Extended optical treatment versus early patching with an intensive patching regimen in children with amblyopia in Europe (EuPatch): a multicentre, randomised controlled trial.

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 ≥0·30 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, ≤0·20 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=0·019) 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. FUNDING: Action Medical Research, NIHR Clinical Research Network, and Ulverscroft Foundation.

ERG Responses in Albinism, Idiopathic Infantile Nystagmus, and Controls.

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.

Visual Field Deficits in Albinism in Comparison to Idiopathic Infantile Nystagmus.

Purpose: This is the first systematic comparison of visual field (VF) deficits in people with albinism (PwA) and idiopathic infantile nystagmus (PwIIN) using static perimetry. We also compare best-corrected visual acuity (BCVA) and optical coherence tomography measures of the fovea, parafovea, and circumpapillary retinal nerve fiber layer in PwA. Methods: VF testing was performed on 62 PwA and 36 PwIIN using a Humphrey Field Analyzer (SITA FAST 24-2). Mean detection thresholds for each eye were calculated, along with quadrants and central measures. Retinal layers were manually segmented in the macular region. Results: Mean detection thresholds were significantly lower than normative values for PwA (-3.10 ± 1.67 dB, P << 0.0001) and PwIIN (-1.70 ± 1.54 dB, P < 0.0001). Mean detection thresholds were significantly lower in PwA compared to PwIIN (P < 0.0001) and significantly worse for left compared to right eyes in PwA (P = 0.0002) but not in PwIIN (P = 0.37). In PwA, the superior nasal VF was significantly worse than other quadrants (P < 0.05). PwIIN appeared to show a mild relative arcuate scotoma. In PwA, central detection thresholds were correlated with foveal changes in the inner and outer retina. VF was strongly correlated to BCVA in both groups. Conclusions: Clear peripheral and central VF deficits exist in PwA and PwIIN, and static VF results need to be interpreted with caution clinically. Since PwA exhibit considerably lower detection thresholds compared to PwIIN, VF defects are unlikely to be due to nystagmus in PwA. In addition to horizontal VF asymmetry, PwA exhibit both vertical and interocular asymmetries, which needs further exploration.

Phenotypic Features Determining Visual Acuity in Albinism and the Role of Amblyogenic Factors.

Albinism is a spectrum disorder causing foveal hypoplasia, nystagmus, and hypopigmentation of the iris and fundus along with other visual deficits, which can all impact vision. Albinism is also associated with amblyogenic factors which could affect monocular visual acuity. The foveal appearance in albinism can range from mild foveal hypoplasia to that which is indistinguishable from the peripheral retina. The appearance can be quickly and easily graded using the Leicester Grading System in the clinic. However, interquartile ranges of 0.3 logMAR for the grades associated with albinism limit the accuracy of the grading system in predicting vision. Here, we discuss the potential role of nystagmus presenting evidence that it may not be a major source of variability in the prediction of visual acuity. We also show that interocular differences in visual acuity are low in albinism despite high levels of amblyogenic factors indicating that active suppression of vision in one eye in albinism is uncommon.

USE OF HAND-HELD OPTICAL COHERENCE TOMOGRAPHY DURING RETINOPATHY OF PREMATURITY SCREENING DEMONSTRATES AN INCREASED OUTER RETINA FROM EARLY POSTMENSTRUAL AGE IN PRETERM INFANTS WITH RETINOPATHY OF PREMATURITY.

PURPOSE: To identify structural markers of active retinopathy of prematurity (ROP) in foveal and parafoveal retinal layers using hand-held optical coherence tomography. METHODS: Hand-held optical coherence tomography images (n = 278) were acquired from a prospective mixed cross-sectional longitudinal observational study of 87 participants (23-36 weeks gestational age; n = 30 with ROP, n = 57 without ROP) between 31 and 44 weeks postmenstrual age excluding treated ROP and features of cystoid macular edema. Six retinal layer thicknesses from the fovea to the parafovea were analyzed at five locations up to 1,000 µ m, temporally and nasally. RESULTS: The mean outer retinal thickness during active ROP increased at the fovea and parafovea from postmenstrual age 33 weeks to 39 weeks ( P < 0.001), whereas the parafoveal inner nuclear layer and retinal nerve fiber layer reduced ( P < 0.001). Outer retinal thickness at the fovea from 33 weeks to 39 weeks postmenstrual age was consistently thicker in infants with ROP across all levels of prematurity (gestational age). CONCLUSION: Increased foveal and parafoveal outer retina measured using hand-held optical coherence tomography shows potential as a marker for ROP screening.

CHIASM-Net: Artificial Intelligence-Based Direct Identification of Chiasmal Abnormalities in Albinism.

Purpose: Albinism is a congenital disorder affecting pigmentation levels, structure, and function of the visual system. The identification of anatomical changes typical for people with albinism (PWA), such as optic chiasm malformations, could become an important component of diagnostics. Here, we tested an application of convolutional neural networks (CNNs) for this purpose. Methods: We established and evaluated a CNN, referred to as CHIASM-Net, for the detection of chiasmal malformations from anatomic magnetic resonance (MR) images of the brain. CHIASM-Net, composed of encoding and classification modules, was developed using MR images of controls (n = 1708) and PWA (n = 32). Evaluation involved 8-fold cross validation involving accuracy, precision, recall, and F1-score metrics and was performed on a subset of controls and PWA samples excluded from the training. In addition to quantitative metrics, we used Explainable AI (XAI) methods that granted insights into factors driving the predictions of CHIASM-Net. Results: The results for the scenario indicated an accuracy of 85 ± 14%, precision of 90 ± 14% and recall of 81 ± 18%. XAI methods revealed that the predictions of CHIASM-Net are driven by optic-chiasm white matter and by the optic tracts. Conclusions: CHIASM-Net was demonstrated to use relevant regions of the optic chiasm for albinism detection from magnetic resonance imaging (MRI) brain anatomies. This indicates the strong potential of CNN-based approaches for visual pathway analysis and ultimately diagnostics.

Achromatopsia-Visual Cortex Stability and Plasticity in the Absence of Functional Cones.

Purpose: Achromatopsia is a rare inherited disorder rendering retinal cone photoreceptors nonfunctional. As a consequence, the sizable foveal representation in the visual cortex is congenitally deprived of visual input, which prompts a fundamental question: is the cortical representation of the central visual field in patients with achromatopsia remapped to take up processing of paracentral inputs? Such remapping might interfere with gene therapeutic treatments aimed at restoring cone function. Methods: We conducted a multicenter study to explore the nature and plasticity of vision in the absence of functional cones in a cohort of 17 individuals affected by autosomal recessive achromatopsia and confirmed biallelic disease-causing CNGA3 or CNGB3 mutations. Specifically, we tested the hypothesis of foveal remapping in human achromatopsia. For this purpose, we applied two independent functional magnetic resonance imaging (fMRI)-based mapping approaches, i.e. conventional phase-encoded eccentricity and population receptive field mapping, to separate data sets. Results: Both fMRI approaches produced the same result in the group comparison of achromatopsia versus healthy controls: sizable remapping of the representation of the central visual field in the primary visual cortex was not apparent. Conclusions: Remapping of the cortical representation of the central visual field is not a general feature in achromatopsia. It is concluded that plasticity of the human primary visual cortex is less pronounced than previously assumed. A pretherapeutic imaging workup is proposed to optimize interventions.

Predicting Acute and Post-Recovery Outcomes in Cerebral Malaria and Other Comas by Optical Coherence Tomography (OCT in CM) - A protocol for an observational cohort study of Malawian children.

Cerebral malaria (CM) remains a significant global health challenge with high morbidity and mortality. Malarial retinopathy has been shown to be diagnostically and prognostically significant in the assessment of CM. The major mechanism of death in paediatric CM is brain swelling. Long term morbidity is typically characterised by neurological and neurodevelopmental sequelae. Optical coherence tomography can be used to quantify papilloedema and macular ischaemia, identified as hyperreflectivity. Here we describe a protocol to test the hypotheses that quantification of optic nerve head swelling using optical coherence tomography can identify severe brain swelling in CM, and that quantification of hyperreflectivity in the macula predicts neurodevelopmental outcomes post-recovery. Additionally, our protocol includes the development of a novel, low-cost, handheld optical coherence tomography machine and artificial intelligence tools to assist in image analysis.

Clinical features and imaging characteristics in achiasmia.

Achiasmia is a rare visual pathway maldevelopment with reduced decussation of the axons in the optic chiasm. Our aim was to investigate clinical characteristics, macular, optic nerve and brain morphology in achiasmia. A prospective, cross-sectional, observational study of 12 participants with achiasmia [8 males and 4 females; 29.6 ± 18.4 years (mean ± standard deviation)] and 24 gender-, age-, ethnicity- and refraction-matched healthy controls was done. Full ophthalmology assessment, eye movement recording, a high-resolution spectral-domain optical coherence tomography of the macular and optic disc, five-channel visual-evoked responses, eye movement recordings and MRI scans of the brain and orbits were acquired. Achiasmia was confirmed in all 12 clinical participants by visual-evoked responses. Visual acuity in this group was 0.63 ± 0.19 and 0.53 ± 0.19 for the right and left eyes, respectively; most participants had mild refractive errors. All participants with achiasmia had see-saw nystagmus and no measurable stereo vision. Strabismus and abnormal head position were noted in 58% of participants. Optical coherence tomography showed optic nerve hypoplasia with associated foveal hypoplasia in four participants. In the remaining achiasmia participants, macular changes with significantly thinner paracentral inner segment (P = 0.002), wider pit (P = 0.04) and visual flattening of the ellipsoid line were found. MRI demonstrated chiasmatic aplasia in 3/12 (25%), chiasmatic hypoplasia in 7/12 (58%) and a subjectively normal chiasm in 2/12 (17%). Septo-optic dysplasia and severe bilateral optic nerve hypoplasia were found in three patients with chiasmic aplasia/hypoplasia on MRI. In this largest series of achiasmia patients to date, we found for the first time that neuronal abnormalities occur already at the retinal level. Foveal changes, optic nerve hypoplasia and the midline brain anomaly suggest that these abnormalities could be part of the same spectrum, with different manifestations of events during foetal development occurring with varying severity.

First-in-Human Gene Therapy Trial of AAV8-hCARp.hCNGB3 in Adults and Children With CNGB3-associated Achromatopsia.

PURPOSE: To assess the safety and efficacy of AAV8-hCARp.hCNGB3 in participants with CNGB3-associated achromatopsia (ACHM). DESIGN: Prospective, phase 1/2 (NCT03001310), open-label, nonrandomized clinical trial. METHODS: The study enrolled 23 adults and children with CNGB3-associated ACHM. In the dose-escalation phase, adult participants were administered 1 of 3 AAV8-hCARp.hCNGB3 dose levels in the worse-seeing eye (up to 0.5 mL). After a maximum tolerated dose was established in adults, an expansion phase was conducted in children ≥3 years old. All participants received topical and oral corticosteroids. Safety and efficacy parameters, including treatment-related adverse events and visual acuity, retinal sensitivity, color vision, and light sensitivity, were assessed for 6 months. RESULTS: AAV8-hCARp.hCNGB3 (11 adults, 12 children) was safe and generally well tolerated. Intraocular inflammation occurred in 9 of 23 participants and was mainly mild or moderate in severity. Severe cases occurred primarily at the highest dose. Two events were considered serious and dose limiting. All intraocular inflammation resolved following topical and systemic steroids. There was no consistent pattern of change from baseline to week 24 for any efficacy assessment. However, favorable changes were observed for individual participants across several assessments, including color vision (n = 6/23), photoaversion (n = 11/20), and vision-related quality-of-life questionnaires (n = 21/23). CONCLUSIONS: AAV8-hCARp.hCNGB3 for CNGB3-associated ACHM demonstrated an acceptable safety and tolerability profile. Improvements in several efficacy parameters indicate that AAV8-hCARp.hCNGB3 gene therapy may provide benefit. These findings, with the development of additional sensitive and quantitative end points, support continued investigation.

Eye movement defects in KO zebrafish reveals SRPK3 as a causative gene for an X-linked intellectual disability.

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.

Severity of cystoid macular oedema in preterm infants observed using hand-held spectral domain optical coherence tomography improves weekly with postmenstrual age.

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 < 0.0001 for thickness, area and peak; P < 0.01 for width). Area and width significantly decreased with PMA for 'dome' and 'fovea' CMO (p = 0.0028; p < 0.001 respectively). No association was found between the presence of ROP and the detection of CMO or detection of CMO with absence of ELM. CONCLUSIONS: HH -OCT in preterm infants demonstrates that the severity of CMO appearance improves each week for both fovea and dome CMO.

Short-term progression of optic disc and macular changes in optic nerve head drusen.

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.

Electrophysiological and fundoscopic detection of intracranial hypertension in craniosynostosis.

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.

Abnormal foveal morphology in carriers of oculocutaneous albinism.

BACKGROUND/AIMS: To investigate the foveal morphology in carriers of oculocutaneous albinism (OCA) using spectral domain optical coherence tomography (SD-OCT). A cross-sectional, observational study. METHODS: Handheld 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. RESULTS: Foveal 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, p<0.001) at the central fovea compared with controls. BCVA of carriers was between -0.16 and 0.18 logMAR (mean: 0.0 logMAR). No significant differences in BCVA was noted between OCA carriers or controls (p=0.83). In the OCA carriers, we identified previously reported pathogenic variants in TYR, OCA2 and SLC45A2, novel OCA2 variants (n=3) and heterozygosity of the pathogenic TYR haplotype. CONCLUSION: We 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.

Retinal Development in Infants and Young Children With Albinism: Evidence for Plasticity in Early Childhood.

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.

Longitudinal Evaluation of Changes in Retinal Architecture Using Optical Coherence Tomography in Achromatopsia.

Purpose: This prospective study investigates longitudinal changes in retinal structure in patients with achromatopsia (ACHM) using optical coherence tomography (OCT). Methods: 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. Results: 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)). Conclusions: 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.

Abnormal Retinal Vessel Architecture in Albinism and Idiopathic Infantile Nystagmus.

Purpose: 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. Methods: 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. Results: Compared with controls, the mean number of arterial branches was reduced by 24% in PWA (15.5 vs. 20.3, P < 0.001), and venous branches were reduced in both PWA (29%; 12.9 vs. 18.2, P < 0.001) 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). Conclusions: 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.

Comprehensive variant spectrum of the CNGA3 gene in patients affected by achromatopsia.

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.