied to real-life clinical settings using fixed parameters and protocols. [ABSTRACT FROM AUTHOR]

Usher syndrome type 2A (USH2A) is a genetic disease characterized by bilateral neuro-sensory hypoacusia and retinitis pigmentosa (RP). While several methods, including electroretinogram (ERG), describe retinal function in USH2A patients, structural alterations can be assessed by optical coherence tomography (OCT). According to a recent collaborative study, RP can be staged considering visual acuity, visual field area and ellipsoid zone (EZ) width. The aim of this study was to retrospectively determine RP stage in a cohort of patients with USH2A gene variants and to correlate the results with age, as well as additional functional and morphological parameters. In 26 patients with established USH2A genotype, RP was staged according to recent international standards. The cumulative staging score was correlated with patients' age, amplitude of full-field and focal flicker ERGs, and the OCT-measured area of sub-Retinal Pigment Epithelium (RPE) illumination (SRI). RP cumulative score (CS) was positively correlated (r = 0.6) with age. CS was also negatively correlated (rho = −0.7) with log10 ERG amplitudes and positively correlated (r = 0.5) with SRI. In USH2A patients, RP severity score is correlated with age and additional morpho-functional parameters not included in the international staging system and can reliably predict their abnormality at different stages of disease. [ABSTRACT FROM AUTHOR]

Background: To evaluate the earliest retinal morphological and functional changes in diabetic eyes without or with early signs of diabetic retinopathy (DR). Methods: Twenty-two eyes with no DR (noDR group), 22 eyes with mild DR (DR group), and 18 healthy nondiabetic eyes (controls) were enrolled. All eyes were studied by means of spectral domain optical coherence tomography (OCT), OCT angiography (OCTA), and multifocal electroretinogram (mfERG). Results: A significantly higher number of OCT hyperreflective intraretinal foci (HRF) was found in both noDR and DR groups versus controls, but not between DR groups. The OCTA parameters of the superficial vascular plexus (SVP) were significantly reduced in the noDR group both versus controls and DR group (p < 0.05). The OCTA parameters of the intermediate capillary plexus (ICP) were significantly reduced in the DR group versus controls. An increased number of altered hexagons on mfERG was found in the noDR versus the DR group (p = 0.0192). Conclusions: Retinal vascular and functional parameters are differently involved in diabetic eyes; major vascular changes in the SVP and functional alterations of the mfERG are present in diabetic eyes with no clinical microvascular signs of DR, while ICP is mainly involved when early ophthalmoscopic signs of DR are present. The integrated use of mfERG and OCTA provides new significant insights into the pathogenesis of diabetic related retinal disease. [ABSTRACT FROM AUTHOR]

Radiation chorioretinopathy, radiation maculopathy, and radiation optic neuropathy are the major complications of ophthalmic radiotherapy. Optical coherence tomography (OCT) and OCT angiography (OCTA) are revolutionary imaging methods, allowing the visualization of the retinal cellular architecture and the retinal vascular system, respectively. In recent years this multimodal imaging approach has been applied to several retinal disease, but its role in the clinical characterization of retinal complications secondary to ophthalmic radiotherapy has not yet been defined. The purpose of this review is to critically evaluate the role of OCT and OCTA in the clinical assessment of radiation-induced chorioretinopathy, maculopathy, and optic neuropathy. [ABSTRACT FROM AUTHOR]

Simple Summary: The treatment of orbital and eyelid B-cell lymphoma remains a field of progress. The aim of our study was to analyze patients diagnosed, staged and treated for orbital and eyelid B-cell lymphoma to assess clinical characteristics, treatment outcomes and recurrence patterns. We included in this study 141 cases of orbital and eyelid B-cell lymphoma. We found five lymphoma subtypes and we confirmed that the histopathologic subtype and the type of treatment were found to be the main factors influencing treatment outcome. Background: The aim of this study was to analyze patients diagnosed, staged and treated for orbital and eyelid B-cell lymphoma (OEL). Methods: One hundred and forty-one cases of OEL were included in this study. Primary endpoints were to analyze the histopathologic findings, the main risk factors and the type of treatment and to correlate them with recurrence of OEL. The secondary endpoint was to determine the progression-free survival (PFS) time. Results: Extranodal marginal zone B-cell lymphoma was the most frequent subtype (66%), followed by small lymphocytic lymphoma (12.7%), diffuse large B-cell lymphoma (DLBCL) (9.2%), follicular lymphoma (6.6%), mantle cell lymphoma (4.3%) and Burkitt lymphoma (1.2%). The probability of relapse was influenced by the histopathologic subtype DLBCL (OR = 7.7, 95% CI 1.8–32.3) and treatment with chemotherapy (OR = 14.9, 95% CI 2.6–83.7). Multivariate analysis showed that the histopathologic subtype DLBCL and chemotherapy treatment retained statistical significance for a poorer PFS, with hazard ratios of 8.581 (p = 0.0112) and 9.239 (p = 0.0094), respectively. Conclusions: Five lymphoma subtypes were found in patients with OEL. The histopathologic subtype and the type of treatment were found to be the main factors influencing treatment outcome. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study was to quantify specific aqueous humor (AH) proteins in eyes affected by posterior uveal melanoma (UM)., Methods: Thirty-six eyes affected by primary UM were included. Tumor thickness and largest basal diameter were specific clinical characteristics. Tumors were staged with the American Joint Commission on Cancer Eighth Edition (AJCC) classification. During the brachytherapy (Iodine-125) surgical procedure, both the AH sample collection and the 25-gauge transscleral fine needle aspiration biopsy (FNAB) were performed. AH samples were analyzed by immunoprecipitation and SDS PAGE techniques to quantify GNAQ, BAP1, SF3B1, and EIF1AX proteins. Cytologic material underwent fluorescence in situ hybridization for chromosome 3. The AH of 36 healthy eyes was used as the control group. Cluster analysis of groups was also performed., Results: Compared with the control group, significantly higher protein levels of: GNAQ (P = 0.02), BAP1 (P = 0.01), and SF3B1 (P = 0.02) were detected in eyes with UM. Cluster analysis of UM group revealed 2 clusters, one showing higher expression of GNAQ and BAP1 protein and one of EIF1AX protein. Moreover, the 2 clusters corresponded with the chromosome 3 status of UM., Conclusions: Specific and selected proteins may be detected in the AH of eyes affected by UM. These findings confirm the possibilities provided by AH analysis in UM.

This study aimed to assess outer retinal layer (ORL), retinal pigment epithelium (RPE), choroid (Ch) and choriocapillaris (CC) modifications in adolescents with long-lasting (>10 years) type 1 diabetes (T1D) without (noDR) or with diabetic retinopathy (DR). ORL and RPE thickness were measured at optical coherence tomography (OCT) macular scans. Vascular parameters of Ch and CC were quantified after elaboration of macular OCT-angiography (OCTA) images. Insulin dose and auxological and metabolic parameters were correlated with OCT and OCTA findings in patients. ORL thickness was higher in DR eyes than in noDR and healthy controls (HC), and RPE thickness was higher in noDR and DR eyes than in HC, with statistical significance for some sectors in noDR versus HC. No OCTA parameters of CC and Ch differed among groups, and no significant correlation was observed with auxological and metabolic parameters. In conclusion, ORL and RPE were both increased in adolescents with long-lasting T1D. Such changes were not associated with insulin dose and glycemia control, nor to any choroid or choriocapillaris flow change clinically detectable at OCTA, and they could be potential imaging biomarkers of disease progression.

Objective: Thyroid eye disease (TED) is an immune-mediated disorder of the eye. Intravenous glucocorticoid (GC) is the first-line treatment for patients with active moderate-to-severe TED. However, the response rate is between 50% and 80%. There are still no simple and reliable markers of responsiveness to GC therapy. We aimed to explore the possible role of miR-146a and miR-21 as predictors of responsiveness to GC treatment in TED., Methods: We carried out a prospective longitudinal study on 30 consecutive adult patients with active moderate-to-severe TED and eligible for GC therapy. All patients received the standard GC treatment with methylprednisolone i.v. In cases of progressive worsening of Gorman Score for diplopia or with duction restriction <30° in at least two consecutive controls, patients also underwent orbital radiotherapy. Response to GC treatment was defined as a decrease of two or more points in the clinical activity score (CAS) or CAS <4/10 at 24 weeks. Circulating miRNAs were extracted from patients' serum and quantified by real-time PCR., Results: Twenty-three (77%) patients responded to GC. Thyroid surgery, higher CAS, greater proptosis and higher pre-treatment circulating levels of miR-146a emerged as predictive factors of responsiveness to GC. A ROC analysis revealed that miR-146a could predict responsiveness to GC with a positive predictive value of 100%., Conclusion: This is the first study investigating the role of pre-treatment circulating miR-21 and miR-146a to predict responsiveness to GC in TED. miR-146a emerged as a simple, objective, new marker of GC sensitivity that could be used to avoid ineffective administration of GC therapy to TED patients.

Purpose: To investigate, by means of spectral domain optical coherence tomography, retinal reflectivity changes as an early biomarker anticipating radiation-induced macular edema (ME) in patients treated by iodine-125 (I-125) brachytherapy., Methods: Thirty patients planned for I-125 brachytherapy because of uveal melanoma were prospectively included and followed every 4 months for five years. Reflectivity alterations, namely hyperreflective retinal foci, were characterized and counted by two independent masked examiners by means of spectral domain optical coherence tomography imaging. Hyperreflective retinal foci were defined as discrete intraretinal reflectivity changes ≤30 µm, with reflectivity similar to nerve fiber layer and without back shadowing., Results: Macular edema occurred in 17 patients (24.2 ±15.1 months) (group 1) after irradiation. Thirteen patients showed no signs of ME at the 5-year follow-up (group 2). The number of hyperreflective retinal foci was statistically higher in sequential visits until the evidence of ME in group 1 vs group 2 (P < 0.0001). In group 1, hyperreflective retinal foci at the follow-up before the evidence of ME were significantly related to the OCT central subfield thickness at ME appearance (P = 0.0002, r2=0.6129). The intergrader agreement was almost perfect (intraclass correlation coefficient = 0.80)., Conclusion: Hyperreflective retinal foci may be considered as an early in vivo imaging biomarker of retinal inflammatory response to ocular irradiation, anticipating the development of radiation maculopathy.

Background: Von Hippel-Lindau (VHL) disease is a neoplastic syndrome caused by a mutation of the VHL tumor suppressor gene. Retinal hemangioblastoma (RH) is a vascularized tumor and represents the most common ocular manifestation of this disease. At the retinal level, VHL protein is able to regulate tumor growth, angiogenic factors, and neuroinflammation, probably stimulating retinal glial cells. The aim of the present study was to analyze in vivo the optical coherence tomography (OCT) biomarkers of retinal macroglia and microglia in a cohort of VHL patients., Methods: The mean thicknesses of macular retinal nerve fiber layer (mRNFL), ganglion cell layer (GCL), and peripapillary retinal nerve fiber layer (pRNFL) were measured with OCT as biomarkers of retinal macroglia. OCT images were also analyzed to detect and quantify hyperreflective retinal foci (HRF), a biomarker of retinal activated microglia., Results: 61 eyes of 61 VHL patients (22 eyes (36.07%) with peripheral RH and 39 eyes (63.93%) without RH) and 28 eyes of 28 controls were evaluated. pRNFL was thinner in VHL patients ( p < 0.05) and in VHL without RH ( p < 0.01) compared to controls, and thicker in VHL patients with RH than in those without RH ( p < 0.05). The thickness of mRNFL ( p < 0.0001) and GCL ( p < 0.05) was reduced in VHL patients and in VHL without RH compared to controls, whereas mRNFL ( p < 0.0001) and GCL ( p < 0.05) were increased in VHL patients with RH compared to those without RH. HRF were significantly higher in number in VHL patients and in VHL without RH, than in controls, and significantly lower ( p < 0.05) in the eyes of VHL patients with RH, than in those without RH., Conclusions: The OCT analysis, which detects and allows to quantify the biomarkers of retinal microglia (HRF) and macroglia (pRNFL, mRNFL and GCL), showed a different behavior of these two retinal glial cells populations in VHL patients, related to the presence or absence of peripheral RH. These data allow to hypothesize a novel pathophysiologic pathway of retinal hemangioblastoma in VHL disease.

Purpose: To analyze and classify neurofibromatosis Type 1 (NF1)-related retinal vascular abnormalities (RVAs), their natural history and correlation with disease severity, in a large cohort of patients., Methods: This was an observational longitudinal study with prospective enrollment. Four hundred and seventy-three patients affected by NF1 and 150 age-matched healthy subjects were consecutively enrolled. Retinal vascular abnormalities were detected by means of near-infrared reflectance and studied by optical coherence tomography angiography. The superficial vascular plexus and the deep vascular complex (DVC) were quantitatively and qualitatively analyzed., Results: We identified RVAs in 82 of 473 (17%) NF1 patients, but in none of the 150 healthy subjects. A comparison revealed that NF1 patients with RVAs showed a higher number of NF1 diagnostic criteria (4.3 ± 1.5 vs. 3.9 ±1.5, respectively; P = 0.02) than patients without RVAs. Three different RVA types were identified on optical coherence tomography angiography: macrovascular angiomatosis of the sole superficial vascular plexus; macrovascular angiomatosis of the superficial vascular plexus combined with microvascular angiomatosis of the deep vascular complex; and combined macrovascular angiomatosis of both superficial vascular plexus and deep vascular complex. The prospective analysis of optical coherence tomography angiography images showed no significant longitudinal evolution of RVAs (mean follow-up: 3.7 ± 2.8 years). A single patient developed a de novo single RVA, and two RVAs showed detectable changes during follow-up., Conclusion: In NF1 patients, RVAs are a characteristic sign that correlates with a more severe systemic disease expression, usually remaining stable during time. Optical coherence tomography angiography allows for the identification of different RVAs subtypes.

Purpose: To report the different uncommon pathogenesis of three cases of severe vertical restrictive strabismus associated with progressive unilateral proptosis with similar clinical features., Methods: Case series of three patients who presented to the Orbit Outpatient Service of Policlinico Gemelli with a history of left progressive unilateral proptosis, slowly worsening vertical strabismus and the left eye fixed in downward position. A thorough hematologic work up was performed. All patients underwent complete abdomen ultrasonography, orbital contrast enhanced magnetic resonance imaging, forced duction test under general anesthesia, and orbital biopsy., Results: Patients were 30, 60, and 46 years old respectively. MRI showed left inferior rectus enlargement in two cases and superior rectus enlargement in one case, with contrast enhanced combined muscle belly and tendon enlargement in all cases. Patients underwent forced duction test, muscle weakening (in two cases), and muscle biopsy with histopathologic examination. The superior rectus appeared infiltrated by an undifferentiated high-grade pleomorphic sarcoma, whereas the two inferior recti were positive for idiopathic orbital inflammatory disease with fibrosis areas and neuromuscular choristoma, respectively., Conclusion: Although proptosis and acquired vertical restrictive strabismus are most commonly associated with thyroid associated orbitopathy (TAO), they can also be a manifestation of many other conditions and the differential diagnosis can be particularly challenging. The three reported cases presented indeed with similar clinical features but had three distinct underlying orbital etiologies, two of which were extremely uncommon.

Purpose: To evaluate hyperreflective retinal spots (HRS), in normal subjects and diabetic patients without and with macular edema (diabetic macular edema, DME), on linear B-scans and corresponding en face image of spectral-domain optical coherence tomography., Methods: Retrospective evaluation of images of 54 eyes/subjects (16 normal subjects, 19 diabetic patients without DME, and 19 with DME). On horizontal B-scan spectral-domain optical coherence tomography, passing through the center of the fovea, the following characteristics of HRS were evaluated: location (inner retina or outer retina), size (≤30 or >30 μm), reflectivity (similar to nerve fiber layer or to retinal pigment epithelium-Bruch complex), and presence or absence of back shadowing. On en face spectral-domain optical coherence tomography, the following patterns were evaluated: 1) isolated HRS (not corresponding to any visible lesion); 2) HRS corresponding to a segment of retinal capillary or microaneurysm wall; and 3) HRS corresponding to hard exudate. All gradings were performed twice by two graders in a masked fashion., Results: Size ≤30 μm, reflectivity similar to nerve fiber layer, and absence of back shadowing were associated with absence of vessels or any other lesion on en face image (P = 0.0001 for all). Size >30 μm, reflectivity similar to retinal pigment epithelium-Bruch complex, presence of back shadowing, and location in the outer retina were all associated with presence of hard exudate on en face imaging (P < 0.0001 for all). Multiple logistic regression analysis showed that HRS present in the inner retina (P < 0.0001), size >30 μm (P = 0.0029), and presence of back shadowing (P < 0.0001) are directly associated with presence of microaneurysms on en face image. Intragrader and intergrader repeatability were excellent for all evaluations., Conclusion: Hyperreflective retinal spots ≤30 μm, reflectivity similar to nerve fiber layer, and absence of back shadowing may represent activated microglial cells; HRS >30 μm, reflectivity similar to retinal pigment epithelium-Bruch complex, presence of back shadowing, and location in the outer retina may represent hard exudate; HRS >30 μm, presence of back shadowing, and location in the inner retina may represent microaneurysms. These hypotheses may be tested in further studies.