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Background/aaims: Congenital stationary night blindness (CSNB) is an inherited retinal disease that is often associated with high myopia and can be caused by pathological variants in multiple genes, most commonly CACNA1F , NYX and TRPM1 . High myopia is associated with retinal degeneration and increased risk for retinal detachment. Slowing the progression of myopia in patients with CSNB would likely be beneficial in reducing risk, but before interventions can be considered, it is important to understand the natural history of myopic progression., Methods: This multicentre, retrospective study explored CSNB caused by variants in CACNA1F , NYX or TRPM1 in patients who had at least 6 measurements of their spherical equivalent of refraction (SER) before the age of 18. A mixed-effect model was used to predict progression of SER overtime and differences between genotypes were evaluated., Results: 78 individuals were included in this study. All genotypes showed a significant myopic predicted SER at birth (-3.076D, -5.511D and -5.386D) for CACNA1F , NYX and TRPM1 respectively. Additionally, significant progression of myopia per year (-0.254D, -0.257D and -0.326D) was observed for all three genotypes CACNA1F , NYX and TRPM1 , respectively., Conclusions: Patients with CSNB tend to be myopic from an early age and progress to become more myopic with age. Patients may benefit from long-term myopia slowing treatment in the future and further studies are indicated. Additionally, CSNB should be considered in the differential diagnosis for early-onset myopia., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: We report a three-generation family with isolated Alport-like retinal abnormalities in the absence of lenticonus, hearing loss, kidney disease, and detectable molecular genetic defects in known Alport-related genes., Methods: Clinical examination includes ocular biomicroscopy, fundus photography, optical coherence tomography, dipstick urinalysis, serum creatinine assessment, and molecular genetic analysis., Results: The proband, her mother, and her maternal grandmother had normal best-corrected visual acuity and normal visual fields in both eyes. The macula presented a petaloid stair-case profile with scarce vessels in both eyes of the proband and a flat temporal macula lacking a foveal avascular zone in her mother and her grandmother. No family member had renal symptoms, unexplained subnormal hearing, or lenticonus. Sequencing and MLPA found no defect in COL4A3 , COL4A4 , and COL4A5 . Common SNPs around the genes ± 1Mb showed no segregation. Furthermore, none of the variants shared between the affected individuals in genes from a gene panel of genes relevant for ophthalmopathy nor whole exome- and genome sequencing explained the phenotype., Conclusion: A new condition with two retinal Alport-like phenotypes was found. No abnormalities of the kidneys and lens were found, neither abnormalities of the type IV collagen genes related to Alport syndrome. Homology with retinal abnormalities seen in patients after surgical removal of the inner limiting membrane of the retina suggests that this is where the defect is located. We therefore suggest that the new retinal phenotypes and similar phenotypes can be described with the new definition "frail inner limiting membrane maculopathy."

Background: In intra-arterial chemotherapy for retinoblastoma, a backflow from unreachable external carotid artery branches in the ophthalmic artery can be challenging., Objective: To describe a new endovascular technique using Gelfoam pledgets to temporarily occlude distal branches of the external carotid artery to reverse the competitive backflow into the ophthalmic artery in order to perform intra-arterial chemotherapy via the ostium of the ophthalmic artery in selected cases., Methods: We queried our prospectively collected database of 327 consecutive patients treated for retinoblastoma by intra-arterial chemotherapy and identified those employing Gelfoam pledgets. We describe this new technique with emphasis on feasibility and safety., Results: We treated 11 eyes with 14 infusions of intra-arterial chemotherapy using Gelfoam pledgets to occlude the distal branches of the external carotid artery. We report no perioperative complications due to this occlusion technique. At the ophthalmologic follow-up 1 month after the injection of Gelfoam pledgets, all cases showed tumor regression or stable disease. Two injections into the same eye as the rescue intra-arterial chemotherapy infusion resulted in a transient exudative retinal detachment, and one injection in a heavily pretreated case was followed by iris neovascularization and retinal ischemia. None of the pledget injections led to irreversible vision-threatening intraocular complications., Conclusions: Intra-arterial chemotherapy in retinoblastoma using Gelfoam to transiently occlude the distal branches of the external carotid artery and reverse the backflow into the ophthalmic artery seems feasible and safe. Larges series will help to confirm the effectiveness of this new technique., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Of the different modalities used to treat retinoblastoma, a chemothermotherapeutic regimen combining carboplatin and thermotherapy (also termed focal therapy), and the application of melphalan as a monotherapy, are particularly successful. Some studies indicate that melphalan shows potential when applied in combination with focal therapy, and yet is not applied in this combination. Here we describe a series of synthetically modified melphalan derivatives that display enhanced cytotoxicity relative to melphalan itself, with some displaying further enhancements in cytotoxicity when applied in combination with heat (used as a model for thermotherapy). The synthetic approach, which involves modifying melphalan with perfluorous chains of varying lengths via an ester linker, could lead to a more effective treatment option for retinoblastoma with reduced side-effects, which is a key limitation of melphalan., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

This retrospective multicenter study examines therapy-induced orbital and ocular MRI findings in retinoblastoma patients following selective intra-arterial chemotherapy (SIAC) and quantifies the impact of SIAC on ocular and optic nerve growth. Patients were selected based on medical chart review, with inclusion criteria requiring the availability of posttreatment MR imaging encompassing T2-weighted and T1-weighted images (pre- and post-intravenous gadolinium administration). Qualitative features and quantitative measurements were independently scored by experienced radiologists, with deep learning segmentation aiding total eye volume assessment. Eyes were categorized into three groups: eyes receiving SIAC (Rb-SIAC), eyes treated with other eye-saving methods (Rb-control), and healthy eyes. The most prevalent adverse effects post-SIAC were inflammatory and vascular features, with therapy-induced contrast enhancement observed in the intraorbital optic nerve segment in 6% of patients. Quantitative analysis revealed significant growth arrest in Rb-SIAC eyes, particularly when treatment commenced ≤ 12 months of age. Optic nerve atrophy was a significant complication in Rb-SIAC eyes. In conclusion, this study highlights the vascular and inflammatory adverse effects observed post-SIAC in retinoblastoma patients and demonstrates a negative impact on eye and optic nerve growth, particularly in children treated ≤ 12 months of age, providing crucial insights for clinical management and future research.

Purpose: The International Committee for the Classification of Corneal Dystrophies (IC3D) was created in 2005 to develop a new classification system integrating current information on phenotype, histopathology, and genetic analysis. This update is the third edition of the IC3D nomenclature., Methods: Peer-reviewed publications from 2014 to 2023 were evaluated. The new information was used to update the anatomic classification and each of the 22 standardized templates including the level of evidence for being a corneal dystrophy [from category 1 (most evidence) to category 4 (least evidence)]., Results: Epithelial recurrent erosion dystrophies now include epithelial recurrent erosion dystrophy, category 1 ( COL17A1 mutations, chromosome 10). Signs and symptoms are similar to Franceschetti corneal dystrophy, dystrophia Smolandiensis, and dystrophia Helsinglandica, category 4. Lisch epithelial corneal dystrophy, previously reported as X-linked, has been discovered to be autosomal dominant ( MCOLN1 mutations, chromosome 19). Classic lattice corneal dystrophy (LCD) results from TGFBI R124C mutation. The LCD variant group has over 80 dystrophies with non-R124C TGFBI mutations, amyloid deposition, and often similar phenotypes to classic LCD. We propose a new nomenclature for specific LCD pathogenic variants by appending the mutation using 1-letter amino acid abbreviations to LCD. Pre-Descemet corneal dystrophies include category 1, autosomal dominant, punctiform and polychromatic pre-Descemet corneal dystrophy (PPPCD) ( PRDX3 mutations, chromosome 10). Typically asymptomatic, it can be distinguished phenotypically from pre-Descemet corneal dystrophy, category 4. We include a corneal dystrophy management table., Conclusions: The IC3D third edition provides a current summary of corneal dystrophy information. The article is available online at https://corneasociety.org/publications/ic3d ., Competing Interests: The other authors have no funding or conflicts of interest to disclose., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Retinoblastoma (rb) is the most frequent intraocular tumor, accounting for 3% of all childhood cancers. Heritable rb survivors are germline carriers for an RB1 mutation and have a lifelong risk to develop non-ocular second primary tumors (SPTs) involving multiple other organs like the bones, soft tissues, or skin. These SPTs usually become manifest several years succeeding the diagnosis of rb. In our instance, however, a non-ocular SPT presented prior to the diagnosis of heritable rb., Case Presentation: We report a rare case of a monozygotic twin who presented with primary rhabdomyosarcoma (RMS) preceding the manifestation of heritable rb. The rb was diagnosed when the child developed strabismus while already on therapy for the RMS. The child underwent therapy for both as per defined treatment protocols. The rb regressed well on treatment, but the RMS relapsed and the child developed multiple refractory metastatic foci and succumbed to his disease., Conclusions: Non-ocular SPTs like sarcomas are usually known to manifest in heritable rb survivors with a lag of two to three decades (earlier if exposure to radiation is present) from the presentation of the rb. However, in our case, this seemed to be reversed with the RMS being manifest at an unusual early age and the rb being diagnosed at a later point in time., (© 2024. The Author(s).)

Introduction: Mutational screening of inherited retinal disorders is prerequisite for gene targeted therapy. Our aim was to report and analyze the proportions of mutations in inherited retinal disease (IRD)-causing genes from a single center in Switzerland in order to describe the distribution of IRDs in Western Switzerland., Methods: We conducted a retrospective study of patient records. Criteria for inclusion were residence in Western Switzerland for patients and relatives presenting a clinical diagnosis of IRDs and an established molecular diagnosis managed by the genetics service of the Jules-Gonin Eye Hospital (JGEH) of Lausanne between January 2002 and December 2022. We initially investigated the IRD phenotypes in all patients (full cohort) with a clinical diagnosis, then calculated the distribution of IRD gene mutations in the entire cohort (genetically determined cohort). We analyzed a sub-group that comprised pediatric patients (≤18 years of age). In addition, we calculated the distribution of gene mutations within the most represented IRDs. Comprehensive gene screening was performed using a combined approach of different generation of DNA microarray analysis, direct sequencing, and Sanger sequencing., Results: The full cohort comprised 899 individuals from 690 families with a clinical diagnosis of IRDs. We identified 400 individuals from 285 families with an elucidated molecular diagnosis (variants in 84 genes) in the genetically determined cohort. The pediatric cohort included 89 individuals from 65 families with an elucidated molecular diagnosis. The molecular diagnosis rate for the genetically determined cohort was 58.2% (family ratio) and the 5 most frequently implicated genes per family were ABCA4 (11.6%), USH2A (7.4%), EYS (6.7%), PRPH2 (6.3%), and BEST1 (4.6%). The pediatric cohort had a family molecular diagnosis rate of 64.4% and the 5 most common mutated genes per family were RS1 (9.2%), ABCA4 (7.7%), CNGB3 (7.7%), CACNA1F (6.2%), CEP290 (4.6%)., Conclusions: This study describes the genetic mutation landscape of IRDs in Western Switzerland in order to quantify their disease burden and contribute to a better orientation of the development of future gene targeted therapies., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Aims: To report long-term results of intracameral chemotherapy (ICC) for aqueous seeding (AS) in retinoblastoma., Methods: Retrospective study including 20 patients with primary (n=4) or secondary non-iatrogenic (n=16) AS treated with ICC according to a previously described technique between 2011 and 2020 with at least 1-year follow-up., Results: AS control was initially achieved in all cases with a mean 5 injections of melphalan (n=13) or topotecan (n=7). Three eyes had an isolated AS relapse at a mean interval of 8 months after the first ICC course, which regressed with a second course of intracameral melphalan. Concomitant interciliary process seed implantation was treated with additional brachytherapy if sectorial (n=3) or proton therapy if annular (n=1). Other therapies including systemic, intra-arterial chemotherapy and/or focal treatments were given in 15 eyes to treat concomitant tumour sites. Eye preservation was achieved in 85% of the eyes (n=17/20) at a mean event-free follow-up of 45 months for aqueous disease, and 40 months for any other intraocular tumour activity. Three cases were enucleated due to refractory non-aqueous disease. All patients are alive without metastasis (mean follow-up of 48 months after first ICC). ICC-related intraocular toxicity included iris atrophy (n=5), cataract (n=4), posterior synechiae (n=2) and iris heterochromia (n=1). No patient suffered irreversible vision loss. Useful to normal vision was found in 82% of the cases (n=14/17)., Conclusion: ICC appears to be safe and efficient for AS without irreversible vision-threatening adverse effects. More data are needed to determine any superiority in efficiency/toxicity of topotecan versus melphalan., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Retinoblastoma is the most common pediatric eye cancer. It is currently treated with a limited number of drugs, adapted from other pediatric cancer treatments. Drug toxicity and relapse of the disease warrant new therapeutic strategies for these young patients. In this study, we developed a robust tumoroid-based platform to test chemotherapeutic agents in combination with focal therapy (thermotherapy) - a treatment option widely used in clinical practice - in accordance with clinically relevant trial protocols. The model consists of matrix-embedded tumoroids that retain retinoblastoma features and respond to repeated chemotherapeutic drug exposure similarly to advanced clinical cases. Moreover, the screening platform includes a diode laser (810 nm, 0.3 W) to selectively heat the tumoroids, combined with an on-line system to monitor the intratumoral and surrounding temperatures. This allows the reproduction of the clinical settings of thermotherapy and combined chemothermotherapy treatments. When testing the two main drugs currently used in clinics to treat retinoblastoma in our model, we observed results similar to those clinically obtained, validating the utility of the model. This screening platform is the first system to accurately reproduce clinically relevant treatment methods and should lead to the identification of more efficient drugs to treat retinoblastoma., (© 2023 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Retinoblastoma is a rare childhood cancer of the eye. Of the small number of drugs are used to treat retinoblastoma, all have been repurposed from drugs developed for other conditions. In order to find drugs or drug combinations better suited to the improved treatment of retinoblastoma, reliable predictive models are required, which facilitate the challenging transition from in vitro studies to clinical trials. In this review, the research performed to date on the development of 2D and 3D in vitro models for retinoblastoma is presented. Most of this research was undertaken with a view to better biological understanding of retinoblastoma, and we discuss the potential for these models to be applied to drug screening. Future research directions for streamlined drug discovery are considered and evaluated, and many promising avenues identified., Competing Interests: Declaration of interest None., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Retinal retinoblastoma growth phenotypes can be endophytic, exophytic, diffuse infiltrating or anterior diffuse. Herein, we describe a novel tumor growth pattern in two patients., Material and Methods: Imaging with spectral-domain optical coherence tomography (SD-OCT)., Results: Both cases were diagnosed with unilateral group D retinoblastoma treated with first-line or bridge intra-arterial chemotherapy (IAC). Case 1 had a new intravitreal/epiretinal relapse 3 months after brachytherapy and intravitreal chemotherapy. SD-OCT showed a disruption of the inner limiting membrane (INL) underneath a parapapillary epiretinal seed. The intravitreal/epiretinal disease completely regressed with intravitreal melphalan. Three months later, an isolated intraretinal growth was documented on SD-OCT at the site of previously INL disruption, which was treated by thermotherapy. He remained disease-free at 1-year follow-up with 0.6 visual acuity. Case 2 was seen 2 months after treatment interruption due to the COVID-19 pandemic. Fundus examination showed a massive intravitreal/epipapillary invasion completely obscuring the papilla. Salvage treatment of this seeing eye consisted of combined intra-arterial and intravitreal melphalan and topotecan injections. An infraclinical papillary regrowth 4 months later was treated with additional IAC. Six months later, enucleation was performed due to an infraclinical papillary relapse with suspicion of intralaminar invasion. Histopathology showed retrolaminar optic nerve invasion with tumor-free surgical section. The child received four cycles of adjuvant chemotherapy and remained disease-free at 1-year follow-up., Conclusion: Epiretinal/epipapillary vitreous seeding can be the source of a secondary intraretinal/optic nerve head relapse. SD-OCT is instrumental to follow such cases. Enucleation remains the safest option if secondary optic nerve invasion is suspected.

Aqueous humor (AH) can be easily and safely used to evaluate disease-specific biomarkers in ocular disease. The aim of this study was to identify specific proteins biomarkers in the AH of retinoblastoma (RB) patients at various stages of the disease. We analyzed the proteome of 53 AH samples using high-resolution mass spectrometry. We grouped the samples according to active vitreous seeding (Group 1), active aqueous seeding (Group 2), naive RB (group 3), inactive RB (group 4), and congenital cataracts as the control (Group 5). We found a total of 889 proteins in all samples. Comparative parametric analyses among the different groups revealed three additional proteins expressed in the RB groups that were not expressed in the control group. These were histone H2B type 2-E (HISTH2B2E), InaD-like protein (PATJ), and ubiquitin conjugating enzyme E2 V1 (UBE2V1). Upon processing the data of our study with the OpenTarget Tool software, we found that glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and CD44 were more highly expressed in the RB groups. Our results provide a proteome database regarding AH related to RB disease that may be used as a source of biomarkers. Further prospective studies should validate our finding in a large cohort of RB patients.

Objective: To investigate in a large global sample of patients with retinoblastoma whether sex predilection exists for this childhood eye cancer., Methods: A cross-sectional analysis including 4351 treatment-naive retinoblastoma patients from 153 countries who presented to 278 treatment centers across the world in 2017. The sex ratio (male/female) in the sample was compared to the sex ratio at birth by means of a two-sided proportions test at global level, country economic grouping, continent, and for selected countries., Results: For the entire sample, the mean retinoblastoma sex ratio, 1.20, was higher than the weighted global sex ratio at birth, 1.07 (p < 0.001). Analysis at economic grouping, continent, and country-level demonstrated differences in the sex ratio in the sample compared to the ratio at birth in lower-middle-income countries (n = 1940), 1.23 vs. 1.07 (p = 0.019); Asia (n = 2276), 1.28 vs. 1.06 (p < 0.001); and India (n = 558), 1.52 vs. 1.11 (p = 0.008). Sensitivity analysis, excluding data from India, showed that differences remained significant for the remaining sample (χ 2  = 6.925, corrected p = 0.025) and for Asia (χ 2  = 5.084, corrected p = 0.036). Excluding data from Asia, differences for the remaining sample were nonsignificant (χ 2  = 2.205, p = 0.14)., Conclusions: No proof of sex predilection in retinoblastoma was found in the present study, which is estimated to include over half of new retinoblastoma patients worldwide in 2017. A high male to female ratio in Asian countries, India in specific, which may have had an impact on global-level analysis, is likely due to gender discrimination in access to care in these countries, rather than a biological difference between sexes., (© 2021. The Author(s).)

Purpose: To evaluate the laterality of Coats disease by analyzing optical coherence tomography angiography features in affected, fellow, and control eyes., Methods: Patients with Coats disease who underwent optical coherence tomography angiography were retrospectively reviewed. Healthy eyes of age-matched patients served as controls. Automated optical coherence tomography angiography determination of foveal avascular zone size and vascular density of superficial capillary plexus and deep capillary plexus was recorded., Results: Thirty-four patients with Coats disease (13 with bilateral optical coherence tomography angiography) and 24 controls were included. The foveal avascular zone was larger in affected eyes compared with fellow eyes (P = 0.004). Vascular density was decreased in affected eyes compared with fellow eyes in the superficial capillary plexus and deep capillary plexus whole images (P = 0.047 and P = 0.007) and in the deep capillary plexus at the fovea (P = 0.001). Vascular density was significantly reduced only in the deep capillary plexus in Stage 1 or 2A patients but in both plexuses in patients with Stage 2B1. No differences were shown on foveal avascular zone and vascular density values between fellow eyes of patients with Coats disease and controls., Conclusion: The foveal avascular zone is enlarged, and vascular density is decreased in affected eyes with Coats disease, but no differences are seen between fellow and control eyes, confirming the unilateral nature of the disease., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Opthalmic Communications Society, Inc.)

Purpose: To report that variants in the gene for a large lamina basal component protein, COL6A6 (collagen type VI alpha 6 chain, Col6α6), linked to chromosome 3p22.1 causes retinitis pigmentosa (RP) in patients with autosomal dominant transmission (adRP)., Methods: A positional-cloning approach, whole exome sequencing, and modeling were used. The proband and several affected family members have been phenotyped and followed for over 12 years., Results: A heterozygous missense variant, c.509C>G (p. Ser170Cys) in exon 2 of COL6A6 (comprised of 36 exons and 2236 amino acids), was observed in a four- generation family and is likely to cause the adRP phenotype. It was identified in 10 affected members. All affected family members had a distinct phenotype: late-onset rod cone dystrophy, with good retained visual acuity, until their late 70s. Immunohistochemistry of human retina showed a dot-like signal at the base of the inner segments of photoreceptors and outer plexiform layer (OPL). The structural modeling of the N7 domain of Col6α6 suggests that the mutant might result in the abnormal cellular localization of collagen VI or malformation of collagen fibers resulting in the loss of its unique filament structure., Conclusions: COL6A6 is widely expressed in human tissues and evolutionary conserved. It is thought to interact with a range of extracellular matrix components. Our findings suggest that this form of RP has long-term useful central visual acuity and a mild progression, which are important considerations for patient counseling.

Objective: To determine whether the clinical presentation of Coats disease differs between males and females., Methods and Analysis: Records of patients diagnosed with Coats disease at a single institution were retrospectively reviewed. Demographic data, main reason for initial consultation, comprehensive ocular examination at diagnosis and modalities of treatments during the follow-up were recorded., Results: Records from 114 patients with Coats disease were analysed. Ninety-eight patients (86%) were male and 16 (14%) female. Mean age at diagnosis was 6.2 years±6.1 in males and 7.4 years±4.7 in females. The main initial reason for consultation was strabismus in males and decreased visual acuity in females. Stage severity at diagnosis was similar in the two groups with half of the patients presenting with stage 2B2 or lower. The extension of peripheral retinal telangiectasia was also similar (mean: 6.2±3.4 and 5.8±4.0, respectively), as was the extension of intraretinal exudation (mean: 5.0±4.5 and 5.8±4.4) and the frequency of a subfoveal nodule at diagnosis (40% vs 30%, respectively). There was no distinction between the number of laser photocoagulation or cryotherapy sessions required for both groups during the follow-up., Conclusions: Coats disease presentation does not differ between genders despite being much rarer in females. We propose a pathogenic mechanism accounting for the gender-dependent incidence combined with gender-independent expressivity of Coats disease., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Importance: High-risk histopathologic features of retinoblastoma are useful to assess the risk of systemic metastasis. In this era of globe salvage treatments for retinoblastoma, the definition of high-risk retinoblastoma is evolving., Objective: To evaluate variations in the definition of high-risk histopathologic features for metastasis of retinoblastoma in different ocular oncology practices around the world., Design, Setting, and Participants: An electronic web-based, nonvalidated 10-question survey was sent in December 2020 to 52 oncologists and pathologists treating retinoblastoma at referral retinoblastoma centers., Intervention: Anonymized survey about the definition of high-risk histopathologic features for metastasis of retinoblastoma., Main Outcomes and Measures: High-risk histopathologic features that determine further treatment with adjuvant systemic chemotherapy to prevent metastasis., Results: Among the 52 survey recipients, the results are based on the responses from 27 individuals (52%) from 24 different retinoblastoma practices across 16 countries in 6 continents. The following were considered to be high-risk features: postlaminar optic nerve infiltration (27 [100%]), involvement of optic nerve transection (27 [100%]), extrascleral tissue infiltration (27 [100%]), massive (≥3 mm) choroidal invasion (25 [93%]), microscopic scleral infiltration (23 [85%]), ciliary body infiltration (20 [74%]), trabecular meshwork invasion (18 [67%]), iris infiltration (17 [63%]), anterior chamber seeds (14 [52%]), laminar optic nerve infiltration (13 [48%]), combination of prelaminar and laminar optic nerve infiltration and minor choroidal invasion (11 [41%]), minor (<3 mm) choroidal invasion (5 [19%]), and prelaminar optic nerve infiltration (2 [7%]). The other histopathologic features considered high risk included Schlemm canal invasion (4 [15%]) and severe anaplasia (1 [4%]). Four respondents (15%) said that the presence of more than 1 high-risk feature, especially a combination of massive peripapillary choroidal invasion and postlaminar optic nerve infiltration, should be considered very high risk for metastasis., Conclusions and Relevance: Responses to this nonvalidated survey conducted in 2020-2021 showed little uniformity in the definition of high-risk retinoblastoma. Postlaminar optic nerve infiltration, involvement of optic nerve transection, and extrascleral tumor extension were the only features uniformly considered as high risk for metastasis across all oncology practices. These findings suggest that the relevance about their value in the current scenario with advanced disease being treated conservatively needs further evaluation; there is also a need to arrive at consensus definitions and conduct prospective multicenter studies to understand their relevance.

Background: Whereas crystals deposit in the retina, the cornea and limbus in Bietty corneo-retinal dystrophy (BCD) is now well established and documented, only two published cases report their findings in the lens and no cases deep in the lens cortex., Material and Methods: Four consecutive adult patients from three different unrelated families presenting lens crystals associated with advanced genetically confirmed BCD were enrolled with advanced disease and long follow up (>12 years). Demographics, visual acuity, slit lamp biomicroscopy, lens and posterior pole photography, optical coherence tomography (OCT), autofluorescence, and screening for CYP4V2 type of mutation were performed. The setting was Jules Gonin Eye Hospital, Switzerland, between 1.1 2013 and 1.11. 2019., Results: All patients were European women. The ages ranged from 40 to 81 years. Best Snellen visual acuity ranged from light perception to 1.0. All patients presented with limbus and retinal crystals deposit that disappeared over time and the development of severe chorioretinal atrophy. With long-term follow up, multiple crystal-like deposits appeared in the anterior, posterior lens capsule and cortex. All patients, but one, had homozygous or compound heterozygous mutations in CYP4V2 gene., Conclusions: To the best of our knowledge, there are no published cases of crystal deposits in the cortex of the lens of patients diagnosed with BCD associated with CYP4V2 gene mutation. This could be a feature of advanced BCD, and their presence in the lens cortex questions the hypothesis of floating deposits from posterior pole although their exact etiology remains to be determined.

Purpose: The purpose of this study was to compare the natural history of visual function change in cohorts of patients affected with retinal degeneration due to biallelic variants in Bardet-Biedl syndrome genes: BBS1 and BBS10., Methods: Patients were recruited from nine academic centers from six countries (Belgium, Canada, France, New Zealand, Switzerland, and the United States). Inclusion criteria were: (1) female or male patients with a clinical diagnosis of retinal dystrophy, (2) biallelic disease-causing variants in BBS1 or BBS10, and (3) measures of visual function for at least one visit. Retrospective data collected included genotypes, age, onset of symptoms, and best corrected visual acuity (VA). When possible, data on refractive error, fundus images and autofluorescence (FAF), optical coherence tomography (OCT), Goldmann kinetic perimetry (VF), electroretinography (ERG), and the systemic phenotype were collected., Results: Sixty-seven individuals had variants in BBS1 (n = 38; 20 female patients and 18 male patients); or BBS10 (n = 29; 14 female patients and 15 male patients). Missense variants were the most common type of variants for patients with BBS1, whereas frameshift variants were most common for BBS10. When ERGs were recordable, rod-cone dystrophy (RCD) was observed in 82% (23/28) of patients with BBS1 and 73% (8/11) of patients with BBS10; cone-rod dystrophy (CORD) was seen in 18% of patients with BBS1 only, and cone dystrophy (COD) was only seen in 3 patients with BBS10 (27%). ERGs were nondetectable earlier in patients with BBS10 than in patients with BBS1. Similarly, VA and VF declined more rapidly in patients with BBS10 compared to patients with BBS1., Conclusions: Retinal degeneration appears earlier and is more severe in BBS10 cases as compared to those with BBS1 variants. The course of change of visual function appears to relate to genetic subtypes of BBS.

Background: The travel distance from home to a treatment centre, which may impact the stage at diagnosis, has not been investigated for retinoblastoma, the most common childhood eye cancer. We aimed to investigate the travel burden and its impact on clinical presentation in a large sample of patients with retinoblastoma from Africa and Europe., Methods: A cross-sectional analysis including 518 treatment-naïve patients with retinoblastoma residing in 40 European countries and 1024 treatment-naïve patients with retinoblastoma residing in 43 African countries., Results: Capture rate was 42.2% of expected patients from Africa and 108.8% from Europe. African patients were older (95% CI -12.4 to -5.4, p<0.001), had fewer cases of familial retinoblastoma (95% CI 2.0 to 5.3, p<0.001) and presented with more advanced disease (95% CI 6.0 to 9.8, p<0.001); 43.4% and 15.4% of Africans had extraocular retinoblastoma and distant metastasis at the time of diagnosis, respectively, compared to 2.9% and 1.0% of the Europeans. To reach a retinoblastoma centre, European patients travelled 421.8 km compared to Africans who travelled 185.7 km (p<0.001). On regression analysis, lower-national income level, African residence and older age (p<0.001), but not travel distance (p=0.19), were risk factors for advanced disease., Conclusions: Fewer than half the expected number of patients with retinoblastoma presented to African referral centres in 2017, suggesting poor awareness or other barriers to access. Despite the relatively shorter distance travelled by African patients, they presented with later-stage disease. Health education about retinoblastoma is needed for carers and health workers in Africa in order to increase capture rate and promote early referral., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Background : Absence of RB1 mutation is rare in retinoblastoma and MYCN amplifications were recently identified in a subset of aggressive retinoblastomas occurring in infants. Here we describe not only the clinical phenotype of MYCN retinoblastoma at presentation, but also the tumor response to the first attempt of conservative management in this context. Methods : Interventional retrospective case report Results : A 6-month-old boy was referred with right leukocoria. Examination under anesthesia revealed a group D unilateral retinoblastoma with an extensive whitish mass and total retinal detachment. Despite partial response following combined sequential intravenous and intra-arterial chemotherapy, tumor relapse in the aqueous humor occurred with posterior chamber involvement over 360°, this transiently controlled by intracameral and intravitreal melphalan injections. Eleven months post-diagnosis the eye was enucleated due to diffuse retinal recurrence invading the ciliary body and obscuring the optic nerve, associated with neovascular glaucoma. Histopathology revealed a poorly differentiated retinoblastoma with diffuse retinal invasion, extending from the superior ciliary body to the inferior equatorial choroid. There was post laminar optic nerve extension without involvement of the surgical margin. RB1 and diffuse MYCN nuclear expression were identified. FISH and SNP-array confirmed MYCN amplification. At 65 months follow-up the patient remained in good health without local recurrence or metastasis. Conclusions : To the best of our knowledge, this study is the first to attempt conservative management of an MYCN retinoblastoma, although secondary enucleation could not be avoided due to highly aggressive recurrence resisting all targeted modalities of chemotherapy.

Introduction: Advanced intraocular retinoblastoma can be cured by enucleation, but spread of retinoblastoma cells beyond the natural limits of the eye is related to a high mortality. Adjuvant therapy after enucleation has been shown to prevent metastasis in children with risk factors for extraocular retinoblastoma. However, histological criteria and adjuvant treatment regimens vary and there is no unifying consensus on the optimal choice of treatment., Method: Data on guidelines for adjuvant treatment in European retinoblastoma referral centres were collected in an online survey among all members of the European Retinoblastoma Group (EURbG) network. Extended information was gathered via personal email communication., Results: Data were collected from 26 centres in 17 countries. Guidelines for adjuvant treatment were in place at 92.3% of retinoblastoma centres. There was a consensus on indication for and intensity of adjuvant treatment among more than 80% of all centres. The majority of centres use no adjuvant treatment for isolated focal choroidal invasion or prelaminar optic nerve invasion. Patients with massive choroidal invasion or postlaminar optic nerve invasion receive adjuvant chemotherapy, while microscopic invasion of the resection margin of the optic nerve or extension through the sclera are treated with combined chemo- and radiotherapy., Conclusion: Indications and adjuvant treatment regimens in European retinoblastoma referral centres are similar but not uniform. Further biomarkers in addition to histopathological risk factors could improve treatment stratification. The high consensus in European centres is an excellent foundation for a common European study with prospective validation of new biomarkers., (© 2021 The Authors. Pediatric Blood & Cancer published by Wiley Periodicals LLC.)

Purpose: To identify risk factors for acute choroidal ischemia (ACI) after intra-arterial chemotherapy (IAC) for retinoblastoma., Design: Retrospective cohort study., Participants: Two hundred twenty patients (248 eyes) treated with IAC in Lausanne between November 2008 and September 2019 (665 procedures). All patients were evaluated on a monthly basis with fundus photography and fluorescein angiography before and after each IAC injection., Methods: Acute choroidal ischemia, defined as any new choroidal ischemia clinically diagnosed within 35 days after an IAC injection, were noted. Eyes with choroidal complications diagnosed later than 35 days after the last IAC injection (n = 7) or those for which the status of the choroid was not assessable (n = 35) were excluded. Specific procedure parameters and treatment regimens were compared between the group of eyes with and without ACI., Main Outcome Measures: Procedure-related risk factors for ACI after IAC injection and visual acuity assessment in the group of eyes with ACI., Results: Acute choroidal ischemia developed in 35 of 206 included eyes after a mean of 2 injections. No differences were found between the two study groups regarding age at first IAC injection, disease grouping at diagnosis, previously administered treatments, number of IAC injections, drug dose, mean injection time, injection method (pulsatile vs. continuous), or concomitant intravitreal melphalan use. Treatment regimen (melphalan vs. combined melphalan plus topotecan; P < 0.05), catheterization route (internal carotid artery vs. external carotid or posterior communicating artery; P < 0.001), and catheterization type (occlusive into the ophthalmic artery [OA] vs. nonocclusive; P < 0.001) were included in multivariate analysis, and occlusive catheterization was identified as an independent risk factor for ACI (P < 0.001). In the subgroup undergoing an occlusive procedure, placement of the catheter tip into the OA distal third versus medial and proximal thirds (P = 0.04) and a mean catheter diameter-to-OA lumen ratio of 0.6 or more (P < 0.001) were correlated significantly with ACI. Complete vision loss was noted in 27% of the eyes with ACI that were old enough for visual assessment (n = 9/33), whereas 33% maintained a useful vision ranging between 0.1 and 0.8 (n = 11/33)., Conclusions: Catheterization of the OA should be attempted from an ostial position or an external carotid approach to minimize the risk of potentially vision-threatening choroidal complications., (Copyright © 2020 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Standardized guidelines for assessing tumor response to therapy are essential for designing and conducting clinical trials. The Response Evaluation Criteria In Solid Tumors (RECIST) provide radiological standards for assessment of solid tumors. However, no such guidelines exist for the evaluation of intraocular cancer, and ocular oncology clinical trials have largely relied on indirect measures of therapeutic response-such as progression-free survival-to evaluate the efficacy of treatment agents. Herein, we propose specific criteria for evaluating treatment response of retinoblastoma, the most common pediatric intraocular cancer, and emphasize a multimodal imaging approach for comprehensive assessment of retinoblastoma tumors in clinical trials., (© 2021 Wiley Periodicals LLC.)

Retinoblastoma mimickers, or pseudoretinoblastoma, are conditions that show similarities with the pediatric cancer retinoblastoma. However, false-positive retinoblastoma diagnosis can cause mistreatment, while false-negative diagnosis can cause life-threatening treatment delay. The purpose of this study is to identify the MR imaging features that best differentiate between retinoblastoma and the most common pseudoretinoblastoma diagnoses: Coats' disease and persistent fetal vasculature (PFV). Here, six expert radiologists performed retrospective assessments (blinded for diagnosis) of MR images of patients with a final diagnosis based on histopathology or clinical follow-up. Associations between 20 predefined imaging features and diagnosis were assessed with exact tests corrected for multiple hypothesis testing. Sixty-six patients were included, of which 33 (50%) were retinoblastoma and 33 (50%) pseudoretinoblastoma patients. A larger eye size, vitreous seeding, and sharp-V-shaped retinal detachment were almost exclusively found in retinoblastoma ( p < 0.001-0.022, specificity 93-97%). Features that were almost exclusively found in pseudoretinoblastoma included smaller eye size, ciliary/lens deformations, optic nerve atrophy, a central stalk between optic disc and lens, Y-shaped retinal detachment, and absence of calcifications ( p < 0.001-0.022, specificity 91-100%). Additionally, three newly identified imaging features were exclusively present in pseudoretinoblastoma: intraretinal macrocysts ( p < 0.001, 38% [9/24] in Coats' disease and 20% [2/10] in PFV), contrast enhancement outside the solid lesion ( p < 0.001, 30% [7/23] in Coats' disease and 57% [4/7] in PFV), and enhancing subfoveal nodules (38% [9/24] in Coats' disease). An assessment strategy was proposed for MR imaging differentiation between retinoblastoma and pseudoretinoblastoma, including three newly identified differentiating MR imaging features.

Background: Intraocular medulloepithelioma is commonly treated with primary enucleation. Conservative treatment options include brachytherapy, local resection and/or cryotherapy in selected cases. We report for the first time the use of targeted chemotherapy to treat a ciliary body medulloepithelioma with aqueous and vitreous seeding., Case Presentation: A 17-month-old boy with a diagnosis of ciliary body medulloepithelioma with concomitant seeding and neovascular glaucoma in the right eye was seen for a second opinion after parental refusal of enucleation. Examination under anesthesia showed multiple free-floating cysts in the pupillary area associated with iris neovascularization and a subluxated and notched lens. Ultrasound biomicroscopy revealed a partially cystic mass adjacent to the ciliary body between the 5 and 9 o'clock meridians as well as multiple nodules in the posterior chamber invading the anterior vitreous inferiorly. Fluorescein angiography demonstrated peripheral retinal ischemia. Left eye was unremarkable. Diagnosis of intraocular medulloepithelioma with no extraocular invasion was confirmed and conservative treatment initiated with combined intracameral and intravitreal melphalan injections given according to the previously described safety-enhanced technique. Ciliary tumor and seeding totally regressed after a total of 3 combined intracameral (total dose 8.1 μg) and intravitreal (total dose 70 μg) melphalan injections given every 7-10 days. Ischemic retina was treated with cryoablation as necessary. Three years later, ab interno trabeculotomy followed by 360° gonioscopy-assisted transluminal trabeculotomy 6 months later was performed for uncontrolled intraocular pressure despite antihypertensive drugs combined to cyclophotocoagulation and 7 intravitreal anti-VEGF injections for recurrent iris neovascularization. Cataract was removed at the same operative time. The child has remained disease- and metastasis-free at a 5-year follow-up since the last melphalan injection (25-month follow-up after the combined lensectomy-trabeculotomy) with a controlled intraocular pressure under topical quadritherapy and a best corrected Snellen visual acuity of 0.08., Conclusions: We report for the first time complete regression of a non-infiltrating ciliary body medulloepithelioma with seeding achieved with only a small number of intracameral and intravitreal melphalan injections. Concomitant secondary neovascular glaucoma and cataract needed appropriate management to allow long-term eye and vision preservation.

Importance: Early diagnosis of retinoblastoma, the most common intraocular cancer, can save both a child's life and vision. However, anecdotal evidence suggests that many children across the world are diagnosed late. To our knowledge, the clinical presentation of retinoblastoma has never been assessed on a global scale., Objectives: To report the retinoblastoma stage at diagnosis in patients across the world during a single year, to investigate associations between clinical variables and national income level, and to investigate risk factors for advanced disease at diagnosis., Design, Setting, and Participants: A total of 278 retinoblastoma treatment centers were recruited from June 2017 through December 2018 to participate in a cross-sectional analysis of treatment-naive patients with retinoblastoma who were diagnosed in 2017., Main Outcomes and Measures: Age at presentation, proportion of familial history of retinoblastoma, and tumor stage and metastasis., Results: The cohort included 4351 new patients from 153 countries; the median age at diagnosis was 30.5 (interquartile range, 18.3-45.9) months, and 1976 patients (45.4%) were female. Most patients (n = 3685 [84.7%]) were from low- and middle-income countries (LMICs). Globally, the most common indication for referral was leukocoria (n = 2638 [62.8%]), followed by strabismus (n = 429 [10.2%]) and proptosis (n = 309 [7.4%]). Patients from high-income countries (HICs) were diagnosed at a median age of 14.1 months, with 656 of 666 (98.5%) patients having intraocular retinoblastoma and 2 (0.3%) having metastasis. Patients from low-income countries were diagnosed at a median age of 30.5 months, with 256 of 521 (49.1%) having extraocular retinoblastoma and 94 of 498 (18.9%) having metastasis. Lower national income level was associated with older presentation age, higher proportion of locally advanced disease and distant metastasis, and smaller proportion of familial history of retinoblastoma. Advanced disease at diagnosis was more common in LMICs even after adjusting for age (odds ratio for low-income countries vs upper-middle-income countries and HICs, 17.92 [95% CI, 12.94-24.80], and for lower-middle-income countries vs upper-middle-income countries and HICs, 5.74 [95% CI, 4.30-7.68])., Conclusions and Relevance: This study is estimated to have included more than half of all new retinoblastoma cases worldwide in 2017. Children from LMICs, where the main global retinoblastoma burden lies, presented at an older age with more advanced disease and demonstrated a smaller proportion of familial history of retinoblastoma, likely because many do not reach a childbearing age. Given that retinoblastoma is curable, these data are concerning and mandate intervention at national and international levels. Further studies are needed to investigate factors, other than age at presentation, that may be associated with advanced disease in LMICs.

Purpose: RPE65-associated retinal dystrophy (RPE65-RD) is an early onset, progressive, severe retinal dystrophy. We sought to characterize the natural history of retinal degeneration in affected individuals., Methods: We performed cross-sectional and longitudinal quantitative and qualitative assessments of retinal architecture in RPE65-RD using spectral domain optical coherence tomography (SD-OCT) and fundus autofluorescence (FAF) imaging. Twenty-six subjects (mean age, 14.8 years, range, 5-24 years) with RPE65-RD underwent SD-OCT and FAF imaging, of whom 14 subjects were followed up over time. Foveal thickness (FT), outer nuclear layer thickness (ONLT), ellipsoid zone width (EZW), and ellipsoid zone area (EZA) were calculated where possible. These were correlated with age, best corrected visual acuity (BCVA), and central 30° retinal sensitivity (V30). Intra-observer agreement, test-retest repeatability, and interocular symmetry were also investigated., Results: We identified structural interocular symmetry, the presence of autofluorescence in 46% (12/26) of subjects, and the presence of foveal hypoplasia (associated with significantly worse BCVA) in 50% of subjects. EZW and EZA were measurable in 67% (35/52) and 37% (19/52) of eyes, respectively, with both demonstrating good agreement on repeated measurement. The annual rate of progression using EZW was -300.63 µm/year, and -1.17 mm2/year in EZA. EZW was found to have a statistically significant correlation with BCVA and V30., Conclusions: We identified the presence of autofluorescence in half of our subjects, with foveal hypoplasia also noted in half of our cohort. EZW, and to a lesser extent EZA, were robust measures of retinal degeneration and represent valuable metrics to determine the impact of intervention. (ClinicalTrials.gov number NCT02714816.).

Purpose: To illustrate Optical Coherence Tomography (OCT) images of active and inactive retinoblastoma (Rb) tumours., Methods: Current observational study included patients diagnosed with retinoblastoma and retinoma who were presented at Amsterdam UMC and Jules-Gonin Eye Hospital, between November 2010 and October 2017. Patients aged between 0 and 4 years were imaged under general anaesthesia with handheld OCT in supine position. Patients older than 4 years were imaged with the conventional OCT (Heidelberg Engineering, Heidelberg Spectralis, Germany). All patients included were divided into two groups: active and inactive tumours (retinoma and regression patterns). Patients' medical records and OCT images were analysed during meetings via discussions by ophthalmologists and physicists., Results: Twelve Dutch and 8 Swiss patients were divided into two groups: 2 patients with active tumour versus 18 patients with inactive tumour. Subsequently, inactive group could be divided in two groups, which consisted of 10 patients with retinoma and 8 patients with different regression pattern types. Of all included patients, 15 were male (75%). Median age at diagnosis was 18.0 months (range 0.19-715.2 months). A total of 12 retinoblastoma (active and inactive) and 8 retinoma foci were investigated by OCT. No distinction could be made between active and inactive tumours using only OCT., Conclusion: Optical coherence tomography alone cannot distinguish between active and inactive Rbs. However, handheld OCT adds useful information to the established imaging techniques in the monitoring and follow-up of retinoblastoma patients. With this study, we provide an overview of OCT images of active and inactive Rbs., (© 2019 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Background: Tractional retinal detachment with or without secondary tear is a rare complication reported in less than 0.5% of in eyes treated for retinoblastoma. Pars plana vitrectomy (PPV) in eyes with history of retinoblastoma has been associated with a significant risk for recurrence, extraocular spread, and systemic metastases. We report here the successful management by PPV under melphalan irrigation of 2 children presenting with tractional retinal detachment after retinoblastoma therapy and scleral buckle surgery., Case Presentation: A 7-year-old girl with a history of bilateral retinoblastoma (group D) presented with light perception best-corrected visual acuity (BCVA) and tractional retinal detachment (RD) in her left eye, 3 years after the last intra-arterial chemotherapy (IAC) injection. Moreover, she had history of left eye rhegmatogenous RD treated by scleral buckle 1 month after the last IAC and cataract surgery 12 months later. PPV associated with retinectomy, laser photocoagulation and silicone oil tamponade was performed. Silicone oil was removed 4 months later. Fifteen months after PPV, BCVA had increased to 20/32 without recurrence of RD and no evidence of tumor activity. A 7-year-old boy with a history of unilateral retinoblastoma (group D) in his left eye presented with rhegmatogenous RD 21 months after the last treatment for retinoblastoma. Scleral buckle surgery was performed, but 3 weeks later the patient presented with tractional RD associated with proliferative vitreo-retinopathy. BCVA was counting fingers. PPV associated with membrane peel, laser photocoagulation and silicone oil tamponade was performed. Silicone oil was removed after 5 months followed by cataract surgery 5 months later. Twenty months after PPV, BCVA was 20/20 and there was no sign of tumor recurrence., Conclusions: PPV under melphalan irrigation, with retinectomy, if necessary, and silicone oil tamponade, allows anatomical and functional improvement in eyes with history of retinoblastoma and scleral buckling developing tractional RD.