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Background and Aims: Ophthalmological abnormalities have been reported in hereditary transthyretin‐related amyloidosis (ATTRv, v for variant) but not in wild‐type transthyretin‐related amyloidosis (ATTRwt). Methods: Patients with ATTRwt, ATTRv, and light chain amyloidosis (AL) and healthy subjects (controls) underwent complete eye examination, including optical coherence tomography (OCT), OCT angiography (OCTA), and in vivo corneal confocal microscopy (CCM). Results: Seventeen ATTRwt, nine ATTRv, two ATTRv carriers, and seven AL patients were enrolled. Compared with other groups, ATTRwt patients had 10 letters lower visual acuity and a higher prevalence of glaucoma, cataract, and retinal pigment epithelium alterations. In the whole group of patients, especially in ATTRwt, we observed (1) a reduced corneal nerve fiber length and more tortuous stromal nerves at CCM, (2) a reduced macular volume and peripapillary nerve fiber layer thickness at OCT, and (3) impairment of peripapillary and macular vascularization at OCTA. Interpretation: Ophthalmological abnormalities are common in ATTRwt, significantly impairing visual acuity. Noninvasive imaging modalities allow for the identification of small nerve fibers and small vessel damage, which may represent further warning signs for early diagnosis of ATTRwt. [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]

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]

Purpose: This article aims to review the impact of detecting and quantifying intraocular biomarkers (liquid biopsy) in both aqueous and vitreous humor in eyes of people affected by diabetes mellitus. Methods: This is a detailed review about aqueous and/or vitreous humor sampling in human diabetic eyes for proteomic and/or metabolomic analysis contributing to the understanding of the pathophysiology and treatment effects of diabetic retinopathy. Results: Aqueous and vitreous humor molecular biomarkers proved to be directly correlated to each other and valuable to study retinal conditions. Moreover, proteomic and metabolomic analysis showed that the biomarkers of neuroinflammation, neurodegeneration, and vasculopathy are detectable in intraocular fluids and that their concentration changes in different stages of disease, and in response to treatment of all diabetic retinopathy aspects, mainly diabetic macular edema and proliferative retinopathy. Conclusions: Liquid biopsy offers the possibility to improve our knowledge of intraocular eye disease induced by diabetes mellitus. The exact quantification of intraocular biomarkers contributes to the precision medicine approach even in the diabetic retinopathy scenario. The diffusion of this approach should be encouraged to have quantifiable information directly from the human model, which may be coupled with imaging data. [ABSTRACT FROM AUTHOR]

Purpose To investigate and quantify peripapillary vascular and neuronal changes secondary to diabetic retinopathy, using spectral-domain optical coherence tomography (OCT) and OCT angiography (OCTA). Design This was a cross-sectional study. Methods 51 eyes of 51 patients affected by nonproliferative diabetic retinopathy (NPDR) and 19 agematched healthy control eyes underwent full ophthalmic examination, including OCT and OCTA in the peripapillary area. Vessel area density (VAD), vessel length fraction (VLF) and vessel diameter index (VDI) were quantified in a ring-shaped region of interest of each OCTA image. Capillaries and larger vessels were separately analysed. The thickness of the peripapillary retinal nerve fibre layer (pRNFL) and macular ganglion cell complex (GCC) was also analysed. Results VAD and VLF of peripapillary capillaries were significantly reduced in NPDR eyes, along with the progression of NPDR (p<0.05). VDI was significantly reduced in mild (p=0.0093) and moderate (p=0.0190) NPDR eyes, but not in severe NPDR (p=0.0841). Larger peripapillary vessels showed a significant increase of both VAD and VDI in NPDR eyes. pRNFL and GCC thickness decreased in NPDR eyes, reaching statistical significance only for GCC. No statistically significant correlation was found between perfusion parameters and pRNFL and GCC thickness. Conclusions Retinal capillary remodelling in NPDR involves the peripapillary vascularisation too, as confirmed by OCTA quantitative parameters. The peripapillary macrovasculature and microvasculature need to be separately evaluated. The lack of direct correlation between peripapillary capillaries changes and the loss of retinal nerve fibres suggests that neuronal damage cannot be simply considered secondary to the microvascular one. [ABSTRACT FROM AUTHOR]

Optical coherence tomography (OCT) allows us to identify, into retinal layers, new morphological entities, which can be considered clinical biomarkers of retinal diseases. According to the literature, solitary, small (<30 µm), medium level hyperreflective (similar to retinal fiber layer) retinal foci (HRF) may represent aggregates of activated microglial cells and an in vivo biomarker of retinal inflammation. The identification and quantification of this imaging biomarker allows for estimating the level and possibly the amount of intraretinal inflammation in major degenerative retinal disorders, whose inflammatory component has already been demonstrated (diabetic retinopathy, age-related macular degeneration, radiation retinopathy). Currently, diabetic retinopathy (DR) probably represents the best clinical model to apply this analysis in the definition of this clinical biomarker. However, the main limitation to the clinical use of HRF is related to the technical difficulty of counting them: a time-consuming methodology, which also needs trained examiners. To contribute to solve this limitation, we developed and validated a new method for the semi-automatic detection of HRF in OCT scans. OCT scans of patients affected by DR, were analyzed. HRF were manually counted in High Resolution spectral domain OCT images. Then, the same OCT scans underwent semi-automatic HRF counting, using an ImageJ software with four different settings profiles. Statistical analysis showed an excellent intraclass correlation coefficient (ICC) between the manual count and each of the four semi-automated methods. The use of the second setting profile allows to obtain at the Bland–Altman graph a bias of −0.2 foci and a limit of agreement of ±16.3 foci. This validation approach opens the way not only to the reliable and daily clinical applicable quantification of HRF, but also to a better knowledge of the inflammatory component—including its progression and regression changes—of diabetic retinopathy. [ABSTRACT FROM AUTHOR]

Purpose: To report multimodal imaging findings in a patient affected by Jeune syndrome-associated retinal dystrophy. Methods: Observational case report. Results: An 18-year-old girl affected by Jeune syndrome was referred to our low vision unit. She presented with bilateral high myopia, reduced visual acuity, exotropia, and nystagmus. Fundus examination detected posterior myopic staphyloma and diffuse retinal dystrophy confirmed using a full-field electroretinogram as a cone-rod dystrophy. Spectral domain optical coherence tomography detected a thick anomalous hyperreflective band located beneath an irregular and disrupted external limiting membrane, showing the primary involvement of the photoreceptors outer segment with relative sparing of the retinal pigment epithelium, as confirmed by fundus autofluorescence. Conclusion: This is a case of Jeune syndrome with retinal abnormalities studied with fundus autofluorescence and optical coherence tomography. Retinal noninvasive multimodal imaging could provide significant insight in the retinal involvement of patients affected by Jeune syndrome and should have an essential role in the multidisciplinary diagnostic approach and follow-up. [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]

Purpose: To analyze the individual value and the contribution of color fundus photography (CFP) and optical coherence tomography (OCT) in the screening of age-related macular degeneration (AMD) of an unselected population. Methods: CFP and OCT images of 15957 eyes of 8069 subjects older than 55 years, obtained during a population-based screening for AMD using a single diagnostic non-mydriatic imaging device, were analyzed by a blinded examiner. The two techniques were preliminary evaluated considering the dichotomous parameter "gradable/ungradable", then gradable images were classified. CFP were graded according to the standardized classification of AMD lesions. OCT images were also categorized considering the presence of signs of early/intermediate AMD, late AMD, or other retinal diseases. Another blinded operator re-graded 1978 randomly selected images (for both CFP and OCT), to assess test reproducibility. Results: Of the 15957 eyes, 8356 CFP (52.4%) and 15594 (97.7%) OCT scans were gradable. Moreover, most of the eyes with ungradable CFP (7339, 96.6%) were gradable at OCT. AMD signs were revealed in 7.4% of gradable CFP and in 10.4% of gradable OCT images. Moreover, at OCT, AMD signs were found in 1110 (6.9%) eyes whose CFP were ungradable or without AMD (847 and 263 eyes, respectively). The inter-operator agreement was good for the gradable versus ungradable parameter, and optimal for the AMD grading parameter of CFP. The agreement was optimal for all OCT parameters. Conclusions: OCT provided gradable images in almost all examined eyes, compared to limited CFP efficiency. Moreover, OCT images allowed to detect more AMD eyes compared to gradable photos. OCT imaging appears to significantly improve the power of AMD screening in a general, unselected population, compared to CFP alone. [ABSTRACT FROM AUTHOR]

Background: The aim of this study was to prospectively analyse, for the first time worldwide by in vivo clinical confocal microscopy (CCM), corneal side effects secondary to the use of epidermal growth factor receptor (EGFR) inhibitor depatuxizumab mafodotin (ABT-414) in a cohort of patients affected by EGFR-amplified recurrent glioblastoma. Methods: Each enrolled patient underwent full ophthalmologic examination including in vivo CCM of the cornea. Each patient was examined at baseline and every 2 weeks during treatment as long as patient conditions allowed it. Results: A total of 10 patients were consecutively enrolled. Median follow-up was 5 months. No Common Terminology Criteria for Adverse Events Version 4.0 grade 4 toxicity was documented. Two (20%) grade 3 toxicities were documented at week 8. CCM examination detected in all eyes multiple and diffuse hyperreflective white round spots in the corneal basal epithelial layers (100%), progressive subbasal nerve plexus layer fibres fragmentation followed by full disappearance (100%) and appearance of round cystic structures in the corneal epithelium (100%). All CCM documented side effects reached the peak of prevalence and severity after a median of 3 infusions. After treatment discontinuation, the reversibility of corneal side effects was documented at CCM after a median of 4 weeks. Conclusion: ABT-414 toxicity is not only directed to the corneal epithelium, but also to corneal nerves. Side effects are detectable in all treated patients and CCM documents early corneal epithelium and subbasal nerve plexus toxicity, with subsequent progressive restoration after treatment discontinuation. Ocular side effects due to ABT-414 can be manageable. [ABSTRACT FROM AUTHOR]

Purpose: To determine if aqueous humour (AH) concentrations of Retinal Pigment Epithelium (RPE)'s biomarkers are modified after subthreshold micropulse laser (SMPL) treatment of diabetic macular edema (DME). Methods: Naïve DME and healthy subjects were enrolled. All DME patients received SMPL treatments (577-nm yellow light, 5%duty cycle of 0.2 s, power 250 mW), according to study protocol. AH of DME eyes was sampled at baseline and periodically after first SMPL treatment. Control eyes were sampled before cataract surgery. Pigment Epithelium Derived Factor (PEDF) and Erythropoietin (EPO) were quantified with glass-chip protein array. Results: Eighteen DME patients (central retinal thickness = 400 µm on Spectral Domain Optical Coherence Tomography (SD-OCT)) and ten controls were enrolled. The main exclusion criteria were high refractive error, proliferative diabetic retinopathy, glaucoma and neurodegenerative disorders. PEDF concentration was decreased in DME patients at baseline versus controls (P=0.012), while EPO was increased (P=0.029). Both molecules' concentrations remained stable during follow-up after treatments, compared with DME-baseline. Conclusions: The AH concentrations of RPE biomarkers were significantly different in DME treatment-naïve eyes versus controls. The expression of PEDF and EPO remained unchanged after treatments with SMPL in DME eyes. These data are relevant for future research and applications of SMPL. [ABSTRACT FROM AUTHOR]

Aims To investigate, with optical coherence tomography angiography (OCTA), short-term changes of type 1 choroidal neovascularisation (CNV), secondary to exudative age-related macular degeneration, after anti-vascular endothelial growth factor (VEGF) treatment. Methods Patients affected by type 1 CNV treated with intravitreal anti-VEGF were consecutively enrolled. All patients underwent OCTA examination before and 48 hours after anti-VEGF treatment. Quantitative and qualitative vascular and morphological macular changes were evaluated. Results Sixteen eyes were included (11 treated with aflibercept and 5 with ranibizumab). Both CNV mean area and pigment epithelium detachment significantly reduced (p=0.0004 and p=0.0007, respectively) after treatment. Cystoid macular oedema (four eyes) decreased in all cases. Neuroretinal detachment (13 eyes) decreased in 85% of cases (11 eyes). Fine CNV vessels density decreased in 75% (12 eyes), whereas larger CNV vessels density remained stable in 66.7% (10 eyes), choroidal flow void signal (7 eyes at baseline) increased in 42.9% (3 eyes) of them and remained stable in 57.1% (4 eyes). Interoperator reproducibility for OCT examination was good for all measurements (intraclass correlation coefficient>0.65). Conclusion Early remodelling of type 1 CNV network after treatment may be non-invasively and reproducibly analysed by means of OCTA. Choroidal perfusion impairment, choroidal flow void signal, surrounding CNV may change during treatment. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate peripapillary retinal nerve fibre layer (RNFL) thickness, measured by spectral‐domain optical coherence tomography (SD‐OCT), as a surrogate of visual function in a population of paediatric patients affected by optic pathway glioma (OPG) associated with neurofibromatosis type 1 (NF1). Methods: A total of 38 paediatric patients (66 eyes) affected by MRI‐proven OPG were included. Each patient underwent complete ophthalmological examination, including age‐appropriate visual acuity (VA) assessment and RNFL analysis by SD‐OCT. Visual acuity was classified as normal or pathologic using age‐based normative data. Visual acuity was correlated to mean RNFL thickness of the whole peripapillary area and of each single analyzed sector (nasal, superior, temporal, inferior). Results: Visual acuity was normal in 43 (65%) and pathologic in 23 (35%) eyes. Mean parapapillary RNFL thickness of each analyzed sector was significantly lower in eyes with abnormal VA (p < 0.05). The best balanced cut‐off value of global RNFL thickness allowing to discriminate between eyes with normal and pathologic VA was 76.25 μm (91%, 76%, 67% and 94% of sensitivity, specificity, positive and negative predicting value, respectively). Considering best balanced cut‐off values of other analyzed RNFL sectors, the superior (p = 0.0029) and the inferior (p = 0.0024) sectors reached the higher sensitivity (87% and 87%, respectively) and specificity (81% and 79%, respectively). Conclusion: Retinal nerve fibre layer thickness is directly related to VA in children affected by NF1‐related OPG, and should be considered as a potential surrogate marker of VA. Retinal nerve fibre layer thickness cut‐off values can be used in paediatric patients to discriminate false‐positive results obtained by VA measurement. [ABSTRACT FROM AUTHOR]

Aims To investigate peripapillary vascular changes secondary to radiation optic neuropathy (RON) using optical coherence tomography angiography (OCT-A) and to propose a clinical grading of RON based on OCT-A findings. Methods Thirty-four patients affected by RON were consecutively included. Each patient underwent best corrected visual acuity measurement (ETDRS score) and OCT-A (Nidek RS-3000 Advance device, Nidek, Gamagori, Japan). The radial peripapillary capillary plexus (RPCP) and the entire peripapillary capillary bed (EPCB) were analysed. Quantitative analysis of the OCT-A images was performed using open-source available ImageJ software (National Institutes of Health, Bethesda, Maryland, USA). Qualitative analysis based on the proposed clinical grading (Grades 0-4) was also performed by two masked graders. results RON clinical (qualitative) classifcation based on RPCP correlated with the quantitative RPCP perfusion analysis (P=0.0001). RON clinical classifcation based on RPCP statistically correlated with ETDRS score (P=0.001). RON clinical classifcation based on EPCB also correlated with the quantitative EPCB perfusion analysis and ETDRS score (P=0.02 and P=0.01, respectively). Compared with the clinical classifcation based on EPCB, the qualitative classifcation based on RPCP reached a higher intergrader agreement (0.96 and 0.86, respectively). Conclusion OCT-A can be used to detect RPCP abnormalities and to clinically classify RON with a high interexaminer agreement. The proposed clinical classifcation is supported by the quantitative analysis based on the use of specifc images elaboration techniques and correlates with visual acuity of the examined eyes. [ABSTRACT FROM AUTHOR]

Purpose: To compare the foveal avascular zone (FAZ) area measurements produced by different optical coherence tomography angiography (OCTA). Methods: Healthy enrolled volunteers underwent OCTA using 2 different devices: Spectralis HRA+OCTA (Heidelberg Engineering, Heidelberg, Germany) and RS-3000 Advance (Nidek, Gamagori, Japan). Two graders measured FAZ in both superficial (SCP) and deep (DCP) retinal capillary plexuses. The SCP and DCP en face images were visualized automatically segmenting 2 separate slabs defined by the arbitrary segmentation lines created by the software of each OCT device. One grader repeated each measure twice. Results: Fifty-nine eyes were included. The mean FAZ was 0.33 ± 0.09 mm2 at the SCP and 0.57 ± 0.17 mm2 at the DCP measured with RS-3000 versus 0.30 ± 0.08 and 0.35 ± 0.08 mm2, respectively, measured with Spectralis. The measurements of the 2 devices were significantly different (p < 0.0001). The intraoperator agreement was excellent at the SCP (intraclass correlation coefficient, ICC: 0.97 with Spectralis and 0.96 with RS-3000). At the DCP, it was good with Spectralis and fair with RS-3000 (ICC: 0.85 and 0.64, respectively). The interoperator agreement was excellent for Spectralis and good for RS-3000 at the SCP (ICC: 0.97 and 0.93, respectively). It was good at the DCP with both devices (ICC: 0.74 with RS-3000 and 0.81 with Spectralis). Conclusions: FAZ measurements obtained with different OCTA devices differ. These findings should be considered in follow-up studies of patients with retinal vascular diseases. [ABSTRACT FROM AUTHOR]

Aims To report long-term clinical outcome of topical 1% 5-fluoruracil (5-FU) as a sole treatment of ocular surface squamous neoplasia (OSSN). Methods 41 patients affected by OSSN were included. Each patient underwent full ophthalmological examination at baseline, with cytological or histological confirmation. Patients were treated by topical chemotherapy with 1% 5-FU four times a day for 4 weeks. One course was defined as 4 weeks of topical chemotherapy. Adjunctive courses were administered after 1 month of chemotherapy-free interval. Results Mean follow-up was 105±32 months (range 60-171 months). Complete tumour regression was achieved in 34 cases (83%) after a mean of 1.5 courses (range, 1-3 courses). Univariate analysis revealed that complete response was significantly related to tumour thickness <1.5 mm (p=0.005), lack of fornix or tarsal involvement (p=0.015 and p=0.009, respectively) and the absence of multifocality (p=0.002). Histopathological diagnosis (intraepithelial neoplasia vs squamous cell carcinoma, p=0.019) and American Joint Committee on Cancer (AJCC) classification (T1 vs T2 or T3) ( p=0.028) were also related to incomplete tumour response. In a multivariate analysis, just tumour thickness >1.5 mm (p=0.045) and multifocality (p=0.023) were correlated with incomplete tumour response. Transient and reversible low-to-mild local side effects were documented in 19 (48%) eyes. Conclusion Topical 5-FU, as a sole therapy, is a longterm safe and effective treatment for patients affected by preinvasive OSSN and for a limited proportion (50%) of invasive OSSN. [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]

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]

Type 1 neurofibromatosis (NF1) is a dominantly inherited condition predisposing to tumor development. Optic pathway glioma (OPG) is the most frequent central nervous system tumor in children with NF1, affecting approximately 15–20% of patients. The lack of well-established prognostic markers and the wide clinical variability with respect to tumor progression and visual outcome make the clinical management of these tumors challenging, with significant differences among distinct centers. We reviewed published articles on OPG diagnostic protocol, follow-up and treatment in NF1. Cohorts of NF1 children with OPG reported in the literature and patients prospectively collected in our center were analyzed with regard to clinical data, tumor anatomical site, diagnostic workflow, treatment and outcome. In addition, we discussed the recent findings on the pathophysiology of OPG development in NF1. This review provides a comprehensive overview about the clinical management of NF1-associated OPG, focusing on the most recent advances from preclinical studies with genetically engineered models and the ongoing clinical trials. [ABSTRACT FROM AUTHOR]

Intraocular tumor diagnosis is based on clinical findings supported by additional imaging tools, such as ultrasound, optical coherence tomography and angiographic techniques, usually without the need for invasive procedures or tissue sampling. Despite improvements in the local treatment of uveal melanoma (UM), the prevention and treatment of the metastatic disease remain unsolved, and nearly 50% of patients develop liver metastasis. The current model suggests that tumor cells have already spread by the time of diagnosis, remaining dormant until there are favorable conditions. Tumor sampling procedures at the time of primary tumor diagnosis/treatment are therefore now commonly performed, usually not to confirm the diagnosis of UM, but to obtain a tissue sample for prognostication, to assess patient's specific metastatic risk. Moreover, several studies are ongoing to identify genes specific to UM tumorigenesis, leading to several potential targeted therapeutic strategies. Genetic information can also influence the surveillance timing and metastatic screening type of patients affected by UM. In spite of the widespread use of biopsies in general surgical practice, in ophthalmic oncology the indications and contraindications for tumor biopsy continue to be under debate. The purpose of this review paper is to critically evaluate the role of uveal melanoma biopsy in ophthalmic oncology. [ABSTRACT FROM AUTHOR]

Subthreshold micropulse laser (SMPL) is a tissue-sparing technique whose efficacy is demonstrated for diabetic macular edema (DME) treatment. However, its mechanism of action is poorly known. A prospective observational study was performed on naïve DME patients treated with SMPL, to evaluate the changes of aqueous humor (AH) inflammatory and vaso-active biomarkers after treatments. AH samples of eighteen DME eyes were collected before and after SMPL. Ten non-diabetic AH samples served as controls. Full ophthalmic evaluation, spectral domain optical coherence tomography (SD-OCT) and fluorescein angiography were performed in DME group. Glass chip protein array was used to quantify 58 inflammatory molecules. Central retinal thickness (CRT) and visual acuity were also monitored. Several molecules showed different concentrations in DME eyes versus controls (p value < 0.05). Fas Ligand (FasL), Macrophage Inflammatory Proteins (MIP)-1α, Regulated on Activation Normal T Cell Expressed and Secreted (RANTES) and Vascular Endothelial Growth Factor (VEGF) were increased in DME at baseline versus controls and decreased after SMPL treatments (p < 0.05). CRT reduction and visual acuity improvement were also found. Inflammatory cytokines, mainly produced by the retinal microglia, were significantly reduced after treatments, suggesting that SMPL may act by de-activating microglial cells, and reducing local inflammatory diabetes-related response. [ABSTRACT FROM AUTHOR]

• Transthyrethin amyloidosis (ATTRv) may present with exclusive autonomic symptoms. • Myocardial uptake at bone scintigraphy is crucial for suspecting ATTRv. • Nuclear medicine physicians should be aware of this diagnostic tool. • Multidisciplinary interaction is crucial for diagnostic and care of ATTRv. [ABSTRACT FROM AUTHOR]