Retinal Structure and Function in a Knock-in Mouse Model for the FAM161A-p.Arg523∗ Human Nonsense Pathogenic Variant.

Purpose: Pathogenic variants in FAM161A are the most common cause of retinitis pigmentosa in Israel. Two founder pathogenic variants explain the vast majority of cases of Jewish origin, 1 being a nonsense variant (p.Arg523∗). The aim of this study was to generate a knock-in (KI) mouse model harboring the corresponding p.Arg512∗ pathogenic variant and characterize the course of retinal disease. Design: Experimental study of a mouse animal model. Subjects/Participants/Controls: A total of 106 Fam161a knock-in mice and 29 wild-type mice with C57BL/6J background particiapted in this study. Methods: Homozygous Fam161a p.Arg512∗ KI mice were generated by Cyagen Biosciences. Visual acuity (VA) was evaluated using optomotor tracking response and retinal function was assessed by electroretinography (ERG). Retinal structure was examined in vivo using OCT and fundus autofluorescence imaging. Retinal morphometry was evaluated by histologic and immunohistochemical (IHC) analyses. Main Outcome Measures: Visual and retinal function assessments, clinical imaging examinations, quantitative histology, and IHC studies of KI as compared with wild-type (WT) mice retinas. Results: The KI model was generated by replacing 3 bp, resulting in p.Arg512∗. Homozygous KI mice that had progressive loss of VA and ERG responses until the age of 18 months, with no detectable response at 21 months. OCT showed complete loss of the outer nuclear layer at 21 months. Fundus autofluorescence imaging revealed progressive narrowing of blood vessels and formation of patchy hyper-autofluorescent and hypo-autofluorescent spots. Histologic analysis showed progressive loss of photoreceptor nuclei. Immunohistochemistry staining showed Fam161a expression mainly in photoreceptors cilia and the outer plexiform layer (OPL) in WT mice retinas, whereas faint expression was evident mainly in the cilia and OPL of KI mice. Conclusions: The Fam161a - p.Arg512∗ KI mouse model is characterized by widespread retinal degeneration with relatively slow progression. Surprisingly, disease onset is delayed and progression is slower compared with the previously reported knock-out model. The common human null mutation in the KI mouse model is potentially amenable for correction by translational read-through-inducing drugs and by gene augmentation therapy and RNA editing, and can serve to test these treatments as a first step toward possible application in patients. Financial Disclosures: The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Physiology of retinal reattachment in humans: Swept source optical coherence tomography imaging data supporting a novel staging system.

This article presents high-resolution swept source optical coherence tomography (SS-OCT) imaging data used to describe the physiology of retinal reattachment in humans. SS-OCT imaging was performed at baseline and every 2 h for the first 6 h and at frequent intervals thereafter up to 6 weeks following the injection of intravitreal gas in eyes undergoing pneumatic retinopexy for rhegmatogenous retinal detachment. Imaging data presented in this article is related to the research paper titled "Real-Time in Vivo Assessment of Retinal Reattachment in Humans using Swept-Source Optical Coherence Tomography" (Bansal et al., 2021). SS-OCT images were assessed longitudinally and used to devise a novel staging system that describes the physiology of retinal reattachment. Multiple examples of each stage and the transition from one stage to the next are provided. SS-OCT images were also assessed to determine the timing associated with each stage, and the anatomic abnormalities, such as outer retinal folds and subretinal fluid blebs that occured as a result of delayed progression through certain stages.

Reliability of Subjective Assessment of Spectral-Domain OCT Pathologic Features by Multiple Raters in Retinal Vein Occlusion.

Purpose: To examine the interrater and intrarater reliability of qualitatively and quantitatively assessed disorganization of retinal inner layers (DRIL) and disorganization of retinal outer layers (DROL) by multiple raters. Subjectively assessing these surrogate biomarkers can be challenging in daily routine, despite the high resolution of spectral-domain (SD) OCT scans. Design: Retrospective trial. Participants: Three hundred six pooled SD OCT scans of 34 patients treated for macular edema caused by retinal vein occlusion (RVO) between January 2016 and December 2017. Methods: SD OCT scans were assessed by 6 raters regarding presence of cystoid macular edema, subretinal fluid (SRF), vitreoretinal traction, and epiretinal membrane and extent of DRIL and DROL. Main Outcome Measures: Interrater and intrarater reliability were calculated applying κ statistics for qualitative assessment regarding each pathologic feature's presence in all evaluated OCT scans, and for quantified horizontal DRIL and DROL extent within each OCT cross-section. Results: Cystoid macular edema and SRF assessments revealed excellent inter- and intrarater reliability with almost perfect strength of agreement, whereas subjective DRIL and DROL evaluations yielded low κ statistics with slight to moderate strength of agreement. Furthermore, the presence of SRF remarkably compromised the reliability of DROL detection. Conclusions: Our data highlight the limited subjective assessibility of DRIL and DROL, underscoring the need for automated image analysis to improve the reliability of OCT biomarkers for clinical studies and daily practice.

Predicting visual outcomes for macular disease using optical coherence tomography.

In recent years, the management of macular disease has undergone radical changes, in part because of new therapeutic approaches, but also due to the introduction of a new imaging modality - optical coherence tomography (OCT). The application of OCT imaging has clarified many aspects of chorioretinal disease pathophysiology and elucidated many hitherto unrecognized disease characteristics. From an early stage in its development, OCT has also been revolutionary in attempting to extract clinically useful measurements from image data in an automated fashion. As a result, OCT-derived measurements of retinal thickness have been rapidly embraced in clinical and research settings. However, as knowledge of OCT image analysis has developed, it has become increasingly clear that even accurate measurements of retinal thickness may fail to predict visual outcomes for many diseases. As a result, the focus of much current clinical imaging research is on the identification of other OCT-derived anatomic biomarkers predictive of visual outcomes - such biomarkers could serve as surrogate endpoints in clinical trials and provide prognostic information in clinical practice. In this review, we begin by highlighting the importance of accurate visual function assessment and describing the fundamentals of OCT image evaluation, before describing the current state-of-the-art with regard to predicting visual outcomes, for a variety of macular diseases, using OCT.