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.

VISION AND METAMORPHOPSIA OUTCOMES OF MACULAR BUCKLING FOR FOVEOSCHISIS-ASSOCIATED MACULAR DETACHMENT IN HIGHLY MYOPIC EYES.

PURPOSE: To assess the functional outcomes in visual acuity, metamorphopsia, and vision-related quality of life (VR-QOL) and to evaluate prognostic factors after macular buckling (MB) surgery in eyes with high myopia and foveoschisis (FS)-associated macular detachment (MD). METHODS: Thirty-nine eyes of 39 patients with FS-associated MD who underwent MB surgery were enrolled. Measured outcomes comprised best-corrected visual acuity (BCVA), metamorphopsia, VR-QOL, axial length (AL), macular reattachment, and resolution of foveoschisis. In addition, factors affecting final BCVA and metamorphopsia were analyzed. RESULTS: At 12 months postoperatively, 36 eyes (92.31%) achieved macular reattachment, 37 eyes (94.87%) achieved complete resolution of foveoschisis, and metamorphopsia diminished in 31 eyes (79.49%). LogMAR BCVAs at baseline and months 1, 3, 6, and 12 postoperatively were 0.62 ± 0.35 (20/83), 0.65 ± 0.3 (20/89), 0.59 ± 0.31 (20/77), 0.54 ± 0.31 (20/69), and 0.46 ± 0.27 (20/57) (P < 0.001), respectively. Metamorphopsia scores by M-CHARTS were 1.36° ± 0.51°, 1.04° ± 0.51°, 0.74° ± 0.47°, 0.59° ± 0.47°, and 0.13° ± 0.29° (P < 0.001). All Visual Function Questionnaire-25 subscales demonstrated significant improvement postoperatively, with the exception of "general health" (P = 0.08) and "driving" (P = 0.111). Preoperative BCVA was an independent risk factor for postoperative BCVA at month 12 (r = 0.638, P < 0.001), and the preoperative M-score was an independent risk factor for postoperative M-score at month 12 (r = 0.187, P = 0.045). CONCLUSION: MB surgery significantly improved BCVA, metamorphopsia, and VR-QOL in patients with FS-associated MD. Preoperative BCVA and metamorphopsia score were prognostic factors for postoperative BCVA and metamorphopsia score at month 12.

MIXED PATHOPHYSIOLOGIES OF LAMELLAR MACULAR HOLES AND RELATED DISEASES: A Multimodal Optical Coherence Tomography-Based Study.

PURPOSE: To investigate the characteristics of mixed pathophysiologies in lamellar macular holes (LMHs) and related diseases using multimodal optical coherence tomography. METHODS: Overall, 126 eyes diagnosed with LMH, epiretinal membrane foveoschisis, or macular pseudohole using the horizontal B-scan image according to the definition proposed by Hubschman et al in 2020 were analyzed using multimodal optical coherence tomography imaging including horizontal and vertical 5-line B-scan, radial scan, and macular three-dimensional volume scan images. If at least two diagnostic criteria for LMH, epiretinal membrane foveoschisis, or macular pseudohole were satisfied in these scans, the patient was diagnosed as having a "mixed type." Retinal traction force was quantitatively evaluated by measuring the maximum depth of the retinal folds using en-face images. RESULTS: Mixed types constituted 34.1% of the cases. The LMH-related mixed group demonstrated intermediate characteristics between the epiretinal membrane foveoschisis/macular pseudohole and true LMH groups in terms of retinal traction and LMH-specific features and had a significant positive correlation between the maximum depth of the retinal folds and mean M-CHARTS scores (P = 0.034). CONCLUSION: A thorough optical coherence tomography analysis is necessary to accurately diagnose LMH and related diseases. A significant positive correlation was observed between the maximum depth of the retinal folds and the degree of metamorphopsia in the LMH-related mixed group.

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.

X-Linked Retinoschisis: Novel Clinical Observations and Genetic Spectrum in 340 Patients.

PURPOSE: To describe the natural course, phenotype, and genotype of patients with X-linked retinoschisis (XLRS). DESIGN: Retrospective cohort study. PARTICIPANTS: Three hundred forty patients with XLRS from 178 presumably unrelated families. METHODS: This multicenter, retrospective cohort study reviewed medical records of patients with XLRS for medical history, symptoms, visual acuity (VA), ophthalmoscopy, full-field electroretinography, and retinal imaging (fundus photography, spectral-domain [SD] OCT, fundus autofluorescence). MAIN OUTCOME MEASURES: Age at onset, age at diagnosis, severity of visual impairment, annual visual decline, and electroretinography and imaging findings. RESULTS: Three hundred forty patients were included with a mean follow-up time of 13.2 years (range, 0.1-50.1 years). The median ages to reach mild visual impairment and low vision were 12 and 25 years, respectively. Severe visual impairment and blindness were observed predominantly in patients older than 40 years, with a predicted prevalence of 35% and 25%, respectively, at 60 years of age. The VA increased slightly during the first 2 decades of life and subsequently transitioned into an average annual decline of 0.44% (P < 0.001). No significant difference was found in decline of VA between variants that were predicted to be severe and mild (P = 0.239). The integrity of the ellipsoid zone (EZ) as well as the photoreceptor outer segment (PROS) length in the fovea on SD OCT correlated significantly with VA (Spearman's ρ = -0.759 [P < 0.001] and -0.592 [P = 0.012], respectively). Fifty-three different RS1 variants were found. The most common variants were the founder variant c.214G→A (p.(Glu72Lys)) (101 patients [38.7%]) and a deletion of exon 3 (38 patients [14.6%]). CONCLUSIONS: Large variabilities in phenotype and natural course of XLRS were seen in this study. In most patients, XLRS showed a slow deterioration starting in the second decade of life, suggesting an optimal window of opportunity for treatment within the first 3 decades of life. The integrity of EZ as well as the PROS length on SD OCT may be important in choosing optimal candidates for treatment and as potential structural end points in future therapeutic studies. No clear genotype-phenotype correlation was found.

Clinical findings and RS1 genotype in 90 Chinese families with X-linked retinoschisis.

Purpose: X-linked retinoschisis (XLRS) is an early-onset retinal degenerative disorder caused by mutations in the RS1 gene. The objective of this study was to describe the clinical and genetic findings in 90 unrelated Chinese patients with XLRS. Methods: All patients underwent clinical examination, including best-corrected visual acuity (BCVA), slit-lamp biomicroscopy, fundus examination, and spectral domain-optical coherence tomography (SD-OCT). A combination of molecular screening methods, including Sanger-DNA sequencing of RS1 and targeted next-generation sequencing (TES), were used to detect mutations. In silico programs were used to analyze the pathogenicity of all the variants. Long-range PCR with subsequent DNA sequencing was employed to find the breakpoints of large deletions. Results: The 90 probands (mean age 17.29±12.94 years; 3-52 years) showed a variety of clinical phenotypes, and their average best correct visual acuity was 0.81±0.48 (logarithm of the minimal angle of resolution, 0-3). Of the 175 eyes analyzed, 140 (80%) had macular retinoschisis, 84 (48%) had peripheral retinoschisis, 28 (16%) had macular atrophy, and five (3%) had a normal macular structure. We identified 68 mutations in this cohort of patients, including 15 novel mutations. Most mutations (65%) were missense; the remaining null mutations included nonsense, splicing effect, frameshift indel, and large genomic DNA deletions. The 62 patients with missense mutations seemed to have relatively milder visual defects than the 28 patients with null mutations. Conclusions: Patients with RS1 mutations present profound phenotypic variability and show no clear genotype-phenotype correlations. Patients with null mutations tend to have more severe XLRS-related visual defects.

High myopic patients with and without foveoschisis: morphological and functional characteristics.

PURPOSE: Myopic foveoschisis (MF) is characterized by the splitting of the retinal layers in the fovea of patients with high myopia (HM). MF may progress into foveal detachment or macular hole formation with consequent loss of central vision. The aim of this study is to investigate morphological and functional changes of the macular region in myopic subjects with and without foveoschisis. DESIGN: Observational, cross-sectional, comparative study. METHODS: Forty-eight patients with HM and 24 healthy controls were evaluated by spectral domain-optical coherence tomography (SD-OCT), multifocal electroretinography (mfERG) and microperimetry (MP-1) tests to assess macular thickness, functionality and sensitivity values, respectively. The results of the diagnostic examinations were compared between three groups: HM patients with MF (N = 24), HM patients without MF (N = 24) and control group (CG) (N = 24). All statistical analyses were performed with STATA 14.0 (Collage Station, Texas, USA). One-way analysis of variance (ANOVA) followed by Tukey's post hoc test was used to analyze differences between groups unless specified; p values < 0.05 were considered as statistically significant. Gender distribution was compared by the Chi square test. RESULTS: The statistical analysis with one-way ANOVA followed by Tukey's post hoc test showed a significant increase in macular thickness in HM patients with MF when compared to both HM patients without MF and CG. Morphological changes were associated with functional impairment as demonstrated by the significant decrease in amplitude of the P1 wave and MP-1 sensitivity (p < 0.05), according to the anatomical landmarks. CONCLUSIONS: This study showed that the morphological changes observed in the central retina of HM patients with MF are associated with functional alterations. High-tech diagnostic tests such as SD-OCT, mfERG and MP-1 could be useful for management in complications of MF.

FUNCTIONAL AND STRUCTURAL OUTCOMES AFTER FOVEA-SPARING INTERNAL LIMITING MEMBRANE PEELING FOR MYOPIC MACULAR RETINOSCHISIS BY MICROPERIMETRY.

PURPOSE: To determine the morphological and physiological outcomes and safety of vitrectomy with fovea-sparing internal limiting membrane peeling for myopic macular retinoschisis (MRS). METHODS: Highly myopic eyes (refractive error greater than -8.0 diopters or an axial length longer than 26.5 mm) with MRS that underwent vitrectomy with fovea-sparing internal limiting membrane peeling were analyzed retrospectively. The best-corrected visual acuity, retinal morphology, and the central and paracentral retinal sensitivities at 2°/6° by microperimetry were evaluated before and after the surgery. Postoperative microscotomas were also determined. RESULTS: Thirty-three eyes with MRS; 16 eyes with and 17 eyes without a foveal retinal detachment, were studied. All 33 eyes had an improvement of MRS and foveal retinal detachment partially or completely after surgery, and none developed a full thickness macular hole. The postoperative best-corrected visual acuity, the central retinal sensitivity, and the retinal sensitivity at 2° were significantly better than the preoperative values. Sixteen eyes developed postoperative microscotomas at paracentral 2° and/or 6°. CONCLUSION: The results showed that vitrectomy with fovea-sparing internal limiting membrane peeling is an effective and safe method to treat an MRS regardless of the presence of a foveal retinal detachment. However, careful follow-up should be performed to detect postoperative microscotomas.

A case of X-linked retinoschisis with atypical fundus appearance.

PURPOSE: Mutations in the RS1 gene are known to cause retinoschisis, an X-linked hereditary retinal degeneration. Here, we present a case of atypical retinoschisis with clinical findings of retinoschisis and retinitis pigmentosa. METHODS: This report is an observational case report. The detailed ophthalmological examinations included visual field determination, multimodal imaging and electrophysiological recordings. Targeted next-generation sequencing of a retinal disease gene panel was performed. RESULTS: The 55-year-old male, highly hyperopic patient, presented with a best-corrected Snellen visual acuity of 20/100 in the right eye and 20/400 in the left eye. In the kinetic visual field, there was a superior scotoma, as well as a ring scotoma in the inferior hemisphere in the right eye and a concentric visual field constriction to 10° in the left eye. Funduscopy revealed marked pigmentary changes (i.e. bone spicules) in the mid-periphery bilaterally and symmetrically, as well as two small intra-retinal haemorrhages in the left eye. Full-field electroretinography recordings showed extinguished rod and cone responses. Diagnostic-genetic testing revealed a hemizygous missense mutation in the RS1 gene (c.305G > A; p.Arg102Gln) was identified. CONCLUSION: We present a case of atypical retinoschisis with clinical findings of retinitis pigmentosa.

PREOPERATIVE FACTORS INFLUENCING VISUAL RECOVERY AFTER VITRECTOMY FOR MYOPIC FOVEOSCHISIS.

PURPOSE: To determine the preoperative factors influencing visual recovery after vitrectomy for myopic foveoschisis. METHODS: Sixty-six eyes of 65 consecutive patients operated on for myopic foveoschisis were retrospectively included. All eyes underwent a preoperative ocular examination including best-corrected visual acuity (BCVA) and spectral domain optical coherence tomography with central foveal thickness measurement and foveal status classification: simple foveoschisis, foveal detachment, or macular hole. To study the impact of preoperative visual acuity, 4 visual acuity groups separated by quartile ranges were defined. Postoperative visits at 1, 3, or 12 months including BCVA measurement and optical coherence tomography were recorded. RESULTS: Mean refraction was -15.90 diopters, mean axial length was 30.30 mm, mean central foveal thickness was 590 µm, and mean baseline logarithm of the maximum angle of resolution visual acuity was 0.68 (Snellen equivalent of 20/96). The final BCVA improved significantly from 3 months after surgery until the last follow-up visit; the mean logarithm of the maximum angle of resolution visual acuity at last follow-up was 0.43 (Snellen equivalent of 20/54). Mean central foveal thickness decreased significantly as soon as the first postoperative month (P < 0.0001). The preoperative BCVA was the only independent factor significantly correlated with the final BCVA as opposed to the foveal status (P < 0.0001). The mean BCVA and mean visual gain at the last follow-up visit were significantly different between the four visual acuity groups (P < 0.0001 and P = 0.017, respectively). CONCLUSION: The main factor influencing the postoperative visual acuity is the preoperative visual acuity. Although the preoperative anatomical status seemed important in surgeon decision making, once normalized on visual acuity, it no longer influenced the postoperative visual acuity.

Macular buckle technique in myopic traction maculopathy: a 16-year review of the literature and a comparison with vitreous surgery.

PURPOSE: The aim of this study is to review anatomical and functional outcomes following macular buckling (MB) in high myopia and to compare such results with those obtained by pars plana vitrectomy (PPV). METHODS: PubMed articles on MB in high myopia (2000-2016) were reviewed. Main outcomes included retinal reattachment and macular hole (MH) closure rates, resolution of myopic foveoschisis (MFS), and postoperative visual acuity. RESULTS: Thirty-one articles included 16 in patients with retinal detachment due to MH (MHRD group), 11 in MFS with or without foveal detachment (MFS group), and 4 in MH patients with MFS (MH-MFS group). Surgical techniques mainly differed in the type of buckle, rectus muscles involvement, and concurrent PPV. In eyes with persistent MH, prognosis in the MHRD and MH-MFS groups differed between eyes receiving MB compared to PPV: functional outcome was markedly poorer and there was a higher risk of retinal redetachment associated with PPV. In the MSF group, secondary MHs were more likely to develop in eyes treated with PPV and internal limiting membrane peeling than those undergoing MB alone or combined with PPV. Retinal pigment epithelium changes, malpositioning, perforation, and choroidal detachment were the main complications. CONCLUSIONS: Although different approaches are used, complete resolution of foveoschisis, retinal reattachment, and MH closure seem to be achieved more frequently with MB than PPV.

Development of macular retinoschisis long after the onset of retinal arterial occlusion (RAO): a retrospective study.

BACKGROUND: To describe a retrospective study of macular retinoschisis that developed long after the onset of retinal artery occlusion (RAO) using optical coherence tomography (OCT). METHODS: We describe changes in macular findings and visual acuity (VA) of 29 patients (21 males and 8 females, mean age: 66.1 ± 16.9 years) with RAO (18 branch RAOs [BRAOs] and 11 central RAOs [CRAOs] who visited Osaka Medical College Hospital over an 8-year period based on a medical chart review. RESULTS: The mean VA (logMAR) increased from 1.06 ± 1.08 (CRAO: 2.04 ± 0.99; BRAO: 0.37 ± 0.40) at the first visit to 0.71 ± 0.87 (CRAO: 1.46 ± 0.86; BRAO: 0.18 ± 0.30) at the final visit. Macular OCT revealed swelling or hyper-reflectivity of the inner retina in the early phase of RAO and retinal thinning in the late phase. Among the 29 patients, two patients (a patient with BRAO and a patient with CRAO) developed macular retinoschisis about 1 year after RAO onset. The VA of the patient with BRAO was 20/300 at the first visit, and it improved to 20/25 two days after onset following eye massage and anterior chamber paracentesis. However, his VA worsened, declining from 20/25 to 20/50, and retinoschisis occurred 13 months after RAO onset. The patient with CRAO showed macular changes including small cystoids at the first follow-up visit more than 3 weeks after onset and developed retinoschisis 11 months after the first visit. In addition, two patients with BRAO and one patient with CRAO developed macular changes including small cystoids 3 weeks after onset, with the BRAO complicated by retinal vein occlusion. In the CRAO patient, the cystoid macular edema was resolved 1 month after the first visit. CONCLUSIONS: Macular retinoschisis is unusual, but a possible complication of RAO that can develop long after the onset of the occlusion, potentially resulting in renewed VA deterioration.

X-linked Juvenile Retinoschisis.

X-linked juvenile retinoschisis (XLRS) occurs exclusively in males and is characterized by visual loss that begins in early childhood; patients are usually school-age and are experiencing visual disturbances, especially in reading. The prevalence is estimated to be 1 in 5000-25,000 men, worldwide. XLRS has complete penetrance but variable expressivity. Carrier females generally remain asymptomatic.

An ex vivo gene therapy approach in X-linked retinoschisis.

PURPOSE: X-linked retinoschisis (XLRS) is juvenile-onset macular degeneration caused by haploinsufficiency of the extracellular cell adhesion protein retinoschisin (RS1). RS1 mutations can lead to either a non-functional protein or the absence of protein secretion, and it has been established that extracellular deficiency of RS1 is the underlying cause of the phenotype. Therefore, we hypothesized that an ex vivo gene therapy strategy could be used to deliver sufficient extracellular RS1 to reverse the phenotype seen in XLRS. Here, we used adipose-derived, syngeneic mesenchymal stem cells (MSCs) that were genetically modified to secrete human RS1 and then delivered these cells by intravitreal injection to the retina of the Rs1h knockout mouse model of XLRS. METHODS: MSCs were electroporated with two transgene expression systems (cytomegalovirus (CMV)-controlled constitutive and doxycycline-induced Tet-On controlled inducible), both driving expression of human RS1 cDNA. The stably transfected cells, using either constitutive mesenchymal stem cell (MSC) or inducible MSC cassettes, were assayed for their RS1 secretion profile. For single injection studies, 100,000 genetically modified MSCs were injected into the vitreous cavity of the Rs1h knockout mouse eye at P21, and data were recorded at 2, 4, and 8 weeks post-injection. The control groups received either unmodified MSCs or vehicle injection. For the multiple injection studies, the mice received intravitreal MSC injections at P21, P60, and P90 with data collection at P120. For the single- and multiple-injection studies, the outcomes were measured with electroretinography, optokinetic tracking responses (OKT), histology, and immunohistochemistry. RESULTS: Two lines of genetically modified MSCs were established and found to secrete RS1 at a rate of 8 ng/million cells/day. Following intravitreal injection, RS1-expressing MSCs were found mainly in the inner retinal layers. Two weeks after a single injection of MSCs, the area of the schisis cavities was reduced by 65% with constitutive MSCs and by 83% with inducible MSCs, demonstrating improved inner nuclear layer architecture. This benefit was maintained up to 8 weeks post-injection and corresponded to a significant improvement in the electroretinogram (ERG) b-/a-wave ratio at 8 weeks (2.6 inducible MSCs; 1.4 untreated eyes, p<0.05). At 4 months after multiple injections, the schisis cavity areas were reduced by 78% for inducible MSCs and constitutive MSCs, more photoreceptor nuclei were present (700/µm constitutive MSC; 750/µm inducible MSC; 383/µm untreated), and the ERG b-wave was significantly improved (threefold higher with constitutive MSCs and twofold higher with inducible MSCs) compared to the untreated control group. CONCLUSIONS: These results establish that extracellular delivery of RS1 rescues the structural and functional deficits in the Rs1h knockout mouse model and that this ex vivo gene therapy approach can inhibit progression of disease. This proof-of-principle work suggests that other inherited retinal degenerations caused by a deficiency of extracellular matrix proteins could be targeted by this strategy.

Abnormal 8-Hz flicker electroretinograms in carriers of X-linked retinoschisis.

PURPOSE: To evaluate rod-isolated, cone-isolated, and combined rod and cone flicker electroretinograms (ERGs) as a possible means to identify electrophysiological abnormalities in carriers of X-linked retinoschisis (XLRS). METHODS: Full-field ERGs were recorded from six carriers of XLRS (aged 34-66 years) and eight normally sighted subjects (aged 27-59 years) under rod-isolated (ERGR), cone-isolated (ERGC), and combined rod and cone (ERGR+C) conditions. ERGs were obtained using a four-primary LED-based ganzfeld photostimulator and standard recording techniques. The four primaries were modulated sinusoidally in phase to achieve combined rod and cone activation (ERGR+C) or in different phases to achieve ERGR and ERGC by means of triple silent substitution. After 30 min of dark adaptation, 8- and 15-Hz ERGR, ERGC, and ERGR+C responses were obtained at a mean luminance level of 24 scot. cd/m(2). Standard ISCEV ERGs were also obtained from each subject. RESULTS: The ISCEV and 15-Hz flicker ERGs were generally within the normal range for the carriers. The 8-Hz ERGR, ERGC, and ERGR+C amplitudes were also generally normal. In contrast, the carriers had ERGR, ERGC, and ERGR+C timing abnormalities, with phase advances beyond the range of normal for the ERGR (four carriers), ERGC (four carriers), and ERGR+C (three carriers). Only one carrier had normal 8-Hz responses under all conditions. CONCLUSIONS: The 8-Hz ERG timing abnormalities in five of six carriers indicate that retinal function is not necessarily normal in carriers of XLRS. The 8-Hz flicker ERG may be useful for studying retinal function in these individuals.

Differentiation of murine models of "negative ERG" by single and repetitive light stimuli.

PURPOSE: Marked attenuation of the single-flash electroretinographic (ERG) b-wave in the presence of a normal-amplitude or less-attenuated a-wave is commonly referred to as the "negative ERG." The purpose of this study was to investigate whether the disparate origins of the negative ERG in three murine models can be discriminated using flickering stimuli. METHODS: Three models were selected: (1) the Nyx (nob) mouse model of complete congenital stationary night blindness, (2) the oxygen-induced retinopathy (OIR) rat model of retinopathy of prematurity (ROP), and (3) the Rs1 knockout (KO) mouse model of X-linked juvenile retinoschisis. Directly after a dark-adapted, single-flash ERG luminance series, a flicker ERG frequency series (0.5-30 Hz) was performed at a fixed luminance of 0.5 log cd s/m(2). This series includes frequency ranges that are dominated by activity in (A) the rod pathways (below 5 Hz), (B) the cone ON-pathway (5-15 Hz), and (C) the cone OFF-pathway (above 15 Hz). RESULTS: All three models produced markedly attenuated single-flash ERG b-waves. In the Nyx (nob) mouse, which features postsynaptic deficits in the ON-pathways, the a-wave was normal and flicker responses were attenuated in ranges A and B, but not C. The ROP rat is characterized by inner-retinal ischemia which putatively affects both ON- and OFF-bipolar cell activity; flicker responses were reduced in all ranges (A-C). Notably, the choroid supplies the photoreceptors and is thought to be relatively intact in OIR, an idea supported by the nearly normal a-wave. Finally, in the Rs1 KO mouse, which has documented abnormality of the photoreceptor-bipolar synapse affecting both ON- and OFF-pathways, the flicker responses were attenuated in all ranges (A-C). The a-wave was also attenuated, likely as a consequence to schisms in the photoreceptor layer. CONCLUSION: Consideration of both single-flash and flickering ERG responses can discriminate the functional pathology of the negative ERG in these animal models of human disease.

VITRECTOMY WITHOUT INNER LIMITING MEMBRANE PEELING FOR MACULAR RETINOSCHISIS IN HIGHLY MYOPIC EYES.

PURPOSE: To determine if it is necessary to peel inner limiting membrane during vitrectomy for macular retinoschisis in highly myopic eyes. METHODS: This retrospective noncomparative interventional case series included 112 eyes of 84 patients with myopic foveoschisis who were treated by 23-gauge 3-port pars plana vitrectomy. During vitrectomy, triamcinolone acetonide was injected into the vitreous cavity to visualize the vitreous. The inner limiting membrane was not peeled, but the posterior hyaloid membrane was removed from the macular surface with active suction or a flute needle. A fluid-gas exchange was carried out using 16% perfluoropropane gas. RESULTS: A total of 106 eyes (95%) exhibited collapse of the foveoschismatic intermediary zone after surgery. Best-corrected visual acuity at baseline and at the end of the follow-up did not differ significantly (1.06 ± 0.74 logarithm of the minimum angle of resolution versus 0.92 ± 0.56 logarithm of the minimum angle of resolution, P = 0.18). An improvement in best-corrected visual acuity of greater than 2 lines was achieved in 84 eyes (75%). A macular hole with retinal detachment was found in 6 eyes (5%) 1 to 8 months after surgery. Intraoperatively, all 112 eyes exhibited vitreous liquefaction. The posterior hyaloid membranes were tightly adherent to the posterior retinal surface and vessels except for 1 eye that had a complete posterior vitreous detachment. There were no or only a very small amount of triamcinolone acetonide particles attached to the surface of posterior retina in 38 eyes, which seemed that a completely posterior vitreous detachment had happened. But these membranes on the surface of the posterior retina can be removed easily, which indicated these membranes were posterior hyaloid membranes instead of internal limiting membranes. CONCLUSION: In the treatment of macular retinoschisis in highly myopic eyes, vitrectomy associated with posterior hyaloid membranes peeling may achieve successful anatomical results. Internal limiting membrane peeling seems unnecessary.

MYOPIC RETINOSCHISIS IN ASIANS: Structural Features and Determinants of Visual Acuity and Prognostic Factors for Progression.

PURPOSE: To describe microstructural changes and schisis extent in eyes with myopic retinoschisis and to determine their influence on visual acuity at baseline and follow-up. METHODS: In this prospective observational study, 50 eyes of 38 patients with myopic retinoschisis were evaluated using spectral domain optical coherence tomography, and the patients were followed for at least 12 months. The presence of microstructural changes and the extent of retinoschisis at baseline on spectral domain optical coherence tomography, and the association between these parameters and the risk of visual acuity deterioration were analyzed. RESULTS: Median presenting visual acuity and central retinal thickness were 0.31 logMAR (≈20/40) and 395 µm, respectively. Twenty-six eyes (52%) had entire macular area retinoschisis. Common microstructural changes included photoreceptor detachment (24%), foveal ellipsoid zone (EZ) disruption (34%), partial-thickness macular hole (26%), and full-thickness macular hole (16%). Visual acuity was poorer in eyes with photoreceptor detachment, EZ disruption, full-thickness macular hole, and central retinal thickness >300 µm. Eyes with entire macular area retinoschisis had the poorest visual acuity and thickest central retinal thickness, and they were more likely to have photoreceptor detachment, EZ disruption, and retinal detachment. Over a mean follow-up of 31.7 ± 7.7 months, 14 eyes (28%) had worsening visual acuity of ≥2 lines. Ten of these 14 eyes had entire macular retinoschisis at baseline. CONCLUSION: Most eyes with myopic retinoschisis remain stable. However, eyes with extensive retinoschisis involving the entire macular area are more likely to progress and have microstructural abnormalities and poorer vision. Early surgery should be considered for these eyes.

ADJUSTABLE MACULAR BUCKLING FOR FULL-THICKNESS MACULAR HOLE WITH FOVEOSCHISIS IN HIGHLY MYOPIC EYES: Long-Term Anatomical and Functional Results.

PURPOSE: To assess functional and structural outcome after adjustable macular buckling for the treatment of foveoschisis (FS), associated with full-thickness macular hole (FTMH) in highly myopic eyes. METHODS: Eighteen consecutive patients who underwent adjustable macular buckling for FS associated with FTMH were included in this prospective study. Three cases were not included in the analysis due to short follow-up period (less than 3 months). Outcome measures included anatomical success rate with FS resolution and FTMH closure, best-corrected visual acuity, mean retinal sensitivity, central retinal thickness, and fixation site and stability. RESULTS: Foveoschisis resolution and FTMH closure were observed in all cases between 1 month to 3 months after surgery. At 24 months of follow-up visit visual acuity improved in 13/15 eyes (86.7%) and remained stable in 2 (13.3%). Mean retinal sensitivity showed significant improvement from baseline 5.69 ± 3.52 dB to final 8.35 ± 3.86 dB; P < 0.001. Fixation stability inside central 4° improved from baseline 58.5 ± 17.8% to final 73.7 ± 23.0%; P = 0.009. Central retinal thickness did not change significantly throughout follow-up. No FTMH or FS recurrence occurred and no surgical complications arose. CONCLUSION: Adjustable macular buckling exoplant may represent an effective surgical option for the treatment of FS associated with FTMH in highly myopic eyes. Adjustable macular buckling showed high closure rate and virtually no tendency to recur. Functional results and safety are also interesting because vision improved and retinal thickness did not reduce significantly at 24 months of follow-up.

CLINICAL CHARACTERISTICS OF IDIOPATHIC FOVEOMACULAR RETINOSCHISIS.

PURPOSE: To describe the clinical features of idiopathic foveomacular retinoschisis not in association with myopia, glaucoma, optic disk pit, or juvenile retinoschisis. METHODS: Retrospective observational case series. Five eyes of five patients with idiopathic foveomacular retinoschisis were included. RESULTS: The patients were 2 men and 3 women (average age, 75.2 years; range, 71-78 years). The average spherical equivalent was +2.40 diopters (range, +0.88 to +5.75 diopters), and the average axial length was 22.0 mm (range, 21.1-23.1 mm). All patients had retinoschisis from the macula to the optic disk in the affected eye. No patients had retinoschisis in the fellow eye. The average best-corrected visual acuity was 20/44 (68 Early Treatment Diabetic Retinopathy Study letter score). CONCLUSION: Idiopathic foveomacular retinoschisis is not inherited or associated with myopia, vitreomacular traction syndrome, optic pit, or glaucoma but is associated with older age, unilaterality, hyperopia with short axial length, complete posterior vitreous detachment, and weak leakage from the optic disk on fluorescein angiography.