Photoreceptor deficits appear at eye opening in Rs1 mutant mouse models of X-linked retinoschisis.

X-linked retinoschisis (XLRS) is an early onset degenerative retinal disease characterized by cystic lesions in the middle layers of the retina. These structural changes are accompanied by a loss of visual acuity and decreased contrast sensitivity. XLRS is caused by mutations in the gene Rs1 which encodes the secreted protein Retinoschisin 1. Young Rs1-mutant mouse models develop key hallmarks of XLRS including intraretinal schisis and abnormal electroretinograms. The electroretinogram (ERG) comprises activity of multiple cellular generators, and it is not known how and when each of these is impacted in Rs1 mutant mice. Here we use an ex vivo ERG system and pharmacological blockade to determine how ERG components generated by photoreceptors, ON-bipolar, and Müller glial cells are impacted in Rs1 mutants and to determine the time course of these changes. We report that ERG abnormalities begin near eye-opening and that all ERG components are involved.

Genetic, morphological and electrophysiological findings in a patient with a rare pathogenic variant in the RS1 gene.

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.

Progression of macular retinoschisis following intravitreal aflibercept injection for myopic macular neovascularization-a case report and review of literature.

BACKGROUND: Macular retinoschisis (MRS) and myopic macular neovascularization (mMNV) are both potentially blinding complications of high myopia. In this case report, we highlight the progression of MRS after intravitreal anti-vascular endothelial growth factor (anti-VEGF) treatment for mMNV, as well as an extensive review of the literature on this topic. CASE DESCRIPTION: A 49-year-old woman presented with two weeks of recent onset blurring and metamorphopsia in her right eye. She had high myopia in both eyes (right eye - 20/60 with - 16D, left eye - 20/20 with - 13D). Slit-lamp ophthalmoscopy found a normal anterior segment in both eyes. On fundus examination, features of pathological myopia with posterior staphyloma and peripapillary atrophy were observed in both eyes. An active mMNV, as well as intraretinal fluid, minimal perifoveal inner and outer MRS, and focal posterior vitreous traction along the inferotemporal retinal arcade, were detected on optical coherence tomography (OCT) of the right eye. The patient received an intravitreal injection of Aflibercept (2 mg/0.05 ml). RESULTS: OCT scans at two- and four-month follow-up visits revealed regressed mMNV with a taut epiretinal membrane, progressive worsening of outer MRS, and the development of multiple perifoveal retinal detachment inferior to the fovea. Pars plana vitrectomy surgery was performed for the progressive MRS with good anatomical (resolved MRS) and functional outcome (maintained visual acuity at 20/60) at the last one-month post-surgery visit. CONCLUSION: Intravitreal anti-VEGF injections for mMNV can cause vitreoretinal interface changes, exacerbating MRS and causing visual deterioration. Vitrectomy for MRS could be one of several treatment options.

Foveal Microstructure and Visual Outcomes after Pars Plana Vitrectomy in Patients with Different Types of Epiretinal Membrane Foveoschisis.

INTRODUCTION: The aim of this study was to evaluate the clinical characteristics and surgical outcomes of the epiretinal membrane foveoschisis (ERM-FS) with different morphological types. METHODS: This retrospective observational study reviewed 44 consecutive ERM-FS patients who underwent ERM surgery. According to the optical coherence tomography images, ERM-FS was classified into three groups: group A, FS crossed the fovea with the foveola elevated; group B, FS located at the foveal edges with a near-normal central foveal point thickness; and group C, FS with undermined foveal edges with a near-normal central foveal point thickness. RESULTS: There were 10 eyes in group A, 20 eyes in group B, and 14 eyes in group C. Preoperatively, eyes in group A had the best best-corrected visual acuity (BCVA), the thickest central foveal point thickness, and the highest ellipsoid zone (EZ) intact rate among the three groups. After surgery, a resolution of foveoschisis was observed in 40.0%, 45.0%, and 50.0% of the eyes in group A, group B, and group C (p = 0.928), respectively. BCVA was significantly improved postoperatively. Although there was no significant difference in BCVA among the three groups at 1 month postoperatively, BCVA of group A was the best at 4 and 10 months. Correlation analysis indicated that the type of ERM-FS, baseline BCVA, central foveal point thickness, and postoperative EZ continuity (all p < 0.05) were important factors for the final BCVA. CONCLUSIONS: The damage to the retinal structure and visual function was milder in group A ERM-FS. Our study emphasized the necessity of OCT-based subtyping in patients with ERM-FS.

Ultrastructural Details of Epiretinal Membrane Foveoschisis.

INTRODUCTION: The aim of this study was to describe differences in the vitreomacular interface (VMI) in idiopathic epiretinal membrane (ERM) foveoschisis compared to macular pseudohole (MPH) and lamellar macular hole (LMH). METHODS: We analysed surgically excised epiretinal material and internal limiting membrane (ILM) specimens obtained from 16 eyes of 16 patients with ERM foveoschisis (6 eyes), MPH (5 eyes), and LMH (5 eyes) during standard pars plana vitrectomy (PPV) with membrane peeling. The three entities were classified according to the newly introduced optical coherence tomography (OCT) terminology. Transmission electron microscopy (TEM) was used to describe the ultrastructural features. RESULTS: We found fibrocellular epiretinal tissues in all samples analysed. However, the cell and collagen composition of the VMI differed between groups. Eyes with ERM foveoschisis were characterized by a higher number of cells, multilayered membranes, and thick strands of vitreous collagen embedding the major cell types of myofibroblasts compared to MPH. Eyes with MPH also showed a predominance of myofibroblasts, but these were located directly on the ILM with no collagen between the cells and the ILM. Eyes with LMH showed a thick, multilayered epiretinal proliferation consisting mainly of non-tractional glial cells, corresponding to hypodense epiretinal proliferation on OCT. Eyes with ERM foveoschisis and MPH were more likely to have incomplete PVD compared to LMH in terms of posterior hyaloid status. DISCUSSION/CONCLUSION: Tractional ERMs in eyes with ERM foveoschisis and MPH differ in their ultrastructure. The main difference is in the amount and topographical distribution of vitreous collagen. However, the epiretinal cell types are predominantly myofibroblasts in both entities. This highlights the importance of distinguishing ERM foveoschisis from both MPH and LMH in terms of pathogenesis and surgical peeling procedures.

The Road towards Gene Therapy for X-Linked Juvenile Retinoschisis: A Systematic Review of Preclinical Gene Therapy in Cell-Based and Rodent Models of XLRS.

X-linked juvenile retinoschisis (XLRS) is an early-onset progressive inherited retinopathy affecting males. It is characterized by abnormalities in the macula, with formation of cystoid retinal cavities, frequently accompanied by splitting of the retinal layers, impaired synaptic transmission of visual signals, and associated loss of visual acuity. XLRS is caused by loss-of-function mutations in the retinoschisin gene located on the X chromosome (RS1, MIM 30083). While proof-of-concept studies for gene augmentation therapy have been promising in in vitro and rodent models, clinical trials in XLRS patients have not been successful thus far. We performed a systematic literature investigation using search strings related to XLRS and gene therapy in in vivo and in vitro models. Three rounds of screening (title/abstract, full text and qualitative) were performed by two independent reviewers until consensus was reached. Characteristics related to study design and intervention were extracted from all studies. Results were divided into studies using (1) viral and (2) non-viral therapies. All in vivo rodent studies that used viral vectors were assessed for quality and risk of bias using the SYRCLE's risk-of-bias tool. Studies using alternative and non-viral delivery techniques, either in vivo or in vitro, were extracted and reviewed qualitatively, given the diverse and dispersed nature of the information. For in-depth analysis of in vivo studies using viral vectors, outcome data for optical coherence tomography (OCT), immunohistopathology and electroretinography (ERG) were extracted. Meta-analyses were performed on the effect of recombinant adeno-associated viral vector (AAV)-mediated gene augmentation therapies on a- and b-wave amplitude as well as the ratio between b- and a-wave amplitudes (b/a-ratio) extracted from ERG data. Subgroup analyses and meta-regression were performed for model, dose, age at injection, follow-up time point and delivery method. Between-study heterogeneity was assessed with a Chi-square test of homogeneity (I2). We identified 25 studies that target RS1 and met our search string. A total of 19 of these studies reported rodent viral methods in vivo. Six of the 25 studies used non-viral or alternative delivery methods, either in vitro or in vivo. Of these, five studies described non-viral methods and one study described an alternative delivery method. The 19 aforementioned in vivo studies were assessed for risk of bias and quality assessments and showed inconsistency in reporting. This resulted in an unclear risk of bias in most included studies. All 19 studies used AAVs to deliver intact human or murine RS1 in rodent models for XLRS. Meta-analyses of a-wave amplitude, b-wave amplitude, and b/a-ratio showed that, overall, AAV-mediated gene augmentation therapy significantly ameliorated the disease phenotype on these parameters. Subgroup analyses and meta-regression showed significant correlations between b-wave amplitude effect size and dose, although between-study heterogeneity was high. This systematic review reiterates the high potential for gene therapy in XLRS, while highlighting the importance of careful preclinical study design and reporting. The establishment of a systematic approach in these studies is essential to effectively translate this knowledge into novel and improved treatment alternatives.

Aland Island Eye Disease with Retinoschisis in the Clinical Spectrum of CACNA1F-Associated Retinopathy-A Case Report.

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.

An Unusual Manifestation of Brucella-Associated Uveitis in a Young Male Patient.

This is a unique case of retinoschisis as an ocular manifestation of brucellosis. A 38-year-old male presented with recurrent episodes of bilateral eye redness, predominately in his left eye. His visual acuity was not affected, and he did not report any other symptoms. On slit lamp examination, binocular Koeppe nodules of the iris and cells in the left anterior chamber were observed. Fundoscopy followed by meticulous multimodal imaging confirmed left inferior retinoschisis. The patient was diagnosed with panuveitis, and a series of laboratory examinations revealed positive anti-IgM Brucella antibodies. Ocular brucellosis can cause variable, atypical, and serious presentations, hence, early diagnosis is paramount to avoid complications.

[Analysis of the therapeutic efficacy of pars plana vitrectomy without intraocular tamponade in the treatment of high myopic eyes with myopic foveoschisis and central foveal detachment].

Objective: To investigate the efficacy of pars plana vitrectomy (PPV) without intraocular tamponade in the treatment of high myopic eyes with myopic foveoschisis (MF) accompanied by foveal detachment (FD). Methods: A retrospective case series study was conducted. The medical records of patients diagnosed with unilateral MF accompanied by FD at the Eye & ENT Hospital of Fudan University between May 2018 and December 2021 were collected. All patients underwent 23-gauge PPV with posterior vitreous cortex clearance, and no intraocular tamponade was applied. The cases were divided into groups based on whether the internal limiting membrane was peeled during surgery or retained. Follow-up was conducted for at least 12 months. The main outcome measures included postoperative best-corrected visual acuity (BCVA, converted to logarithm of the minimum angle of resolution), central foveal thickness (CFT), MF resolution, and complications. Statistical analyses were performed using t-tests, chi-square tests, Fisher's exact tests, and univariate and multivariate linear regression. Results: A total of 40 patients (40 eyes) with MF and FD were included in the study, with 30.0% being male and 70.0% female. The mean age was (56.9±11.7) years, and the axial length of the eyes was (29.1±1.9) mm. At 12 months postoperatively, BCVA improved from baseline 1.15±0.58 to 0.73±0.39 (t=6.11, P<0.001), and CFT decreased from baseline (610.1±207.2) µm to (155.9±104.1) µm (t=13.47, P<0.001). Complete resolution of MF with foveal reattachment was observed in 80.0% of eyes, with a median time of 6 (5, 8) months. There was no significant difference in BCVA and CFT between the internal limiting membrane peeled group and retained group [0.68±0.39 vs. 0.79±0.40, t=0.85, P=0.403; (148.3±63.8)vs.(164.3±137.2)um,t=0.48, P=0.634]. One eye experienced macular hole and another eye developed retinal detachment postoperatively. Correlation analysis showed a positive correlation between BCVA at 12 months postoperatively and baseline BCVA (ß=0.433, P<0.001). Conclusions: Pars plana vitrectomy without intraocular tamponade is effective in treating MF accompanied by FD. The choice between internal limiting membrane peeling and retention does not significantly affect visual prognosis.

[Emphasizing the timing and procedure selection for vitrectomy in pathological myopic traction maculopathy].

Myopic maculopathy is the primary cause of irreversible visual impairment in patients with pathologic myopia, and myopic traction maculopathy often requires vitrectomy for treatment. Myopic traction maculopathy encompasses epiretinal membrane, foveoschisis, macular hole, and macular hole-related retinal detachment. It is recommended to perform vitrectomy combined with inner limiting membrane peeling for Type II epiretinal membrane, foveal-sparing inner limiting membrane peeling for foveoschisis, inverted inner limiting membrane flap technique for macular hole, and vitrectomy combined with macular buckle for refractory macular hole-related retinal detachment. Myopic traction maculopathy is a chronically progressive condition, and surgeons need to accurately determine the timing of surgery and choose appropriate procedures to maximize the benefits for patients.

Do the retinal abnormalities in X-linked juvenile retinoschisis include impaired phototransduction?

X-linked juvenile retinoschisis (XLRS), a hereditary retinal disorder primarily affecting males, is characterized by the formation of cystic spaces between the outer plexiform layer and outer nuclear layer of the retina. Mutations in the RS1 gene, which encodes the extracellular binding protein retinoschisin, are responsible for XLRS pathogenesis. While the role of retinoschisin in maintaining retinal integrity is well established, there is growing evidence suggesting compromised photoreceptor function in XLRS. To investigate the molecular pathways affected by RS1 deficiency, particularly in phototransduction, we performed electroretinographic (ERG) and proteomic analyses on retinae from Rs1 knockout mice, a model of human XLRS. The Rs1 knockout mice had reduced ERG a-wave amplitudes. Correspondingly, differential expression analysis revealed downregulation of proteins crucial for phototransduction, with Ingenuity Pathway Analysis (IPA) highlighting "phototransduction" as the most significantly downregulated biological theme. Compensatory mechanisms were also observed in the IPA, including upregulation of synaptic remodeling, inflammation, cell adhesion, and G-protein signaling. These findings strongly implicate an underrecognized role of photoreceptor dysfunction in XLRS pathology. We speculate that entrapment of mutant retinoschisin protein within photoreceptor inner segments as well as disrupted reciprocal regulation between L-type voltage-gated calcium channels and retinoschisin contribute to the dysfunction in photoreceptors.

A novel compound heterozygous PEX1 variant in Heimler syndrome.

Heimler syndrome (HS) is a rare autosomal recessive hereditary disease that is caused by biallelic variants in peroxisomal biogenic factor 1 gene (PEX1), peroxisomal biogenic factor 6 gene (PEX6) or peroxisomal biogenic factor 26 gene (PEX26), resulting in intracellular peroxisomal dysfunction (PBDs). We report a patient with HS with a new compound heterozygous PEX1 variant. Exon sequencing was used to screen pathologic variants in the patient. Retinal characteristics and serum metabolome alterations were evaluated. Scanning laser ophthalmoscope showed a large area of retinal choroidal atrophy at the posterior pole of the retina, with scattered patchy subretinal pigmentation. Optical coherence tomography showed fovea atrophy accompanied by retinal retinoschisis in the right eye and macular retinoschisis and edema in the left eye. The electroretinogram showed obviously reduced amplitudes of a-waves and b-waves under photopic and scotopic conditions in both eyes. Visual field tests showed a reduced central visual field in both eyes. Exon sequencing identified the compound heterozygous variant including c.2966T > C and c.1670+1G > T of the PEX1 gene, with the latter being novel. Nontargeted determination of total lipid metabolites and targeted determination of medium- and long-chain fatty acids in the serum of the patient and his healthy sibling were tested. This study identified a new compound heterozygous PEX1 variant, expanding our understanding of phenotypes in HS.

Genotype-phenotype association of PITX2 and FOXC1 in Axenfeld-Rieger syndrome.

PITX2 and FOXC1 are the most common pathogenic genes associated with Axenfeld-Rieger syndrome (ARS). In this study, we aimed to explore the variation spectrum of PITX2 and FOXC1 and their associated phenotype based on data from our study and previously reported literatures. Whole exome sequencing was performed on eight probands in our study. Multistep bioinformatic and co-segregation analyses were performed to detect pathogenic variants. Genotype-phenotype correlations of PITX2 and FOXC1 and the differences between them were determined. We detected three variants of FOXC1 and two variants of PITX2 in five unrelated families with ARS. Macular retinoschisis had been observed in AR1 with variant in PITX2 and it is not reported before. Additionally, a review of published literature and our study led to the identification of 593 families with variants of PITX2 or FOXC1, including 316 families with heterozygous variants in FOXC1, 251 families with heterozygous variants in PITX2, 13 families with variants in double genes, seven families with homozygous or compound heterozygous variants in FOXC1, and six families with variants in ADAMTS17, PRDM5, COL4A1 or CYP1B1. Significant differences were observed between the prevalence of missense and in-frame, truncation, and large deletion variants in PITX2 (32.00%, 42.67%, and 25.33%, respectively) and FOXC1 (34.49%, 35.13%, 30.38%, respectively) (p = 1.16E-43). Enrichment and frequency analyses revealed that missense variants were concentrated in the forkhead domain of FOXC1 (76.14%) and homeodomain of PITX2 (87.50%). The percentage of Caucasians with variants in FOXC1 was significantly higher than that of PITX2 (p = 2.00E-2). Significant differences between PITX2 and FOXC1 were observed in glaucoma (p = 3.00E-2), corectopia (p = 3.050E-6), and polycoria (p = 5.21E-08). Additionally, we observed a significant difference in best-corrected visual acuity (BCVA) between FOXC1 and PITX2 (p = 3.80E-2). Among all the family members with PITX2 or FOXC1 variants, the prevalence of systemic abnormalities was significantly higher in PITX2 than in FOXC1 (89.16% vs. 58.77%, p = 5.44E-17). In conclusion, macular retinoschisis as a novel phenotype had been observed in patient with variant in PITX2. Significant differences were detected in phenotypes and genotypes between PITX2 and FOXC1.

Identification and molecular characterization of two recurrent missense mutations in the RS1 gene in two families with X-linked retinoschisis from North India.

X-linked retinoschisis (XLR) is a rare medical condition that involves in the splitting of neurosensory layers and the impairment of vision in the retina. In majority of the XLR cases, pathogenic variants in Retinoschisin 1 (RS1) gene have been implicated in males with an early age of onset during early childhood. In the present study, we have recruited two North Indian families having multiple affected male members, who were diagnosed with XLR. The entire protein-coding region of RS1 was screened by PCR-Sanger sequencing and two recurrent pathogenic variants (p.I81N and p.R102Q) were unraveled. The in vitro study of these variants demonstrated the aggregation of mutant RS1 within the endoplasmic reticulum. Furthermore, mutant forms of this protein showed significant intracellular retention, which was evident by the absence of retinoschisin protein fractions in the extracellular media. These inferences were also supported by extensive bioinformatics analysis of the mutants, which showed dramatic conformational changes in the local structure of retinoschisin. Thus, our study suggests that the identified pathogenic variants interfere with proper protein folding, leading to anomalous structural changes ultimately resulting in intracellular retention of retinoschisin within the retina.

Pediatric abusive head trauma: visual outcomes, evoked potentials, diffusion tensor imaging, and relationships to retinal hemorrhages.

PURPOSE: Function and anatomy of the visual system were evaluated in children with abusive head trauma (AHT). The relationships between retinal hemorrhages at presentation were examined with outcome measures. METHODS: Retrospective review of data in children with AHT for 1) visual acuity at last follow-up, 2) visual evoked potentials (VEP) after recovery, 3) diffusion metrics of white matter tracts and grey matter within the occipital lobe on diffusion tensor imaging (DTI), and 4) patterns of retinal hemorrhages at presentation. Visual acuity was converted into logarithm of minimum angle of resolution (logMAR) after correction for age. VEPs were also scored by objective signal-to-noise ratio (SNR). RESULTS: Of 202 AHT victims reviewed, 45 met inclusion criteria. Median logMAR was reduced to 0.8 (approximately 20/125 Snellen equivalent), with 27% having no measurable vision. Thirty-two percent of subjects had no detectable VEP signal. VEPs were significantly reduced in subjects initially presenting with traumatic retinoschisis or hemorrhages involving the macula (p < 0.01). DTI tract volumes were decreased in AHT subjects compared to controls (p < 0.001). DTI metrics were most affected in AHT victims showing macular abnormalities on follow-up ocular examination. However, DTI metrics were not correlated with visual acuity or VEPS. There was large inter-subject variability within each grouping. DISCUSSION: Mechanisms causing traumatic retinoschisis, or traumatic abnormalities of the macula, are associated with significant long-term visual pathway dysfunction. AHT associated abnormalities of the macula, and visual cortical pathways were more fully captured by VEPs than visual acuity or DTI metrics.

Retinoschisin and novel Na/K-ATPase interaction partners Kv2.1 and Kv8.2 define a growing protein complex at the inner segments of mammalian photoreceptors.

The RS1 gene on Xp 22.13 encodes retinoschisin which is known to directly interact with the retinal Na/K-ATPase at the photoreceptor inner segments. Pathologic mutations in RS1 cause X-linked juvenile retinoschisis (XLRS), a hereditary retinal dystrophy in young males. To further delineate the retinoschisin-Na/K-ATPase complex, co-immunoprecipitation was performed with porcine and murine retinal lysates targeting the ATP1A3 subunit. This identified the voltage-gated potassium (Kv) channel subunits Kv2.1 and Kv8.2 as direct interaction partners of the retinal Na/K-ATPase. Colocalization of the individual components of the complex was demonstrated at the membrane of photoreceptor inner segments. We further show that retinoschisin-deficiency, a frequent consequence of molecular pathology in XLRS, causes mislocalization of the macromolecular complex during postnatal retinal development with a simultaneous reduction of Kv2.1 and Kv8.2 protein expression, while the level of retinal Na/K-ATPase expression remains unaffected. Patch-clamp analysis revealed no effect of retinoschisin-deficiency on Kv channel mediated potassium ion currents in vitro. Together, our data suggest that Kv2.1 and Kv8.2 together with retinoschisin and the retinal Na/K-ATPase are integral parts of a macromolecular complex at the photoreceptor inner segments. Defective compartmentalization of this complex due to retinoschisin-deficiency may be a crucial step in initial XLRS pathogenesis.

Characterization and diagnosis of retinoschisis and schisis detachments using spectral domain optical coherence tomography.

PURPOSE: To characterize retinoschisis in a large series using spectral domain optical coherence tomography (SD-OCT), including rates of schisis detachment and macular involvement in cases of peripheral retinoschisis. METHODS: In this retrospective, cross-sectional, descriptive study, consecutive patients with diagnosis of retinoschisis in at least one eye were identified using billing codes between January 2012 and May 2021. Charts were reviewed to verify diagnosis of retinoschisis or schisis detachment. SD-OCT and clinical examination was used to identify frequency of macular schisis, peripheral schisis, and schisis detachment, and characteristics of retinoschisis including frequency of inner and outer wall breaks, distribution of layers split, and location of involvement of peripheral pathology. SD-OCT images of insufficient quality were excluded from the pertinent analysis. RESULTS: 281 eyes of 191 patients were included. 195 (69.4%) eyes had peripheral retinoschisis, 15 (5.3%) had schisis detachment, 66 (23.5%) had macular retinoschisis alone, and 5 (1.8%) had combined macular and peripheral retinoschisis. Of the eyes without macular retinoschisis, 7.0% had schisis detachment. Of the remainder, 4 (2.1%) had inner wall breaks, and 24 (12.3%) had outer wall breaks. In eyes with peripheral retinoschisis, splitting occurred in the outer plexiform layer in 58.9%, the retinal nerve fiber layer in 8.9%, a combination of layers in 26.8%, and indeterminate in 5.4%. Location of peripheral involvement was inferotemporal in 58.5%, superotemporal in 14.1%, temporal in 13.7%, and inferior in 12.2%. CONCLUSION: SD-OCT helped to identify the presence of schisis detachment and breaks, confirmed diagnosis in challenging cases, and demonstrated the layer of splitting within the neurosensory retina. This series represents the largest such study to date.

Observation of macular hole associated with retinoschisis in patients with high myopia.

PURPOSE: To observe the characteristics of highly myopic macular holes (HMMHs) with macular retinoschisis (MRS) by optical coherence tomography (OCT) and explore the possible relationship between HMMHs and different types of MRS. METHODS: We consecutively reviewed the clinical data and OCT images of the patients with HMMHs from June 2015 to February 2021. Then we picked eyes with MRS from these HMMHs for analysis. The minimum linear diameter (MLD), basal diameter (BD), and height (H) of HMMHs were measured. HMMHs were grouped according to the extent or layer involvement of the concomitant MRS and the characteristics were compared among groups. The impact of MRS on the MLD of macular hole was analyzed with multivariable linear regression. RESULTS: We included 127 patients with MRS from 168 HMMHs (75.5%) for analysis. According to the different classification systems, the most frequent type of MRS in HMMHs was S3 (foveal but not entire macular area MRS) (62.2%) and both inner- and outer- (I/O-MRS) involved types. In our study, HMMHs with more extensive MRS had larger MLD, larger BD, larger H, and poorer best-corrected visual acuity (BCVA). Meanwhile, HMMHs with outer layer-involved MRS (outer MRS and I/O-MRS) had larger BD than HMMH with only inner layer-involved MRS. (All P < 0.05) Multivariable linear regression further illustrated only the extent of MRS was significantly associated with the MLD of HMMH, while there was no significant correlation between the involved retinal layers and the MLD of HMMH. CONCLUSION: HMMH with MRS presented as a predominant type in HMMHs. The MRS was always with a relatively large extent and involved both inner and outer layers. MLD of HMMH was mainly affected by the extent of MRS.

Clinical characteristics of patients with epiretinal membrane-Foveoschisis.

PURPOSE: The purpose of this study is to investigate the clinical and morphological characteristics of epiretinal membrane (ERM)-Foveoschisis. METHODS: Medical charts of 2088 patients diagnosed with idiopathic ERM were screened and eyes with ERM-Foveoschisis were included. All eyes underwent a complete ophthalmological examination including spectral domain optical coherence tomography (SD-OCT). OCT features and best corrected visual acuity (BCVA) were analysed. ERM-Foveoschisis was defined as open, closed, elevated or flat based on the OCT features. Ellipsoidal zone (EZ) abnormality, intraretinal cystoid spaces, central foveal thickness (CFT), posterior vitreous detachment (PVD) and lens status were assessed. RESULTS: One hundred-sixty-six patients (175 eyes) (72% female, mean age 70.46 years) were included. Incidence of ERM-Foveoschisis was 6.7%. Open type was seen in 86.8% and had a significantly better mean BCVA than closed type (p = 0.01). No statistically significant difference of mean BCVA was noted between the elevated and flat types. Mean BCVA was significantly lower in eyes with EZ abnormality (p = 0.03) and eyes with intraretinal cystoid spaces (p = 0.02). Patients with 'closed' ERM-Foveoschisis showed a significant higher median CFT than 'open' ERM-Foveoschisis (respectively, 364 µm and 176 µm, p < 0.001). A total of 81.9% eyes had PVD. CONCLUSION: We differentiated four morphological types of ERM-Foveoschisis based on the OCT examination. Closed ERM-Foveoschisis presented with a higher CFT and lower BCVA than the open type. ERM-Foveoschisis with cystoid intraretinal spaces presented with a lower BCVA. The impact of the morphological types of the ERM-Foveoschisis on the clinical course and for therapy decision requires further long-term studies.

SYMPTOMATIC EARLY-ONSET X-LINKED RETINOSCHISIS: Clinical Presentation and Outcomes.

PURPOSE: To describe clinical characteristics and outcomes of children with early-onset X-linked retinoschisis. METHODS: In this retrospective consecutive case series, we included children diagnosed with symptomatic X-linked retinoschisis younger than 2 years. Presenting signs, clinical characteristics, treatments, and outcomes were recorded. RESULTS: Seven patients (14 eyes) with a mean age of 17.14 ± 6.28 months were included. Strabismus was the most common presenting symptom (6 of 7 patients, 86%). Clinical signs at the first diagnosis included peripheral retinoschisis in 13 eyes (13/14, 93%), of which 5 (5/13, 38%) were bullous, vitreous hemorrhage in 3 eyes (3/14, 21%), and retinal detachment in 3 eyes (3/14, 21%). The macula was involved in all eyes: It was detached in 2 eyes (2/14, 14%) and involved in the peripheral schisis in 4 eyes (4/14, 29%). In all remaining eyes, optical coherence tomography revealed foveoschisis. Six eyes (6/14, 42%) received surgery. At the last follow-up, visual acuity, when available, ranged from no light perception to 20/40, and no children had persistent retinal detachment. CONCLUSION: Children with early-onset X-linked retinoschisis had severe forms. All children had peripheral retinoschisis which was often bullous and extended to the macula. Diagnosis is often clinical but handheld optical coherence tomography can be helpful in atypical forms. Complications requiring surgical management are frequent.