Papilledema describes optic nerve head (ONH) swelling due to raised intracranial pressure which can lead to complications including visual loss. Differentiating it from pseudopapilledema is often challenging and may require invasive investigations. Optical Coherence Tomography (OCT) is a non-invasive imaging modality, allowing visualisation of the ONH. We identified OCT-derived biomarkers for papilledema and pseudopapilledema in the existing literature. 213 patients with confirmed papilledema, optic disc drusen (ODD), tilted optic discs (TOD) or crowded optic discs (COD) were included. OCT scans were analysed for qualitative and quantitative biomarkers, with sensitivity, specificity, and AUC calculated for individual and combined biomarkers. Logistic regression modelling including qualitative biomarkers to differentiate papilledema from ODD and COD demonstrated a sensitivity and specificity of 89% and AUC of 0.96. Inclusion of TOD reduced the sensitivity of the model to 66%. In a model differentiating papilledema from TOD, the best-performing biomarker achieved a sensitivity of 87%, specificity of 61% and AUC of 0.83. Using qualitative biomarkers, we identified a model with high sensitivity and specificity to differentiate papilledema from ODD and COD. Quantitative biomarkers displayed high AUCs for differentiating TOD from papilledema. Our findings show that OCT demonstrates promising utility in differentiating papilledema from pseudopapilledema.

Purpose:To define the genetic architecture of foveal morphology and explore its relevance to foveal hypoplasia (FH), a hallmark of developmental macular disorders. Methods:We applied deep-learning algorithms to quantify foveal pit depth from central optical coherence tomography (OCT) B-scans in 61,269 UK Biobank participants. A genome-wide association study (GWAS) was conducted using REGENIE, adjusting for age, sex, height, and ancestry. Rare coding variants (frequency <1%) were analyzed in an exome-wide rare-variant association study (RVAS). Candidate genes were prioritized using integrative mapping; pathway, cross-ancestry, and genetic-correlation analyses were exploratory. Results:GWAS identified 126 sentinel variants, including 47 novel associations. Integrative mapping prioritized 129 putative causal genes, with 64 not previously implicated in foveal biology. Enriched pathways included retinoic acid metabolism (e.g., CYP26A1), photoreceptor differentiation (e.g., VSX2), extracellular matrix organization, and pigmentation. RVAS identified missense variants in ACTN3 and ESYT3 (P < 5 × 10-⁹) associated with FH features. Polygenic scores were predictive across African and South Asian ancestries. Overlap was observed with monogenic FH genes (TYR, OCA2, PAX6, AHR) and with genes underlying systemic diseases (COL11A1, KIF11, TUBB4B, PHYH). Re-examination of OCTs in affected individuals confirmed FH in select cases, including those with recurrent TUBB4B p.(Arg390Trp) variants. Conclusions:This is the first GWAS of human foveal morphology. Our findings redefine the genetic and biological framework underlying normal foveal development and foveal hypoplasia (FH). By linking common variation to rare monogenic disease, we establish a continuum model of FH with implications for future mechanistic and clinical investigation.

center dot OBJECTIVE: To evaluate optic nerve head (ONH) morphology in children with craniosynostosis versus healthy controls. center dot DESIGN: Single-center, prospective cohort study. center dot METHODS: Handheld optical coherence tomography (OCT) was performed in 110 eyes of 58 children (aged 0-13 years) with craniosynostosis. Inclusion criteria were as follows: normal intracranial pressure on invasive overnight monitoring, or clinically stable intracranial pressure. The latter was defined as stable VA within 1 logMAR line and no papilledema on fundoscopy for at least 4 months following OCT, and normal/stable visual evoked potentials. Control data for 218 eyes of 218 children were obtained from a published normative dataset. The main outcome measures were disc width, cup width, rim width, and retinal nerve layer thickness (nasal and temporal). Outcome measures were compared using three-way linear mixed model regression analysis (fibroblast growth factor receptor [FGFR] 1/2-associated craniosynostosis, non-FGFR 1/2-associated craniosynostosis, and controls). center dot RESULTS: Out of 63 eligible children with craniosynostosis, handheld OCT imaging was successful in 110 eyes of 58 children (92%). Of these, 22 (38%) were female. Median subject age at OCT examination was 53 months (range: 2-157; IQR: 39-73). Twelve children (21%) had FGFR1/2-associated syndromes (Crouzon, n = 6; Apert, n = 4; Pfeiffer, n = 2). Control data were available for 218 eyes of 218 healthy children. 122 controls (56%) were female. Median control age at OCT examination was 20 months (range: 0-163; IQR: 6-59). When comparing ONH morphology in craniosynostosis (n = 58) versus controls (n = 218), disc width was 6% greater (P = .001), temporal cup width was 13% smaller (P = .027), rim width was 16% greater (P < .001) and temporal retinal nerve fiber layer was 11% smaller (P = .027). When comparing FGFR1/2-associated syndromes (Crouzon, Apert, and Pfeiffer syndromes, n = 12) to the rest of the craniosynostosis group (n = 46), disc width was 10% smaller (P = .014) and temporal cup width was 38% smaller (P = .044). center dot CONCLUSIONS: This cohort demonstrated morphological differences of the ONH in craniosynostosis, most markedly in Crouzon, Apert, and Pfeiffer syndromes. These findings could help improve ophthalmological monitoring and surgical decision-making in children with craniosynostosis. Further work on longitudinal ONH changes in syndromic and nonsyndromic craniosynostosis would be valuable. (c) 2024 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/ )

Here we report the first genome-wide association study of foveal pit depth. In a cohort of 61,269 individuals, we identified 123 genome-wide significant loci associated with pit depth, including 47 novel associations not previously linked to macular traits. Using 12 complementary variant-to-gene mapping strategies, we prioritised 128 putative causal genes, 64 of which have not previously been implicated in foveal development. Our findings reveal previously unrecognised biological influences on foveal morphogenesis, including retinoic acid metabolism (implicating CYP26A1 for the first time in human foveal development), extracellular matrix and cytoskeletal dynamics, and retinal cell fate determination. In addition, rare-variant analysis uncovered two further gene associations, including ESYT3, a gene not previously linked to foveal structure. Together, these results provide new insights into the genetic architecture and molecular pathways underlying human foveal development, and offer a foundation for future functional studies aimed at characterising foveal development and disease.

Background/Objectives: The diagnosis and prognosis of arrested foveal development or foveal hypoplasia (FH) can be made using the Leicester grading system for FH and optical coherence tomography (OCT). In clinical practice, ophthalmologists and ophthalmic health professionals with varying experience consult patients with FH; however, to date, the FH grading system has only been validated amongst experts. We compare the inter-grader and intra-grade agreement of healthcare professionals against expert consensus across all grades of FH. Methods: Handheld and table-mounted OCT images (n = 341) were graded independently at a single centre by experts (n = 3) with over six years of experience and “novice” medical and allied health professionals (n = 5) with less than three years of experience. Sensitivity, specificity, and Cohen’s kappa scores were calculated for each grader, and expert vs. novice performance was compared. Results: All graders showed high sensitivity (median 97% (IQR: 94–99)) and specificity (median 94% (IQR: 90–95)) in identifying the presence or absence of FH. No significant difference was seen in specificity between expert and novice graders, but experts had significantly greater diagnostic sensitivity (median difference = 5.3%, H = 5.00, p = 0.025). Expert graders had the highest agreement with the ground truth and novice graders showed great variability in grading uncommon grades, such as atypical FH. The proposed causes of misclassification included macular decentring in handheld OCT scans in children. Conclusions: Ophthalmologists of varying experience and allied health professionals can accurately identify FH using handheld and table-mounted OCT images. FH identification and paediatric OCT interpretation can be improved in wider ophthalmic clinical settings through the education of ophthalmic staff.

Visual behaviour in zebrafish, often measured by the optokinetic reflex (OKR), serves as a valuable model for studying aspects of human neurological and ocular diseases and for conducting therapeutic or toxicology assays. Traditional methods for OKR analysis often rely on binarization techniques (threshold-based conversion of images to black and white) or costly software, which limits their utility in low-contrast settings or hypopigmented disease models. Here, we present a novel deep learning pipeline for OKR analysis, using ResNet-50 within the DeepLabCut framework in a Python Version 3.10 environment. Our approach employs object tracking to enable robust eye movement quantification, regardless of variations in contrast or pigmentation. OKR responses were elicited in both wild-type and slc45a2 (albino) mutant zebrafish larvae at 5 days post-fertilisation, using a mini-LED arena with a rotating visual stimulus. Eye movements were recorded and analysed using both conventional software and our deep learning approach. We demonstrate that the deep learning model achieves comparable accuracy to traditional methods, with the added benefits of applicability in diverse lighting conditions and in hypopigmented larvae. Statistical analyses, including Bland-Altman tests, confirmed the reliability of the deep learning model. While this study focuses on 5-day-old zebrafish larvae under controlled conditions, the pipeline is adaptable across developmental stages, pigmentation types, and behavioural assays. With appropriate adjustments to experimental parameters, it could be applied to broader behavioural studies, including social interactions and predator-prey dynamics in ocular and neurological disease models.

The development of the retina is under tight temporal and spatial control. To gain insights into the molecular basis of this process, we generate a single-nuclei dual-omic atlas of the human developing retina with approximately 220,000 nuclei from 14 human embryos and fetuses aged between 8 and 23-weeks post-conception with matched macular and peripheral tissues. This atlas captures all major cell classes in the retina, along with a large proportion of progenitors and cell-type-specific precursors. Cell trajectory analysis reveals a transition from continuous progression in early progenitors to a hierarchical development during the later stages of cell type specification. Both known and unrecorded candidate transcription factors, along with gene regulatory networks that drive the transitions of various cell fates, are identified. Comparisons between the macular and peripheral retinae indicate a largely consistent yet distinct developmental pattern. This atlas offers unparalleled resolution into the transcriptional and chromatin accessibility landscapes during development, providing an invaluable resource for deeper insights into retinal development and associated diseases.

The optokinetic reflex (OKR) serves as a vital index for visual system development in early life, commonly observed within the first six months post-birth in humans. Zebrafish larvae offer a robust and convenient model for OKR studies due to their rapid development and manageable size. Existing OKR assays often involve cumbersome setups and offer limited portability. In this study, we present an innovative OKR assay that leverages the flexible screen of the Samsung Galaxy Z Flip to optimize setup and portability. We conducted paired slow-phase velocity measurements in 5-day post-fertilization (dpf) zebrafish larvae (n = 15), using both the novel flip-phone-based assay and a traditional liquid–crystal display (LCD) arena. Utilizing Bland–Altman plots, we assessed the agreement between the two methods. Both assays were efficacious in eliciting OKR, with eye movement analysis indicating high tracking precision in the flip-phone-based assay. No statistically significant difference was observed in slow-phase velocities between the two assays (p = 0.40). Our findings underscore the feasibility and non-inferiority of the flip-phone-based approach, offering streamlined assembly, enhanced portability, and the potential for cost-effective alternatives. This study contributes to the evolution of OKR assay methodologies, aligning them with emerging research paradigms.

PURPOSE . Our primary aim was to compare adult full -field ERG (ffERG) responses in albinism, idiopathic infantile nystagmus (IIN), and controls. A secondary aim was to investigate the effect of within -subject changes in nystagmus eye movements on ffERG responses. METHODS . Dilated Ganzfeld flash ffERG responses were recorded using DTL electrodes under conditions of dark (standard and dim flash) and light adaptation in 68 participants with albinism, 43 with IIN, and 24 controls. For the primary aim, the effect of group and age on ffERG responses was investigated. For the secondary aim, null region characteristics were determined using eye movements recorded prior to ffERG recordings. ffERG responses were recorded near and away from the null regions of 18 participants also measuring the success rate of recordings. RESULTS . For the primary aim, age -adjusted photopic a- and b -wave amplitudes were consistently smaller in IIN compared with controls ( P < 0.0001), with responses in both groups decreasing with age. In contrast, photopic a -wave amplitudes increased with age in albinism ( P = 0.0035). For the secondary aim, more intense nystagmus significantly reduced the success rate of measurable responses. Within -subject changes in nystagmus intensity generated small, borderline significant differences in photopic b -wave peak times and a -and b -wave amplitudes under scotopic conditions with standard flash. CONCLUSIONS . Age -adjusted photopic ffERG responses are significantly reduced in IIN adding to the growing body of evidence of retinal abnormalities in IIN. Differences between photopic responses in albinism and controls depend on age. Success at obtaining ffERG responses could be improved by recording responses at the null region.

Introduction: Albinism is a heterogenous disease with variable phenotypic and genotypic presentations. Diagnosis can be challenging and clinical evaluation strategies vary. Areas covered: This review examines the phenotypic and genotypic characteristics of albinism and discusses evaluation strategies used to assess its variable clinical presentations. Additionally, it explores the challenges faced by clinicians in diagnosing albinism and issues related to genetic testing, interpretation and subsequent counseling of affected patients and their families. It is important to note that although current management of albinism is mainly supportive and focuses on optimizing vision, there are emerging therapies with promising translational benefit. Expert opinion: Ongoing research in the field of albinism is benefiting from recent advances, particularly in retinal imaging and phenotyping. Similarly, access to advanced technologies like next-generation and long-read sequencing has improved diagnostic accuracy for previous cases with missing heritability. Deeper genotyping and phenotyping as well as multicentre collaborative approaches have allowed better understanding of genotype-phenotype correlations. There is still a need for more research on the psychosocial aspects of albinism. Encouraging involvement of patients and the public in determining research priorities in this area is essential for a better understanding of the psychosocial impact on individuals with albinism.

OBJECTIVE:Intellectual disability is often the outcome of neurodevelopmental disorders and is characterized by significant impairments in intellectual and adaptive functioning. X-linked intellectual disability (XLID) is a subset of these disorders caused by genetic defects on the X chromosome, affecting about 2 out of 1,000 males. In syndromic form, it leads to a broad range of cognitive, behavioral, ocular, and physical disabilities. METHODS:Employing exome or genome sequencing, here we identified 4 missense variants (c.475C > G; p.H159D, c.1373C > A; p.T458N, and c.1585G > A; p.E529K, c.953C > T; p.S318L) and a putative truncating variant (c.1413_1414del; p.Y471*) in the SRPK3 gene in 9 XLID patients from 5 unrelated families. To validate SRPK3 as a novel XLID gene, we established a knockout (KO) model of the SRPK3 orthologue in zebrafish. RESULTS:The 8 patients ascertained postnatally shared common clinical features including intellectual disability, agenesis of the corpus callosum, abnormal eye movement, and ataxia. A ninth case, ascertained prenatally, had a complex structural brain phenotype. Together, these data indicate a pathological role of SRPK3 in neurodevelopmental disorders. In post-fertilization day 5 larvae (free swimming stage), KO zebrafish exhibited severe deficits in eye movement and swim bladder inflation, mimicking uncontrolled ocular movement and physical clumsiness observed in human patients. In adult KO zebrafish, cerebellar agenesis and behavioral abnormalities were observed, recapitulating human phenotypes of cerebellar atrophy and intellectual disability. INTERPRETATION:Overall, these results suggest a crucial role of SRPK3 in the pathogenesis of syndromic X-linked intellectual disability and provide new insights into brain development, cognitive and ocular dysfunction in both humans and zebrafish. ANN NEUROL 2024;96:914-931.

Intellectual disability (ID) is a common neurodevelopmental disorder characterized by significantly impaired intellectual and adaptive functioning. X-linked ID (XLID) disorders, caused by defects in genes on the X chromosome, affect 1.7 out of 1,000 males. Employing exome sequencing, we identified three missense mutations (c.475C > G; p.H159D, c.1373C > A; p.T458N, and c.1585G > A; p.E529K) in the SRPK3 gene in seven XLID patients from three independent families. Clinical features common to the patients are intellectual disability, agenesis of the corpus callosum, abnormal smooth pursuit eye movement, and ataxia. SRPK proteins are known to be involved in mRNA processing and, recently, synaptic vesicle and neurotransmitter release. In order to validate SRPK3 as a novel XLID gene, we established a knockout (KO) model of the SRPK3 orthologue in zebrafish. In day 5 of larval stage, KO zebrafish showed significant defects in spontaneous eye movement and swim bladder inflation. In adult KO zebrafish, we found agenesis of cerebellar structures and impairments in social interaction. These results suggest an important role of SRPK3 in eye movements, which might reflect learning problems, intellectual disability, and other psychiatric disorders.