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Purpose To quantify in patients with optic nerve head drusen (ONHD)changes after 1-year observation in: (i) optic disc and (ii) macular optical coherence tomography (OCT) parameters and (iii) the effect of age at enrolment in the study. Design Prospective, cross-sectional observational study using Spectral Domain-OCT (Copernicus; OPTOPOL Technology S.A., Zawiercie, Poland) imaging was carried out in 35 patients with ONHD (age–42.8 ± 19.9 years; males = 15; females = 20) at baseline and after 12 months follow-up. Results Patients with ONHD had significant thinning of the surface nerve fibre layer in the central (p = 0.03), superior (p = 0.05) and inferior (p = 0.04) areas; mean ppRNFL thinning (p = 0.0 4) and ppRNFL thinning in the nasal segment (p = 0.028). Retinal thinning in the central (p = 0.001), inner (p = 0.01) and outer (p = 0.002) temporal, outer superior (p = 0.03) and inferior (p = 0.02) areas; borderline ganglion cell layer thinning (p = 0.051) and outer nuclear layer (p = 0.03) thinning in the central retina and outer segment layer thinning nasally (p = 0.01) between the first and the second visit in macula. Correlation of the difference in optic disc and macular parameters with the age at enrolment did not reveal any significance. Conclusions Statistically detectable thinning of the optic nerve and macula structures occurred already after 12 months. The proximity of optic nerve changes to the vascular arcades can possibly be explained by involvement of retinal vessels in the pathophysiology of ONHD.

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.

Objective To investigate the relationship between cystoid macular oedema (CMO) measured in preterm infants using hand-held spectral domain optical coherence tomography (HH SD-OCT), with gestational age at birth (GA), birthweight (BW), diagnosis of retinopathy of prematurity (ROP) and the presence or absence of the external limiting membrane (ELM). Methods We conducted a prospective mixed cross-sectional/longitudinal observational study of 112 participants (23 to 36 weeks GA; n = 25 with, and n = 87 without, CMO). Retinal images were acquired using 344 HH SD-OCT (n = 66 with and n = 278 without, CMO) between 31 to 44 weeks postmenstrual age (PMA). CMO type (‘fovea’ and ‘dome’) was measured using thickness, width, area and peak. Results CMO was observed in 22.9% of preterm infants, and 19.2% of images. The mean values for thickness, width, area and peak of ‘dome’ CMO were 128.47 µm (SD +/- 34.23), 3624.45 µm (SD +/- 1323.03), 0.49 mm2 (SD +/- 0.28) and 279.81 µm (SD +/- 13.57) respectively. The mean values for thickness, width, area and peak of ‘fovea’ CMO were 64.37 µm (SD +/- 17.11), 2226.28 µm (SD +/- 1123.82), 0.16 mm2 (SD +/- 0.11) and 95.03 µm (SD +/- 26.99) respectively. Thickness, area width and peak were significantly greater for ‘dome CMO compared with ‘fovea’ CMO (P P p = 0.0028; p Conclusions HH -OCT in preterm infants demonstrates that the severity of CMO appearance improves each week for both fovea and dome CMO.

Aims To assess the diagnostic accuracy of fundoscopy and visual evoked potentials (VEPs) in detecting intracranial hypertension (IH) in patients with craniosynostosis undergoing spring-assisted posterior vault expansion (sPVE). Methods Children with craniosynostosis undergoing sPVE and 48-hour intracranial pressure (ICP) monitoring were included in this single-centre, retrospective, diagnostic accuracy study. Data for ICP, fundoscopy and VEPs were analysed. Primary outcome measures were papilloedema on fundoscopy, VEP assessments and IH, defined as mean ICP > 20 mmHg. Diagnostic indices were calculated for fundoscopy and VEPs against IH. Secondary outcome measures included final visual outcomes. Results Fundoscopic examinations were available for 35 children and isolated VEPs for 30 children, 22 of whom had at least three serial VEPs. Sensitivity was 32.1% for fundoscopy (95% confidence intervals [CI]: 15.9–52.4) and 58.3% for isolated VEPs (95% CI 36.6–77.9). Specificity for IH was 100% for fundoscopy (95% CI: 59.0–100) and 83.3% for isolated VEPs (95% CI: 35.9–99.6). Where longitudinal deterioration was suspected from some prVEPs but not corroborated by all, sensitivity increased to 70.6% (95% CI: 44.0–89.7), while specificity decreased to 60% (95% CI: 14.7–94.7). Where longitudinal deterioration was clinically significant, sensitivity decreased to 47.1% (23.0–72.2) and specificity increased to 100% (47.8–100). Median final BCVA was 0.24 logMAR (n = 36). UK driving standard BCVA was achieved by 26 patients (72.2%), defined as ≥0.30 logMAR in the better eye. Conclusion Papilloedema present on fundoscopy reliably indicated IH, but its absence did not exclude IH. VEP testing boosted sensitivity at the expense of specificity, depending on method of analysis.

Meeting Presentation: Presented at the 2016 Association for Research in Vision and Ophthalmology meeting and at the 2015 British Isles Paediatric, Ophthalmology and Strabismus Association meeting. Purpose: To investigate the time course of foveal development after birth in infants with albinism. Design: Prospective, comparative cohort optical coherence tomography study. Methods: Thirty-six children with albinism were recruited. All participants were between 0 and 6 years of age and were seen at Leicester Royal Infirmary. A total of 181 mixed cross-sectional and longitudinal optical coherence tomography examinations were obtained, which were analyzed for differences in retinal development in comparison to 297 cross-sectional control examinations. Results: Normal retinal development involves migration of the inner retinal layers (IRLs) away from the fovea, migration of the cone photoreceptors into the fovea, and elongation of the outer retinal layers (ORLs) over time. In contrast to controls where IRL migration from the fovea was almost completed at birth, a significant degree of IRL migration was taking place after birth in albinism, before arresting prematurely at 40 months postmenstrual age (PMA). This resulted in a significantly thicker central macular thickness in albinism (Δ = 83.8 ± 6.1, P < .0001 at 69 months PMA). There was evidence of ongoing foveal ORL elongation in albinism, although reduced in amplitude compared with control subjects after 21 months PMA (Δ = -17.3 ± 4.3, P < .0001). Conclusions: We have demonstrated evidence of ongoing retinal development in young children with albinism, albeit at a reduced rate and magnitude compared with control subjects. The presence of a period of retinal plasticity in early childhood raises the possibility that treatment modalities, which aim to improve retinal development, could potentially optimize visual function in albinism.

Infantile nystagmus syndrome (INS) consists of involuntary oscillation of the eyes, that usually develop within the first months of life. INS can be idiopathic or associated with albinism, retinal ...

Infantile nystagmus syndrome (INS) causes altered visual development and can be associated with abnormal retinal structure, to which vascular development of the retina is closely related. Abnormal retinal vasculature has previously been noted in albinism but not idiopathic infantile nystagmus. We compared the number and diameter of retinal vessels in participants with albinism (PWA) and idiopathic infantile nystagmus (PWIIN) with controls.Fundus photography data from 24 PWA, 10 PWIIN, and 34 controls was analyzed using Automated Retinal Image Analyzer (ARIA) software on a field of analysis centered on the optic disc, the annulus of which extended between 4.2 mm and 8.4 mm in diameter.Compared with controls, the mean number of arterial branches was reduced by 24% in PWA (15.5 vs. 20.3, P0.001), and venous branches were reduced in both PWA (29%; 12.9 vs. 18.2, P0.001) and PWIIN (17%; 15.1 vs. 18.2, P = 0.024). PWA demonstrated 7% thinner "primary" (before branching) arteries (mean diameter: 75.39 µm vs. 80.88 µm, P = 0.043), and 13% thicker (after branching) "secondary" veins (66.72 µm vs. 59.01 µm in controls, P = 0.009).PWA and PWIIN demonstrated reduced retinal vessel counts and arterial diameters compared with controls. These changes in the superficial retinal vascular network may be secondary to underdevelopment of the neuronal network, which guides vascular development and is also known to be disrupted in INS.

Foveal hypoplasia, optic nerve decussation defects and anterior segment dysgenesis is an autosomal recessive disorder arising from SLC38A8 mutations. SLC38A8 is a putative glutamine transporter with strong expression within the photoreceptor layer in the retina. Previous studies have been limited due to lack of quantitative data on retinal development and nystagmus characteristics. In this multi-centre study, a custom-targeted next generation sequencing (NGS) gene panel was used to identify SLC38A8 mutations from a cohort of 511 nystagmus patients. We report 16 novel SLC38A8 mutations. The sixth transmembrane domain is most frequently disrupted by missense SLC38A8 mutations. Ninety percent of our cases were initially misdiagnosed as PAX6-related phenotype or ocular albinism prior to NGS. We characterized the retinal development in vivo in patients with SLC38A8 mutations using high-resolution optical coherence tomography. All patients had severe grades of arrested retinal development with lack of a foveal pit and no cone photoreceptor outer segment lengthening. Loss of foveal specialization features such as outer segment lengthening implies reduced foveal cone density, which contributes to reduced visual acuity. Unlike other disorders (such as albinism or PAX6 mutations) which exhibit a spectrum of foveal hypoplasia, SLC38A8 mutations have arrest of retinal development at an earlier stage resulting in a more under-developed retina and severe phenotype.

Purpose To evaluate structural grading and quantitative segmentation of foveal hypoplasia using handheld OCT, versus preferential looking (PL), as predictors of future vision in preverbal children with infantile nystagmus. Design Longitudinal cohort study. Participants Forty-two patients with infantile nystagmus (19 with albinism, 17 with idiopathic infantile nystagmus, and 6 with achromatopsia) were examined. Methods Spectral-domain handheld OCT was performed in preverbal children up to 36 months of age. Foveal tomograms were graded using our 6-point grading system for foveal hypoplasia and were segmented for quantitative analysis: photoreceptor length, outer segment (OS) length, and foveal developmental index (FDI; a ratio of inner layers versus total foveal thickness). Patients were followed up until they could perform chart visual acuity (VA) testing. Data were analyzed using linear mixed regression models. Visual acuity predicted by foveal grading was compared with prediction by PL, the current gold standard for visual assessment in infants and young children. Main Outcome Measures Grade of foveal hypoplasia, quantitative parameters (photoreceptor length, OS length, FDI), and PL VA were obtained in preverbal children for comparison with future chart VA outcomes. Results We imaged 81 eyes from 42 patients with infantile nystagmus of mean age 19.8 months (range, 0.9–33.4 months; standard deviation [SD], 9.4 months) at the first handheld OCT scan. Mean follow-up was 44.1 months (range, 18.4–63.2 months; SD, 12.0 months). Structural grading was the strongest predictor of future VA (grading: r = 0.80, F = 67.49, P < 0.0001) compared with quantitative measures (FDI: r = 0.74, F = 28.81, P < 0.001; OS length: r = 0.65; F = 7.94, P < 0.008; photoreceptor length: r = 0.65; F = 7.94, P < 0.008). Preferential looking was inferior to VA prediction by foveal grading (PL: r = 0.42, F = 3.12, P < 0.03). Conclusions Handheld OCT can predict future VA in infantile nystagmus. Structural grading is a better predictor of future VA than quantitative segmentation and PL testing. Predicting future vision may avert parental anxiety and may optimize childhood development.

IntroductionPaediatric intracranial hypertension (IH) is a rare but serious condition that can pose deleterious effects on the brain and vision. Estimating intracranial pressure (ICP) in children is difficult. Gold standard direct ICP measurement is invasive and carries risk. It is impractical to routinely perform direct ICP measurements over time for all children at risk of IH. This study proposes to assess the diagnostic accuracy of handheld optical coherence tomography (OCT), a non-invasive ocular imaging method, to detect IH in children.Methods and analysisThis is a prospective study evaluating the diagnostic accuracy of handheld OCT for IH in at risk children. Inclusion criteria include clinical and/or genetic diagnosis of craniosynostosis, idiopathic intracranial hypertension, space occupying lesion or other conditions association with IH and age 0–18 years old. Exclusion criteria include patients older than 18 years of age and/or absence of condition placing the child at risk of IH. The primary outcome measures are handheld OCT and 48-hour ICP assessments, which will be used for diagnostic accuracy testing (sensitivity, specificity, positive predictive value, negative predictive value and accuracy). Main secondary outcome measures include visual acuity, fundoscopic examination, contrast sensitivity, visual field testing and visual evoked potentials, wherever possible.Ethics and disseminationEthical approval was granted for this study by the East Midlands Nottingham 2 Research Ethics committee (UOL0348/IRAS 105137). Our findings will be disseminated through presentation at relevant meetings, peer-reviewed publication and via the popular media.Trial registration numberISRCTN52858719

Achromatopsia (ACHM) is a congenital cone photoreceptor disorder characterized by impaired color discrimination, low visual acuity, photosensitivity, and nystagmus. To date, six genes have been associated with ACHM (CNGA3, CNGB3, GNAT2, PDE6C, PDE6H, and ATF6), the majority of these being implicated in the cone phototransduction cascade. CNGA3 encodes the CNGA3 subunit of the cyclic nucleotide-gated ion channel in cone photoreceptors and is one of the major disease-associated genes for ACHM. Herein, we provide a comprehensive overview of the CNGA3 variant spectrum in a cohort of 1060 genetically confirmed ACHM patients, 385 (36.3%) of these carrying "likely disease-causing" variants in CNGA3. Compiling our own genetic data with those reported in the literature and in public databases, we further extend the CNGA3 variant spectrum to a total of 316 variants, 244 of which we interpreted as "likely disease-causing" according to ACMG/AMP criteria. We report 48 novel "likely disease-causing" variants, 24 of which are missense substitutions underlining the predominant role of this mutation class in the CNGA3 variant spectrum. In addition, we provide extensive in silico analyses and summarize reported functional data of previously analyzed missense, nonsense and splicing variants to further advance the pathogenicity assessment of the identified variants.

We describe a collection of T1-, diffusion- and functional T2*-weighted magnetic resonance imaging data from human individuals with albinism and achiasma. This repository can be used as a test-bed to develop and validate tractography methods like diffusion-signal modeling and fiber tracking as well as to investigate the properties of the human visual system in individuals with congenital abnormalities. The MRI data is provided together with tools and files allowing for its preprocessing and analysis, along with the data derivatives such as manually curated masks and regions of interest for performing tractography., Measurement(s)brain white matterTechnology Type(s)magnetic resonance imagingSample Characteristic - OrganismHomo sapiens Machine-accessible metadata file describing the reported data: 10.6084/m9.figshare.16726246

To quantify in patients with optic nerve head drusen (ONHD)changes after 1-year observation in: (i) optic disc and (ii) macular optical coherence tomography (OCT) parameters and (iii) the effect of age at enrolment in the study.Prospective, cross-sectional observational study using Spectral Domain-OCT (Copernicus; OPTOPOL Technology S.A., Zawiercie, Poland) imaging was carried out in 35 patients with ONHD (age-42.8 ± 19.9 years; males = 15; females = 20) at baseline and after 12 months follow-up.Patients with ONHD had significant thinning of the surface nerve fibre layer in the central (p = 0.03), superior (p = 0.05) and inferior (p = 0.04) areas; mean ppRNFL thinning (p = 0.0 4) and ppRNFL thinning in the nasal segment (p = 0.028). Retinal thinning in the central (p = 0.001), inner (p = 0.01) and outer (p = 0.002) temporal, outer superior (p = 0.03) and inferior (p = 0.02) areas; borderline ganglion cell layer thinning (p = 0.051) and outer nuclear layer (p = 0.03) thinning in the central retina and outer segment layer thinning nasally (p = 0.01) between the first and the second visit in macula. Correlation of the difference in optic disc and macular parameters with the age at enrolment did not reveal any significance.Statistically detectable thinning of the optic nerve and macula structures occurred already after 12 months. The proximity of optic nerve changes to the vascular arcades can possibly be explained by involvement of retinal vessels in the pathophysiology of ONHD.

PurposeWe aimed to investigate structural retinal changes in malarial retinopathy (MR) using hand-held optical coherence tomography (HH-OCT) to investigate its diagnostic potential.MethodsChildren with MR (n=43) underwent ophthalmoscopy, fluorescein angiography and HH-OCT during admission, one month (n=31) and one year (n=8) post-discharge. Controls were comatose patients without malaria (n=6) and age/sex-matched healthy children (n=43). OCT changes and retinal layer thicknesses were compared.ResultsOn HH-OCT, hyper-reflective areas (HRAs) were seen in the inner retina of 81% of MR patients, corresponding to ischaemic retinal whiteningon fundus photography. Cotton wool spots were present in 37% and abnormal hyper-reflective dots, co-localized to capillary plexus, in 93%. Hyper-reflective vessel walls were present in 84%, and intra-retinal cysts in 9%. Vascular changes and cysts resolved within 48 hours. HRAs developed into retinal thinning at one month (p=0.027) whichwas more pronounced after one year (p=0.009).ConclusionsIschaemic retinal whitening is located within inner retinal layers, distinguishing it from cotton wool spots. Vascular hyper-reflectivity may represent the sequestration of parasitized erythrocytes in vessels, a key CM feature. The mechanisms of post-ischemic retinal atrophy and cerebral atrophy with cognitive impairment may be similar in CM survivors. HH-OCT has potential for monitoring patients, treatment response and predicting neurological deficits.

Autosomal recessive Achromatopsia (ACHM) is a rare inherited disorder associated with dysfunctional cone photoreceptors resulting in a congenital absence of cone input to visual cortex. This might lead to distinct changes in cortical architecture with a negative impact on the success of gene augmentation therapies. To investigate the status of the visual cortex in these patients, we performed a multi-centre study focusing on the cortical structure of regions that normally receive predominantly cone input. Using high-resolution T1-weighted MRI scans and surface-based morphometry, we compared cortical thickness, surface area and grey matter volume in foveal, parafoveal and paracentral representations of primary visual cortex in 15 individuals with ACHM and 42 normally sighted, healthy controls (HC). In ACHM, surface area was reduced in all tested representations, while thickening of the cortex was found highly localized to the most central representation. These results were comparable to more widespread changes in brain structure reported in congenitally blind individuals, suggesting similar developmental processes, i.e., irrespective of the underlying cause and extent of vision loss. Our findings indicate that there may be an optimum time window for gene therapy to counteract developmental cortical changes related to the absence of sensory input.HighlightsWe assessed cortical anatomy of a large cohort of patients with genetically confirmed cone photoreceptor dysfunction (achromatopsia) using surface-based morphometry.We found widespread reduction in cortical surface area across foveal, parafoveal and paracentral proportions of primary visual cortex in participants with achromatopsia.highly localized cortical thickening in participants with achromatopsia at the region of visual cortex that lacked inputs from the retinal region occupied solely by cones.Further evidence that the visual cortex is unlikely to take on normal properties if vision were restored after the developmental plastic period.Early intervention is preferable when considering vision restoration treatment in achromatopsia.

Purpose To determine whether handheld optical coherence tomography (OCT) is feasible and repeatable in children with craniosynostosis. Methods This was a prospective cross-sectional study. Children with syndromic and non-syndromic craniosynostosis 0 to 18 years of age were recruited between February 13, 2020, and October 1, 2020. Main outcome measures included feasibility (patient recruitment and handheld OCT success rates) and repeatability, which were assessed using intraclass correlation coefficients (ICCs) where repeated images of the optic nerve head (ONH) within the same visit were available. ONH parameters used for repeatability analysis included cup depth, width, and area; disc width; rim height; retinal thickness; retinal nerve fiber layer thickness; and Bruch's membrane opening minimum rim width. Results Fifty children were approached, and all 50 (100%) were successfully recruited. Median age was 51.1 months (range, 1.9-156.9; interquartile range, 37.0-74.2), and 33 of the children (66%) were male. At least one ONH image was obtained in 43 children (86%), and bilateral ONH imaging was successful in 38 children (76%). Factors boosting the likelihood of success included good understanding and cooperation of the child and parent/guardian and availability of an assistant. Repeatability analysis was performed in 20 children, demonstrating good repeatability (ICC range, 0.77-0.99; the majority exceeded 0.90). OCT correctly identified two cases of intracranial hypertension, one of which was undetected by prior fundoscopy. Conclusions Handheld OCT is feasible and repeatable in children with syndromic and non-syndromic forms of craniosynostosis. Translational relevance Our handheld OCT approach could be used for the clinical surveillance of children with craniosynostosis.

Herein we present a consanguineous family with three children affected by foveal hypoplasia with infantile nystagmus, following an autosomal recessive mode of inheritance. The patients showed normal electroretinography responses, no signs of albinism, and no anterior segment or brain abnormalities. Upon whole exome sequencing (WES), we identified a homozygous mutation (c.1861C>T;p.Q621*) in the aryl hydrocarbon receptor (AHR) gene that perfectly co-segregated with the disease in the larger family. The aryl hydrocarbon receptor is a ligand-activated transcription factor that has been intensively studied in xenobiotic-induced toxicity. It was further shown to play a physiological role under normal cellular conditions, such as in immunity, inflammatory response and neurogenesis. Notably, knockout of the Ahr gene in the mouse impairs optic nerve myelin sheath formation and results in oculomotor deficits sharing many features with our patients: the eye movement disorder in the Ahr(-/-) mice appears early in development and presents as conjugate horizontal pendular nystagmus (Chevallier et al., 2013; Juricek et al., 2017). We therefore propose AHR to be a novel disease gene for a new, recessively inherited disorder in humans, characterized by infantile nystagmus and foveal hypoplasia.

Purpose To investigate the potential of handheld optical coherence tomography (HH-OCT) in assessing the anterior segment of the eye in patients with primary congenital glaucoma. Design A prospective, case-controlled observational study. Participants Twenty-two patients with primary congenital glaucoma (PCG, 9 females and 13 males; mean age 4.36 ± 3.4 years) and age-, gender- and ethnicity-matched healthy participants. Methods Anterior OCT was performed in all participants using a high-resolution HH SD-OCT device (Envisu 2300, Leica Microsystems, Germany) without anaesthesia or sedation. Results Anterior HH-OCT in PCG visualised Haab’s striae in 14.3%, uneven internal cornea in 9.5% and epithelial thickening in 11.9% of patients with central corneal thickening (CCT, p

This prospective study investigates longitudinal changes in retinal structure in patients with achromatopsia (ACHM) using optical coherence tomography (OCT).Seventeen patients (five adults, 12 children) with genetically confirmed CNGA3- or CNGB3-associated ACHM underwent ocular examination and OCT over a follow-up period of between 2 and 9.33 years (mean = 5.7 years). Foveal tomograms were qualitatively graded and were segmented for quantitative analysis: central macular thickness (CMt), outer nuclear layer thickness (ONLt), and size of the foveal hyporeflective zone (vertical HRZ thickness: HRZt and horizontal HRZ width: HRZw) were measured. Data were analyzed using linear mixed regression models. Both age and visit were included into the models, to explore the possibility that the rate of disease progression depends on patient age.Fifteen of 17 patients (88%) showed longitudinal changes in retinal structure over the follow-up period. The most common patterns of progression was development of ellipsoid zone (EZ) disruption and HRZ. There was a significant increase in HRZt (P = 0.01) and HRZw (P = 0.001) between visits and no significant change in CMt and ONLt. Retinal parameters showed no difference in changes by genetic mutation (CNGA3 (n = 11), CNGB3 (n = 6)).This study demonstrates clear longitudinal changes in foveal structure mainly in children, but also in adults with ACHM, over a long follow-up period. The longitudinal foveal changes suggest that treatment at an earlier age should be favored.

To assess the diagnostic accuracy of fundoscopy and visual evoked potentials (VEPs) in detecting intracranial hypertension (IH) in patients with craniosynostosis undergoing spring-assisted posterior vault expansion (sPVE).Children with craniosynostosis undergoing sPVE and 48-hour intracranial pressure (ICP) monitoring were included in this single-centre, retrospective, diagnostic accuracy study. Data for ICP, fundoscopy and VEPs were analysed. Primary outcome measures were papilloedema on fundoscopy, VEP assessments and IH, defined as mean ICP 20 mmHg. Diagnostic indices were calculated for fundoscopy and VEPs against IH. Secondary outcome measures included final visual outcomes.Fundoscopic examinations were available for 35 children and isolated VEPs for 30 children, 22 of whom had at least three serial VEPs. Sensitivity was 32.1% for fundoscopy (95% confidence intervals [CI]: 15.9-52.4) and 58.3% for isolated VEPs (95% CI 36.6-77.9). Specificity for IH was 100% for fundoscopy (95% CI: 59.0-100) and 83.3% for isolated VEPs (95% CI: 35.9-99.6). Where longitudinal deterioration was suspected from some prVEPs but not corroborated by all, sensitivity increased to 70.6% (95% CI: 44.0-89.7), while specificity decreased to 60% (95% CI: 14.7-94.7). Where longitudinal deterioration was clinically significant, sensitivity decreased to 47.1% (23.0-72.2) and specificity increased to 100% (47.8-100). Median final BCVA was 0.24 logMAR (n = 36). UK driving standard BCVA was achieved by 26 patients (72.2%), defined as ≥0.30 logMAR in the better eye.Papilloedema present on fundoscopy reliably indicated IH, but its absence did not exclude IH. VEP testing boosted sensitivity at the expense of specificity, depending on method of analysis.

Congenital fibrosis of the extraocular muscles (CFEOM) is a congenital cranial dysinnervation disorder caused by developmental abnormalities affecting cranial nerves/nuclei innervating the extraocular muscles. Autosomal dominant CFEOM arises from heterozygous missense mutations of KIF21A or TUBB3. Although spatiotemporal expression studies have shown KIF21A and TUBB3 expression in developing retinal ganglion cells, it is unclear whether dysinnervation extends beyond the oculomotor system. We aimed to investigate whether dysinnervation extends to the visual system by performing high-resolution optical coherence tomography (OCT) scans characterizing retinal ganglion cells within the optic nerve head and retina. Sixteen patients with CFEOM were screened for mutations in KIF21A, TUBB3, and TUBB2B. Six patients had apparent optic nerve hypoplasia. OCT showed neuro-retinal rim loss. Disc diameter, rim width, rim area, and peripapillary nerve fiber layer thickness were significantly reduced in CFEOM patients compared to controls (p &lt, 0.005). Situs inversus of retinal vessels was seen in five patients. Our study provides evidence of structural optic nerve and retinal changes in CFEOM. We show for the first time that there are widespread retinal changes beyond the retinal ganglion cells in patients with CFEOM. This study shows that the phenotype in CFEOM extends beyond the motor nerves.

Infantile nystagmus (IN) may result from aetiologies including albinism and FRMD7 mutations. IN has low prevalence, and twins with IN are rare. Whilst discordant presentation has been previously reported for IN, we present for the first time the comprehensive assessment of diagnostically discordant monozygotic twins. From a cohort of over 2000 patients, we identified twins and triplets discordant for nystagmus. Using next-generation sequencing, high-resolution infra-red pupil tracking and optical coherence tomography, we characterised differences in genotype and phenotype. Monozygotic twins (n = 1), dizygotic twins (n = 3) and triplets (n = 1) were included. The monozygotic twins had concordant TYR variants. No causative variants were identified in the triplets. Dizygotic twins had discordant variants in TYR, OCA2 and FRMD7. One unaffected co-twin demonstrated sub-clinical nystagmus. Foveal hypoplasia (FH) was noted in four of five probands. Both co-twins of the monozygotic pair and triplets displayed FH. In three families, at least one parent had FH without nystagmus. FH alone may be insufficient to develop nystagmus. Whilst arrested optokinetic reflex pathway development is implicated in IN, discordant twins raise questions regarding where differences in development have arisen. In unaffected monozygotes therefore, genetic variants may predispose to oculomotor instability, with variable expressivity possibly responsible for the discordance observed.

Background/aimsTo investigate the foveal morphology in carriers of oculocutaneous albinism (OCA) using spectral domain optical coherence tomography (SD-OCT). A cross-sectional, observational study.MethodsHandheld SD-OCT (Envisu C2300) was used to acquire horizontal scans through the centre of the fovea in biological parents of patients with OCA (n=28; mean age±SD=40.43±8.07 years) and age-matched and ethnicity-matched controls (n=28; mean age±SD=38.04±10.27 years). Sequence analysis was performed for variants in known genes associated with OCA. Best-corrected visual acuity (BCVA), presence of foveal hypoplasia and grade, foveal, parafoveal and perifoveal thickness measurements of total retinal layers (TRL), inner retinal layers (IRL) and outer retinal layers (ORL) thickness were measured.ResultsFoveal hypoplasia was identified in 32.14% of OCA carriers; grade 1 in all cases. OCA carriers demonstrated significant thicker TRL thickness (median difference: 13.46 µm, p=0.009) and IRL thickness (mean difference: 8.98 µm, pTYR, OCA2 and SLC45A2, novel OCA2 variants (n=3) and heterozygosity of the pathogenic TYR haplotype.ConclusionWe have, for the first time, identified foveal abnormalities in OCA carriers. This provides clinical value, particularly in cases where limited phenotype data are available. Our findings raise the possibility that previously reported mild cases of foveal hypoplasia or isolated foveal hypoplasia could correspond to OCA carrier status.

Normal foveal development begins in utero at midgestation with centrifugal displacement of inner retinal layers (IRLs) from the location of the incipient fovea. The outer retinal changes such as increase in cone cell bodies, cone elongation and packing mainly occur after birth and continue until 13 years of age. The maturity of the fovea can be assessed invivo using optical coherence tomography, which in normal development would show a well-developed foveal pit, extrusion of IRLs, thickened outer nuclear layer and long outer segments. Developmental abnormalities of various degrees can result in foveal hypoplasia (FH). This is a characteristic feature for example in albinism, aniridia, prematurity, foveal hypoplasia with optic nerve decussation defects with or without anterior segment dysgenesis without albinism (FHONDA) and optic nerve hypoplasia. In achromatopsia, there is disruption of the outer retinal layers with atypical FH. Similarly, in retinal dystrophies, there is abnormal lamination of the IRLs sometimes with persistent IRLs. Morphology of FH provides clues to diagnoses, and grading correlates to visual acuity. The outer segment thickness is a surrogate marker for cone density and in foveal hypoplasia this correlates strongly with visual acuity. In preverbal children grading FH can help predict future visual acuity.

ObjectiveTo investigate the morphology of the retina and optic nerve (ON) in microcephaly.MethodsThis was a prospective case-control study including 27 patients with microcephaly and 27 healthy controls. All participants underwent ophthalmologic examination and handheld optical coherence tomography (OCT) of the macula and ON head. The thickness of individual retinal layers was quantified at the foveal center and the parafovea (1,000 μm nasal and temporal to the fovea). For the ON head, disc diameter, cup diameter, cup-to-disc ratio, cup depth, horizontal rim diameter, rim area, peripapillary retinal thickness, and retinal nerve fiber layer thickness were measured.ResultsSeventy-eight percent of patients had ophthalmologic abnormalities, mainly nystagmus (56%) and strabismus (52%). OCT abnormalities were found in 85% of patients. OCT revealed disruption of the ellipsoid zone, persistent inner retinal layers, and irregular foveal pits. Parafoveal retinal thickness was significantly reduced in patients with microcephaly compared to controls, nasally (307 ± 44 vs 342 ± 19 μm, p = 0.001) and temporally (279 ± 56 vs 325 ± 16 μm, p < 0.001). There was thinning of the ganglion cell layer and the inner segments of the photoreceptors in microcephaly. Total peripapillary retinal thickness was smaller in patients with microcephaly compared to controls for both temporal (275 vs 318 μm, p < 0.001) and nasal sides (239 vs 268 μm, p = 0.013).ConclusionsRetinal and ON anomalies in microcephaly likely reflect retinal cell reduction and lamination alteration due to impaired neurogenic mitosis. OCT allows diagnosis and quantification of retinal and ON changes in microcephaly even if they are not detected on ophthalmoscopy.

Optical coherence tomography (OCT) is a noninvasive imaging technique that can produce images of the eye at the microscopic level. OCT image segmentation to detect retinal layer boundaries is a fundamental procedure for diagnosing and monitoring the progression of retinal and optical nerve diseases. In this paper, we introduce a novel and accurate segmentation method based on geodesic distance for both two and three dimensional OCT images. The geodesic distance is weighted by an exponential function, which takes into account both horizontal and vertical intensity variations in the image. The weighted geodesic distance is efficiently calculated from an Eikonal equation via the fast sweeping method. Segmentation then proceeds by solving an ordinary differential equation of the geodesic distance. The performance of the proposed method is compared with manual segmentation. Extensive experiments demonstrate that the proposed method is robust to complex retinal structures with large curvature variations and irregularities and it outperforms the parametric active contour algorithm as well as graph based approaches for segmenting retinal layers in both healthy and pathological images.

We present handheld optical coherence tomography (OCT) diagnosis of Grade 4 foveal hypoplasia (fovea plana) in a 28-day-old infant with albinism. Grade 4 foveal hypoplasia is characterized by the absence of the foveal pit, absence of outer segment lengthening, and absence of outer nuclear layer widening. Binocular visual acuity at 58 months follow-up was 1.2 logarithm of the minimal angle of resolution (logMAR). We describe our handheld OCT acquisition protocol and compare the morphological features with a healthy, age-matched control subject.