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Purpose: Description of retinal phenotype by structural and functional testing, ornithine plasma levels and mutational data of OAT gene in patients with Gyrate Atrophy (GA)., Methods: Ophthalmologic examination, fundus photography (CFP), autofluorescence (FAF), spectral-domain optical coherence tomography (SD-OCT), Goldmann perimetry (GP), full-field electroretinogram (ffERG) and chromatic perimetry (CP) testing were performed. Ornithine plasma levels were measured. Sanger sequencing mutational analysis of the coding exons and exon-intron junctions of the OAT gene were analyzed., Results: Twelve eyes of seven Mexican patients with GA were included. CFF showed peripheric patches of chorioretinal atrophy; FAF revealed peripheric oval areas of hypoautofluorescence; SD-OCT exhibited outer retinal tubulations in 58%, cystoid macular edema in 50%, epiretinal membrane in 42%, foveoschisis and staphyloma in 17%, and hyperreflective deposits in 100% of the eyes; GP showed constricted visual fields in 100% of the eyes; ffERG revealed preserved photopic response in 17% and preserved scotopic response in 17% of the eyes; CP exposed a deficit in generalized response of rods and cones in 100% of the eyes. Mean ornithine plasma levels were 509.5 µmol/L. One patient with genetic confirmation of GA had normal ornithine plasma levels (48 µmol/L). Molecular findings in OAT gene detected two novel pathogenic variants: c.796 C > T (p.Gln266*) and c.721_722dupCC (p.Asp242ArgfsTer6)., Conclusion: This study provides new information regarding functional and structural diagnosis in patients with GA, expands the understanding of retinal phenotype in patients with GA, reports two novel mutations and presents the first case of GA confirmed by genetic testing with normal ornithine levels., Competing Interests: Declarations. Conflict of interest: The authors declare no competing interests. Consent to participate: Informed consent was obtained from all individual participants included in the study. Consent to publish: The authors affirm that human research participants provided informed consent for publication of the images in this manuscript. Ethical approval: This study was performed in line with the principles of the Declaration of Helsinki., (© 2024. The Author(s).)

Purpose: The purpose of this study was to explore the succession of the central and peripheral neurovascular and microstructural impairments in patients with full-course diabetic retinopathy (DR), consisting of preclinical DR, nonproliferative DR (NPDR), and proliferative DR (PDR)., Methods: Our analysis included 81 participants (including 23 healthy controls, 23 with preclinical DR [diabetes without retinopathy], 13 with NPDR, and 22 with PDR) from the Guangdong Diabetic Retinopathy Multiple Omics Study. Retinal structure and function were evaluated and quantified using ultra-widefield swept-source optical coherence tomography angiography (UWF-SS-OCTA), electroretinography (ERG), and adaptive optics scanning laser ophthalmoscopy (AOSLO). Correlation analysis was conducted to explore the relationship between structural parameters and functional parameters., Results: In the preclinical DR group, decreased amplitude in the DR assessment protocol were observed (P = 0.003), with no changes in structure and photoreceptor cells (all P > 0.05). In the NPDR group, photoreceptor cells were impaired (all P < 0.05) with delayed implicit time in the International Society for Clinical Electrophysiology of Vision (ISCEV) Photopic flicker protocol, increased macular and inner nuclear layer thickness, and decreased vessel density and perfusion area of the deep capillary plexus (all P < 0.05). In the PDR group, delayed implicit time and decreased amplitude in the ISCEV Photopic flicker and photopic negative response (PhNR) protocol, and neurovascular impairments were observed (all P < 0.05). Correlation analysis demonstrated a significant correlation between functional parameters and various structural indicators (all P < 0.05)., Conclusions: The cone pathway function began to decline in preclinical DR and distinct photoreceptor cell disorders were observed in NPDR. Notably, instruments with a wider field of view or more detailed microscopic techniques will provide enhanced neurovascular imaging, offering fresh insights into full-course DR.

Purpose: The California National Primate Research Center contains a colony of rhesus macaques with a homozygous missense mutation in PDE6C (R565Q) which causes a cone disorder similar to PDE6C achromatopsia in humans. The purposes of this study are to characterize the phenotype in PDE6C macaques in detail to determine the onset of the cone phenotype, the degree to which the phenotype progresses, if heterozygote animals have an intermediate phenotype, and if rod photoreceptor function declines over time., Methods: We analyzed spectral-domain optical coherence tomography (SD-OCT), fundus autofluorescence (FAF), and electroretinography (ERG) data from 102 eyes of 51 macaques (aged 0.25 to 16 years). Measurements of retinal layers as well as cone and rod function over time were quantitatively compared., Results: Homozygotes as young as 3 months postnatal showed absent cone responses on electroretinogram. Infant homozygotes had reduced foveal outer nuclear layer (ONL) thickness compared with wildtype infants (P < 0.0001). Over 4 years of study, no consistent changes in retinal layer thicknesses were found within 5 adult homozygotes. However, comparisons between infants and adults revealed reductions in foveal ONL thickness suggesting that cone cells slowly degenerate as homozygotes age. The oldest homozygote (11 years) had reduced rod responses. Heterozygotes could not be distinguished from wildtypes in any parameters., Conclusions: These data suggest that, like humans, macaque PDE6C heterozygotes are normal, and homozygote primates have absent cone function and reduced foveal ONL thickness from infancy. Cone photoreceptors probably degenerate over time and macular atrophy can occur. Rod photoreceptor function may wane in late stages.

Introduction: Nephronophthisis 12 is a rare condition and only two cases have been reported to associate with retinopathy. Herein we present the third case in scientific literature, and the first with vision-quality exams., Clinical Case: The case was a 28-year-old male with the mutations c.626C > T (p.Pro209Leu) and c.1317T > G (p.Tyr439*). Bilateral atrophy of outer retinal layers and retinal pigmented epithelium were observed, resembling a bull's eye maculopathy. Visual acuity, as well as contrast sensitivity dropped with mesopic conditions. He presented more difficulties in differentiating colors within blue-yellow range, and some degree of halos were detected. Multifocal electroretinogram detected little retinal function, and visual field detected a full scotoma. He referred poorer quality of life due to emotional wellbeing, more than to difficulties in reading or accessing information., Conclusion: Although rare, nephronophthisis 12 may be caused by genetic mutations that associate severe retinopathy., Competing Interests: Declarations. Conflict of interest: All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers’ bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript. Informed consent: Informed consent was obtained the participant included in the study. Human rights: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Electrophysiological examinations are used in ophthalmology to determine the functionality of the neurons of the visual pathway. As electrophysiological examinations are independent of the subjective perception and response of the patient, they are considered to be objective functional diagnostics of vision. Electroretinography (ERG) is used to examine the retina (especially the photoreceptors), electro-oculography (EOG) is used to examine the functionality of the retinal pigment epithelium and visually evoked potentials (VEP) are used to evaluate the integrity of the entire visual pathway. Abnormalities in electrophysiological responses should always be interpreted in the context of other functional and morphological findings., Competing Interests: Einhaltung ethischer Richtlinien. Interessenkonflikt: Gemäß den Richtlinien des Springer Medizin Verlags werden Autoren und Wissenschaftliche Leitung im Rahmen der Manuskripterstellung und Manuskriptfreigabe aufgefordert, eine vollständige Erklärung zu ihren finanziellen und nichtfinanziellen Interessen abzugeben. Autoren: L. Kühlewein: A. Finanzielle Interessen: Tistou und Charlotte Kerstan Stiftung, Novartis, Rhythm: alle nicht im Zusammenhang mit dieser Arbeit und alle im Sinne von Geldzuwendungen für Forschungsprojekte. – Novartis, Rhythm: Honorar und Reisekostenerstattung. – B. Nichtfinanzielle Interessen: Angestellte Fachärztin für Augenheilkunde, Department für Augenheilkunde, Medizinische Fakultät, Eberhard Karls Universität Tübingen | – Mitgliedschaft: DOG. K. Stingl: A. Finanzielle Interessen: EURETINA Kongess 2023 Reisekostenerstattung: Okuvision GmbH; UKE Augenklinik Hamburg 2022 Honorar für Vorträge; Eurofins Humagenetik webinar 2024 Honorar für Vorträge; Ärztekammer Westfalen-Lippe 2021–2024 Honorar für Vorträge; EVICRnet 2021 Honorar fürs Erstellen von Webinaren; FOMF 2024 Honorar für Vorträge; Bundesministerium für Arbeit und Soziales 2024 Honorar für Vorträge. – Beraterin im Rahmen von Dienstaufgabe am Universitätsklinikum Tübingen für Novartis, ProQR, Therapeutics ViGeneron, Santen, Janssen, Lundbeck, THEA. – B. Nichtfinanzielle Interessen: Angestellte Oberärztin (Augenärztin) an der Universitäts-Augenklinik Tübingen | Mitgliedschaften: DOG Mitglied & Sprecherin der Sektion Genetik, ISCEV, Expert Committee member for Retinal Dystrophies in EVICR.net. Wissenschaftliche Leitung: Die vollständige Erklärung zum Interessenkonflikt der Wissenschaftlichen Leitung finden Sie am Kurs der zertifizierten Fortbildung auf www.springermedizin.de/cme . Der Verlag: erklärt, dass für die Publikation dieser CME-Fortbildung keine Sponsorengelder an den Verlag fließen. Für diesen Beitrag wurden von den Autorinnen keine Studien an Menschen oder Tieren durchgeführt. Für die aufgeführten Studien gelten die jeweils dort angegebenen ethischen Richtlinien., (© 2024. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Purpose: This case report aims to describe a rare case of asymptomatic retained metallic intraocular foreign body (IOFB) in the retina with reduced full-field electroretinography (ff-ERG) in a Chinese woman., Methods: This is a clinical investigation of a patient who unexpectedly presented with a metallic IOFB at the superior-temporal region of the left eye ring during a brain computed tomography., Results: Her best-corrected visual acuity was 20/20 in both eyes. The dilated fundus photograph of the left eye revealed a metallic IOFB in the retina. She reported no ocular symptoms. A diagnosis of asymptomatic metallic IOFB was made definitely. The subsequent ff-ERG demonstrated subnormal amplitudes of dark and light adaption in the left eye, whereas responses were normal in the right eye., Conclusions: Our findings suggest the application of ff-ERG has important benefits for evaluating the visual function in patients with retained IOFB., Competing Interests: Declarations. Conflict of interest: The authors have no conflicts of interest to disclose. Ethical approval: The study was approved by the Institutional Review Board of Nanjing Lishui People's Hospital. Consent to participate: Informed written consent had been obtained from the patient. Statement of human rights: All procedures involving human participants were performed in accordance with the ethical standards of the Institutional and National Research Committee and the Declaration of Helsinki and its later amendments or comparable ethical standards. Statement on the welfare of animals: This study did not involve the use of animal subjects. Informed consent: Informed consent was obtained from the patient for publication of this case report., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: To describe the clinical and genetic features of Korean patients with peripheral retinal flecks unrelated to aging., Methods: A retrospective analysis was conducted on the clinical characteristics of patients with symmetric peripheral retinal flecks. Age-related deposits such as reticular pseudodrusen were excluded, as well as secondary deposits related to intraocular inflammation, tumor, and drug toxicity. Multimodal imaging, electrophysiological examinations, and genetic testing were analyzed., Results: A total of 10 patients (two men and eight women) with bilateral peripheral flecks were enrolled in this study. A mean age at diagnosis was 30.5 ± 19.6 years (range, 4-59 years). Within the 10 patients, six were genetically confirmed with monogenic retinal disorders. Biallelic pathogenic variants in RDH5 were found in five patients, and one patient was diagnosed with retinopathy related to Alport syndrome due to a pathogenic variant in COL4A5. Although not genetically confirmed, one case associated with nanophthalmos and another case showing chorioretinal mottling in a carrier of ocular albinism have been identified. In one patient, genetic testing also revealed unknown causes. The mean logarithm of the minimum angle of resolution initial visual acuity was 0.12 ± 0.18 and 0.07 ± 0.18 in right and left eyes, respectively. Night blindness was reported by four patients (40%), with three showing decreased or delayed rod response in electroretinogram, particularly those with RDH5 mutations. Differences in the deposit layers and the patterns of flecks were observed on multimodal imaging., Conclusions: In the study population, we observed various causes and clinical differences in the retinal fleck patterns among Koreans, including RDH5-related fundus albipunctatus and Alport syndrome. Despite reports of night blindness symptoms in some cases, all patients demonstrated satisfactory corrected visual acuity.

Retinal electrophysiological alterations are implicated in psychosis, but their relationship with cognition in early course psychosis (ECP) is understudied. The Brief Assessment of Cognition (BAC) and flash electroretinography (fERG) were conducted in 24 controls (HC) and 27 ECP individuals. Partial Spearman correlations were performed between fERG and BAC. Lower Photopic-1b and Scotopic-3b amplitudes were identified in ECP vs. HCs. Correlations were significant (p<0.05) between BAC Composite score and a-wave S3a and S2a and b-wave S2b and S3b conditions. Thus, ECP was characterized by lower ERG responses, and lower rod/cone/bipolar cell responses were related to poorer cognition., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests that could have influenced the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objective: To describe various presentations of autoimmune retinopathy (AIR) associated with systemic autoimmune diseases., Design: Case series., Patients and Methods: Four patients with systemic autoimmune disorders and AIR are described in this report. The clinical and multimodal imaging characteristics, systemic work-up, genetic testing results, management, and course of disease are detailed., Results: The multimodal retinal features of 4 cases of AIR including the findings of fundus autofluorescence, optical coherence tomography, and electrophysiology necessary to document progressive photoreceptor loss are described. Each case of AIR was associated with a complicated autoimmune disorder. Case 1 was associated with chronic inflammatory demyelinating polyneuropathy and showed marked improvement with systemic steroid and intravenous immunoglobulin therapy. Case 2 was associated with rheumatoid arthritis, and the AIR condition progressed despite systemic immune therapy. Case 3 was associated with Lambert-Eaton myasthenic syndrome, and AIR developed 6 years later and stabilized with systemic immune therapy. Case 4 was associated with necrobiotic xanthogranuloma followed by AIR and was managed by systemic immune therapy., Conclusions: AIR in association with these systemic conditions is rarely reported. Our cases highlight the gaps in our current understanding of the definition, systemic associations, pathogenesis, and management of AIR and the importance of multimodal imaging and a multidisciplinary approach in managing patients with suspected AIR., Competing Interests: Footnotes and Disclosure David Sarraf receives grants and personal fees from Amgen, personal fees from Bayer, grants and personal fees from Boehringer, grants from Genentech, personal fees from Novartis, personal fees and nonfinancial support from Visionix/Optovue, and nonfinancial support from Topcon. The remaining authors have no financial disclosures. Supported by: This work was supported by Research to Prevent Blindness (RPB) Inc (David Sarraf), New York, NY., (Published by Elsevier Inc.)

Introduction: Variants in the CABP4 gene cause a phenotype to be included in the spectrum of congenital stationary night blindness, though some reports suggest that the clinical abnormalities are more accurately categorized as a synaptic disease of the cones and rods. We report a novel homozygous nonsense variant in CABP4 in a patient complaining of non-progressive reduced visual acuity and photophobia but not nyctalopia., Methods: Complete ocular examination, fundus photographs, autofluorescence, optical coherence tomography, electroretinography, and targeted sequencing of known inherited retinal disease-associated genes., Results: A 25-year-old man monitored for 13 years complains of a lifelong history of stable reduced visual acuity (20/150), impaired color vision (1 of 14 plates), small-amplitude nystagmus, and photophobia without nyctalopia. He is also hyperopic (+7D), and his electroretinography shows significantly reduced rod and cone responses. Targeted genetic analysis revealed a novel homozygous variant in the CABP4 gene at c.181C>T, p. (Gln61*) underlying his clinical presentation., Conclusions: A novel variant in CABP4 is associated with stationary cone and rod dysfunction resulting in decreased acuity, color deficit, and photophobia, but not nyctalopia.

Purpose: To evaluate the efficacy of the dexamethasone implant on the electrophysiological profile of Diabetic Macular Oedema (DMO) patients over six months., Methods: In this prospective, single-center study 30 eyes of 22 patients were examined using comprehensive baseline assessments including best-corrected visual acuity (BCVA), central retinal thickness (CRT), contrast sensitivity (CS) and multifocal electroretinogram (mfERG), before and after 0.7mg dexamethasone implant injection, with follow-ups at months 1, 2, 4, and 6. The study employed mixed models to analyse within-subject and between-subject correlations, considering the complexities of multiple measurements per subject., Results: At baseline, BCVA was 0.66 ± 0.104 logMAR, improving to 0.568 ± 0.104 logMAR by month 6 (P > 0.05). CRT significantly reduced from 521 ± 28.7 μm to 336 ± 28.7 μm (P < 0.05). CS slightly increased from 26.8 ± 1.23 letters to 28.5 ± 1.05 letters (P > 0.05). P wave amplitude saw a notable rise from 33.4 ± 5.66 μV to 47.9 ± 5.43 μV (P < 0.05). P wave implicit time changed minimally from 47.4 ± 0.503 seconds to 48.0 ± 0.503 seconds (P > 0.05). No severe adverse events were recorded., Conclusion: These results underscore the 0.7mg dexamethasone implant's potential in improving certain electrophysiological markers in DMO, while also highlighting the need for further investigation into its comprehensive impact on retinal function., Competing Interests: The authors have no other conflict of interest to declare., (© 2024 Tranos et al.)

Background: Optical coherence tomography and electroretinography studies have revealed structural and functional retinal alterations in individuals with schizophrenia spectrum disorders (SSDs). However, it remains unclear which specific retinal layers are affected; how the retina, brain, and clinical symptomatology are connected; and how alterations of the visual system are related to genetic disease risk., Methods: Optical coherence tomography, electroretinography, and brain magnetic resonance imaging were applied to comprehensively investigate the visual system in a cohort of 103 patients with SSDs and 130 healthy control individuals. The sparse partial least squares algorithm was used to identify multivariate associations between clinical disease phenotype and biological alterations of the visual system. The association of the revealed patterns with individual polygenic disease risk for schizophrenia was explored in a post hoc analysis. In addition, covariate-adjusted case-control comparisons were performed for each individual optical coherence tomography and electroretinography parameter., Results: The sparse partial least squares analysis yielded a phenotype-eye-brain signature of SSDs in which greater disease severity, longer duration of illness, and impaired cognition were associated with electrophysiological alterations and microstructural thinning of most retinal layers. Higher individual loading onto this disease-relevant signature of the visual system was significantly associated with elevated polygenic risk for schizophrenia. In case-control comparisons, patients with SSDs had lower macular thickness, thinner retinal nerve fiber and inner plexiform layers, less negative a-wave amplitude, and lower b-wave amplitude., Conclusions: This study demonstrates multimodal microstructural and electrophysiological retinal alterations in individuals with SSDs that are associated with disease severity and individual polygenic burden., (Copyright © 2024 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Anesthetics are widely used in electrophysiological tests to assess retinal and visual system functions to avoid experimental errors caused by movement and stress in experimental animals. To determine the most suitable anesthetic for visual electrophysiological tests, excluding ketamine and chloral hydrate due to regulatory and side effect concerns, this study investigated the effects of ethyl carbamate (EC), avertin (AR), and pentobarbital sodium (PS) on visual signal conduction in the retina and primary visual cortex. Assessments included flash electroretinogram (FERG), pattern electroretinogram (PERG), pattern visual evoked potentials (PVEP), and flash visual evoked potentials (FVEP), FERG and FVEP were used to evaluate the responses of the retina and visual cortex to flash stimuli, respectively, while PERG and PVEP assessed responses to pattern stimuli. The research showed that AR demonstrates the least disruption to the visual signal pathway, as evidenced by consistently high characteristic peaks in the AR group across various tests. In contrast, mice given EC exhibited the lowest peak values in both FERG and FVEP, while subjects anesthetized with PS showed suppressed oscillatory potentials and PERG responses. Notably, substantial PVEP characteristic peaks were observed only in mice anesthetized with AR. Consequently, among the three anesthetics tested, AR is the most suitable for visual electrophysiological studies., Competing Interests: Declarations Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Diabetic retinopathy is a prevalent complication of type 2 diabetes mellitus, characterized by progressive damage to the retinal structure and function. Photobiomodulation therapy, using red or near-infrared light, has been proposed as a non-invasive intervention to mitigate retinal damage, but has been tested generally with short-term stimuli. This study aimed to evaluate the effects of prolonged photobiomodulation with deep red light on retinal structure and function in a type 2 diabetes mouse model. Transgenic LepRdb/J (db/db) mice were exposed to photobiomodulation therapy via LED devices emitting 654 nm light for 12 h daily over ten weeks and compared to untreated mice. Retinal function was evaluated by flash electroretinography, while structural changes were assessed through histology and immunohistochemistry to detect astro- and microgliosis. At 33 weeks of age, db/db mice were obese and severely diabetic, but exhibited only incipient indicators of retinal deterioration. Electroretinogram b-wave peak latencies were prolonged at intermediate flash intensities, while the outer plexiform layer displayed significantly elevated IBA1 expression. Photobiomodulation therapy prevented these two markers of early retinal deterioration but had no effect on other morphological and functional parameters. Photobiomodulation is well-tolerated and maintains potential as a complementary treatment option for diabetic retinopathy but requires further optimization of therapeutic settings and combinatory treatment approaches.

Mutations in PRPH2 are a relatively common cause of sight-robbing inherited retinal degenerations (IRDs). Peripherin-2 (PRPH2) is a photoreceptor-specific tetraspanin protein that structures the disk rim membranes of rod and cone outer segment (OS) organelles, and is required for OS morphogenesis. PRPH2 is noteworthy for its broad spectrum of disease phenotypes; both inter- and intra-familial heterogeneity have been widely observed and this variability in disease expression and penetrance confounds efforts to understand genotype-phenotype correlations and pathophysiology. Here we report the generation and initial characterization of a gene-edited animal model for PRPH2 disease associated with a nonsense mutation (c.1095:C>A, p.Y285X), which is predicted to truncate the peripherin-2 C-terminal domain. Young (P21) Prph2Y285X/WT mice developed near-normal photoreceptor numbers; however, OS membrane architecture was disrupted, OS protein levels were reduced, and in vivo and ex vivo electroretinography (ERG) analyses found that rod and cone photoreceptor function were each severely reduced. Interestingly, ERG studies also revealed that rod-mediated downstream signaling (b-waves) were functionally compensated in the young animals. This resiliency in retinal function was retained at P90, by which time substantial IRD-related photoreceptor loss had occurred. Altogether, the current studies validate a new mouse model for investigating PRPH2 disease pathophysiology, and demonstrate that rod and cone photoreceptor function and structure are each directly and substantially impaired by the Y285X mutation. They also reveal that Prph2 mutations can induce a functional compensation that resembles homeostatic plasticity, which can stabilize rod-derived signaling, and potentially dampen retinal dysfunction during some PRPH2-associated IRDs., (© The Author(s) 2024. Published by Oxford University Press.)

Purpose: To explore the effect of cobalt toxicity on vision., Methods: A total of 103 wild-type (WT) mice were injected with cobalt chloride by two routes in different concentrations: single intravenous (IV) high or low doses (total, n = 43); or daily repeated intraperitoneal (IP) high (three days) or low (28 days, 56 days) dose, and low-dose cobalt with added minocycline (56 days) (total, n = 60); 10 WT mice served as a control group. An additional group of 17 immunodeficient NOD scid gamma (NSG) mice were injected IV or IP with cobalt, and 10 NSG mice served as control. Cobalt levels were measured in blood, urine, and tears by particle-induced X-ray emission (PIXE). Macroscopic, immunohistochemical, electroretinography (ERG), and molecular studies were done., Results: PIXE revealed cobalt elimination from the blood by two hours, with increased levels in urine but under the detection limit in tears. In the retina, ERG recordings showed decreased b-wave amplitude. Apoptosis mainly involved the inner retina, with inner retinal inflammatory reaction in both WT and less in the NSG mice. In the optic nerves, an increased microglial and astrocytic activation was noted., Conclusions: This study demonstrated functional visual impairment with extensive inflammatory reaction secondary to cobalt toxicity in mice.

Purpose: Remyelination therapies are advancing for multiple sclerosis, focusing on visual pathways and using visual evoked potentials (VEPs) for de/remyelination processes. While the cuprizone (CZ) model and VEPs are core tools in preclinical trials, many overlook the posterior visual pathway. This study aimed to assess functional and structural changes across the murine visual pathway during de/remyelination., Methods: One group of C57BL/6 mice underwent a CZ diet for 6 weeks to simulate demyelination, with a subset returning to a regular diet to induce remyelination. An additional group was fed a protracted CZ diet for 12 weeks to maintain chronic demyelination. Visual function was evaluated using electrophysiological recordings, including scotopic threshold responses (STRs) and electroretinograms (ERGs), with VEPs serving as a key biomarker for overall pathway health. Tissues from eyes, brains, and optic nerves (ONs) were collected at different time points for structural analysis., Results: Our results demonstrated significant effects on VEPs, including increased N1 latencies and reduced amplitudes in the CZ mouse model. However, retinal function remained unaffected, as evidenced by unchanged STRs, ERGs, and retinal ganglion cell counts. Analysis of ONs revealed morphological changes, characterized by a significantly decreased axon diameter in the core region compared to the subpial region. Additionally, there was a significant increase in the g-ratio of the core region at 12 weeks CZ compared to controls. Immunofluorescence further demonstrated a decrease in myelin basic protein levels at 6 and 12 weeks in CZ animals. Interestingly, the dorsal lateral geniculate nucleus and primary visual cortex (V1) exhibited similar myelin changes, correlating with VEP latency alterations., Conclusions: These data reveal that interpreting VEP latency solely as a marker for ON demyelination is incomplete. Previous preclinical studies have overlooked the posterior visual pathways, necessitating a broader interpretation of VEP latency to cover the entire visual pathway.

Purpose: Diabetic retinopathy (DR) is a significant complication of diabetes mellitus that can lead to progressive visual impairment. This study aimed to elucidate the role of fibrinogen, a protein whose serum and intraocular concentrations are elevated in patients with diabetes and DR, in the pathogenesis of DR., Methods: The changes in the protein levels of the neuronal marker tubulin-β3 (TUBB3) and retinal response induced by the intravitreal injections of 1× phosphate-buffered saline, 40 mg/mL of fibrinogen, and 40 mg/mL of fibrinogen in combination with anti-intracellular adhesion molecule-1 (ICAM-1) antibody in normal mice were observed using immunofluorescence, western blotting, and electroretinography., Results: High concentrations of fibrinogen led to a decrease in the expression of TUBB3 in immunofluorescence and western blotting. The amplitudes of the positive scotopic threshold response and b-wave were notably reduced after the injection of fibrinogen, indicating potential damage to the retinal ganglion cells. The co-administration of anti-ICAM-1 antibody effectively mitigated these fibrinogen-induced changes, indicating that fibrinogen-induced damage is mediated via the ICAM-1 pathway., Conclusions: The present study underscores the significance of elevated intraocular fibrinogen levels as a pathogenic factor in DR. Involvement of the fibrinogen/ICAM-1 pathway presents new avenues for therapeutic intervention, especially in patients with treatment-resistant conditions.

Purpose: One of the strongest genetic associations with myopia is near the GJD2 gene. Recently, this locus was associated with cone-driven electroretinograms (ERGs), with findings highlighting OFF pathway signals specifically. The ERG i-wave is thought to originate in retinal OFF pathways. We explored this component and tested the hypothesis that it would be associated with the myopia risk locus., Methods: International standard LA3 ERGs, recorded with conductive fiber electrodes, were analyzed, first from patients with rare monogenic deficits impairing the ON pathway, or both ON and OFF pathways, to explore effects on the i-wave. Responses were then analyzed from adult participants from the TwinsUK cohort: i-wave amplitudes were measured by two investigators independently, blinded to genotype at the GJD2 locus. We investigated the association between i-wave amplitude and allelic identity at this locus, adjusting for age, sex, and familial relatedness., Results: Patient recordings showed the i-wave persisted in the absence of ON pathway signals, but was abolished when both ON and OFF pathways were impaired. For TwinsUK participants, recordings and genotypes were available in 184 individuals (95% female participants; mean standard deviation [SD] age, 64.1 [9.7] years). Mean (SD) i-wave amplitude was 14.5 (SD = 6.5) microvolts. Allelic dosage at the risk locus was significantly associated with i-wave amplitude (P = 0.027)., Conclusions: Patient ERGs were consistent with the i-wave arising from cone-driven OFF pathways. Amplitudes associated significantly with allelic dosage at the myopia risk locus, supporting the importance of cone-driven signaling in myopia development and further highlighting relevance of the OFF pathway in relation to this locus.

Purpose: CLN3 Batten disease (also known as juvenile neuronal ceroid lipofuscinosis) is a lysosomal storage disorder that typically initiates with retinal degeneration but is followed by seizure onset, motor decline and premature death. Patient-derived CLN3 disease induced pluripotent stem cell-RPE cells show defective phagocytosis of photoreceptor outer segment (POS). Because modifier genes are implicated in CLN3 disease, our goal here was to investigate a direct link between CLN3 mutation and POS phagocytosis defect., Methods: Isogenic control and CLN3 mutant stem cell lines were generated by CRISPR-Cas9-mediated biallelic deletion of exons 7 and 8. A transgenic CLN3Δ7-8/Δ7-8 (CLN3) Yucatan miniswine was also used to study the impact of CLN3Δ7-8/Δ7-8 mutation on POS phagocytosis. POS phagocytosis by cultured RPE cells was analyzed by Western blotting and immunohistochemistry. Electroretinogram, optical coherence tomography and histological analysis of CLN3Δ7-8/Δ7-8 and wild-type miniswine eyes were carried out at 6, 36, or 48 months of age., Results: CLN3Δ7-8/Δ7-8 RPE (CLN3 RPE) displayed decreased POS binding and consequently decreased uptake of POS compared with isogenic control RPE cells. Furthermore, wild-type miniswine RPE cells phagocytosed CLN3Δ7-8/Δ7-8 POS less efficiently than wild-type POS. Consistent with decreased POS phagocytosis, lipofuscin/autofluorescence was decreased in CLN3 miniswine RPE at 36 months of age and was followed by almost complete loss of photoreceptors at 48 months of age., Conclusions: CLN3Δ7-8/Δ7-8 mutation (which affects ≤85% of patients) affects both RPE and POS and leads to photoreceptor cell loss in CLN3 disease. Furthermore, both primary RPE dysfunction and mutant POS independently contribute to impaired POS phagocytosis in CLN3 disease.

Purpose: Growth hormone (GH) has neuroprotective effects that have not been evaluated in the mammalian visual system. This study tested the hypothesis that GH administration can promote retinal neuroprotection in an optic nerve crush (ONC) model in male rats., Methods: The ON was compressed for 10 seconds, and bovine GH was injected concomitantly to injury for 14 days (0.5 µg/g every 12 hours). At 24 hours and 14 days after ONC, we evaluated the effects of GH upon several markers by quantitative PCR (qPCR), Western blot, and immunohistochemistry; the ON integrity was assessed using CTB Alexa 488 anterograde tracer, and retinal function was tested by full-field electroretinogram., Results: GH partially prevented the ONC-induced death of retinal ganglion cells (RGCs), as well as the increase in gliosis marker GFAP at 14 days. Most of the ONC-induced changes in mRNA retinal levels of several neurotrophic, survival, synaptogenic, gliosis, and excitotoxicity markers were prevented by GH, both at 24 hours and 14 days, and treatment also stimulated the expression of antiapoptotic proteins Bcl-2 and Bcl-xL at 24 hours. Additionally, GH partially maintained the ON integrity and active anterograde transport, as well as retinal function by avoiding the reduced amplitude and slowing of the A- and B-waves and oscillatory potentials associated with the ONC at 14 days., Conclusions: GH has neuroprotective effects in the ONC model in male rats, it promoted RGC survival, gliosis reduction, and axonal transport increase, likely through the regulation of genes involved in neuroprotection, survival, and synaptogenesis. Furthermore, GH prevented functional impairment, indicating its potential as a therapeutic option for retinal neurodegenerative diseases.

Purpose: Optic nerve head (ONH) atrophy is frequently associated with hydrocephalic conditions. Cerebrospinal fluid (CSF)-containing meninges form a subarachnoid space that terminates at the ONH, which physically impacts it. This study aims to characterize optic neuropathy in congenital hydrocephalic mice with genetic disruption of the Ccdc13 gene., Methods: The ccdc13 germline knockout mice were generated. The hydrocephalus phenotype and subarachnoid space surrounding the optic nerve were evaluated using routine histology and Evans blue stain. Optic neuropathy was examined with immunohistochemistry and transmission electron microscopy (TEM). Axon transport was indicated by cholera toxin subunit B (CTB) fluorescence conjugate. Retinal function was evaluated by electroretinography (ERG), and Ccdc13 expression was revealed by a knock-in Gfp reporter., Results: Ccdc13 mutant mice manifested hydrocephalus at birth. ONH displacement, or negative cupping, and enlarged subarachnoid space at the optic terminus occurred as early as 1 month after birth. Intraocular pressure (IOP) was normal. Optic neuropathy was first observed at the ONH, followed by a distal-to-proximal progression of optic nerve pathology indicated by alteration of axonal ultrastructure and deposition of unphosphorylated neurofilament heavy chain. Anterograde axonal transport was also hampered. Retinal ganglion cell (RGC) function was compromised as early as postnatal day 21 (P21), along with reduced neurofilament heavy chain expression. Optic neuropathy caused by disruption of Ccd13 was non-cell autonomous, stemming from hydrocephalus with presumed high intracranial pressure (ICP), which physically impacts the ONH by increasing the translaminar pressure gradient., Conclusions: We provided knowledge of optic neuropathy from a congenital mouse model for hydrocephalus. The hydrocephalus in mice could damage the ONH by increasing the translaminar pressure gradient and negative cupping, leading to impairment in axoplasmic transport and RGC pathology. Our findings highlight the importance of the interplay between IOP and ICP in the development of glaucoma.

Purpose: People with multiple sclerosis (pwMS) experience autoimmunity-mediated inflammation and neurodegeneration throughout the central nervous system. There remains a need for clinically accessible, reliable functional markers of neurodegeneration in MS. Previous research has described changes to electroretinography (ERG)-derived measures of retinal bipolar cell function in pwMS early in the disease course. We, therefore, investigated ERG as a potential outcome measure in individuals with more advanced disease., Methods: This cross-sectional observational study included pwMS with Expanded Disability Status Scale (EDSS) scores of ≥3.0 and healthy control (HC) participants who underwent ERG, optical coherence tomography, high- and low-contrast visual acuity measurement, and an ophthalmological examination. ERG findings in MS eyes with and without previous optic neuritis (MS +ON; MS -ON) were compared with those in HC eyes. Effects of EDSS, disease duration, ON, and treatment status on selected ERG outcomes were measured. Additional exploratory analyses assessed potential influences of MS phenotype and disease status (clinically active, radiologically active, and disease progression)., Results: Delays to two ERG peak times (dark-adapted 3.0 b-wave; light-adapted flicker) were recorded in MS +ON and MS -ON eyes. No influences of EDSS score, disease duration, previous ON, or treatment status were observed. Exploratory analyses were consistent with no effects of MS phenotype or disease status., Conclusions: ERG findings are abnormal in individuals with moderate-severe disability caused by MS; however, these findings are not distinct from those observed earlier in the disease course. Although bipolar dysfunction appears to be common in pwMS throughout the disease course, ERG is likely not useful in monitoring or prognostication of MS.

This study demonstrated the functions and molecular mechanisms of the IL-33/ST2 axis in experimental optic neuropathy. C57BL/6J mice were used to establish an optic nerve crush (ONC) model. ONC mice were administered with IL-33 intraperitoneal injection, with PBS vehicle as control. Immunofluorescence, quantitative RT-PCR, and western blot techniques were utilized to assess the expression of the IL-33/ST2 axis. The electroretinography (ERG), optical coherence tomography (OCT), H&E, and luxol fast blue were used to assess the structural and functional changes. Western blot was employed to detect the activation of the mTOR/S6 pathway. The IL-33 expression level in the inner nuclear layer of the retina in ONC mice reached its peak on day 3, accompanied by a significant increase in IL-33 receptor ST2 expression. IL-33 treatment promoted the survival of retinal ganglion cells, restored the thickness of inner retina layer (IRL), alleviated the demyelination of the optic nerve, and recovered the decreased amplitude of b-wave in ONC mice. Furthermore, administration of IL-33 activated the mTOR/S6 signaling pathway in RGCs, which was significantly suppressed in the ONC condition. This study indicated that boosting the IL-33/ST2/mTOR/S6 pathway can protect against structural and functional damage to the retina and optic nerve induced by ONC. As a result, the IL-33/ST2 axis holds potential as a therapeutic option for treating various optic neuropathies., (Copyright © 2024. Published by Elsevier Ltd.)

This study aimed to investigate potential functional changes in retinal ganglion cells (RGCs) in a mouse model of hyperglycemia and explore possible therapeutic approaches. Hyperglycemia resembling type 1 diabetes mellitus (DM) was induced in C57BL/6 mice through intraperitoneal injection of streptozotocin (STZ). Blood glucose levels were confirmed to be elevated after 1 week and 4 weeks of injection. Mice with blood glucose levels above 350 mg/mL after 4 weeks of one-dose STZ injection were considered hyperglycemic. The light sensitivity of ON alpha (α) retinal ganglion cells (RGCs), not OFF αRGCs, was reduced in the hyperglycemic mouse model. The number of apoptotic cells, RGCs, and amacrine cells (ACs) remained unaffected at this stage. Similarly, the eletroretinogram (ERG) and optokinetic test results showed no significant differences. The application of picrotoxin (PTX) to block GABA receptors could increase the light sensitivity of ON αRGCs by 1 log unit in hyperglycemic mice. The results show that ON αRGCs may be more susceptible to microenvironmental changes caused by hyperglycemia than OFF αRGCs. This decline in light sensitivity may occur before cell apoptosis during the early stages of the hyperglycemic mouse model but has the potential to be reversed., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Oxygen-induced retinopathy (OIR) mouse model is widely used to study retinal neovascular diseases. Although the OIR procedure has been well established in detail, few studies to date have examined the effect of intravitreal injection using different-sized syringe needles at different time intervals after mouse pups returned to room air on this model. Initially, the significant reduction of NV and VO areas in the vehicle-controls of OIR drew our attention. We found that intravitreal injection performed using a 33 g-needle at 2 h after the pups returned to room air resulted in minimal NV and VO areas, causing a failure of OIR model. The results of ERG and OCT testing showed that 34 g-needle was more suitable than a 33 g-needle for intravitreal injection in the OIR model. We then investigated the effect of time interval after pups returned to room air on the OIR model. The results indicated that 8-24 h was a more suitable time for performing intravitreal injection. In conclusion, appropriate control of the effects of intravitreal injection on OIR requires attention to gauge of needle used, and the time interval after return of pups to room air., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Purpose: Achromatopsia (ACHM) is a genetically heterogenous relatively stationary congenital autosomal recessive cone disorder characterized typically by photophobia, low vision, nystagmus, hyperopia, grossly normal retinal appearance, and absent photopic responses by full-field electroretinography. Incomplete forms occur as well. This study investigates the genetic basis of clinically suspected ACHM in the United Arab Emirates., Methods: Retrospective case series (January 2016-December 2023) of patients with (1) clinically suspected ACHM or (2) mutations in ACHM-associated genes ( CNGA3 , CNGB3 , GNAT2 , PDE6C , PDE6H , AT6 )., Results: Twenty-two clinically suspected patients (19 probands) were identified. Biallelic disease genes and the number of probands were CNGA3 (9), CNGB3 (6), PDE6C (1), GNAT2 (1), RGS9BP (1), and CNNM4 (1). Some mutant alleles were recurrent across different families. Two probands had their diagnoses revised after genetic testing and phenotypic reassessment to RGS9BP -related bradyopsia and CNNM4 -related Jalili syndrome. Three additional cases (making 22 total probands) were identified from ACHM gene mutation review-one each related to PDE6C , to AT6 , and to CNGB3 in concert with CNGA3 (triallelic disease). All three presented with macular discoloration, an atypical finding for classic ACHM., Conclusion: CNGA3 was the single most frequent implicated gene. Bradyopsia and Jalili syndrome can resemble incomplete ACHM. Recurrent mutant alleles may represent founder effects. Macular discoloration on presentation can occur in PDE6C -related disease, AT6 -related disease, and triallelic CNGB3 / CNGA3 -related disease. The possibility for triallelic disease exists and requires genetic counseling beyond that of simple autosomal recessive inheritance.

Purpose: To investigate the clinical, functional, and imaging characteristics in patients affected by inherited retinal diseases associated with RDH5 and RLBP1 gene variants, and to report novel genotype-phenotype correlations., Design: Retrospective single-center cohort study., Methods: Twenty-two patients with molecularly confirmed RLBP1-associated retinopathy and 5 with RDH5-associated retinopathy. Medical records were reviewed to obtain data on family history and ophthalmologic examinations, including retinal imaging and full-field electroretinography (ffERG). Genotype was determined by targeted next-generation sequencing followed by confirmation and familial segregation by Sanger sequencing., Results: The median (interquartile ranges) age at baseline for the RDH5 and RLBP1 cohort was 44.6 (38.2-67.9) years and 36.9 (23.1-45.2) years, respectively. Macular atrophy (MA) was found in approximately 80% of eyes from both cohorts. The RLBP1 genotype was associated with a lower macular volume by 0.28 mm 3 (95% CI, -0.46 to -0.11; P = .005) compared to the RDH5 genotype. In both genotypic cohorts, we found a significant annual rate of macular volume loss, estimated at -0.007 mm 3 /y (95% CI, -0.012 to -0.001; P = .02), without any significant difference between the two genotypes. Three unrelated patients homozygous for the c.361C>T p.(Arg121Trp) RLBP1 variant showed minimal impairment of both the rod and cone systems function on ffERG and absence of MA., Conclusions: Progressive MA in addition to congenital night blindness can be identified in adult patients with RDH5-associated retinopathy. Vice versa, hypomorphic RLBP1 variants may cause milder retinal phenotypes rather than the typical severe rod-cone dystrophy with MA. These findings could prove beneficial to improve the prognostication of patients and help in designing future interventional trials., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: To describe different clinical presentations of a same NR2E3 recessive mutation in two families and within one family., Design: Interventional family study., Results: Our first case was a one-year-old male child with high hyperopia and refractive accommodative esotropia. In retinal examination, peri-papillary sub-retinal fibrosis with a helicoid configuration was observed in both eyes. The parents and the only sibling had no pathologic findings in the eyes. The child showed to have severely reduced responses in both photopic and scotopic electroretinogram components. In the genetic investigation, a homozygous autosomal recessive mutation in the NR2E3 gene (IVS1-2A > C) was discovered in the affected child, while the other family members were heterozygous for this mutation. We followed up with the patient for 3 years and no new lesion developed during this period. The second case was a 13-year-old male child referred to the retina clinic for decreased vision in the right eye. In retina examination, there were nummular pigmentary changes at the level of retinal pigment epithelium and along the vascular arcades with foveo-schitic changes in both eyes. A choroidal neovascularization (CNV) was noticed in the macula of his right eye. The genetic evaluation proved the same mutation in the NR2E3 gene as in the first case. Family history was remarkable for an uncle, an aunt, and two cousins with night blindness., Conclusion: Same NR2E3 gene mutation can cause heterogeneous clinical manifestations such as slight retinal changes in the absence of any visual symptoms to high hyperopia associated with helicoid peri-papillary sub-retinal fibrosis., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Purpose: Exfoliation syndrome (XFS) is a systemic connective tissue disorder with elusive pathophysiology. We hypothesize that a mouse model with elastic fiber defects caused by lack of lysyl oxidase like 1 (LOXL1 encoded by Loxl1), combined with microfibril deficiency due to Fbn1 mutation (encoding fibrillin-1, Fbn1 C1041G/+ ) will display ocular and systemic phenotypes of XFS., Methods: Loxl1 -/- was crossed with Fbn1 C1041G/+ to create double mutant (dbm) mice. Intraocular pressure (IOP), visual acuity (VA), electroretinogram (ERG), and biometry were characterized in 4 genotypes (wt, Fbn1 C1041G/+ , Loxl1 -/- , dbm) at 16 weeks of age. Optic nerve (ON) area was measured by ImageJ, and axon counting was achieved by AxonJ. Deep whole-body phenotyping was performed in wt and dbm mice. Two-tailed Student t test was used for statistical analysis., Results: There was no difference in IOP between the 4 genotypes. VA was significantly reduced only in dbm mice. The majority of biometric parameters showed significant differences in all 3 mutant genotypes compared with wt, and dbm had exacerbated anomalies compared with single mutants. Dbm mice showed reduced retinal function and significantly enlarged ON area compared with wt. Dbm mice exhibited severe systemic phenotypes related to abnormal elastic fibers, such as pelvic organ prolapse and cardiovascular and pulmonary abnormalities., Conclusions: Ocular and systemic findings in dbm mice support functional overlap between fibrillin-1 and LOXL1, 2 prominent components of exfoliation material. Although no elevated IOP or reduction of axon numbers was detected in dbm mice at 16 weeks of age, their reduced retinal function and enlarged ON area indicate early retinal ganglion cell dysfunction. Dbm mice also provide insight on the link between XFS and systemic diseases in humans. NOTE: Publication of this article is sponsored by the American Ophthalmological Society., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Myopia-26, a Mendelian form of early-onset high-myopia (eoHM) caused by mutations in the X-chromosomal ARR3 gene and predominantly affecting females, curiously, may provide an alternative route of investigation to unveil retinal mechanisms underlying pathological eye growth. We conducted a case-control cross-sectional prospective electrophysiological study in genetically characterized Myopia-26 patients (ARR3 heterozygous symptomatic females) compared with high myopes harboring intact ARR3 alleles and one carrier hemizygous male., Results: Participants were 26 volunteers: 10 healthy control females (E-CTRL, mean age = 31.5 ± 8.8 years), one healthy control male, one carrier male of the mutant ARR3 allele and 14 female eoHM patients (mean age = 27.0 ± 13.1 years) divided in two groups: seven without (M-CTRL) and seven with (MYP-26) genetic alteration in the ARR3 gene. The clinical evaluation included complete eye screening and full-field electroretinograms (ERGs) recorded from both eyes under mydriasis. Spherical equivalent was comparable (mean=-9.55 ± 2.46 and - 10.25 ± 3.22 for M-CTRL and MYP-26, respectively) and best corrected visual acuity (BCVA) was significantly different between M-CTRL and MYP-26 (1.0 vs. 0.406 ± 0.253, respectively). E-CTRL and M-CTRL showed similar light-adapted flash and flicker ERG amplitudes; however, the prior values were reduced by ~ 35% (a- and b-waves alike), the latter by ~ 55% in the MYP-26 group (F (2, 45)  > 21.821, p < 0.00001). Dark-adapted a-wave amplitudes were slightly reduced (by ~ 20%) in all myopic patients compared to E-CTRL, irrespective of the ARR3 genotype (E-CTRL vs. eoHM, p = 0.038)., Conclusions: The cone dysfunction observed in Myopia-26 patients is specifically linked to the mutation of ARR3, and is not the consequence of eoHM, i.e. elongation of the eye. It may play a role in myopic refractive error development through a yet unconfirmed pathomechanism., (© 2024. The Author(s).)

Aim: The aim of this study was to evaluate the potential protective effect of Qiju Granule in a rat model of age-related macular degeneration (AMD) and investigate the underlying mechanisms involved., Methods: Rats were injected intravenously with 40 mg/kg of sodium iodate (SI) to induce a dry AMD model. The rats in the treatment group received three different doses of Qiju Granule once a day via gavage, while the rats in the control group were given an equal volume of physiological saline. On day 14 and day 28 following the intervention, various methods were employed to evaluate retinal function and structure, including electroretinography (ERG), optical coherence tomography (OCT), and histological examination. The expression of glial fibrillary acidic protein (GFAP), basic fibroblast growth factor (bFGF), brain-derived neurotrophic factor (BDNF), and ciliary neurotrophic factor (CNTF) was assessed via immunofluorescence. Beyond immunofluorescence, the mRNA levels of bFGF, BDNF, and CNTF were quantitatively determined using real-time polymerase chain reaction (qRT-PCR)., Results: Rats treated with Qiju Granule exhibited significant improvements in both retinal function and structure compared to the model group. The most noteworthy effects were observed at a high dose of Qiju Granule. Furthermore, the expression levels of bFGF, BDNF, and CNTF were significantly unregulated in the treated groups compared to the model group., Conclusions: Qiju Granule demonstrated a protective effect on the retina in the SI-induced rat model of AMD. The protective mechanism may be attributed to the upregulation of retinal neurotrophic factors expression., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests related to this study. There are no financial or personal relationships with other people or organizations that could influence the conduct or interpretation of the research., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

To determine the characteristics of the changes in the amplitude of the flicker electroretinograms (ERGs) after combined cataract surgery and vitrectomy for an idiopathic epiretinal membrane (ERM). To accomplish this, we conducted a prospective study on 20 patients. Flicker ERGs and central macular thickness (CMT) were measured before the surgery (baseline), and at 1 week, 1 month, 3 months, and 6 months postoperatively. The mean amplitude of the flicker ERGs increased significantly by 63.5% at 1 week after surgery (P < 0.001) and then gradually decreased. The amplitude at 6 months was not significantly different from the baseline amplitude. This transient increase in the flicker ERG amplitudes after ERM surgery suggests that electrophysiologic evaluations of the therapeutic effects of vitrectomy should be performed 6 months postoperatively. The mean CMT decreased significantly at 1 week postoperatively (P < 0.001) and continued to decrease progressively over six months. The relative increase of amplitude at 1 week was significantly associated with the relative decrease of CMT at 6 months, and evaluation of retinal functional changes at 1 week may be able to predict the postoperative course of the ERM., (© 2024. The Author(s).)

Purpose: To define the location of mglur6 paralogs in the outer zebrafish retina and delineate their contribution to retina light responses across the visual spectrum., Methods: In situ hybridization and immunolocalization with custom-made antibodies were used to localize mglur6 transcripts, proteins, and additional components of the mGluR6 signaling complex. Gene editing was used to generate knockout mutants that were analyzed with white light and spectral electroretinography., Results: Both mglur6 paralogs colocalized with known downstream pathway genes, such as trpm1a, nyctalopin, and gnaoβ. All rod photoreceptors contacted mGluR6-positive cells, while cone connectivity presented a more complex situation with no red cones and only a few UV and blue-sensitive cones connecting to mGluR6a-positive bipolar cells. All cone subtypes contacted mGluR6b-positive cells with markedly fewer red-sensitive cones. Retinas of knockout animals displayed no morphologic alterations. While ERG responses were unaffected in mglur6a knockout animals, mglur6b mutants displayed decreased responses over all spectral wavelengths., Conclusions: We demonstrated that mGlurR6 signalplex components are similar in the zebrafish and the mammalian retina. Despite mglur6b knockout animals having significantly impaired ERG b-wave responses, a residual b-wave persists, even in double knockouts, suggesting additional pathway components yet to be identified.

Purpose: Retinal degeneration 1 and 10 (rd1 and rd10) mice are useful animal models of retinitis pigmentosa (RP) with rapidly and slowly progressive pathologies, respectively. Our study aims were to determine the effect of adeno-associated viral vector 2 (AAV2)-delivered multi-characteristic opsin (MCO-010; under the control of a metabotropic glutamate receptor-6 promoter enhancer) on the morphological and functional characteristics of vision in both rd1 and rd10 mice., Methods: Various retinal measures of MCO-010 transduction and electrophysiological, behavioral, and other routine blood analyses were performed in the rd1 and/or rd10 mice after intravitreal injection of 1 µL of MCO-010 or AAV2 vehicle. Functional tests included electroretinogram, visually evoked potential, and behavior assay (optomotor and water maze). Retinal thickness, intraocular pressure, and plasma cytokine levels were also determined., Results: Following intravitreal MCO-010 injection, approximately 80% of bipolar cells were transduced in the retina, and no alterations in retinal thickness were observed at 4 months post-injection. However, retinal thickness significantly decreased in control mice. MCO-010 treatment increased head movements and induced faster navigation of mice to the platform in a water-maze test. The MCO-010 gene therapy helped preserve visually evoked electrical response in the retina and visual cortex. No ocular toxicity, immunotoxicity, or phototoxicity was observed in the MCO-010-treated mice, even under chronic intense light conditions., Conclusions: Intravitreal MCO-010 was well tolerated in rd1 and rd10 mice models of RP, and it appeared to attenuate retinal photoreceptor degeneration based on retinal structure and functional outcome measures., Translational Relevance: As reported here, optogenetic treatment of the inner retina attenuates further retinal degeneration in addition to photosensitizing higher order neurons, and this disease-modifying aspect should be evaluated in optogenetic clinical trials.

Early-onset, severe retinal dystrophy can be isolated or syndromic, presenting as part of an underlying systemic disease. Mainzer-Saldino syndrome, a rare systemic ciliopathy characterized by skeletal and renal disease, is caused by recessive mutations in the intraflagellar transport 140 chlamydomonas homologue (IFT140) gene. We present a series of 13 cases of early-onset retinal dysfunction with confirmed IFT140 mutations from 8 unrelated Saudi families belonging to 3 well-known tribes. All carried the same homozygous missense IFT140 mutation (c.1990G>A; p.Glu664Lys) except for a single family, which included 4 affected subjects, 3 of whom were aborted fetuses, with compound heterozygous pathogenic IFT140 variants (c.1525-1G>A and c.1990G>A; p.Glu664Lys). Severe retinal dystrophy was present in all living subjects, phenotypically apparent as hyperopia, nystagmus, nyctalopia, poor vision and nonrecordable full-field electroretinography. All affected individuals had skeletal abnormalities, and neurological abnormalities were common, but there was no evidence of chronic renal failure., (Copyright © 2024 American Association for Pediatric Ophthalmology and Strabismus. Published by Elsevier Inc. All rights reserved.)

Purpose: To present a series of patients with RPE65-related retinal dystrophy showing a partial rescue of the full-field electroretinogram (ERG) following gene replacement therapy with voretigene neparovec-rzyl (Luxturna®)., Methods: This retrospective chart review examined 17 patients treated with voretigene neparovec-rzyl (VN) at the Casey Eye Institute (2018-2022). The last pre-operative ERG and all available post-operative ERGs were analyzed to identify subjects with functional rescue. Measurements of amplitudes and implicit times were compared to data from age-matched controls and the attenuation relative to the lower limit of normal (LLN) was calculated. For comparison with other functional exams, the last pre-operative and all post-treatment best-corrected visual acuity (BCVA) data, visual field (VF) tests and full-field threshold stimulus tests (FST) were also described., Results: Of patients who underwent ERGs, most had unrecordable ERGs that did not change after treatment. However, we identified three patients, treated bilaterally, who demonstrated partial rescue of the full-field ERG in both eyes which was sustained during the course of the study., Conclusions: This is the largest series of patients treated with VN showing a partial rescue of the ERG. This is also the first report of bilateral ERG rescue, as well as the first description of ERG recovery occurring in non-pediatric subjects. Full-field ERG could be used in combination with other psychophysical tests and imaging modalities to detect and deepen our understanding of the response to this gene therapy approach., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Biallelic pathogenic variants in CDH23 can cause Usher syndrome type I (USH1), typically characterized by sensorineural hearing loss, variable vestibular areflexia, and a progressive form of rod-cone dystrophy. While missense variants in CDH23 can cause DFNB12 deafness, other variants can affect the cadherin 23 function, more severely causing Usher syndrome type I D. The main purpose of our study is to describe the genotypes and phenotypes of patients with mild retinitis pigmentosa (RP), including sector RP with two pathogenic variants in CDH23 ., Materials and Methods: Clinical examination included medical history, comprehensive ophthalmologic examination, and multimodal retinal imaging, and in case 1 and 2, full-field electroretinography (ERG). Genetic analysis was performed in all cases, and segregation testing of proband relatives was performed in case 1 and 3., Results: Three unrelated cases presented with variable clinical phenotype for USH1 and were found to have two pathogenic variants in CDH23 , with missense variant, c.5237 G > A: p.Arg1746Gln being common to all. All probands had mild to profound hearing loss. Case 1 and 3 had mild RP with mid peripheral and posterior pole sparing, while case 2 had sector RP. ERG results were consistent with the marked loss of retinal function in both eyes at the level of photoreceptor in case 1 and case 2, with normal peak time in the former., Conclusion: Patients harbouring c.5237 G > A: p.Arg1746Gln variants in CDH23 can present with a mild phenotype including sector RP. This can aid in better genetic counselling and in prognostication.

Our previous studies have shown the benefit of intravitreal injection of a mesenchymal stem cell (MSC)- derived secretome to treat visual deficits in a mild traumatic brain injury (mTBI) mouse model. In this study, we have addressed whether MSC-derived extracellular vesicles (EV) overexpressing miR424, which particularly targets neuroinflammation, show similar benefits in the mTBI model. Adult C57BL/6 mice were subjected to a 50-psi air pulse on the left side, overlying the forebrain, resulting in mTBI. Sham-blast mice were controls. Within an hour of blast injury, 3 μl (∼7.5 × 10 8 particles) of miR424-EVs, native-EVs, or saline was delivered intravitreally. One month later, retinal morphology was observed through optical coherence tomography (OCT); visual function was assessed using optokinetic nystagmus (OKN) and electroretinogram (ERG), followed by immunohistological analysis. A separate study in adult mice tested the dose-response of EVs for safety. Blast injury mice with saline showed decreased visual acuity compared with the sham group (0.30 ± 0.03 vs. 0.39 ± 0.01 c/d, p < 0.02), improved with miR424-EVs (0.39 ± 0.02 c/d, p < 0.01) but not native-EVs (0.33 ± 0.04 c/d, p > 0.05). Contrast sensitivity thresholds of blast mice receiving saline increased compared with the sham group (85.3 ± 5.9 vs. 19.9 ± 4.8, %, p < 0.001), rescued by miR424-EVs (23.6 ± 7.3 %, p < 0.001) and native-EVs (45.6 ± 10.7 %, p < 0.01). Blast injury decreased "b" wave amplitude compared to sham mice (94.6 ± 24.0 vs. 279.2 ± 25.3 μV, p < 0.001), improved with miR424-EVs (173.0 ± 27.2 μV, p < 0.03) and native-EVs (230.2 ± 37.2 μV, p < 0.01) with a similar decrease in a-wave amplitude in blast mice improved with both miR424-EVs and native-EVs. Immunohistology showed increased GFAP and IBA1 in blast mice with saline compared with sham (GFAP: 11.9 ± 1.49 vs. 9.1 ± 0.8, mean intensity/100,000 μm 2 area, p < 0.03; IBA1: 36.08 ± 4.3 vs. 24.0 ± 1.54, mean intensity/100,000 μm 2 area, p < 0.01), with no changes with native-EVs (GFAP: 12.6 ± 0.79, p > 0.05; IBA1: 32.8 ± 2.9, p > 0.05), and miR424-EV (GFAP: 13.14 ± 0.76, p > 0.05; IBA1: 31.4 ± 2.7, p > 0.05). Both native-EVs and miR424-EVs exhibited vitreous aggregation, as evidenced by particulates in the vitreous by OCT, and increased vascular structures, as evidenced by αSMA and CD31 immunostainings. The number of capillary lumens in the ganglion cell layer increased with increased particles in the eye, with native EVs showing the worst effects. In conclusion, our study highlights the promise of EV-based therapies for treating visual dysfunction caused by mTBI, with miR424-EVs showing particularly strong neuroprotective benefits. Both miR424-EVs and native-EVs provided similar protection, but issues with EV aggregation and astrogliosis or microglial/macrophage activation at the current dosage call for improved delivery methods and dosage adjustments. Future research should investigate the mechanisms behind EVs' effects and optimize miR424 delivery strategies to enhance therapeutic outcomes and reduce complications., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Purpose: Our aim was to explore the effect of ambient lighting on the pattern ERG (PERG)., Methods: We compared PERGs recorded in two conditions; room lights on and room lights off. PERGs from 21 adult participants were recorded from each eye to high contrast checks of 50' side width, reversing 3rps in a large (30°) and then standard (15°) field. This was performed first in lights-ON conditions, then 2 min after the room lights were switched off. A minimum of 2 averages of 300 trials were acquired for each condition. A subset of 10 participants had PERGs recorded to a 50' check width with a range of stimulus contrasts (96-18%), also to a range of different check widths (100'-12') at high contrast in both ambient lighting conditions in a 30° field., Results: The lights-ON P50 median peak time (PT) was 3 ms earlier than the lights-OFF P50 from the 30° field (range 0-5 ms) and 15° field (range 0-6 ms). The earlier lights-ON P50 PT was evident at different stimulus contrasts, even after accounting for stimulus contrast reductions associated with stray ambient lighting in lights-ON conditions. Lights-OFF and lights-ON P50 PT were similar to different check widths; the lights-OFF P50 PT to a 50' check width matched the lights-ON P50 PT to a 25' check width., Conclusion: PERG P50 PT in lights-ON ambient light conditions can be earlier than in lights-OFF ambient light conditions. The difference in P50 PT with ambient light may reflect alterations in spatial sensitivity associated with retinal adaptation. These results emphasise the clinical importance of consistent ambient lighting for PERG recording and calibration., (© 2024. The Author(s).)

Usher syndrome (USH) is a recessive genetic disorder manifested by congenital sensorineural hearing loss and progressive retinitis pigmentosa, which leads to audiovisual impairment. We report a patient with Usher syndrome type 1 with new compound heterozygous MYO7A variants. A total of four members from the USH family were included. Medical history and retinal examinations were taken and genomic DNA from peripheral blood was extracted in the proband and other members. 381 retinal disease-associated genes were screened using targeted sequence capture array technology and Sanger sequencing was used to confirm the screening results. Scanning laser ophthalmoscope showed bone spicule pigmentary deposits in the mid-peripheral retina and whitish and thin retinal blood vessels especially in the arterioles. Optical coherence tomography showed that the centrality of the macular ellipsoid band disappeared in both eyes, and only remained near the fovea. Visual field examination showed a progressive loss of the visual field in a concentric pattern in both eyes. The electroretinography showed a significant decrease in the amplitudes of a- and b-waves in the scotopic and photopic condition. DNA sequencing identified the compound heterozygous variants including c.1003+1G > A: p. (?) and c.5957&#95;5958del: p.G1987Lfs*50 of MYO7A, with the latter being novel. In this study, we found a novel compound heterozygous variant in MYO7A, which enriched the mutation spectrum and expanded our understanding of the heterogeneity of phenotype and genotype of Usher syndrome type 1., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Purpose: To present the clinical characteristics, retinal features, natural history, and genetics of RPGRIP1-associated early-onset severe retinal dystrophy (EOSRD)/Leber congenital amaurosis (LCA)., Design: Retrospective case series., Methods: Review of clinical notes, multimodal retinal imaging, and molecular diagnosis of 18 patients (17 families) with EOSRD/LCA and disease-causing variants in RPGRIP1., Results: The mean age of visual symptoms onset was 0.87 ± 1 year (birth to 3 years), and the mean age at baseline visit was 11.4 ± 10.2 years (1-39 years). At the baseline visit, 44% of patients were legally blind (range, 2-39 years), and there was no significant association found between age and best-corrected visual acuity (BCVA) in cross-sectional analysis. Retinal evaluation showed an abolished electroretinogram or a cone-rod dystrophy pattern, no or minimal pigment deposits, a hyperautofluorescent ring at the posterior pole, and a largely preserved central macular architecture, with retained outer nuclear layer and ellipsoid zone island into adulthood. Eleven variants (48%) were previously unreported, and 13 families (76%) had a double-null (DN) genotype. Twelve patients (67%) had follow-up assessments over a 15.7 ± 9.5-year period. The rate of BCVA decline was 0.02 logarithm of the minimum angle of resolution (1 letter)/year., Conclusions: RPGRIP1 EOSRD/LCA often presents at birth or early infancy, with nystagmus, decreased visual acuity, hyperopia, and photophobia. Patients with a DN genotype may develop symptoms earlier and have worse vision. Multimodal imaging may show a hyperautofluorescent posterior pole ring and relatively preserved central macular architecture, suggesting that the condition is a promising candidate for gene supplementation., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: Bardet-Biedl Syndrome (BBS) is an autosomal recessive disorder characterized by pleiotropism that affects multiple organ systems. The primary features of BBS include rod-cone dystrophy, renal anomalies, post axial polydactyly, and neurologic deficits. The clinical picture of BBS is extensively heterogenous, with inter and intra familial patients varying in levels of syndromic manifestations and severity of symptoms., Methods: In this study we examined a monocular BBS patient who was compound heterozygous for mutations in the ARL6 (BBS3) gene., Results: The patient reported visual complaints consistent with a clinical picture of cone or cone-rod dystrophy. Fundus imaging showed retinal mottling on color photos and a parafoveal hyperfluorescent ring on short wave autofluorescence (SW-AF). Full field electroretinogram (ffERG) revealed normal scotopic step tracings and diminished amplitudes in the photopic steps., Conclusion: This rod-sparing result was consistent with cone-dystrophy and is the first known case of a rod-sparing ffERG phenotype in a BBS patient with mutations in the ARL6 gene. This contributes to the existing phenotype and may potentially contribute to furthering our understanding of BBS pathophysiology., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: This study aimed to characterize the clinical features, genetic findings, and genotype-phenotype correlations of patients with Leber congenital amaurosis (LCA) or early-onset severe retinal dystrophy (EOSRD) harboring biallelic AIPL1 pathogenic variants., Design: Retrospective case series., Methods: This study consecutively enrolled 51 patients from 47 families with a clinical diagnosis of LCA/EOSRD harboring disease-causing variants in the AIPL1 gene, from October 2021 to September 2023. Molecular genetic findings, medical history, and ophthalmic evaluation including visual acuity (VA), multimodal retinal imaging, and electrophysiologic assessment were reviewed., Results: Of the 51 patients (32 with LCA and 19 with EOSRD), 27 (53%) were females, and age at last review ranged from 0.5 to 58.4 years. We identified 28 disease-causing AIPL1 variants, with 18 being novel. In patients with EOSRD, the mean (range) VA was 1.3 (0.7-2.7) logMAR and 1.3 (0.5-2.3) logMAR for right and left eyes respectively, with an average annual decline of 0.03 logMAR (R 2 = 0.7547, P < .01). For patients with LCA, the VA ranged from light perception to counting fingers. Optical coherence tomography imaging demonstrated preservation of foveal ellipsoid zone in the 5 youngest EOSRD patients and 9 LCA children. Electroretinography showed severe cone-rod patterns in 78.6% (11/14) of patients with EOSRD, while classical extinguished pattern was documented in all patients with LCA available for the examination. The most common mutation was the nonsense variants of c.421C>T, with an allele frequency of 53.9%. All patients with EOSRD carried at least one missense mutation, of whom 13 identified with c.152A>G and 5 with c.572T>C. Twenty-six patients with LCA harbored two null AIPL1 variants, while 18 were homozygous for c.421C>T and 6 were heterozygous for c.421C>T with another loss-of-function variant., Conclusions: This study reveals distinct clinical features and variation spectrum between AIPL1-associated LCA and EOSRD. Patients harboring at least one nonnull mutation, especially c.152A>G and c.572T>C, were significantly more likely to have a milder EOSRD phenotype than those with two null mutations. Residual foveal outer retinal structure observed in the youngest proportion of patients suggests an early window for gene augmentation therapy., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objectives: Animal studies have suggested that dietary iron deficiency (ID) negatively affects dopamine (DA) synthesis and re-uptake, which in turn negatively affects memory and cognition. This study was intended to assess whether the pattern electroretinogram (pattern ERG) could be used as an indirect measure of DA in college-age women with and without ID by determining the extent to which features of the ERG were sensitive to iron status and were related to other indirect measures of DA., Methods: The pattern ERG was measured in 21 iron deficient non-anemic (IDNA) and 21 iron sufficient (IS) women, who also performed a contrast detection and probabilistic selection task, both with concurrent electroencephalography (EEG). Both spontaneous and task-related blink rates were also measured., Results: The implicit times of the A- and B-waves were significantly longer for the IDNA than for the IS women. Both the amplitudes and implicit times of the A- and B-waves were significantly correlated with levels of serum ferritin (sFt). Only the amplitude of the A-wave was correlated with spontaneous blink rate. It was possible to accurately identify a woman's iron status solely on the basis of the implicit time of the B-wave. Finally, the implicit times of the ERG features mediated the relationship between iron levels and accuracy in the probabilistic selection task., Conclusions: Results suggest the utility of the pattern ERG in testing the hypothesis that iron deficiency affects DA levels in humans and that this may be one of the mechanisms by which iron deficiency negatively affects cognition.

Purpose: To gain an insight into the pathophysiology of RAB28- associated inherited retinal degeneration through detailed phenotyping and long-term longitudinal follow-up., Methods: The patient underwent complete ophthalmic examinations. Visual function was assessed with microperimetry, full-field electroretinography (ffERG), imaging with optical coherence tomography (OCT), short-wave (SW), and near-infrared (NIR) fundus autofluorescence (FAF)., Results: A healthy Haitian woman with homozygous pathogenic variants (c.68C > T; p.Ser23Phe) in RAB28 presented at 16 years of age with a four-year history of blurred vision. Visual acuities were 20/125 in each eye, which remained relatively stable since. At age 27, cone ffERGs were non-detectable and borderline for rod-mediated responses. Kinetic fields were full to a V-4e target, undetectable to a small I-4e stimulus. Microperimetry showed an absolute central scotoma surrounded by a pericentral relative scotoma. SD-OCT showed an undetectable or barely detectable foveal and parafoveal photoreceptor outer nuclear layer (ONL), photoreceptor outer segment (POS), and retinal pigment epithelium (RPE) signals and loss of the SW- and NIR-FAF signals. This atrophic region was separated from a normally laminated retina by a narrow transition zone (TZ) of hyper SW- and NIR-FAF that co-localized with preserved ONL but abnormally thinned POS and RPE. There was minimal centrifugal (<100 μ m) expansion over a six-year period., Conclusion: The cone-rod dystrophy phenotype documented herein supports a critical role of RAB28 for cone function and POS maintenance. Severe central photoreceptor and RPE loss with a predilection for POS loss in TZs suggests possible disruptions of complex mechanisms that maintain central cone photoreceptor and RPE homeostasis.

Aging is accompanied by an increased prevalence of degenerative conditions, including those affecting ocular health, which significantly impact quality of life and increase the burden on healthcare systems. Among these, retinal aging is of particular concern due to its direct link to vision impairment, a leading cause of disability in the elderly. Vision loss in the aging population is associated with heightened risks of cognitive decline, social isolation, and morbidity. This study addresses the critical gap in our understanding of modifiable lifestyle factors, such as physical exercise, that may mitigate retinal aging and its related pathologies. We investigated the effects of different exercise regimens-voluntary (recreational-type) and forced (high-intensity)-on the retinal health of aging Wistar rats (18-month-old), serving as a model for studying the translational potential of exercise interventions in humans. Male Wistar rats were divided into four groups: a young control (3-month-old) for baseline comparison, an aged sedentary control, an aged group engaging in voluntary exercise via a running wheel in their cage, and an aged group subjected to forced exercise on a treadmill for six sessions of 20 min each per week. After a 6-month experimental period, we assessed retinal function via electroretinography (ERG), measured retinal thickness histologically, and analyzed protein expression changes relevant to oxidative stress, inflammation, and anti-aging mechanisms. Our findings reveal that voluntary exercise positively impacts retinal function and morphology, reducing oxidative stress and inflammation markers while enhancing anti-aging protein expression. In contrast, forced exercise showed diminished benefits. These insights underscore the importance of exercise intensity and preference in preserving retinal health during aging. The study highlights the potential of recreational physical activity as a non-invasive strategy to counteract retinal aging, advocating for further research into exercise regimens as preventative therapies for age-related ocular degenerations., (© 2024. The Author(s).)

Ceramides with varying acyl-chain lengths can have unique biological actions and hence, cellular responses to ceramides may depend not on their overall concentration but on that of individual ceramide species. The purpose of this study was to determine individual ceramide species impacting retinal ganglion cell (RGC) loss under the ocular hypertensive condition. Induced pluripotent stem cell (iPSC)-derived RGCs and primary cultures of human astrocytes were used to determine the effect of individual ceramide species on both RGC viability and astrocyte secretion of inflammatory cytokines in vitro. In in vivo experiments with wild-type (WT) and ceramide synthase 5 (CerS5) knockout mice, intraocular pressure was unilaterally elevated with microbead injection. Retinal function and morphology were evaluated using pattern electroretinography (pERG) and immunofluorescence, respectively. Ceramide levels were determined by LC-MS/MS analysis. Exposure to C16:0-, C18:0-, C18:1-, C20:0- and C24:0-ceramides significantly reduces RGC viability in vitro, with the very long chain C24:0-ceramide being the most neurotoxic; treatment with C18:0-, C18:1- and C24:0-ceramides stimulates an increase of TNF-α secretion by astrocytes. The retinas of CerS5 KO mice have significantly reduced levels of C16:0- and C18:1-ceramides compared to WT; ocular hypertensive eyes of these mice maintain higher pERG amplitudes and RGC numbers compared to WT. Individual ceramides with different chain lengths have different effects on RGCs and astrocytes. Our results demonstrate that suppressing C16:0- and C18:1-ceramide species effectively protects RGCs against ocular hypertensive injury. These results provide a basis for targeting specific ceramide species in the treatment of glaucoma., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Purpose: To explore patterns of disease expression in Alagille syndrome (ALGS)., Methods: Patients underwent ophthalmic examination, optical coherence tomography (OCT) imaging, fundus intravenous fluorescein angiography (IVFA), perimetry and full-field electroretinograms (ffERGs). An adult ALGS patient had multimodal imaging and specialized perimetry., Results: The proband (P1) had a heterozygous pathogenic variant in JAG1 ; (p.Gln410Ter) and was incidentally diagnosed at age 7 with a superficial retinal hemorrhage, vascular tortuosity, and midperipheral pigmentary changes. The hemorrhage recurred 15 months later. Her monozygotic twin sister (P2) had a retinal hemorrhage at the same location at age 11. Visual acuities for both patients were 20/30 in each eye. IVFA was normal. OCT showed thinning of the outer nuclear in the peripapillary retina. A ffERG showed normal cone-mediated responses in P1 (rod-mediated ERGs not documented), normal ffERGs in P2. Coagulation and liver function were normal. An unrelated 42-year-old woman with a de-novo pathogenic variant (p. Gly386Arg) in JAG1 showed a similar pigmentary retinopathy and hepatic vascular anomalies; rod and cone function was normal across large expanses of structurally normal retina that sharply transitioned to a blind atrophic peripheral retina., Conclusion: Nearly identical recurrent intraretinal hemorrhages in monozygotic twins with ALGS suggest a shared subclinical microvascular abnormality. We hypothesize that the presence of large areas of functionally and structurally intact retina surrounded by severe chorioretinal degeneration, is against a predominant involvement of JAG1 in the function of the neurosensory retina, and that instead, primary abnormalities of chorioretinal vascular development and/or homeostasis may drive the peculiar phenotypes.

Purpose: Vitamin A is a lipid-soluble compound that is critical in maintaining phototransduction. Ocular manifestations of hypovitaminosis A may present with anterior segment signs of xeropthalmia, with advanced cases also causing classic retinal and electrophysiologic changes of vitamin A deficiency retinopathy. We present a case of vitamin A deficiency retinopathy, with corresponding retinal imaging and electrophysiology, in an adult patient with celiac disease and liver fibrosis., Methods: A single case report was conducted in Toronto, Canada., Results: A 77-year-old male with known celiac disease and liver fibrosis presented progressively worsening vision noticed primarily when driving. Vision was 20/50 OD and 20/200 OS. Bitot spots were noted on anterior segment examination. Fundus photography demonstrated bilateral peripheral macular hypopigmentation and far-peripheral granular retinal hypopigmentation with focal yellow dots and hyper-pigmented deposits. Optical coherence tomography (OCT) imaging demonstrated indistinct outer retinal banding with mild outer nuclear layer thinning, focal hyper-reflective deposits, and a thin choroid bilaterally. Full-field electroretinography (ERG) testing demonstrated reduced rod-isolated and combined rod-cone response amplitudes, and multifocal ERG testing demonstrated blunted individual responses throughout the field. The patient was treated with pulse vitamin A therapy. After 6 months of therapy, ERG responses were back within reference range, and the outer retinal changes reversed; visual acuity improved to 20/30 OD and 20/40 OS., Conclusion: This case represents the classic findings of vitamin A deficiency retinopathy on fundus examination and electrophysiologic testing secondary to gastrointestinal pathology. Prompt treatment of high dose vitamin A supplementation led to improvement of full-field and multifocal ERG results, as well as reconstitution of outer retinal architecture., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)