Infantile nystagmus (IN) is a common neuro-ophthalmological disorder that presents as early-onset involuntary oscillations of the eyes. Here, we report a novel genotype-phenotype correlation that associates sequence alterations in the calcium voltage-gated channel auxiliary subunit beta 3 (CACNB3) gene, encoding the CaVβ3 protein, with idiopathic infantile nystagmus (IIN). Linkage analysis, whole exome and Sanger sequencing identified a homozygous missense mutation (c.316G>C) in CACNB3 co-segregating with IIN. Our calcium imaging experiments suggest that the p.Gly106Arg mutation in the Src homology 3 domain of CaVβ3 may impair voltage-gated calcium channel function at the plasma membrane and may increase ligand-triggered inositol trisphosphate receptor mediated calcium release at the endoplasmic reticulum. Co-localization studies indicate reduced plasma membrane localization of the calcium channel. We propose CACNB3 to be a novel gene associated with IIN. Our findings point towards an important role of calcium-signalling in IIN and may contribute to deciphering its aetiology.

Purpose:Aggressive (posterior) retinopathy of prematurity (A-ROP/AP-ROP) may progress rapidly into tractional retinal detachment if not treated timely. Fortunately, this type of treatment-warranted ROP is rare in developed countries. As a consequence, data on risk factors for development of this aggressive form of ROP is sparse. In this study, we aim to analyse the risk factors for the development of AP-ROP using data from the German Retina.net ROP registry and report functional outcomes of patients treated for AP-ROP. Methods:We assessed the observational German Retina.net ROP registry for infants born between 2011 and 2020 and treated for unilateral or bilateral aggressive posterior ROP (AP-ROP) (N = 21). These infants were compared to infants treated for ROP without AP-ROP (control group; N = 329) regarding demographics, neonatal parameters, ROP management and functional outcomes. Results:Of 350 infants treated for any ROP, 21 (6%) were diagnosed with unilateral or bilateral AP-ROP [38 of 686 eyes (5.5%)], predominantly in zone I (77%). Infants with AP-ROP were born at a significantly younger gestational age (24.3 vs. 25.4 weeks; p = 0.0001) and with a lower birth weight (595 vs. 697 g; p = 0.0262). Treatment occurred at a significantly lower postmenstrual age (PMA) and postnatal age (PNA). Treatment consisted mainly of intravitreal anti-VEGF therapy (79% of eyes) [compared to laser photocoagulation for controls (60%)]. Eyes with AP-ROP required more retreatments (39% vs. 15%; p = 0.0002). At follow-up of approximately 12 months PNA, 12/15 eyes with AP-ROP had central fixation and 6/15 eyes exhibited strabismus. Median spherical equivalent of eyes with AP-ROP (N = 16) was 0.0 dpt (interquartile range: -2.6 to 1.0 dpt). One child developed complete retinal detachment in 1 eye and 1 child partial retinal detachment in 1 eye. Conclusion:Our study confirmed known risk factors for the development of AP-ROP such as low GA and low birth weight, whereas other previously reported risk factors such as male sex and certain comorbidities were not observed in our cohort. Our data provide additional insight into AP-ROP treatment patterns including earlier time of treatment, higher risk for retreatment, and therapy preference for intravitreal anti-VEGF therapy.

RPE65 biallelic mutation-associated inherited retinal degeneration (IRD) is currently the only IRD for which gene therapy is approved. This narrative review provides a brief overview of the disease and an update of the current literature on outcomes following the approval of treatment with voretigene neparvovec (LuxturnaTM) in 2017 (USA) and Europe (2018). Post-marketing results confirm a significant therapeutic effect of this gene augmentation on rod function similar to that seen in the phase 1 to 3 clinical trials. The full-field chromatic light sensitivity test is an appropriate test to demonstrate early and sustained effects of treatment. Visual acuity and visual fields may improve in less advanced disease. Accelerated chorioretinal atrophy (CRA) is a previously unrecognised adverse effect that is now reported in 13 % to 50 % of treated eyes. If central, visual acuity loss and paracentral visual field defects may occur. Further studies are needed to identify patients at risk of CRA in order to maximize patient benefit from a costly intervention.

Background/Aaims Congenital stationary night blindness (CSNB) is an inherited retinal disease that is often associated with high myopia and can be caused by pathological variants in multiple genes, most commonly CACNA1F, NYX and TRPM1. High myopia is associated with retinal degeneration and increased risk for retinal detachment. Slowing the progression of myopia in patients with CSNB would likely be beneficial in reducing risk, but before interventions can be considered, it is important to understand the natural history of myopic progression.Methods This multicentre, retrospective study explored CSNB caused by variants in CACNA1F, NYX or TRPM1 in patients who had at least 6 measurements of their spherical equivalent of refraction (SER) before the age of 18. A mixed-effect model was used to predict progression of SER overtime and differences between genotypes were evaluated.Results 78 individuals were included in this study. All genotypes showed a significant myopic predicted SER at birth (-3.076D, -5.511D and -5.386D) for CACNA1F, NYX and TRPM1 respectively. Additionally, significant progression of myopia per year (-0.254D, -0.257D and -0.326D) was observed for all three genotypes CACNA1F, NYX and TRPM1, respectively.Conclusions Patients with CSNB tend to be myopic from an early age and progress to become more myopic with age. Patients may benefit from long-term myopia slowing treatment in the future and further studies are indicated. Additionally, CSNB should be considered in the differential diagnosis for early-onset myopia.

Rare pediatric retinal disorders present significant challenges in diagnosis and management due to their limited prevalence and diverse clinical manifestations. This paper provides a comprehensive review of select rare retinal disorders affecting the pediatric population, focussing a brief on their epidemiology, clinical characteristics, diagnostic modalities, and therapeutic interventions. Through a systematic examination of current literature and clinical case studies, this review aims to elucidate the distinct features and challenges associated with each disorder. Despite the rarity of these conditions, their impact on visual function and quality of life necessitates heightened awareness among clinicians and researchers to facilitate timely diagnosis, appropriate management, and improved outcomes for affected children as their visual systems are still developing. Furthermore, advancements in diagnostic modalities such as fundus fluorescein angiography, optical coherence tomography, electroretinography, and genetic testing are examined for their role in enhancing our understanding of rare pediatric retinal disorders and facilitating early intervention strategies. The literature selection for this article was conducted through PubMed, Google Scholar, and the Cochrane Library databases. A thorough systematic search was carried out for the concerned diseases. Relevant review articles, original research studies, case series, and reports were examined. Additionally, references from these sources were reviewed and included if they provided pertinent information on the topic. The search was not restricted by publication date.

Spiroplasma ixodetis has been reported to cause the rare combination of cataract and uveitis in infants. Through a retrospective analysis of available literature and additional unpublished cases, we identified 28 eyes from 18 infants from 8 countries in Europe with cataracts and intraocular inflammation. The cataracts were bilateral in 55.6%, unilateral in 44.4%, and progressive in 46.4% of patients. Granulomatous anterior uveitis was found in all infants. Presence of S. ixodetis was supported by PCR (positive in 89.3% of eyes tested), transmission electron microscopy (positive in 90% of eyes tested), or culture of aspirated lens material (positive in 87.5% of eyes tested). Treatment with macrolide antimicrobial drugs, corticosteroids, and lensectomy appeared to be effective. Two patients had a recurrence of the uveitis after lens extraction and needed prolonged treatment. To increase awareness of S. ixodetis, we suggest its inclusion with the organisms of the TORCH acronym.

Purpose: To quantify relevant fundus autofluorescence (FAF) features cross-sectionally and longitudinally in a large cohort of patients with inherited retinal diseases (IRDs). Design: Retrospective study of imaging data. Participants: Patients with a clinical and molecularly confirmed diagnosis of IRD who have undergone 55 degrees FAF imaging at Moorfields Eye Hospital (MEH) and the Royal Liverpool Hospital between 2004 and 2019. Methods: Five FAF features of interest were defined: vessels, optic disc, perimacular ring of increased signal (ring), relative hypo-autofluorescence (hypo-AF), and hyper-autofluorescence (hyper-AF). Features were manually annotated by 6 graders in a subset of patients based on a defined grading protocol to produce segmentation masks to train an artificial intelligence model, AIRDetect, which was then applied to the entire imaging data set. Main Outcome Measures: Quantitative FAF features, including area and vessel metrics, were analyzed cross-sectionally by gene and age, and longitudinally. AIRDetect feature segmentation and detection were validated with Dice score and precision/recall, respectively. Results: A total of 45 749 FAF images from 3606 patients with IRD from MEH covering 170 genes were automatically segmented using AIRDetect. Model-grader Dice scores for the disc, hypo-AF, hyper-AF, ring, and vessels were, respectively, 0.86, 0.72, 0.69, 0.68, and 0.65. Across patients at presentation, the 5 genes with the largest hypo-AF areas were CHM, ABCC6, RDH12, ABCA4, and RPE65, with mean per-patient areas of 43.72, 29.57, 20.07, 19.65, and 16.92 mm(2), respectively. The 5 genes with the largest hyper-AF areas were BEST1, CDH23, NR2E3, MYO7A, and RDH12, with mean areas of 0.50, 047, 0.44, 0.38, and 0.33 mm(2), respectively. The 5 genes with the largest ring areas were NR2E3, CDH23, CRX, EYS, and PDE6B, with mean areas of 3.60, 2.90, 2.89, 2.56, and 2.20 mm(2), respectively. Vessel density was found to be highest in EFEMP1, BEST1, TIMP3, RS1, and PRPH2 (11.0%, 10.4%, 10.1%, 10.1%, 9.2%) and was lower in retinitis pigmentosa (RP) and Leber congenital amaurosis genes. Longitudinal analysis of decreasing ring area in 4 RP genes (RPGR, USH2A, RHO, and EYS) found EYS to be the fastest progressor at-0.178 mm(2)/year. Conclusions: We have conducted the first large-scale cross-sectional and longitudinal quantitative analysis of FAF features across a diverse range of IRDs using a novel AI approach.

Purpose:To quantify outer retina structural changes and define novel biomarkers of inherited retinal degeneration associated with biallelic mutations in RPE65 (RPE65-IRD) in patients before and after subretinal gene augmentation therapy with voretigene neparvovec (Luxturna). Methods:Application of advanced deep learning for automated retinal layer segmentation, specifically tailored for RPE65-IRD. Quantification of five novel biomarkers for the ellipsoid zone (EZ): thickness, granularity, reflectivity, and intensity. Estimation of the EZarea in single and volume scans was performed with optimized segmentation boundaries. The control group was age similar and without significant refractive error. Spherical equivalent refraction and ocular length were evaluated in all patients. Results:We observed significant differences in the structural analysis of EZ biomarkers in 22 patients with RPE65-IRD compared with 94 healthy controls. Relative EZ intensities were already reduced in pediatric eyes. Reductions of EZ local granularity and EZ thickness were only significant in adult eyes. Distances of the outer plexiform layer, external limiting membrane, and Bruch's membrane to EZ were reduced at all ages. EZ diameter and area were better preserved in pediatric eyes undergoing therapy with voretigene neparvovec and in patients with a milder phenotype. Conclusions:Automated quantitative analysis of biomarkers within EZ visualizes distinct structural differences in the outer retina of patients including treatment-related effects. The automated approach using deep learning strategies allows big data analysis for distinct forms of inherited retinal degeneration. Limitations include a small dataset and potential effects on OCT scans from myopia at least -5 diopters, the latter considered nonsignificant for outer retinal layers.

Purpose: To define the clinical characteristics of centrosomal protein 290 (CEP290)-associated inherited retinal degeneration (IRD) and determine which assessments may provide reliable endpoints in future interventional trials. Design: Participants in this natural history study were enrolled into 2 best-corrected visual acuity (BCVA) cohorts: light perception to > 1.0 logarithm of the minimum angle of resolution (logMAR) and 1.0 logMAR to 0.4 logMAR. Each comprised 4 age cohorts (3-5, 6-11, 12-17, and >= 18 years). Participants: Patients with CEP290-associated IRD caused by the intron 26 c.2991+1655A>G mutation and BCVA ranging from light perception to 0.4 logMAR. Methods: Best-corrected visual acuity, full-field stimulus threshold (FST) sensitivity, Ora-Visual Navigation Challenge (Ora-VNC) composite score, and OCT-outer nuclear layer (OCT-ONL) average thickness were assessed at screening, baseline, 3 months, 6 months, and 12 months. Main outcome measures: Best-corrected visual acuity, FST sensitivity, Ora-VNC composite score, and OCT-ONL average thickness. Results: Twenty-six participants were included in this analysis. Nineteen were female. All participants were White and 4 reported Hispanic ethnicity. At screening, 13 of 16 adult and 9 of 10 pediatric participants had BCVA > 1.0 logMAR. Baseline BCVA was variable (median [range] = 2.0 [0.5, 3.9] logMAR) and was uncorrelated with age, as were VNC composite score, FST sensitivity, and OCT-ONL average thickness. Mean (95% confidence interval [CI]) test-retest variability was -0.04 (-0.09, 0.01) logMAR for BCVA (n = 25); 0.6 (-0.1, 1.3) for VNC composite score (n = 18); and 0.10 (-0.07, 0.27) log cd.s/m(2) for red FST (n = 14). A greater than expected test-retest variability (5 [0, 10] mu m, n = 14) was observed for OCT-ONL average thickness as nystagmus impacted ability to repeat measures at the same retinal location. Functional assessments were stable over 12 months. Mean (95% CI) change from baseline was 0.06 (-0.17, 0.29) logMAR for BCVA (n = 23); -0.1 (-1.2, 1.0) for VNC composite score (n = 21); and -0.15 (-0.43, 0.14) log cd.s/m(2) for red FST (n = 16). Conclusions: Vision was stable over 12 months. Best-corrected visual acuity, FST, and VNC composite score are potentially viable endpoints for future studies in CEP290-associated IRD. Repeatability of OCT measures poses challenges for quantifying anatomical changes in this population.

Background/Aims To describe the patterns of pre-operative aberrant regeneration and motility outcomes reported in an international registry of patients with 3rd-nerve palsy treated with nasal transposition of the split lateral rectus muscle (NTSLR). Methods This cross-sectional study used data from an international, multicentre registry of patients with 3rd-nerve palsy treated with NTSLR. Patients with aberrant regeneration were identified, and patterns of innervation described. Demographics and postoperative success defined as horizontal alignment ≤15 PD were compared based on the presence, and type, of aberrant regeneration using Wilcoxon rank sum and Fisher's exact tests. Results Aberrant regeneration was reported in 16% (21/129) of patients. Age at diagnosis, sex, and aetiology of palsy were not significantly associated with aberrant regeneration. Abnormal movements were triggered by adduction in 52% (11/21), infraduction in 23% (5/21), and supraduction in 23% (5/21) of cases. Presentation patterns involved rectus muscle innervation in 29% (6/21) and levator muscle innervation in 71% (15/21) of cases. Although patients with aberrant regeneration had similar probability of success in comparison to those without following NTLSR (76% vs. 69%, p = 0.5), those with abnormal innervation of a rectus muscle had a lower success rate than those with abnormal innervation of the levator palpebrae superioris muscle (17% vs. 93%; p = 0.002). Conclusion Successful treatment of a 3rd nerve palsy with NTSLR was not influenced by aberrant regeneration involving the levator muscle. Alternative surgical interventions should be considered when aberrant regeneration alters rectus muscle function given its adverse impact on motor outcomes with NTSLR.

PURPOSE:To assess the impact of baseline data on psychophysical and morphological outcomes of subretinal voretigene neparvovec (VN) (Luxturna, Spark Therapeutics, Inc.) treatment. DESIGN:Single-center, retrospective, longitudinal, consecutive case series. PARTICIPANTS:Patients with RPE65-biallelic mutation-associated inherited retinal degeneration (RPE65-IRD) treated between February 2020 and March 2022 with VN and oral immunosuppression according to the manufacturer's recommendation by one surgeon (F.G.H.). METHODS:Retrospective analysis of surgical and clinical records, ancillary testing, and retinal imaging after VN therapy for RPE65-IRD. Descriptive statistics compared data at baseline up to 32 months post-treatment. MAIN OUTCOME MEASURES:Best-corrected visual acuity (BCVA), low-luminance VA (LLVA), Goldmann visual fields (GVFs), chromatic full-field stimulus threshold (FST) testing (FST), scotopic and photopic 2-color threshold perimetry (2CTP), and multimodal retinal imaging. RESULTS:Thirty eyes of 19 patients were analyzed (10 pediatric patients < 20 years; 20 adult patients > 20 years of age; overall range: 8-40 years) with a median follow-up of 15 months (range, 1-32). The fovea was completely or partially detached in 16 eyes, attached in 12 eyes, and not assessable in 2 eyes on intraoperative imaging. Median BCVA at baseline was better in the pediatric group (P < 0.05) and did not change significantly independent of age. Meaningful loss of BCVA (≥ 0.3 logarithm of the minimal angle of resolution [logMAR]) occurred in 5 of 18 adult eyes, and a meaningful gain (≥-0.3 logMAR) occurred in 2 of 18 adult and 2 of 8 pediatric eyes. The LLVA and scotopic 2CTP improved considerably in pediatric patients. Scotopic blue FST improved at all ages but more in pediatric patients (8/8 eyes gained ≥ 10 decibels [dB]; P < 0.05). In pediatric patients, median GVF improved by 20% for target V4e and by 50% for target III4e (target I4e not detected). Novel atrophy developed in 13 of 26 eyes at the site of the bleb or peripheral of vascular arcades. Improvements in FST did not correlate with development of chorioretinal atrophy at 12 months. Mean central retinal thickness was 165.87 μm (± 26.26) at baseline (30 eyes) and 157.69 μm (± 30.3) at 12 months (26 eyes). Eight adult patients were treated unilaterally. The untreated eyes did not show meaningful changes during follow-up. CONCLUSIONS:These data in a clinical setting show the effectiveness of VN therapy with stable median BCVA and mean retinal thickness and improvements of LLVA, FST, and 2CTP up to 32 months. Treatment effects were superior in the pediatric group. We observed new chorioretinal atrophy in 50% of the treated eyes. FINANCIAL DISCLOSURE(S):Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

OBJECTIVE:To quantify changes in ductions following nasal transposition of the split lateral rectus muscle (NTSLR) for treating third nerve palsy. DESIGN:Retrospective cohort study. PARTICIPANTS:A single eye from each patient with third nerve palsy treated with NTSLR with ocular motility measurements. METHODS:Observation of changes in pre- and postoperative ductions. Outcome measures including patient demographic and surgical factors associated with the ability to adduct beyond the midline after NTSLR were evaluated using multivariable logistic regression. RESULTS:A total of 116 patients met the inclusion criteria for this study. The NTSLR significantly decreased abduction (median of 0 limitation [interquartile range (IQR), 0-0] prior to surgery to -4 [IQR, -4 to -3] after NTSLR; p < 0.001), with a corresponding improvement in adduction (median, -5 [IQR, -5 to -4] prior to surgery to -4 [IQR, -4 to -3] after NTSLR; p < 0.001). There was no change in median supraduction or infraduction after NTSLR (p > 0.05). The ability to adduct beyond the midline after NTSLR was demonstrated in 42% of patients. Although not statistically significant, a trend toward a postoperative ability to adduct beyond the midline was seen in patients who had concurrent superior oblique muscle tenotomy (odds ratio [OR] = 5.08; 95% CI, 0.91-40.9) or who were designated with partial rather than complete third nerve palsy (OR = 2.29; 95% CI, 0.82-6.70). CONCLUSIONS:NTSLR improves the horizontal midline positioning of eyes with third nerve palsy. Most eyes lose the ability to abduct, but some regain a modest ability to adduct while vertical ductions remain unchanged.

Background: Retinopathy of prematurity (ROP) is one of the most common causes of childhood blindness in Germany and worldwide and adequate screening is essential. The telemedical approach with objective documentation of retinal findings opens up the possibility of reliably diagnosing all ROP stages independent of the examiner, if a team of ophthalmologists specialized in ROP evaluates the images. Objective: A 10-year comparison of ROP screening at two level-1 neonatal intensive care units (NICU): university and on-site vs. non-university and telemedical. Material and methods: Retrospective analysis of screened premature infants by gestational age (GA), birth weight (BW), sex, multiple births, time of ROP occurrence, treatment needs and time as well as examination frequency. Results: From 2009 to 2019, we screened 1191 infants of whom 29 had been screened before by an external clinic. The internal 1162 infants were screened on-site with 3713 retinal examinations. We diagnosed 34% with ROP and treated 5.4% (3.7% in Giessen, 7.2% in Siegen). Mean GA was 28.9 weeks (+/- 2.5 weeks); mean BW 1155 g (+/- 417.5 g). The number of ROP diagnoses increased by 227.3% in Giessen and by 111.1% in Siegen due to the increasing number of premature births in neonatal care. Conclusion: Comparative analysis confirmed nationally and internationally increasing ROP screening and children with acute ROP. Telemedical screening was equivalent to on-site screening and safe. Both screening methods identified infants requiring treatment on time. No child with GA > 29 weeks required treatment, analogous to Swedish ROP registry results; however, in the German ROP registry some premature babies with GA = 30 weeks required treatment.