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Background/Objective: To utilize ultra‐widefield multimodal imaging (Optos PLC) to describe novel findings in degenerative retinoschisis. Methods: This retrospective, non‐comparative case series of degenerative retinoschisis received a waiver of consent from Advarra IRB, Protocol 00066379. Initial ultra‐widefield pseudocolour, colour‐separated, autofluorescence, and peripheral OCT imaging were analysed for characterizing features. Results: In total, 139 eyes were included. A hyporeflective reticular pattern associated with retinoschisis was seen on pseudocolour images in 39% of cases, but visible in 53% on green‐separated images. Fine hyper‐reflective foci were observed in 49%. In 27%, retinoschisis was confirmed with OCT. Conclusions: Ultra‐widefield pseudocolour and green‐separated images are valuable for the diagnosis and characterization of degenerative retinoschisis. The findings described may prompt the evaluation of subtle retinoschisis with peripheral OCT. [ABSTRACT FROM AUTHOR]

Abstract Background In severe Proliferative Diabetic Retinopathy (PDR), fibrovascular membrane (FVM) causes macular tractional retinal detachment (MTRD) which threatens vision and eventually leads to blindness. Here we present a case of separation between the inner and outer retina in tractional retinoschisis, induced during intraoperative FVM delamination. Case presentation A 68-year-old woman presented with PDR in the right eye, characterized by a combined FVM and retinal detachment, for which a vitrectomy was performed. Multiple holes, large retinal detachment extending to all quadrants, and white-lined blood vessels with FVM were found during the procedure. When membrane delamination was performed, it strayed into the space between the inner and outer retinal layers without being noticed due to retinoschisis and multiple retinal holes. After removing the FVM and detaching the separated inner retina, fluid-gas and photocoagulation were performed. Retinal reattachment was successfully achieved after surgery, and the postoperative visual acuity was improved and maintained for 26 months postoperatively. Conclusions When tractional retinoschisis due to FVM is combined with retinal holes in tractional retinal detachment (TRD), care must be taken to prevent delamination from straying into retinoschisis during separation.

X-linked juvenile retinoschisis (XLRS) is a hereditary retinal degeneration affecting young males caused by mutations in the retinoschisin (RS1) gene. We generated human induced pluripotent stem cells (hiPSCs) from XLRS patients and established three-dimensional retinal organoids (ROs) for disease investigation. This disease model recapitulates the characteristics of XLRS, exhibiting defects in RS1 protein production and photoreceptor cell development. XLRS ROs also revealed dysregulation of Na/K-ATPase due to RS1 deficiency and increased ERK signaling pathway activity. Transcriptomic analyses of XLRS ROs showed decreased expression of retinal cells, particularly photoreceptor cells. Furthermore, relevant recovery of the XLRS phenotype was observed when co-cultured with control ROs derived from healthy subject during the early stages of differentiation. In conclusion, our in vitro XLRS RO model presents a valuable tool for elucidating the pathophysiological mechanisms underlying XLRS, offering insights into disease progression. Additionally, this model serves as a robust platform for the development and optimization of targeted therapeutic strategies, potentially improving treatment outcomes for patients with XLRS. [ABSTRACT FROM AUTHOR]

Background: In severe Proliferative Diabetic Retinopathy (PDR), fibrovascular membrane (FVM) causes macular tractional retinal detachment (MTRD) which threatens vision and eventually leads to blindness. Here we present a case of separation between the inner and outer retina in tractional retinoschisis, induced during intraoperative FVM delamination. Case presentation: A 68-year-old woman presented with PDR in the right eye, characterized by a combined FVM and retinal detachment, for which a vitrectomy was performed. Multiple holes, large retinal detachment extending to all quadrants, and white-lined blood vessels with FVM were found during the procedure. When membrane delamination was performed, it strayed into the space between the inner and outer retinal layers without being noticed due to retinoschisis and multiple retinal holes. After removing the FVM and detaching the separated inner retina, fluid-gas and photocoagulation were performed. Retinal reattachment was successfully achieved after surgery, and the postoperative visual acuity was improved and maintained for 26 months postoperatively. Conclusions: When tractional retinoschisis due to FVM is combined with retinal holes in tractional retinal detachment (TRD), care must be taken to prevent delamination from straying into retinoschisis during separation. [ABSTRACT FROM AUTHOR]

Purpose: Retinoschisis is a distinctive condition characterized by intraretinal layer clefts, primarily associated with X‑linked recessive inheritance due to RS1 gene mutations. This study aims to uncover the RS1 mutation spectrum in a cohort of 22 X‑linked retinoschisis cases from South India and emphasizes the genotypic and phenotypic associations within patients harboring only RS1 mutations. Methods: A total of 22 probands were suspected of having X‑linked retinoschisis. All study subjects underwent ophthalmic investigations, including assessments of visual acuity, fundus examination, optical coherence tomography (OCT), and electroretinogram (ERG). RS1 gene screening was conducted using Sanger sequencing, and the pathogenicity of the variants was assessed through Sorting Intolerant from Tolerant (SIFT) and PolyPhen‑2 in silico tools. Results: The study found that the probands had an average visual acuity of 0.79 ± 0.39 log of minimum angle of resolution (logMAR), ranging from 0.17 to 1.77. During fundus examination, the probands exhibited a characteristic spoke wheel‑like pattern in the macular region. Furthermore, OCT analysis revealed distinct alterations in the inner retinal microstructure, and ERG results consistently showed a reduction in b‑wave amplitude. Eventually, Sanger sequencing results showed hemizygous mutations in the RS1 gene in only 12 probands, including a novel missense mutation in the RS1 gene’s signal sequence. Conclusion: This study provides valuable insights into the spectrum of RS1 mutations in X‑linked retinoschisis probands from South India. It reveals distinct genotypic–phenotypic associations and highlights the clinical manifestations associated with the disease pathogenesis. [ABSTRACT FROM AUTHOR]

X-linked retinoschisis (XLRS) is the most common juvenile macular degeneration in males. Unlike most other X-linked retinal dystrophies, carrier heterozygous females are very rarely reported to show clinical features of the disease. Herein, we describe unusual retinal features in a 2-year-old female infant with family history and genetic testing consistent with XLRS.

PurposeFoveoschisis involves the pathologic splitting of retinal layers at the fovea, which may occur congenitally in X-linked retinoschisis (XLRS) or as an acquired complication of myopia. XLRS is attributed to functional loss of the retinal adhesion protein retinoschisin 1 (RS1), but the pathophysiology of myopic foveoschisis is unclear due to the lack of animal models. Here, we characterized a novel nonhuman primate model of myopic foveoschisis through clinical examination and multimodal imaging followed by morphologic, cellular, and transcriptional profiling of retinal tissues and genetic analysis.MethodsWe identified a rhesus macaque with behavioral and anatomic features of myopic foveoschisis, and monitored disease progression over 14 months by fundus photography, fluorescein angiography, and optical coherence tomography (OCT). After necropsy, we evaluated anatomic and cellular changes by immunohistochemistry and transcriptomic changes using single-nuclei RNA-sequencing (snRNA-seq). Finally, we performed Sanger and whole exome sequencing with focus on the RS1 gene.ResultsAffected eyes demonstrated posterior hyaloid traction and progressive splitting of the outer plexiform layer on OCT. Immunohistochemistry showed increased GFAP expression in Müller glia and loss of ramified Iba-1+ microglia, suggesting macro- and microglial activation with minimal photoreceptor alterations. SnRNA-seq revealed gene expression changes predominantly in cones and retinal ganglion cells involving chromatin modification, suggestive of cellular stress at the fovea. No defects in the RS1 gene or its expression were detected.ConclusionsThis nonhuman primate model of foveoschisis reveals insights into how acquired myopic traction leads to phenotypically similar morphologic and cellular changes as congenital XLRS without alterations in RS1.

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PURPOSE: To assess central and peripheral retinal and choroidal diseases using ultra-widefield (UWF) fundus imaging in combination with navigated central and peripheral cross-sectional and three-dimensional (3D) swept source optical coherence tomography (SS-OCT) scans. METHODS: Retrospective study involving 332 consecutive patients, with a nearly equal distribution of males and females. The mean age of patients was 52 years (range 18-92 years). Average refractive error was -3.80 D (range +7.75 to -20.75 D). RESULTS: The observations in this study demonstrate the efficacy of peripheral navigated SS-OCT in assessing various ocular conditions. The technology provides high-quality images of the peripheral vitreous, vitreoretinal interface, retina, and choroid, enabling visualization of vitreous floaters and opacities, retinal holes and tears, pigmented lesions, and peripheral retinal degenerations. 3D OCT scans enhance the visualization of these abnormalities and improve diagnostic and therapeutic decisions. CONCLUSION: Navigated central and peripheral cross-sectional and 3D SS-OCT scans offer significant complementary benefits in the assessment and management of retinal diseases. Their addition to UWF imaging provides a comprehensive view of central and peripheral ocular structures, aiding in early detection, precise anatomical measurements, and objective monitoring of disease progression. In addition, this technology serves as a valuable tool for patient education, a teaching tool for trainees, and documentation for medico-legal purposes. [ABSTRACT FROM AUTHOR]

Aland island eye disease (AIED), an incomplete form of X-linked congenital stationary night blindness (CSNB2A), and X-linked cone-rod dystrophy type 3 (CORDX3) display many overlapping clinical findings. They result from mutations in the CACNA1F gene encoding the α1F subunit of the Cav1.4 channel, which plays a key role in neurotransmission from rod and cone photoreceptors to bipolar cells. Case report: A 57-year-old Caucasian man who had suffered since his early childhood from nystagmus, nyctalopia, low visual acuity and high myopia in both eyes (OU) presented to expand the diagnostic process, because similar symptoms had occurred in his 2-month-old grandson. Additionally, the patient was diagnosed with protanomalous color vision deficiency, diffuse thinning, and moderate hypopigmentation of the retina. Optical coherence tomography of the macula revealed retinoschisis in the right eye and foveal hypoplasia in the left eye. Dark-adapted (DA) 3.0 flash full-field electroretinography (ffERG) amplitudes of a-waves were attenuated, and the amplitudes of b-waves were abolished, which resulted in a negative pattern of the ERG. Moreover, the light-adapted 3.0 and 3.0 flicker ffERG as well as the DA 0.01 ffERG were consistent with severely reduced responses OU. Genetic testing revealed a hemizygous form of a stop-gained mutation (c.4051C>T) in exon 35 of the CACNA1F gene. This pathogenic variant has so far been described in combination with a phenotype corresponding to CSNB2A and CORDX3. This report contributes to expanding the knowledge of the clinical spectrum of CACNA1F-related disease. Wide variability and the overlapping clinical manifestations observed within AIED and its allelic disorders may not be explained solely by the consequences of different mutations on proteins. The lack of distinct genotype–phenotype correlations indicates the presence of additional, not yet identified, disease-modifying factors. [ABSTRACT FROM AUTHOR]

PurposeLoss of retinoschisin (RS1) function underlies X-linked retinoschisis (XLRS) pathology. In the retina, both photoreceptor inner segments and bipolar cells express RS1. However, the loss of RS1 function causes schisis primarily in the inner retina. To understand these cell type-specific phenotypes, we decoupled RS1 effects in bipolar cells from that in photoreceptors.MethodsBipolar cell transgene RS1 expression was achieved using two inner retina-specific promoters: (1) a minimal promoter engineered from glutamate receptor, metabotropic glutamate receptor 6 gene (mini-mGluR6/ Grm6) and (2) MiniPromoter (Ple155). Adeno-associated virus vectors encoding RS1 gene under either the mini-mGluR6 or Ple-155 promoter were delivered to the XLRS mouse retina through intravitreal or subretinal injection on postnatal day 14. Retinal structure and function were assessed 5 weeks later: immunohistochemistry for morphological characterization, optical coherence tomography and electroretinography (ERG) for structural and functional evaluation.ResultsImmunohistochemical analysis of RS1expression showed that expression with the MiniPromoter (Ple155) was heavily enriched in bipolar cells. Despite variations in vector penetrance and gene transfer efficiency across the injected retinas, those retinal areas with robust bipolar cell RS1 expression showed tightly packed bipolar cells with fewer cavities and marked improvement in inner retinal structure and synaptic function as judged by optical coherence tomography and electroretinography, respectively.ConclusionsThese results demonstrate that RS1 gene expression primarily in bipolar cells of the XLRS mouse retina, independent of photoreceptor expression, can ameliorate retinoschisis structural pathology and provide further evidence of RS1 role in cell adhesion.

Purpose: Retinoschisis is a distinctive condition characterized by intraretinal layer clefts, primarily associated with X-linked recessive inheritance due to RS1 gene mutations. This study aims to uncover the RS1 mutation spectrum in a cohort of 22 X-linked retinoschisis cases from South India and emphasizes the genotypic and phenotypic associations within patients harboring only RS1 mutations. Methods: A total of 22 probands were suspected of having X-linked retinoschisis. All study subjects underwent ophthalmic investigations, including assessments of visual acuity, fundus examination, optical coherence tomography (OCT), and electroretinogram (ERG). RS1 gene screening was conducted using Sanger sequencing, and the pathogenicity of the variants was assessed through Sorting Intolerant from Tolerant (SIFT) and PolyPhen-2 in silico tools. Results: The study found that the probands had an average visual acuity of 0.79 ± 0.39 log of minimum angle of resolution (logMAR), ranging from 0.17 to 1.77. During fundus examination, the probands exhibited a characteristic spoke wheel-like pattern in the macular region. Furthermore, OCT analysis revealed distinct alterations in the inner retinal microstructure, and ERG results consistently showed a reduction in b-wave amplitude. Eventually, Sanger sequencing results showed hemizygous mutations in the RS1 gene in only 12 probands, including a novel missense mutation in the RS1 gene’s signal sequence. Conclusion: This study provides valuable insights into the spectrum of RS1 mutations in X-linked retinoschisis probands from South India. It reveals distinct genotypic–phenotypic associations and highlights the clinical manifestations associated with the disease pathogenesis.

Animal models of X-linked juvenile retinoschisis (XLRS) are valuable tools for understanding basic biochemical function of retinoschisin (RS1) protein and to investigate outcomes of preclinical efficacy and toxicity studies. In order to work with an eye larger than mouse, we generated and characterized an Rs1h-/y knockout rat model created by removing exon 3. This rat model expresses no normal RS1 protein. The model shares features of an early onset and more severe phenotype of human XLRS. The morphologic pathology includes schisis cavities at postnatal day 15 (p15), photoreceptors that are misplaced into the subretinal space and OPL, and a reduction of photoreceptor cell numbers by p21. By 6 mo age only 1-3 rows of photoreceptors nuclei remain, and the inner/outer segment layers and the OPL shows major changes. Electroretinogram recordings show functional loss with considerable reduction of both the a-wave and b-wave by p28, indicating early age loss and dysfunction of photoreceptors. The ratio of b-/a-wave amplitudes indicates impaired synaptic transmission to bipolar cells in addition. Supplementing the Rs1h-/y exon3-del retina with normal human RS1 protein using AAV8-RS1 delivery improved the retinal structure. This Rs1h-/y rat model provides a further tool to explore underlying mechanisms of XLRS pathology and to evaluate therapeutic intervention for the XLRS condition.

Purpose: In this study, we report a case of a young adult with X-linked juvenile retinoschisis (XLRS) with a rare pathogenic variant in the RS1 gene (c.522 + 2 T > A). Methods: Ophthalmological evaluation, optical coherence tomography, full-field and multifocal electroretinograms and extensive genetic screening of genes related to visual loss were carried out in the participant. Results: Clinical ophthalmological exams revealed a mild to moderate impairment of visual acuity. Retinal imaging showed bilateral foveal schisis, as well as normal a-wave, reduction in the b-wave amplitudes in dark- and light- adapted full-field electroretinograms, and abnormal oscillatory potentials. We found also diffuse amplitude reduction in multifocal electroretinogram arrays. A canonical splice variant was identified in the RS1 gene (c.522 + 2 T > A). Conclusion: A rare pathogenic variant of the RS1 gene was associated with diffuse retinal involvement (central and peripheral retina), probably in inner retina, and mild to moderate visual acuity impairment. The phenotypical characterization of rare mutations is relevant to provide information about the disease. [ABSTRACT FROM AUTHOR]

To report the causes of childhood-onset uveitis in a tertiary pediatric ophthalmology hospital in Egypt. Retrospective study of the medical records of all uveitis patients following up at a tertiary pediatric ophthalmology hospital in Egypt from January 2017 to December 2020. The present study included 388 patients. The most common anatomical category was intermediate uveitis (30.4%), and around half of these children had pars planitis. This was followed by panuveitis (25.5%), posterior uveitis (23.5%), and anterior uveitis (20.6%), in decreasing frequency. Juvenile idiopathic arthritis, toxoplasmosis, and Vogt–Koyanagi–Harada syndrome were the most common causes of anterior uveitis, posterior uveitis, and panuveitis respectively. Cataract (40.5%), glaucoma (33.8%), and cystoid macular edema (31.6%) were the most frequent ocular complications. The present report provides the relative prevalence of the different anatomical types of uveitis, as well as their main causes in a cohort of Egyptian patients with childhood-onset uveitis. [ABSTRACT FROM AUTHOR]

We generated a Long Evans transgenic rat with targeted deletion of the whole Rs1 exon-1 and evaluated the pathological retinal phenotype of this Rs1-/Y rat model of X-linked retinoschisis (XLRS). The Rs1-/Y rat exhibited very early onset and rapidly progressive photoreceptor degeneration. The outer limiting membrane (OLM) was disrupted and discontinuous by post-natal day (P15) and allowed photoreceptor nuclei to dislocate from the outer nuclear layers (ONL) into the sub-retinal side of the OLM. Dark-adapted electroretinogram (ERG) a-wave and b-wave amplitudes were considerably reduced to only 20-25% of WT by P17. Microglia and Müller glial showed cell marker activation by P7. Intravitreal application of AAV8-RS1 at P5-6 induced RS1 expression by P15 and rescued the inner nuclear layer (INL) and outer plexiform layer (OPL) cavity formation otherwise present at P15, and the outer-retinal structure was less disrupted. This Rs1-/Y exon-1-del rat model displays substantially faster rod cell loss compared to the exon-1-del Rs1-KO mouse. Most unexpected was the rapid appearance of schisis cavities between P7 and P15, and then cavities rapidly disappeared by P21/P30. The rat model provides clues on the molecular and cellular mechanisms underlying XLRS pathology in this model and points to a substantial and early changes to normal retinal development.

For disorders with X-linked inheritance, variants may be transmitted through multiple generations of carrier females before an affected male is ascertained. Pathogenic RS1 variants exclusively cause X-linked retinoschisis (XLRS). While RS1 is constrained to variation, recurrent variants are frequently observed in unrelated probands. Here, we investigate recurrent pathogenic variants to determine the relative burden of mutational hotspot and founder allele events to this phenomenon. A cohort RS1 variant analysis and standardized classification, including variant enrichment in the XLRS cohort and in RS1 functional domains, were performed on 332 unrelated XLRS probands. A total of 108 unique RS1 variants were identified. A subset of 19 recurrently observed RS1 variants were evaluated in 190 probands by a haplotype analysis, using microsatellite and single nucleotide polymorphisms. Fourteen variants had at least two probands with common variant-specific haplotypes over ~1.95 centimorgans (cM) flanking RS1. Overall, 99/190 of reportedly unrelated probands had 25 distinct shared haplotypes. Examination of this XLRS cohort for common RS1 haplotypes indicates that the founder effect plays a significant role in this disorder, including variants in mutational hotspots. This improves the accuracy of clinical variant classification and may be generalizable to other X-linked disorders.

X-linked juvenile retinoschisis (XLRS) is a hereditary retinal degeneration affecting young males caused by mutations in the retinoschisin (RS1) gene. We generated human induced pluripotent stem cells (hiPSCs) from XLRS patients and established three-dimensional retinal organoids (ROs) for disease investigation. This disease model recapitulates the characteristics of XLRS, exhibiting defects in RS1 protein production and photoreceptor cell development. XLRS ROs also revealed dysregulation of Na/K-ATPase due to RS1 deficiency and increased ERK signaling pathway activity. Transcriptomic analyses of XLRS ROs showed decreased expression of retinal cells, particularly photoreceptor cells. Furthermore, relevant recovery of the XLRS phenotype was observed when co-cultured with control ROs derived from healthy subject during the early stages of differentiation. In conclusion, our in vitro XLRS RO model presents a valuable tool for elucidating the pathophysiological mechanisms underlying XLRS, offering insights into disease progression. Additionally, this model serves as a robust platform for the development and optimization of targeted therapeutic strategies, potentially improving treatment outcomes for patients with XLRS.

Abstract Purpose To describe imaging characteristics of severe macular complications occurring in glaucoma and discuss available treatments. Methods Retrospective case series of glaucomatous patients with macular retinoschisis (MR) and/or serous retinal detachment (SRD). Patients underwent a complete ophthalmological examination and multimodal imaging including retinography, SD-OCT, fluorescein and indocyanine green angiography (FA & ICGA) and adaptive optics (AO). Results Ten eyes (8 patients) were included. Initial BCVA was 1.04 ± 1.12 logMAR and IOP was 24.0 ± 9.3mmHg. All eyes presented with MR while SRD was present in 5 eyes (5 patients), with a central macular thickness of 573 ± 152 μm. FA and ICGA allowed to exclude leakage in all cases. A focal lamina cribrosa defect (LCD) was found in four eyes (4 patients) using OCT, with AO providing en-face visualization of the defect in one eye. Outer retinal hole was present in 3 eyes (3 patients). No visual improvement or resolution of the macular retinoschisis was observed in eyes with medical or surgical IOP control (N = 9). Vitrectomy with internal membrane limiting peeling and gas tamponade was performed in one eye with good visual results. Conclusions Multimodal high-resolution imaging is essential to diagnose severe macular complications associated with advanced glaucoma.

Background: To investigate the changes in macular cystic schisis (MCS) and sensitivity during the day in X-linked retinoschisis (XLRS) patients. Methods: Treatment-naïve patients with genetically verified XLRS underwent best-correlated visual acuity (BCVA) testing with ETDRS charts, spectral domain optical coherence tomography, and microperimetry (MP) twice a day, at 9 a.m. and 4 p.m., to measure changes in central retinal thickness (CRT), macular volume (MV), average threshold (AT), and fixation stability parameters (P1 and P2). Results: At baseline, the BCVA of the 14 eyes of 8 patients amounted 0.73 (± 0.23) LogMAR. Between timepoints, the BCVA increased in 3.21 letters (p =.021), the AV improved in 1.84 dB (p =.03, 9.73%), the CRT decreased in 24.43 µm (p =.007, − 4.05%), and the MV dropped in 0.27 µm3 (p =.016, − 2.68%). P1 and P2 did not variate. The collapse of the MCS led to the reduction of macula thickness. CRT at baseline correlated with the decrease of CRT (Spearman's ρ: − 0.83 [p =.001]). Age and change of BCVA, CRT, and AV did not correlate among one another. Eyes with disrupted ellipsoid zone showed a more prominent change in CRT (p =.050). Photoreceptor outer segment length and integrity of the external limiting membrane and cone outer segment tips were not associated with BCVA, AT, or CRT variation. Conclusion: Eyes of treatment-naïve XLRS patients show diurnal macular thickness and function changes. Eyes with pronounced macular thickness show a greater reduction of the MCS. These results should be taken into consideration in upcoming clinical trials in XLRS. Trial registration number: Institutional Review Board of the Hamburg Medical Chamber (Ethik-Kommission der Ärztekammer Hamburg): 2020–10,328. [ABSTRACT FROM AUTHOR]

Purpose: To assess the retinal modifications after cataract surgery in a patient presenting with stellate nonhereditary idiopathic foveomacular retinoschisis. Methods: Retrospective analysis of the evolution of retinal status in a 64-year-old patient with unilateral stellate nonhereditary idiopathic foveomacular retinoschisis who underwent cataract surgery in the affected eye. Results: Visual acuity improved after surgery, reaching back the level described by the patient before the cataract onset, whereas fundus retinographies and optical coherence tomographies were stable at one month after surgery, compared with the preoperative images. Discussion: This first case-report of the evolution of stellate nonhereditary idiopathic foveomacular retinoschisis after cataract surgery suggests that this retinal condition is not modified by the surgical procedure, which however needs to confirmed by larger cohorts. [ABSTRACT FROM AUTHOR]

Introduction: An 18-year old highly myopic woman presented with bilateral retinoschisis associated with a unilateral macular hole in the right eye and vitreomacular traction in the left eye. Methods: Genetic studies disclosed a heterozygous pathogenic variant in the KCNJ13 gene was identified (c.484C>T (p.Arg162Trp)), consistent with a diagnosis of snowflake vitreoretinal degeneration (SVD). Results: While there were no corneal guttata, juvenile cataracts, or perivascular sheathing in this case, salient features of SVD included a fibrillar vitreous structure, crystalline retinopathy, and flattened optic nerves. The patient developed a FTMH in the left eye at 17 months follow up, followed by a rhegmatogenous retinal detachment (RRD) requiring 2 surgical repairs. Conclusion: This case expands on the spectrum of clinical features in SVD, including retinoschisis and FTMH. It also characterizes optical coherence tomography findings in this rare disease entity. We emphasize the importance of using panel-based genetic testing to clinically distinguish and further define atypical vitreoretinopathies. [ABSTRACT FROM AUTHOR]

To understand RS1 gene interaction networks in the X-linked retinoschisis (XLRS) mouse retina (Rs1-/y), we analyzed the transcriptome by RNA sequencing before and after in vivo expression of exogenous retinoschisin (RS1) gene delivered by AAV8. RS1 is a secreted cell adhesion protein that is critical for maintaining structural lamination and synaptic integrity of the neural retina. RS1 loss-of-function mutations cause XLRS disease in young boys and men, with splitting ("schisis") of retinal layers and synaptic dysfunction that cause progressive vision loss with age. Analysis of differential gene expression profiles and pathway enrichment analysis of Rs1-KO (Rs1-/y) retina identified cell surface receptor signaling and positive regulation of cell adhesion as potential RS1 gene interaction networks. Most importantly, it also showed massive dysregulation of immune response genes at early age, with characteristics of a microglia-driven proinflammatory state. Delivery of AAV8-RS1 primed the Rs1-KO retina toward structural and functional recovery. The disease transcriptome transitioned toward a recovery phase with upregulation of genes implicated in wound healing, anatomical structure (camera type eye) development, metabolic pathways, and collagen IV networks that provide mechanical stability to basement membrane. AAV8-RS1 expression also attenuated the microglia gene signatures to low levels toward immune quiescence. This study is among the first to identify RS1 gene interaction networks that underlie retinal structural and functional recovery after RS1 gene therapy. Significantly, it also shows that providing wild-type RS1 gene function caused the retina immune status to transition from a degenerative inflammatory phenotype toward immune quiescence, even though the transgene is not directly linked to microglia function. This study indicates that inhibition of microglial proinflammatory responses is an integral part of therapeutic rescue in XLRS gene therapy, and gene therapy might realize its full potential if delivered before microglia activation and photoreceptor cell death. Clinical Trials. gov Identifier NTC 02317887.

This study explored systemic immune changes in 11 subjects with X-linked retinoschisis (XLRS) in a phase I/IIa adeno-associated virus 8 (AAV8)-RS1 gene therapy trial (ClinicalTrials.gov: NCT02317887). Immune cell proportions and serum analytes were compared to 12 healthy male controls. At pre-dosing baseline the mean CD4/CD8 ratio of XLRS subjects was elevated. CD11c+ myeloid dendritic cells (DCs) and the serum epidermal growth factor (EGF) level were decreased, while CD123+ plasmacytoid DCs and serum interferon (IFN)-γ and tumor necrosis factor (TNF)-α were increased, indicating that the XLRS baseline immune status differs from that of controls. XLRS samples 14 days after AAV8-RS1 administration were compared with the XLRS baseline. Frequency of CD11b+CD11c+ DCc was decreased in 8 of 11 XLRS subjects across all vector doses (1e9-3e11 vector genomes [vg]/eye). CD8+human leukocyte antigen-DR isotype (HLA-DR)+ cytotoxic T cells and CD68+CD80+ macrophages were upregulated in 10 of 11 XLRS subjects, along with increased serum granzyme B in 8 of 11 XLRS subjects and elevated IFN-γ in 9 of 11 XLRS subjects. The six XLRS subjects with ocular inflammation after vector application gave a modestly positive correlation of inflammation score to their respective baseline CD4/CD8 ratios. This exploratory study indicates that XLRS subjects may exhibit a proinflammatory, baseline immune phenotype, and that intravitreal dosing with AAV8-RS1 leads to systemic immune activation with an increase of activated lymphocytes, macrophages, and proinflammatory cytokines.

Aland island eye disease (AIED), an incomplete form of X-linked congenital stationary night blindness (CSNB2A), and X-linked cone-rod dystrophy type 3 (CORDX3) display many overlapping clinical findings. They result from mutations in the CACNA1F gene encoding the α1F subunit of the Cav1.4 channel, which plays a key role in neurotransmission from rod and cone photoreceptors to bipolar cells. Case report: A 57-year-old Caucasian man who had suffered since his early childhood from nystagmus, nyctalopia, low visual acuity and high myopia in both eyes (OU) presented to expand the diagnostic process, because similar symptoms had occurred in his 2-month-old grandson. Additionally, the patient was diagnosed with protanomalous color vision deficiency, diffuse thinning, and moderate hypopigmentation of the retina. Optical coherence tomography of the macula revealed retinoschisis in the right eye and foveal hypoplasia in the left eye. Dark-adapted (DA) 3.0 flash full-field electroretinography (ffERG) amplitudes of a-waves were attenuated, and the amplitudes of b-waves were abolished, which resulted in a negative pattern of the ERG. Moreover, the light-adapted 3.0 and 3.0 flicker ffERG as well as the DA 0.01 ffERG were consistent with severely reduced responses OU. Genetic testing revealed a hemizygous form of a stop-gained mutation (c.4051C>T) in exon 35 of the CACNA1F gene. This pathogenic variant has so far been described in combination with a phenotype corresponding to CSNB2A and CORDX3. This report contributes to expanding the knowledge of the clinical spectrum of CACNA1F-related disease. Wide variability and the overlapping clinical manifestations observed within AIED and its allelic disorders may not be explained solely by the consequences of different mutations on proteins. The lack of distinct genotype–phenotype correlations indicates the presence of additional, not yet identified, disease-modifying factors.

Purpose: To describe imaging characteristics of severe macular complications occurring in glaucoma and discuss available treatments. Methods: Retrospective case series of glaucomatous patients with macular retinoschisis (MR) and/or serous retinal detachment (SRD). Patients underwent a complete ophthalmological examination and multimodal imaging including retinography, SD-OCT, fluorescein and indocyanine green angiography (FA & ICGA) and adaptive optics (AO). Results: Ten eyes (8 patients) were included. Initial BCVA was 1.04 ± 1.12 logMAR and IOP was 24.0 ± 9.3mmHg. All eyes presented with MR while SRD was present in 5 eyes (5 patients), with a central macular thickness of 573 ± 152 μm. FA and ICGA allowed to exclude leakage in all cases. A focal lamina cribrosa defect (LCD) was found in four eyes (4 patients) using OCT, with AO providing en-face visualization of the defect in one eye. Outer retinal hole was present in 3 eyes (3 patients). No visual improvement or resolution of the macular retinoschisis was observed in eyes with medical or surgical IOP control (N = 9). Vitrectomy with internal membrane limiting peeling and gas tamponade was performed in one eye with good visual results. Conclusions: Multimodal high-resolution imaging is essential to diagnose severe macular complications associated with advanced glaucoma. [ABSTRACT FROM AUTHOR]

A rare presentation of a patient with macular and peripapillary retinoschisis in the setting of narrow-angle glaucoma is described, and this is the first study to demonstrate complete spontaneous resolution with conservative management. Purpose: To present a rare case of retinoschisis in the setting of narrow-angle glaucoma that demonstrated spontaneous resolution with conservative management. Methods: Case report presentation from the Vitreous Retina Macula Specialists of Toronto in December 2020. Results: A 65-year-old woman with previous bilateral laser peripheral iridotomies for narrow-angle glaucoma was referred to a tertiary retina clinic for the assessment of query macular edema in the left eye. The patient presented with a blunted foveal reflex in the left eye, and optical coherence tomography imaging demonstrated diffuse retinoschisis of outer retinal layers in the peripapillary region and nasal macula. The patient elected for conservative management, and by 10-month follow-up, her retinoschisis resolved spontaneously. Conclusion: Only seven cases of retinoschisis in the setting of narrow-angle glaucoma have been identified in the literature. This is the first case in this setting to demonstrate spontaneous resolution with conservative management. Although laser peripheral iridotomies have been shown to resolve retinoschisis in narrow-angle glaucoma patients, clinicians should be aware of a conservative management approach to yield a positive improvement in retinal integrity. [ABSTRACT FROM AUTHOR]

Introduction: Dome-shaped macula is characterized by a convex anterior protrusion of the macula towards the vitrous cavity, associated with high myopia and a posterior staphyloma. The etiology is not fully understood. Case report: We report a case of a 29-year-old woman, with myopia and astigmatism presented to our department complaining of painless deterioration of vision and metamorphopsia in both eyes. The anterior segment and vitreous were unremarkable, fundoscopy showed central chorioretinal atrophy and retinal pigment epithelial changes in OU. Optical coherence tomography scans showed excessive macular edema and numerous hyporeflective sub- and intraretinal spaces in both eyes. Fundus fluorescein angiography revealed numerous punctate areas of contrast leakage at the upper-temporal vascular arch in right eye and a focus of contrast leakage at the superior- temporal vascular arch in left eye. Indocyanine green angiography presented areas with a visible intensified vascular pattern in the posterior pole of both eyes, slightly enhancing in the intermediate phase and extinguishing in the late phase. The diagnosis of dome-shaped macula was established. After antiinflammatory and diuretic treatment, there was no improvement in visual acuity and morphological changes. The clinical picture remains stable after 1.5 year follow-up. Conclusions: Dome-shaped macula is still not a fully understood condition. Inconclusive clinical picture may simulate other ocular pathologies. The visual acuity and macular changes seem to be stable over the years even without treatment. [ABSTRACT FROM AUTHOR]

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We report a patient with enhanced S-cone syndrome because of pathogenic (p.Arg309Gly), and likely pathogenic (p.Arg77Trp) variants in the NR2E3 gene with atypical electroretinogram responses and atypical double hyperautofluorescent ring in both eyes. Purpose: To describe the clinical phenotype and molecular diagnosis of a patient with atypical presentation of enhanced S-cone syndrome. Methods: This is a case report of a patient who underwent best-corrected visual acuity, slit-lamp exam, fundus examination, autofluorescence, optical coherence tomography, kinetic perimetry, and full-field electroretinography. Genetic testing was performed via next-generation sequencing. Results: A 33-year-old female patient presented with mild nyctalopia, but normal rod function measured by electroretinogram and foveoschisis on optical coherence tomography. She also presented a double hyperautofluorescent ring on autofluorescence. Genetic testing found a pathogenic variant c.925C>G (p.Arg309Gly) and a likely pathogenic variant c.299C>T (p.Arg77Trp) in NR2E3 gene. Conclusion: Enhanced S-cone syndrome may present without the pathognomonic findings of decreased rod function on electroretinogram, suggesting the importance of genetic testing in retinal diseases for diagnosis. [ABSTRACT FROM AUTHOR]

BackgroundTo assess the functional and structural outcomes of macular buckling using a silicone sponge-titanium exoplant for the treatment of foveoschisis (FS) and full-thickness macular holes (FTMHs) in highly myopic eyes.MethodsForty-nine consecutive patients with high myopia who underwent macular buckling for the treatment of FS and FTMHs were included. The outcomes measured included the anatomical success rate with FS resolution, retinal reattachment, MH closure, best corrected visual acuity (BCVA), axial length (AL) and complications of surgery. Moreover, the correlations between the BCVA at year three and series of factors, including age, duration of symptoms, baseline BCVA, AL, surgical type, preoperative macular status and severity of myopic maculopathy, were analysed.ResultsThis study involved 28 patients (28 eyes) with FS and 21 patients (21 eyes) with FTMHs with macular detachment. Retinal reattachment was achieved in 100% of cases, while MH closure was achieved in 76.19% of cases. The BCVA significantly improved one year after macular buckling in the FS cases and two years after macular buckling in the FTMH cases, and it remained stable throughout the rest of the follow-up period. The mean AL decreased by 2.09 mm postoperatively. No major perioperative complications were observed, although one patient needed to explant the buckling device due to intolerable diplopia.ConclusionMacular buckling with a silicone sponge-titanium exoplant may represent a safe and effective surgical option for the treatment of FS and FTMH in highly myopic eyes. Macular buckling showed a high closure rate and virtually no tendency to recur.

PurposeTo explore the experiences of parents of sons with X-linked retinoschisis (XLRS).DesignMixed methods-qualitative interviews with quantitative survey.MethodsParents of sons with XLRS who were evaluated at the National Eye Institute between December 2017 and January 2019 were eligible for this study. Participation involved engaging in a semistructured interview and completing a survey assessing optimism, anxiety, personality traits, and sociodemographics using valid and reliable scales. Interview transcripts were coded and analyzed thematically, and scales were scored and used descriptively.ResultsEleven mothers and 8 fathers from 13 families participated. Optimism, anxiety, and personality traits fell into the normative ranges for the scales. Parents described a process of continuous adaptation to their son's condition. The initial diagnosis was characterized by shock, grief, and "devastation" for most parents. Maternal guilt was common, but usually lessened over time. As parents adjusted to life postdiagnosis, they attempted to achieve a state of normalcy while balancing a desire to protect their sons. Significant sources of stress included decisions around sports participation and driving. Among all parents, the fear of retinal detachment was an ongoing concern. Most parents did identify perceived benefits from their experiences, such as feelings of gratitude or family cohesion.ConclusionsMost parents viewed XLRS as a significant challenge in their sons' lives, but one that could be overcome. Clinical encounters may be enhanced for families with XLRS by providing accurate information, preparing families for potential challenges, anticipating stressful decisions, and meeting other families with XLRS.

BackgroundTo explore the role of foveal and parafoveal Müller cells in the morphology and pathophysiology of tractional macular disorders with a mathematical model of mechanical force transmission.MethodsIn this retrospective observational study, spectral-domain optical coherence tomography images of tractional lamellar macular holes and patients with myopic foveoschisis were reviewed and analysed with a mathematical model of force transmission. Parafoveal z-shaped Müller cells were modelled as a structure composed of three rigid rods, named R1, R2 and R3. The angle formed between the rods was referred to as θ . R1, R2 and R3 lengths as well as the variation of the angle θ were measured and correlated with best corrected visual acuity (BCVA).ResultsIn tractional lamellar macular holes, there was a significant reduction of the angle θ towards the foveal centre (p

An asymptomatic patient presented with bilateral nanophthalmos, optic disk drusen, and foveal hypoplasia without foveoschisis, cataract, and occludable angles. Salivary genetic testing revealed homozygosity of a novel mutation of the MFRP gene consistent with a clinically distinct phenotype of autosomal recessive nanophthalmos. Ultra-widefield optical coherence tomography demonstrated extensive multilevel peripheral retinoschisis. Purpose: To describe with multimodal imaging including the use of ultra-widefield optical coherence tomography imaging a distinct phenotype of autosomal recessive nanophthalmos associated with a novel mutation of the MFRP gene (membrane-type frizzled-related protein). Methods: Case report of a single patient followed by the Weill Cornell Medicine Department of Ophthalmology Retina and Glaucoma Services, and review of the relevant literature. Results: A patient with a novel homozygous mutation in the MFRP gene (c.472C>T) presented with nanophthalmos, optic disk drusen, foveal hypoplasia, and extensive peripheral retinoschisis, which was revealed to be multilevel retinoschisis on ultra-widefield optical coherence tomography. Unlike other reported cases, the findings associated with this novel mutation did not include foveoschisis or clinically obvious retinitis pigmentosa. The patient underwent prophylactic peripheral laser iridotomy in both eyes. Conclusion: Here, we present a patient with nanophthalmos, optic disk drusen, and foveal hypoplasia associated with extensive peripheral retinoschisis imaged by ultra-widefield optical coherence tomography, but not foveal retinoschisis or prominent retinitis pigmentosa. The findings may expand the clinical spectrum of MFRP -associated nanophthalmos. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the clinical characteristics, internal correlations and risk factors for different locations of retinoschisis (RS) in an elderly high myopia (HM) population. Methods: A total of 448 eyes (304 participants) were analysed and classified into no retinoschisis (no‐RS), paravascular retinoschisis (PVRS), peripapillary retinoschisis (PPRS) and macular retinoschisis (MRS) groups. Each participant underwent comprehensive ophthalmic examinations, and posterior scleral height (PSH) was measured in swept‐source optical coherence tomography images. PSH, vitreoretinal interface abnormities and myopic atrophy maculopathy (MAM) were compared among groups. Results: Retinoschisis was found in 195 (43.5%) eyes, among which 170 (37.9%) had PVRS, 123 (27.5%) had PPRS, and 103 (23.0%) had MRS. MRS was found to be combined with PVRS in 96 of 103 (93.2%) eyes. MAM was one of the risk factors for RS (odds ratio [OR], 2.459; p = 0.005). Higher nasal PSH was the only risk factor for PVRS (OR, 9.103; p = 0.008 per 1‐mm increase). Elongation of axial length (AL) (OR, 1.891; p < 0.001 per 1‐mm increase), higher PSH in nasal (OR, 5.059; p = 0.009 per 1‐mm increase) and temporal (OR, 13.021; p = 0.012 per 1‐mm increase), epiretinal membrane (ERM; OR, 2.841; p = 0.008) and vitreomacular traction (VMT; OR, 7.335; p = 0.002) were risk factors for MRS. Conclusions: Paravascular retinoschisis is the most common type of RS in HM and MRS is mostly combined with PVRS. MAM is one of the risk factors for RS. In addition to longer AL and higher PSH, the presence of VMT and ERM also play an important role in the formation of MRS. [ABSTRACT FROM AUTHOR]

Optic disc pits are a rare but significant anomaly of the optic nerve head that can lead to visual impairment and associated complications. These pits are characterized by a small, oval-shaped depression in the disc, which can cause fluid accumulation and subsequent damage to the adjacent retina. Although the etiology and pathogenesis of optic disc pits are not fully understood, several theories have been proposed, including abnormal embryonic development and degenerative changes. Diagnosis is typically made through a comprehensive eye examination, including a dilated fundus exam and optical coherence tomography. Management options vary depending on the severity of the condition and associated complications, ranging from observation to surgical intervention.

IntroductionX-linked retinoschisis (XLRS) is an inherited retinal disease (IRD) caused by pathogenic mutations in the retinoschisin gene, RS1. Affected individuals develop retinal layer separation, leading to loss of visual acuity (VA). Several XLRS gene therapy trials have been attempted but none have met their primary endpoints. An improved understanding of XLRS natural history and clinical outcomes may better inform future trials. Here, we report the long-term functional and structural outcomes of XLRS and the relevance of RS1 genotypes to the visual prognosis of affected individuals.MethodsA retrospective chart review of patients with molecularly confirmed X-linked retinoschisis was performed. Functional and structural outcomes, and RS1 genotype data, were included for analysis.ResultsFifty-two patients with XLRS from 33 families were included in the study. Median age at symptom onset was 5 years (range 0–49) and median follow-up was 5.7 years (range 0.1–56.8). Macular retinoschisis occurred in 103 of 104 eyes (99.0%), while peripheral retinoschisis occurred in 48 of 104 eyes (46.2%), most often in the inferotemporal quadrant (40.4%). Initial and final VA were similar (logMAR 0.498 vs. 0.521; p = 0.203). Fifty of 54 eyes (92.6%) developed detectable outer retinal loss by age 20, and 29 of 66 eyes (43.9%) had focal or diffuse outer retinal atrophy (ORA) by age 40. ORA but not central subfield thickness (CST) was associated with reduced VA. Inter-eye correlation was modest for VA (r-squared = 0.03; p = 0.08) and CST (r-squared = 0.15; p = 0.001). Carbonic anhydrase inhibitors (CAIs) improved CST (p = 0.026), but not VA (p = 0.380). Eight of 104 eyes (7.7%) had XLRS-related retinal detachment (RD), which was associated with poorer outcomes compared to eyes without RD (median final VA 0.875 vs. 0.487; p

Retinoschisis is a poorly documented form of retinal degeneration characterized by cyst-like splitting that occurs between the inner nuclear and outer plexiform layers. The pathogenesis of retinoschisis is incompletely understood, but congenital, acquired and secondary aetiologies (glaucoma, inflammation, neoplasia) are described in humans. This retrospective study investigated the prevalence and associated histological and clinical features of retinoschisis in cats and dogs submitted for biopsy over a 10-year period. Of 140 samples with documented 'retinal vacuolation', four out of 120 (3%) canine samples and one out of 20 (5%) feline samples had changes consistent with retinoschisis. In most cases (80%), there was concurrent retinal detachment. In cases with available histories, increased intraocular pressure, proptosis and retinal detachment were reported clinical findings. In cats and dogs, retinoschisis is a retinal change that is generally secondary to other ocular lesions. [ABSTRACT FROM AUTHOR]