The fovea is the small depression at the neurosensory retina that underlies high-resolution central vision. It is vulnerable to disease and disruption of its architecture causes visual disability. Foveal morphology varies significantly across individuals. The molecular causes and functional consequences of this anatomical diversity are incompletely understood. Here, we extracted six foveal morphological parameters from Optical Coherence Tomography (OCT) images of 55,604 UK Biobank participants. We found notable variability in foveal morphology, and detected significant links with sex and genetic ancestry. Genome-wide association studies identified 197 lead loci across the six foveal morphological parameters, implicating genes involved in pigmentation (e.g., TYR, TSPAN10, GPR143) and patterning (e.g., FGFR2, PTPRD, CYP1A1). Heritability estimates ranged from 29-43%. Foveal pit volume was associated with future risk of age-related macular degeneration (HR>3.5, p=0.001), a finding supported by Mendelian randomization. These results establish foveal morphology as a highly-heritable trait with substantial influence over retinal disease risk.

Background: Visual evoked potentials (VEPs) are used to detect chiasmal misrouting associated with albinism. However, VEPs are only performed in specialist centres and typically have long waiting lists. The portable electrophysiology device RETeval® shows promise as a clinical screening tool across a range of ophthalmic conditions. Here, we explore its utility in detecting chiasmal abnormalities associated with albinism. Methods: Flash VEPs were recorded on the RETeval® and by standard ISCEV techniques for 27 patients with suspected albinism and 40 control patients as part of routine appointments. We retrospectively investigated the agreeability between the two methods. The amplitude/latency of the main component was measured for standard VEPs whilst a correlation value of interhemispheric difference was calculated for the RETeval® data. Results: We demonstrate a significant difference between albinism patients and controls (p < 0.001) with respect to the interhemispheric difference identified by the RETeval®. By applying a threshold of 0.001865 to the correlation value, the RETeval® detected chiasmal misrouting in all 27 patients with albinism and had 97% agreeability to standard testing. Conclusions:This study shows the potential of using the RETeval® as a clinical tool for the diagnosis of chiasmal anomalies in albinism. The RETeval® has significant time/cost savings which could hasten diagnoses.

Age-related macular degeneration (AMD) is the commonest cause of irreversible blindness in developed societies. AMD coincides with advanced age to which genetic and lifestyle factors contribute additional risks. High levels of the Alzheimer’s-linked Amyloid beta (Aβ) proteins are correlated with aged/AMD retinas. To delineate the role of Aβ in retinopathy from age-related changes, we used transgenic 5xFAD mice in a longitudinal study to recapitulate the aged/AMD Aβ-burden of the human retina. Mice were genotyped to exclude the retinal degeneration alleles Pde6brd1, Pde6brd8, Agouti, Tyr and Oca2. Retinas of 5xFAD and wildtype littermates (97 males/females in total) were longitudinally assessed until 15 months using non-invasive retinal scans: multi-focal electroretinography, optokinetic tracking, optical coherence tomography (OCT), colour fundus photography and fluorescein angiography. Mice were killed at 4, 8 and 15 months, and eyes enucleated for analyses by light, confocal and electron microscopy. Age-related changes included a gradual decline of retinal activity in all mice. Subretinal/drusen-like deposits increased with age, but, like retinal vessel morphology and vessel integrity, showed no differences between cohorts. Diminished PSD95 levels indicated impaired photoreceptor-bipolar connectivity which correlated with age. Ultrastructural imaging showed increased electron-dense granules and undigested outer segments within retinal pigment epithelial cells with age. 5xFAD pathology included significant weight reduction vs. wildtype/littermates, which were pronounced in females. 8 month old 5xFAD mice had diminished A and B waves, though the age-related decline in wildtype mice abolished these subsequently. Visual acuity/function was also reduced in 14 month 5xFAD eyes. OCT revealed thickened photoreceptor nuclei and inner segments in 8 month 5xFAD retinae. Scrutiny of chorioretinal tissues revealed diminished photoreceptor nuclei in 4 month 5xFAD eyes, though differences were abolished as both cohorts aged. From 8 months onwards, 5xFAD mice possessed fewer bipolar cell nuclei. Chronic Aβ exposure led to the earlier development of retinopathy-linked features, the identification of which advances our understanding of how Aβ contributes to multifaceted retinopathies. These were distinguishable from wider age-related changes and non-specific influences of retinal degeneration alleles in 5xFAD mice. Longitudinal analyses revealed sex and age-related limitations and important 3Rs considerations for future studies using 5xFAD mice.

Visual Electro-Diagnostic Testing (EDTs) are a highly specialised service in the NHS. The high cost of tests and a paucity of trained visual electrophysiologists has resulted in very few services across the UK and, when combined with increasing patient backlogs, has caused significant travel burden and variable waiting times. Here, we study the potential for impact on patients and services by adding a screening step to traditional referral pathways using an Electroretinogram (ERG) test from a relatively inexpensive, portable, hand-held EDT device; the RETeval® (LKC technologies, Gaithersburg, MD, USA). We model a large regional-referral EDT service using Discrete Event Simulation (DES) modelling based on retrospective patient data and published best evidence for the device. We evaluate the potential impact that adding the screening step in referral pathways could have on patient waiting times should the device prove to be safe and useable in clinical practice. We demonstrate that should the RETeval® ERG be safe and useable in real-world clinical practice, it has the potential to significantly reduce patient waiting times by avoiding lab-based EDT assessment for up to 45% of patients. We also show that the impact on services and patients is likely to be resilient to realistic changes in referral numbers, sensitivity/specificity of the device and changes in clinical capacity. This work demonstrates that a RETeval® ERG screening step, performed at the point of referral, has the potential to result in significantly reduced EDT waiting lists through fewer patients requiring lab-based EDT assessment and that DES modelling is a useful tool in making this assessment. However, many questions remain about using the device in the real-world setting for this purpose. Future studies are needed to assess its sensitivity/specificity, test/retest variability, changes in referral patterns due to the device, useability, acceptability to patients and importantly, the consequences of screening errors. Our work, using only retrospective data and a DES model, shows that using the device as an ERG screening tool warrants further investigation due to the potential impact on both patients and clinical services.

Children presenting with nystagmus can pose significant challenges for clinicians for a variety of reasons. Here, the authours discuss the diverse clinical context in which these patients present and the unique impact nystagmus has on visual function. This provides the context for a more methodical, robust approach to a core workup, adaptable to all patients and settings which can identify important red flags and direct further specialist testing. The role of conventional and nystagmus-specific treatments are discussed with particular attention drawn to the importance of ongoing education and support for patients and families.

Background Amblyopia, the most common visual impairment of childhood, is a public health concern. An extended period of optical treatment before patching is recommended by the clinical guidelines of several countries. The aim of this study was to compare an intensive patching regimen, with and without extended optical treatment (EOT), in a randomised controlled trial. Methods EuPatch was a randomised controlled trial conducted in 30 hospitals in the UK, Greece, Austria, Germany, and Switzerland. Children aged 3-8 years with newly detected, untreated amblyopia (defined as an interocular difference >= 0 center dot 30 logarithm of the minimum angle of resolution [logMAR] best corrected visual acuity [BCVA]) due to anisometropia, strabismus, or both were eligible. Participants were randomly assigned (1:1) via a computer-generated sequence to either the EOT group (18 weeks of glasses use before patching) or to the early patching group (3 weeks of glasses use before patching), stratified for type and severity of amblyopia. All participants were initially prescribed an intensive patching regimen (10 h/day, 6 days per week), supplemented with motivational materials. The patching period was up to 24 weeks. Participants, parents or guardians, assessors, and the trial statistician were not masked to treatment allocation. The primary outcome was successful treatment (ie, <= 0 center dot 20 logMAR interocular difference in BCVA) after 12 weeks of patching. Two primary analyses were conducted: the main analysis included all participants, including those who dropped out, but excluded those who did not provide outcome data at week 12 and remained on the study; the other analysis imputed this missing data. All eligible and randomly assigned participants were assessed for adverse events. This study is registered with the International Standard Randomised Controlled Trial Number registry (ISRCTN51712593) and is no longer recruiting. Findings Between June 20, 2013, and March 12, 2020, after exclusion of eight participants found ineligible after detailed screening, we randomly assigned 334 participants (170 to the EOT group and 164 to the early patching group), including 188 (56%) boys, 146 (44%) girls, and two (1%) participants whose sex was not recorded. 317 participants (158 in the EOT group and 159 in the early patching group) were analysed for the primary outcome without imputation of missing data (median follow-up time 42 weeks [IQR 42] in the EOT group vs 27 weeks [27] in the early patching group). 24 (14%) of 170 participants in the EOT group and ten (6%) of 164 in the early patching group were excluded or dropped out of the study, mostly due to loss to follow-up and withdrawal of consent; ten (6%) in the EOT group and three (2%) in the early patching group missed the 12 week visit but remained on the study. A higher proportion of participants in the early patching group had successful treatment (107 [67%] of 159) than those in the EOT group (86 [54%] of 158; 13% difference; p=0 center dot 019) after 12 weeks of patching. No serious adverse events related to the interventions occurred. Interpretation The results from this trial indicate that early patching is more effective than EOT for the treatment of most children with amblyopia. Our findings also provide data for the personalisation of amblyopia treatments. Copyright (c) 2024 The Author(s). Published by Elsevier Ltd.

A guideline is proposed that comprises the minimum items to be reported in research studies involving an eye tracker and human or non-human primate participant(s). This guideline was developed over a 3-year period using a consensus-based process via an open invitation to the international eye tracking community. This guideline will be reviewed at maximum intervals of 4 years.

Nystagmus (involuntary, rhythmical eye movements) can arise due to sensory eye defects, in association with neurological disorders or as an isolated condition. We identified a family with early onset nystagmus and additional neurological features carrying a partial duplication of FGF14, a gene associated with spinocerebellar ataxia type 27 (SCA27) and episodic ataxia. Detailed eye movement analysis revealed oculomotor anomalies strikingly similar to those reported in a previously described four-generation family with early onset nystagmus and linkage to a region on chromosome 13q31.3-q33.1 (NYS4). Since FGF14 lies within NYS4, we revisited the original pedigree using whole genome sequencing, identifying a 161 kb heterozygous deletion disrupting FGF14 and ITGBL1 in the affected individuals, suggesting an FGF14-related condition. Therefore, our study reveals the genetic variant underlying NYS4, expands the spectrum of pathogenic FGF14 variants, and highlights the importance of screening FGF14 in apparently isolated early onset nystagmus.

Nystagmus is a type of eye movement which can be physiological (normal), or associated with myriad eye disorders and neurological conditions. As such, it is commonly encountered in paediatric practice and context is key. Accordingly, children who present with apparently isolated nystagmus can cause significant clinical concern due to the bewildering number of underlying aetiologies in an otherwise broadly well child. This is compounded by the complexity of eye movement disorder definitions, descriptions, features and classification systems. Clinical workup and subsequent management of these children can be extremely variable and depend on how, and to whom the child has presented, availability of investigations and cultural familiarity with single specific causes. In this article we take the non-specialist clinician through a methodical approach to managing children with apparently isolated nystagmus in an Q and A format. We provide some key clinical practice points and discuss subsequent management.

Background Home visual acuity tests could ease pressure on ophthalmic services by facilitating remote review of patients. Home tests may have further utility in giving service users frequent updates of vision outcomes during therapy, identifying vision problems in an asymptomatic population, and engaging stakeholders in therapy. Methods Children attending outpatient clinics had visual acuity measured 3 times at the same appointment: Once by a registered orthoptist per clinical protocols, once by an orthoptist using a tablet-based visual acuity test (iSight Test Pro, Kay Pictures), and once by an unsupervised parent/carer using the tablet-based test. Results In total, 42 children were recruited to the study. The mean age was 5.6 years (range 3.3 to 9.3 years). Median and interquartile ranges (IQR) for clinical standard, orthoptic-led and parent/carer-led iSight Test Pro visual acuity measurements were 0.155 (0.18 IQR), 0.180 (0.26 IQR), and 0.300 (0.33 IQR) logMAR respectively. The iSight Test Pro in the hands of parents/carers was significantly different from the standard of care measurements ( P = 0.008). In the hands of orthoptists. There was no significant difference between orthoptists using the iSight Test Pro and standard of care ( P = 0.289), nor between orthoptist iSight Test Pro and parents/carer iSight Test Pro measurements ( P = 0.108). Conclusion This technique of unsupervised visual acuity measures for children is not comparable to clinical measures and is unlikely to be valuable to clinical decision making. Future work should focus on improving the accuracy of the test through better training, equipment/software or supervision/support.

Advances in genomic technology including the development of next-generation sequencing (NGS) have enabled the identification of thousands of variations at a time, allowing the discovery of novel genetic diseases. Given the volume of data generated by these investigations, attention is drawn towards reporting relevant clinical features by clinicians to guide the diagnosis and management of their patients. The Human Phenotype Ontology (HPO) developed in 2008, revolutionized the semantic vocabulary of phenotypic descriptions in genomic medicine allowing researchers, laboratories and clinical geneticists to better understand each other. In this era of personalized medicine where genetic tests are becoming more accessible, non-geneticist clinicians are expected to be more involved than ever in the process of ordering genetic tests and interpreting genetic reports. It is therefore essential that they understand and adequately apply HPO nomenclature to integrate the patient care chain and seize the opportunity offered by this tailored language. The current article highlights the importance of using HPO vocabularies in clinical practice and advocates for its wider use by non-geneticist clinicians. Correct use of HPO will reduce misunderstandings between healthcare professionals and ultimately improve the healthcare system.

Visual evoked potentials (VEPs) are an important prognostic indicator of visual ability in patients with nystagmus. However, VEP testing requires stable fixation, which is impossible with nystagmus. Fixation instability reduces VEP amplitude, and VEP reliability is therefore low in this important patient group. We investigated whether VEP amplitude can be increased using an eye tracker by triggering acquisition only during slow periods of the waveform. Data were collected from 10 individuals with early-onset nystagmus. VEP was obtained under continuous (standard) acquisition, or triggered during periods of low eye velocity, as detected by an eye tracker. VEP amplitude was compared using Bonferroni corrected paired samples t-tests. VEP amplitude is significantly increased when triggered during low eye velocity (95% CI 1.42–6.83 µV, t(15) = 3.25, p = 0.0053). This study provides proof-of-concept that VEP amplitude (and therefore prognostic reliability) can be increased in patients with early onset nystagmus by connecting an eye tracker and triggering acquisition during periods of lower eye velocity.

l -DOPA is deficient in the developing albino eye, resulting in abnormalities of retinal development and visual impairment. Ongoing retinal development after birth has also been demonstrated in the developing albino eye offering a potential therapeutic window in humans. To study whether human equivalent doses of l -DOPA/Carbidopa administered during the crucial postnatal period of neuroplasticity can rescue visual function, OCA C57BL/6 J-c2J OCA1 mice were treated with a 28-day course of oral l -DOPA/Carbidopa at 3 different doses from 15 to 43 days postnatal age (PNA) and for 3 different lengths of treatment, to identify optimum dosage and treatment length. Visual electrophysiology, acuity, and retinal morphology were measured at 4, 5, 6, 12 and 16 weeks PNA and compared to untreated C57BL/6 J (WT) and OCA1 mice. Quantification of PEDF, βIII-tubulin and syntaxin-3 expression was also performed. Our data showed impaired retinal morphology, decreased retinal function and lower visual acuity in untreated OCA1 mice compared to WT mice. These changes were diminished or eliminated when treated with higher doses of l -DOPA/Carbidopa. Our results demonstrate that oral l -DOPA/Carbidopa supplementation at human equivalent doses during the postnatal critical period of retinal neuroplasticity can rescue visual retinal morphology and retinal function, via PEDF upregulation and modulation of retinal synaptogenesis, providing a further step towards developing an effective treatment for albinism patients.

BACKGROUND:Acute acquired concomitant esotropia (AACE) is usually a benign form of strabismus that infrequently is associated with intracranial pathology. Clinicians have noted an increase in its incidence and theorize that it may be related to public health "lockdown" measures taken in response to the COVID-19 pandemic. With an increased incidence of AACE clinicians must firstly differentiate AACE from common accommodative esotropia and secondly recognize AACE as a possible sign of serious neuropathology.Diffuse Intrinsic Pontine Glioma (DIPG) is a devastating diagnosis for affected families. Children typically present at age 6-7 years with cranial nerve palsies, long tract signs, and/or cerebellar signs. Diagnosis is made from characteristic findings on magnetic resonance brain imaging (MRI brain) and treatment includes radiotherapy and palliative care. Two years from diagnosis, 90% of affected children will have died from their disease.CASE SERIES:We present four cases that attended our pediatric ophthalmology clinic with AACE either as a presenting sign of DIPG or as a clinical finding following a DIPG diagnosis. Patient A (age 5 years) presented to the emergency eye clinic with sudden onset diplopia and intermittent esotropia. Suppression later developed, they had 0.00 logMAR visual acuity either eye, and bilateral physiological hypermetropia. MRI brain imaging requested as a result of the unusual presentation led to the DIPG diagnosis. The other 3 cases (ages 11, 5 & 5 years) were assessed post DIPG diagnosis and found to have an esotropia measuring bigger on 1/3-meter fixation than 6-meter fixation, full ocular motility, physiological hypermetropia or emmetropia, and visual acuity normal for age. Other than patient B (age 11 years), who had papilledema and gaze evoked nystagmus when they were assessed 2 weeks prior to death, no patient had any other clinical eye findings.CONCLUSIONS:This small series of 4 patients attending our clinic within a 12-month period supports the notion that children presenting with AACE should routinely be offered brain MRI. Not all children with DIPG-associated AACE have significant ophthalmic findings indicative of intracranial pathology. With the potential for increased incidence of AACE related to lockdowns, clinicians should be reminded of the infrequent possibility their patient has a more serious condition.

Background Home visual acuity tests could ease pressure on ophthalmic services by facilitating remote review of a variety of patients. Home tests may have further utility in giving service users frequent updates of vision outcomes during therapy, identifying vision problems in an asymptomatic population, and engaging stakeholders in therapy.The accuracy of home vision tests for children when completed without supervision from a professional is unknown.Methods Children attending outpatient clinics had their visual acuity measured 3 times in a randomised order at the same appointment. Once by a registered orthoptist as per standard clinical protocols, once by an orthoptist using a tablet-based visual acuity test (iSight Pro, Kay Pictures), and once by an unsupervised parent or carer using the tablet-based test.Results 42 children were recruited to the study. The mean age was 5.6 years (range 3.3 to 9.3 years). Median measurements (interquartile range) for clinical standard, orthoptic-led and parent/carer-led iSight visual acuity measurements were 0.155 (0.18), 0.180 (0.26), and 0.300 (0.33) respectively.The iSight app in the hands of parents/carers was significantly different from the standard of care measurements (P=0.009). In the hands of orthoptists, there was no significant difference between the iSight app and standard of care (P=0.551), nor was there significant difference between parents/carers using the app and orthoptists using the app (P=0.133).Conclusion This technique of unsupervised home visual acuity measures for children is not comparable to clinical measures and is unlikely to be valuable to clinical decision making and screening. Future work should focus on improving the technique through, for example, gamification of vision tests.What is already known on this topic? Children’s game visual acuity tests could improve things for hospital services and patients. The tablet-based tests are accurate when used by professionals to tests adults’ vision.What this study adds This study provides data about the accuracy of home tests when used by untrained parents or carers on their children.How this study might affect research, practice, or policy Current policy recommends apps home tests are not used to test children’s eyes for clinical decision-making purposes. Our data supports this policy and highlights the need for future research to focus on improving the tests.Synopsis / precis (“At a glance”) Visual acuity testing at home could improve patient care and reduce clinical visits, but data to show clinicians that they can rely upon the results in children are lacking. Our study shows the tests cannot be relied upon for clinical purposes. Improvements to the tests are required before they become useful and can be implemented into practice.### Competing Interest StatementThe authors have declared no competing interest.### Funding StatementDO is funded by a National Institute for Health Research Pre-doctoral Clinical Academic Fellowship and equipment for the study was purchased by Gift of Sight (Southampton, UK).### Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:The study adhered to the tenets of the Declaration of Helsinki. The study was approved by the NHS Health Research Authority (HRA) and an NHS Research Ethics Committee (Queen Square NHS REC, Reference: 20/HRA/2585). Parents or carers gave written informed consent for their child to take part in the study.I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesAll data produced in the present study are available upon reasonable request to the authors

Oculocutaneous albinism type 1 (OCA1) is caused by pathogenic variants in the TYR (tyrosinase) gene which encodes the critical and rate-limiting enzyme in melanin synthesis. It is the most common OCA subtype found in Caucasians, accounting for ~50% of cases worldwide. The apparent ‘missing heritability’ in OCA is well described, with ~25–30% of clinically diagnosed individuals lacking two clearly pathogenic variants. Here we undertook empowered genetic studies in an extensive multigenerational Amish family, alongside a review of previously published literature, a retrospective analysis of in-house datasets, and tyrosinase activity studies. Together this provides irrefutable evidence of the pathogenicity of two common TYR variants, p.(Ser192Tyr) and p.(Arg402Gln) when inherited in cis alongside a pathogenic TYR variant in trans . We also show that homozygosity for the p.(Ser192Tyr)/p.(Arg402Gln) TYR haplotype results in a very mild, but fully penetrant, albinism phenotype. Together these data underscore the importance of including the TYR p.(Ser192Tyr)/p.(Arg402Gln) in cis haplotype as a pathogenic allele causative of OCA, which would likely increase molecular diagnoses in this missing heritability albinism cohort by 25–50%.