Retinopathy of prematurity (ROP) is the most important cause of vision loss premature infants. With a continuous growth in this vulnerable population, the number of newborns at risk for severe,... Show moreRetinopathy of prematurity (ROP) is the most important cause of vision loss premature infants. With a continuous growth in this vulnerable population, the number of newborns at risk for severe, sight threatening ROP increases. In this thesis the results of the national Dutch inventory on risk factors, screening, treatment and sequelae of ROP are presented. The principal aims of the study were to determine characteristics of newborns who are at highest risk to develop severe ROP to assess quality of screening and treatment and to evaluate the national ROP guideline. Following these studies together with extensive cost-effectiveness analyses, the current Dutch ROP screening and treatment guideline was adapted and implemented in November 2023. The NEDROP 2 allowed for more stringent screening inclusion criteria, lowering the number of infants that need to undergo burdensome screening under the precondition that no severe ROP would be missed. Annually, this will lower the screening costs by nearly 60,000 euros. Show less
Mutations in the CRB1 gene can cause retinal dystrophies such as Retinitis Pigmentosa or Leber Congenital Amaurosis . These patients experience progressive vision loss which ultimately leads to... Show moreMutations in the CRB1 gene can cause retinal dystrophies such as Retinitis Pigmentosa or Leber Congenital Amaurosis . These patients experience progressive vision loss which ultimately leads to blindness. Currently, there are no treatment options available for these patients.This thesis provides novel information on AAV.hCRB gene augmentation therapy in CRB1 mutant animal and human-derived models. We show the phenotype of (1) a novel mouse model with CRB2 ablation specifically in rod photoreceptor cells with loss of retinal function (Chapter 2), (2) a Crb1 mutant brown Norway rat with severe and early onset progressive vision loss (Chapter 3), (3) CRB1 patient-derived retinal organoids (Chapter 4), and (4) CRB1KO and CRB1KOCRB2+/- LCA-like retinal organoids (Chapter 5). Next, AAV-mediated gene augmentation was explored in Crb1 mutant rats (Chapter 3) and CRB1 patient-derived and CRB1KO LCA retinal organoids (Chapter 4 and 5). Finally, single-cell RNA sequencing was performed on AAV.hCRB treated CRB1 patient-derived retinal organoids (Chapter 4). To our knowledge this is the first time that an improved phenotype after AAV.hCRB gene augmentation in CRB1 RP patient-derived and CRB1KO LCA retinal organoids is observed, providing essential information for future gene therapy possibilities in patients with a mutation in the CRB1 gene. Show less
Guimaraes, T.A.C. de; Georgiou, M.; Robson, A.G.; Fujinami, K.; Vincent, A.; Nasser, F.; ... ; Michaelides, M. 2023
Background/aims To investigate genotype-phenotype associations in patients with KCNV2 retinopathy.Methods Review of clinical notes, best-corrected visual acuity (BCVA), molecular variants,... Show moreBackground/aims To investigate genotype-phenotype associations in patients with KCNV2 retinopathy.Methods Review of clinical notes, best-corrected visual acuity (BCVA), molecular variants, electroretinography (ERG) and retinal imaging. Subjects were grouped according to the combination of KCNV2 variants-two loss-of-function (TLOF), two missense (TM) or one of each (MLOF)-and parameters were compared.Results Ninety-two patients were included. The mean age of onset (mean +/- SD) in TLOF (n=55), TM (n=23) and MLOF (n=14) groups was 3.51 +/- 0.58, 4.07 +/- 2.76 and 5.54 +/- 3.38 years, respectively. The mean LogMAR BCVA ( +/- SD) at baseline in TLOF, TM and MLOF groups was 0.89 +/- 0.25, 0.67 +/- 0.38 and 0.81 +/- 0.35 for right, and 0.88 +/- 0.26, 0.69 +/- 0.33 and 0.78 +/- 0.33 for left eyes, respectively. The difference in BCVA between groups at baseline was significant in right (p=0.03) and left eyes (p=0.035). Mean outer nuclear layer thickness ( +/- SD) at baseline in TLOF, MLOF and TM groups was 37.07 +/- 15.20 mu m, 40.67 +/- 12.53 and 40.38 +/- 18.67, respectively, which was not significantly different (p=0.85). The mean ellipsoid zone width (EZW) loss ( +/- SD) was 2051 mu m ( +/- 1318) for patients in the TLOF, and 1314 mu m ( +/- 965) for MLOF. Only one patient in the TM group had EZW loss at presentation. There was considerable overlap in ERG findings, although the largest DA 10 ERG b-waves were associated with TLOF and the smallest with TM variants.Conclusions Patients with missense alterations had better BCVA and greater structural integrity. This is important for patient prognostication and counselling, as well as stratification for future gene therapy trials. Show less
PurposeThis study is to assess the possible correlation between findings on fundus autofluorescence (FAF) and fluorescein angiography (FA) in patients with chronic central serous chorioretinopathy ... Show morePurposeThis study is to assess the possible correlation between findings on fundus autofluorescence (FAF) and fluorescein angiography (FA) in patients with chronic central serous chorioretinopathy (cCSC).MethodsThis multicentre retrospective cohort study included 71 cCSC patients (92 eyes) with at least 6 months of follow-up, who had a FAF-FA imaging discrepancy larger than 0.5 optic disc diameters in size in the corresponding areas of hyperfluorescent abnormalities. A comparison was performed between progression in size of areas of hyperautofluorescent retinal pigment epithelium (RPE) abnormalities on FAF (HF-FAF) and the hyperfluorescent areas on FA (HF-FA) at first visit and last visit. The possible correlations were estimated between FAF-FA discrepancy and disease characteristics.ResultsThe median area of HF-FAF at first visit was 7.48 mm(2) (1.41-27.9). The median area of HF-FA at first visit and last visit was 2.40 mm(2) (0.02-17.27) and 5.22 mm(2) (0.53-25.62), respectively. FAF-FA discrepancy was associated with follow-up duration and the area of HF-FAF at first visit. A mathematical algorithm for grading FAF-FA discrepancy in time was suggested, which predicted the enlargement of hyperfluorescent RPE abnormalities on FA in 82.6% of cases.ConclusionThere is a statistically significant relationship between the areas of HF-FAF and HF-FA in cCSC patients with FAF-FA imaging discrepancy at first presentation. Long-term changes in RPE alterations in cCSC on FA can be predicted based on baseline HF-FAF and follow-up duration. Show less
Ocular manifestations are observed in approximately one third of all inherited metabolic disorders (IMDs). Although ocular involvement is not life-threatening, it can result in severe vision loss,... Show moreOcular manifestations are observed in approximately one third of all inherited metabolic disorders (IMDs). Although ocular involvement is not life-threatening, it can result in severe vision loss, thereby leading to an additional burden for the patient. Retinal degeneration with or without optic atrophy is the most frequent phenotype, followed by oculomotor problems, involvement of the cornea and lens, and refractive errors. These phenotypes can provide valuable clues that contribute to its diagnosis. In this issue we found 577 relevant IMDs leading to ophthalmologic manifestations. This article is the seventh of a series attempting to create and maintain a comprehensive list of clinical and metabolic differential diagnoses according to system involvement. (C) 2022 The Authors. Published by Elsevier Inc. Show less
Agrawal, R.; Testi, I.; Lee, C.S.; Tsui, E.; Blazes, M.; Thorne, J.E.; ... ; COVID-19 Imt Study Grp 2021
Background Immunomodulatory therapy (IMT) is often considered for systemic treatment of non-infectious uveitis (NIU). During the evolving coronavirus disease-2019 (COVID-19) pandemic, given the... Show moreBackground Immunomodulatory therapy (IMT) is often considered for systemic treatment of non-infectious uveitis (NIU). During the evolving coronavirus disease-2019 (COVID-19) pandemic, given the concerns related to IMT and the increased risk of infections, an urgent need for guidance on the management of IMT in patients with uveitis has emerged. Methods A cross-sectional survey of international uveitis experts was conducted. An expert steering committee identified clinical questions on the use of IMT in patients with NIU during the COVID-19 pandemic. Using an interactive online questionnaire, guided by background experience and knowledge, 139 global uveitis experts generated consensus statements for IMT. In total, 216 statements were developed around when to initiate, continue, decrease and stop systemic and local corticosteroids, conventional immunosuppressive agents and biologics in patients with NIU. Thirty-one additional questions were added, related to general recommendations, including the use of non-steroidal anti-inflammatory drugs (NSAIDs) and hydroxychloroquine. Results Highest consensus was achieved for not initiating IMT in patients who have suspected or confirmed COVID-19, and for using local over systemic corticosteroid therapy in patients who are at high-risk and very high-risk for severe or fatal COVID-19. While there was a consensus in starting or initiating NSAIDs for the treatment of scleritis in healthy patients, there was no consensus in starting hydroxychloroquine in any risk groups. Conclusion Consensus guidelines were proposed based on global expert opinion and practical experience to bridge the gap between clinical needs and the absence of medical evidence, to guide the treatment of patients with NIU during the COVID-19 pandemic. Show less
By investigating the roles of CRB proteins in mouse, non-human-primate, human fetal retina, and iPSC-derived retinal organoids, this thesis describes important insights to pathobiology in CRB1... Show moreBy investigating the roles of CRB proteins in mouse, non-human-primate, human fetal retina, and iPSC-derived retinal organoids, this thesis describes important insights to pathobiology in CRB1-retinitis pigmentosa (RP) and CRB1-Leber congenital amaurosis (LCA) disease models. The thesis describes AAV gene and cell therapy-based tools as therapeutic strategies for alleviation of RP and LCA due to loss of CRB1. Show less
Inherited retinal diseases encompass a large group of clinically and genetically heterogeneous diseases estimated to affect two million people worldwide. Among these people, approximately 80,000... Show moreInherited retinal diseases encompass a large group of clinically and genetically heterogeneous diseases estimated to affect two million people worldwide. Among these people, approximately 80,000 are or will become blind in their first decades of life due to mutations in both alleles of the Crumbs homologue-1 (CRB1) gene. Microglia are the resident immune surveyor cells in the retina, and their roles have been heavily studied in several retinal diseases, including retinitis pigmentosa (RP), age-related macular degeneration, and diabetic retinopathy. However, very little is known about the role of microglia in CRB1-associated retinopathies. Thus, we here summarize the main findings described in the literature concerning inflammation and the role of microglia in CRB1-patients and CRB1-rodent models. Show less
Mura, M.; Iannetta, D.; Buschini, E.; Smet, M.D. de 2017
De draaiing van de aarde zorgt voor dagelijkse veranderingen in licht en donker. Om op deze dagelijkse veranderingen te kunnen anticiperen hebben alle organismen een ingebouwd mechanisme, namelijk... Show moreDe draaiing van de aarde zorgt voor dagelijkse veranderingen in licht en donker. Om op deze dagelijkse veranderingen te kunnen anticiperen hebben alle organismen een ingebouwd mechanisme, namelijk de biologische klok. De biologische klok bevindt zich in de suprachiasmatische nucleus (SCN) en bestaat uit ongeveer 20 000 neuronen. De SCN ontvangt lichtinformatie uit de omgeving via lichtgevoelige cellen in het netvlies van het oog. Deze cellen geven de informatie door aan de SCN. In het netvlies zijn drie typen lichtgevoelige cellen aanwezig, de staafjes, de kegeltjes en retinale ganglion cellen met melanopsine. In dit proefschrift is de relatieve bijdrage van de verschillende lichtgevoelige cellen op de verwerking van lichtinformatie door de SCN onderzocht. Het onderzoek heeft zich met name gericht op de specifieke bijdragen van de kegeltjes. Ook is onderzocht welke neurotransmitters van invloed zijn op de lichtgevoeligheid van de SCN. Samenvattend laten de resultaten zien dat de hoeveelheid lichtinformatie die de SCN bereikt kan worden bepaald door zowel staafjes, kegeltjes als melanopsine en dat dit afhankelijk is van golflengte, duur en intensiteit van het licht. Daarnaast kan de hoeveelheid lichtinformatie die de SCN bereikt ook afhankelijk zijn van de neurotransmitters adenosine en VIP. Show less
