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Introduction: Microglia (MG) is suggested to play an immunopathological role of in Multiple Sclerosis (MS). Since hyper-reflective foci (HRF) might mark MG activation, in vivo analysis by Optic Coherence Tomography (OCT) in MS patients under disease modifying therapies may help to clarify MS immunopathology as well as drug's mechanism of intrathecal action. Objective: To analyze HRF in patients treated with Natalizumab (NTZ), a high efficacy therapy for MS. Materials and methods: The effect of NTZ on the retina of 36 Relapsing-Remitting MS patients was investigated in a prospective, single-center study. OCT was performed immediately before the first infusion and then between infusion 3 and 4, infusion 6 and 7, infusion 11 and 13. Peripapillary and macular scans were acquired, evaluating peripapillary RNFL thickness, macular volumes (vertical scans), and HRF count (horizontal scan) in Ganglion Cell Layer (GCL), Inner Plexiform Layer (IPL) and Inner Nuclear Layer (INL). Clinical examination was performed every six months. Results: HRF count significantly increased under NTZ therapy (p<0.001) in both GCL (18.85 ± 6.93 at baseline, 28.24 ± 9.55 after 12 months) and IPL (25.73 ± 7.03 at baseline, 33.21 ± 8.50 after 12 months) but remained stable in INL (33.65 ± 7.76 at baseline, 36.06 ± 6.86 after 12 months, p=0.87), while no relevant modification of pRNFL and macular volumes were observed during the study. EDSS remained stable and no clinical relapse was observed between month 6 and 12. Conclusion: In RRMS NTZ affects HRF count in GCL and IPL, but not in INL, suggesting that NTZ does not impact on some aspects of MS immunopathology. [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]

Purpose: This study reviews evidence and provides recommendations for the ideal setting of intravitreal injection (IVI) administration of vascular endothelial growth factor (VEGF) inhibitors. Methods: A multi-step approach was employed, including content analysis of regulations and guidelines, a systematic literature review, and an international survey assessing perioperative complications and endophthalmitis incidence in relation to injection settings. The literature review searched PubMed and Cochrane databases from 2006 to 2022, focusing on studies reporting correlations between complications and treatment settings. The survey utilized a web-based questionnaire distributed to clinical sites and the international ophthalmic community, with data managed using electronic capture tools. Results: We reviewed regulations and guidelines from 23 countries across five continents, finding significant variation in IVI administration settings. In most countries, IVI is primarily administered in outpatient clean rooms (96%) or offices (39%), while in others, it is restricted to ambulatory surgery rooms or hospital-based operating theatres (4%). The literature review found that endophthalmitis risk after IVI is generally low (0.01% to 0.26% per procedure), with no significant difference between office-based and operating room settings. The international survey (20 centers, 96,624 anti-VEGF injections) found low overall incidences of severe perioperative systemic adverse events and endophthalmitis, independent of injection settings. Conclusion: No significant differences in perioperative complications were observed among various settings, including operating theatres, ambulatory surgery rooms, offices, hospitals, or extra-hospital environments. Choosing the appropriate clinical setting can optimize patient management, potentially increasing effectiveness, quality, productivity, and capacity. [ABSTRACT FROM AUTHOR]

Purpose: To analyse morpho‐functional foveal changes in eyes with lamellar macular hole (LMH) by an integrated assessment of short‐wavelength fundus autofluorescence (SW‐FAF) and microperimetry (SW‐FAF/microperimetry integrated assessment) before and after treatment with a technique of double‐inverted flaps of epiretinal proliferation (EP) and internal limiting membrane (ILM). Methods: Clinical and tomographic parameters were best‐corrected visual acuity (BCVA), LMH size, central retinal thickness (CRT) and outer retinal layer integrity. SW‐FAF/microperimetry integrated assessment allowed to analyse retinal sensitivity (RS) and FAF status of the fovea by an overlay of RS map on SW‐FAF image. Follow‐up was at baseline, 1, 3, 6 and 12 postoperative months. Results: Forty pseudophakic eyes. Hyper‐FAF area was associated with larger LMH size (p = 0.0073) and inversely correlated with CRT (p = 0.021). Lower preoperative RS was observed in hyper‐FAF than normo‐FAF areas (p = 0.0117). External limiting membrane (ELM) defect was associated with worse BCVA (p = 0.0004). After surgery, BCVA improved (p = 0.001) and it was related to ELM recovery (p = 0.00483), hyper‐FAF area decreased (p = 0.001), and RS increased (p = 0.440). Hyper‐FAF points that normalized their FAF were associated with higher RS improvement compared to unchanged points. Conclusion: Short‐wavelength fundus autofluorescence/microperimetry integrated assessment provides important information on the entity of damage of LMH and on postoperative recovery. Double‐inverted EP and ILM flap technique is safe and effective for LMH treatment. [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]

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]

Introduction: The aim of this study was to evaluate the current management of RPE65 biallelic mutation-associated inherited retinal degeneration (RPE65-IRD) in Europe since market authorization of voretigene neparvovec (VN, LuxturnaTM) in 2018. By July 2022, over 200 patients have been treated outside the USA, of whom about 90% in Europe. We conducted among all centers of the European Vision Institute Clinical Research Network (EVICR.net) and health care providers (HCPs) of the European Reference Network dedicated to Rare Eye Diseases (ERN-EYE) the second multinational survey on management of IRDs in Europe elaborated by EVICR.net with a special focus on RPE65-IRD. Methods: An electronic survey questionnaire with 48 questions specifically addressing RPE65-IRD (2019 survey 35) was developed and sent by June 2021 to 95 EVICR.net centers and 40 ERN-EYE HCPs and affiliated members. Of note, 11 centers are members of both networks. Statistical analysis was performed with Excel and R. Results: The overall response rate was 44% (55/124); 26 centers follow RPE65 biallelic mutation-associated IRD patients. By June 2021, 8/26 centers have treated 57 RPE65-IRD cases (1–19/center, median 6) and 43 planned for treatment (range 0–10/center, median 6). The overall age range was 3–52 years, and on average 22% of the patients did not (yet) qualify for treatment (range 2–60%/center, median 15%). Main reasons were too advanced (range 0–100, median 75%) or mild disease (range 0–100, median 0). Eighty-three percent of centers (10/12) that follow RPE65 mutation-associated IRD patients treated with VN participate in the PERCEIVE registry (EUPAS31153, http://www.encepp.eu/encepp/viewResource.htm?id=37005). Quality of life and full-field stimulus test improvements had the highest scores of the survey-reported outcome parameters in VN treatment follow-up. Conclusion: This second multinational survey on management of RPE65-IRD by EVICR.net centers and ERN-EYE HCPs in Europe indicates that RPE65-IRD might be diagnosed more reliably in 2021 compared to 2019. By June 2021, 8/26 centers reported detailed results including VN treatment. Main reasons for non-treatment were too advanced or mild disease, followed by absence of 2 class 4 or 5 mutations on both alleles or because of a too young age. Patient satisfaction with treatment was estimated to be high by 50% of the centers. [ABSTRACT FROM AUTHOR]

Histopathologic studies of diabetic choroid suggest that diabetic choroidopathy is a key aspect secondary to diabetes. Recently, hyperreflective choroidal foci (HCF) have been introduced as novel optical coherence tomography (OCT) parameter. The aim of this study was to identify and quantify HCF in diabetic subjects with retinopathy, with or without diabetic macular edema (DME). Eighty-five diabetic subjects with different degrees of DR were enrolled: 37 without DME and 48 with DME. All subjects underwent full ophthalmologic examination including spectral domain optical coherence tomography (OCT). OCT images were analyzed to quantify and localize HCF. Each image was analyzed by two independent, masked examiners. OCT images showed that all subjects (100%) had HCF in the different layers of the choroid. The number of HCF was significantly higher in diabetics with DME versus those without DME (p < 0.0001). HCF showed variable size, shape and location inside the choroid. They were mainly located in choriocapillaris and Sattler's layer, on the edges of blood vessels. The intraobserver and interobserver agreement was almost perfect (ICC >0.9). This study suggests that hyperreflective foci in the choroid of subjects with DR may be accurately identified with structural OCT. Their number significantly increases with the progression of DME. These HCF may represent, as in the retina, a sign of infiltration of inflammatory cells (mainly migrating microglia) into the choroid, according to the hypothesis raised by Jerry Lutty. HCF may confirm in vivo the histopathologic findings suggesting that diabetic choroidopathy may be primarily a neuroinflammatory disorder., Competing Interests: Declaration of competing interest The authors declare no relevant conflicts of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Diabetic macular edema (DME) and neovascular age-related macular degeneration (nAMD) are multifactorial disorders that affect the macula and cause significant vision loss. Although inflammation and neoangiogenesis are hallmarks of DME and nAMD, respectively, they share some biochemical mediators. While inflammation is a trigger for the processes that lead to the development of DME, in nAMD inflammation seems to be the consequence of retinal pigment epithelium and Bruch membrane alterations. These pathophysiologic differences may be the key issue that justifies the difference in treatment strategies. Vascular endothelial growth factor inhibitors have changed the treatment of both diseases, however, many patients with DME fail to achieve the established therapeutic goals. From a clinical perspective, targeting inflammatory pathways with intravitreal corticosteroids has been proven to be effective in patients with DME. On the contrary, the clinical relevance of addressing inflammation in patients with nAMD has not been proven yet. We explore the role and implication of inflammation in the development of nAMD and DME and its therapeutical relevance., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: S. Vujosevic is a consultant for Abbvie, Boehringer and Ingelheim, Bayer, Novartis, Roche, Zeiss. C. Astarita and V. Gallinari are AbbVie employee and may own AbbVie stocks/options., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

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.

Introduction: An increasing number of gene-specific therapies are being developed for inherited retinal degenerations (IRDs). Identification of well-characterized patients is an emerging need. We conducted the second multinational survey among the www.evicr.net and ERN-EYE members to understand the management and treatment of IRDs in Europe and compared it to the 2019 survey., Methods: An electronic survey questionnaire was developed and sent to 124 clinical centers (25 countries) by June/July 2021. Statistical analysis was performed with Excel and R., Results: The overall response rate was 44% but varied among countries. Only 9% of responding centers do not see IRD patients (2019 survey 14%), 42% follow at least 200 patients per year, 18% follow 500-999, and 2% more than 1,000. Databases exist in 86% of the centers (local 86%; national web based 12%). IRD patients are referred to www.evicr.net and ERN-EYE centers mainly by general ophthalmologists, patient self-referral, or medical retina specialists. Most IRD patients are first seen as adults. Signs and symptoms depend on age of onset: in infancy, nystagmus; at older age, night blindness and reduced visual field; reduced visual acuity is described at any age. Comprehensive ophthalmic examination always includes visual acuity and almost always visual field multimodal retinal imaging, electrophysiology, color vision testing, and refraction. Identification of genotypes is successful in 72% of centers in 40-80% of cases (2019 survey 69% of centers). The time for confirmation of the genetic diagnosis varies from 2-4 weeks to 24 months (2019 survey &gt;4 weeks ≤10 years). Genetic testing is covered by public health service in 83%, private health insurance in 29%, research funds in 24%; 5% do not have access to genetic testing (2019 survey 15%). The most striking result is the high increase in the involvement of centers in natural history and gene therapy trials that more than doubled for the latter., Discussion: This second multinational survey on management of IRDs in Europe highlights persistent important differences in the number of IRD patients managed per center, comparable diagnostic work-up, and increasing genotyping in diagnostic laboratories. The important increase in involvement of centers in natural history and gene therapy trials reflects the rapidly evolving field of gene therapy development. The survey provides important follow-up data for researchers, clinicians, caregivers, patient advocate groups, pharmaceutical companies, and investors., (© 2023 The Author(s). Published by S. Karger AG, Basel.)