Clinical and Genetic Features of NR2E3-Associated Retinopathy: A Report of Eight Families with a Longitudinal Study and Literature Review.

(1) Background: NR2E3 encodes a nuclear receptor transcription factor that is considered to promote cell differentiation, affect retinal development, and regulate phototransduction in rods and cones. This study aimed to analyze the clinical characteristics and observe the prognosis of autosomal dominant retinopathy (ADRP) and autosomal recessive retinopathy (ARRP) associated with NR2E3; (2) Methods: NR2E3 variants were collected from our exome sequencing data and identified per the American College of Medical Genetics and Genomics criteria. Data from our cohort and a systemic literature review were conducted to explore the NR2E3 variants spectrum and potential genotype-phenotype correlations; (3) Results: Nine pathogenic variants/likely pathogenic variants in NR2E3, including five novel variants, were detected in eight families (four each with ADRP and ARRP). Follow-up data showed schisis/atrophy in the macula and retinal degeneration initiation around the vascular arcades with differences in ADRP and ARRP. A systemic literature review indicated patients with ADRP presented better visual acuity (p < 0.01) and later onset age (p < 0.0001) than did those with ARRP; (4) Conclusions: Macular schisis and retinal degeneration around vascular arcades may present as the prognosis of NR2E3-retinopathy, dominant, or recessive. Our data might further enrich our understanding of NR2E3 variants and associated inherited retinopathy.

Inverted ILM Flap Technique in Optic Disc Pit Maculopathy.

Purpose: To present the outcome of optic disc pit maculopathy (ODPM) managed successfully with an inverted internal limiting membrane (ILM) flap over the optic disc. A narrative review of ODPM pathogenesis and surgical management techniques are also provided. Case Report: This prospective interventional case series included three eyes of three adult patients (25-39 years old) with unilateral ODPM and a mean duration of unilaterally decreased visual acuity of 7.33 ± 2.40 months (4-12 months). The pars plana vitrectomy with posterior vitreous detachment induction was performed on eyes, followed by an inverted ILM flap insertion over the optic disc and gas tamponade. Patients were followed for 7-16 weeks postoperatively; best-corrected visual acuity (BCVA) improved dramatically in one patient from 2/200 to 20/25. BCVA in other patients improved two and three lines - to 20/50 and 20/30, respectively. A significant anatomical improvement was achieved in all three eyes, and no complication was detected throughout the follow-up period. Conclusion: Vitrectomy with inverted ILM flap insertion over the optic disc is safe and can yield favorable anatomical improvement in patients with ODPM.

Myopic macular schisis: Insights into distinct morphological subtypes and novel biomechanical hypothesis.

PURPOSE: To analyze the features of myopic macular schisis (MMS) in different retinal layers and to explore the role of Müller cells in the pathophysiology of such condition. METHODS: Spectral-domain optical coherence tomography (SD-OCT) images of myopic eyes with staphyloma and macular schisis were reviewed. The morphological features of MMS were analyzed and correlated with their geographical location in the parafoveal and perifoveal region. A biomechanical model was adopted to explain MMS morphological differences. The effect of the different schisis subtypes with best corrected visual acuity (BCVA) was also explored. RESULTS: A total of 36 eyes from 26 patients were included in this study. MMS was classified into inner, middle and outer retinal subtypes. The prevalence of middle retinal schisis was significantly lower in the parafovea, within a central 3 mm-diameter circle (p < 0.001) centered at the fovea . The prevalence of inner retinal schisis was significantly higher outside the central 3-mm diameter circle, in the perifoveal region (p < 0.001). No significant differences were noted in the prevalence of outer retinal schisis for these two locations (p = 0.475). The presence of middle retinal schisis within the central 3-mm diameter circle showed a weak association with lower BCVA (p = 0.058). The presence of outer retinal schisis within the central 3-mm diameter circle was significantly related with lower BCVA (p = 0.024). CONCLUSION: Three major forms of MMS are distinguished: inner, middle and outer retinal schisis. This classification may have clinical importance as only the outer grade of schisis was associated with vision loss.

Typical and atypical clinical presentations of X-Linked retinoschisis: A case series and literature review.

X-linked retinoschisis (XLRS) is an X-linked inherited retinal dystrophy characterized by mild-to-severe visual impairment, splitting of the retinal layers, and a reduction in the dark-adapted b-wave amplitude on the electroretinogram. Typical clinical features include macular and peripheral schisis. Relatively common features reported include rhegmatogenous or tractional retinal detachment, vitreous hemorrhage, retinal pigment epithelial changes, vitreous veils, and various retinal vascular abnormalities with or without exudation. Macular hole and macular folds are atypical presentations of XLRS, along with several other rare findings. Here, we report 4 cases of XLRS with atypical clinical presentations and review the literature on XLRS, with a focus on the variable clinical features of this condition.

Visual, Anatomic Outcomes, and Natural History of Retinal Nerve Fiber Layer Schisis in Patients Undergoing Epiretinal Membrane Surgery.

PURPOSE: To evaluate the anatomic and visual outcomes of patients with idiopathic epiretinal membranes (ERMs) complicated by schisis of the retinal nerve fiber layer (sRNFL) in routine clinical practice. DESIGN: Retrospective case-control study. PARTICIPANTS: Patients undergoing idiopathic ERM surgery at Cole Eye Institute from 2013 to 2021. METHODS: Patients were grouped by the presence or absence of sRNFL before surgery. Preoperative and postoperative data were collected regarding visual acuity (VA), changes in central subfield thickness (CST) over time, and presence of cystoid macular edema. MAIN OUTCOME MEASURES: Frequency of sRNFL in patients undergoing idiopathic ERM surgery. RESULTS: Overall, 48 (53.9%) of 89 patients presented with sRNFL. Schisis of the retinal nerve fiber layer patients presented with significantly decreased VA compared with those without (58.63 ± 12.48 vs. 67.68 ± 7.84 ETDRS letters, P < 0.001, respectively). At the final follow-up after ERM removal, there was no significant difference in final VA in patients with sRNFL compared with those without (71.16 ± 2.93 vs. 74.11 ± 2.76, P = 0.467). At presentation, patients with sRNFL had greater CST than those without (454 ± 10.01 vs. 436 ± 0.23, P = 0.23). This difference persisted at the 90-day follow-up after ERM removal (402 ± 8.08 vs. 375 ± 10.19 µm, P = 0.043). The resolution of sRNFL was reported at postoperative week 1 in 30 (96.7%) of 31 cases. CONCLUSIONS: Schisis of the retinal nerve fiber layer is a microstructural feature in > 50% of idiopathic ERMs in routine clinical practice and carries visual significance on presentation and anatomic significance postoperatively. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

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.

Unilateral double optic nerve head pits with foveo-schisis detachment treated by modified internal limiting membrane peeling technique.

A 44-year-old female with a vision of 10/200 in the right eye had double pits in the temporal segment of the optic disc with serous macular detachment. Spectral-domain optical coherence tomography (SD-OCT) confirmed serous retinal detachment, an outer layer hole, and double optic disc pits. The patient underwent pars plana vitrectomy with modified ILM flap surgery involving fovea-sparing internal limiting membrane peeling (FSIP) technique with inverted ILM flap tucking with gas tamponade. Post surgery, the communications between perineural and intraretinal spaces were obliterated with flaps of ILM covering the pits, with reduced serous macular detachment and BCVA of 20/120. FSIP with inverted internal limiting membrane flap tuck can be an effective technique to manage rare cases of double ODP-M.

Diagnosis and management of degenerative retinoschisis and related complications.

Degenerative retinoschisis is a common condition characterized by elevation of the inner layers of the peripheral retina. While uncomplicated retinoschisis (i.e., with no associated retinal layer breaks) is almost invariably a benign process, retinal detachment associated with isolated outer layer breaks (termed schisis-detachment) is fairly common. Historically, schisis-detachment has been treated with a variety of interventions, ranging from retinopexy to intraocular surgery. Based on published descriptions of the natural history of the disease, these interventions are likely unnecessary in many cases and may place the patient's vision at unnecessary risk. Progressive symptomatic schisis-related retinal detachment, on the other hand, is a vision threatening condition that requires intervention. While clinical examination remains the mainstay of diagnosis, recent advances in multimodal imaging can provide supplemental information in subtle cases and may prove valuable for long-term disease monitoring. When evaluating patients with peripheral retinal elevation, it is important for ophthalmologists to make an accurate diagnosis and to understand the risk-benefit ratio associated with intervention. Thus, we summarize the current literature on the natural history, clinical and imaging diagnosis, and surgical management of degenerative retinoschisis and its related complications.

The effect of vitrectomy combined total versus fovea-sparing peeling of internal limiting membrane for myopic foveoschisis / 中华眼底病杂志

Objective:To systematically evaluate the effect of pars plana vitrectomy (PPV) combined total peeling of internal limiting membrane (ILM) versus fovea-sparing peeling of ILM for myopic foveoschisis.Methods:A evidence-based medicine study. Chinese and English as search terms for myopic foveoschisis, vitrectomy, and peeling of internal limiting membrane were used to search literature in China National Knowledge Infrastructure, Wanfang database, VIP database, PubMed of National Library of Medicine, Medline, Embase, and Cochrane Library. The high myopic macular schisis was selected as the research object, the intervention method was PPV combined with complete ILM peeling and combined with foveal preservation ILM peeling surgery clinical control study between Jan 1, 2010, and Jun 31, 2021. Incomplete or irrelevant literature and review literature were excluded. The method of Newcastle-Ottawa Scale system was used to evaluate the included literature. The literature was meta-analyzed by RevMan5.3 software. The mean difference ( MD) and a confidence interval ( CI) of 95% were used to describe the effect sizes of continuous data, fixed effects model was performed. The data including the best corrected visual acuity (BCVA), central fovea thickness (CFT), and postoperative macular hole (MH) were analyzed. Results:In those databases, 232 articles based search stratery were totally retrieved, and 10 articles (417 eyes) were finally included for meta-analysis with 245 eyes for PPV combined total peeling of ILM and 172 eyes for PPV combined fovea-sparing peeling of ILM. Meta-analysis results showed there was no significant difference in BCVA and CFT between the two groups (BCVA: MD=0.05, 95% CI 0.00-0.11; P>0.05; CFT: MD=-4.79, 95% CI -18.69-9.11, P>0.05). It was compared with the incidence of MH, the difference was statistically significant (odds ratio=5.70, 95% CI 2.22-14.61, P<0.05). Conclusion:BCVA and CFT could be improved by PPV combined total and fovea-sparing peeling of ILM for myopic foveoschisis; compared with complete ILM peeling, the incidence of MH was lower after foveal-sparing ILM peeling.

Repair of progressive retinal detachment complicating degenerative retinoschisis: surgical management and outcomes in phakic eyes.

BACKGROUND: Degenerative retinoschisis is a common condition defined by the splitting of the neurosensory retina that may rarely be associated with progressive retinal detachment (RD). Here, we aim to describe the anatomic and functional outcomes of surgical treatment of progressive symptomatic retinal detachment complicating degenerative retinoschisis (PSRDCR) using pars plana vitrectomy (PPV), scleral buckle (SB), or combined PPV/SB procedure. METHODS: A retrospective chart review of patients with PSRDCR between Jan 1, 2008 and Dec 31, 2019 was conducted. Data regarding demographics, surgical approach, and anatomic/functional outcomes were collected. RESULTS: Of the 4973 charts with RD repair during the study period, 36 eyes (0.7%) had retinoschisis with RD. 18 eyes met inclusion criteria (0.4%). The median age was 54 years (range 18-74) and all eyes were phakic. All eyes had outer layer breaks (OLBs) and 16 eyes (89%) had identifiable inner layer breaks. All OLBs were posterior to the equator in charts where position was recorded (16 eyes). The single surgery anatomic success (SSAS) and final anatomical success rates were 66% (12/18) and 100%, respectively. Eyes treated with PPV/SB had an SSAS rate of 75% (9/12), while PPV and SB had SSAS rates of 66% (2/3) and 33% (1/3), respectively. CONCLUSIONS: PSRDCR is an exceedingly rare complication of degenerative retinoschisis associated with an SSAS rate lower than for uncomplicated rhegmatogenous RD. The majority of PSRDCR were repaired via combined PPV/SB in our study, and the rarity of this complication limits statistical support of an optimal surgical method in our and prior studies. The role of SB combined with PPV for PSRDCR requires further investigation.

Treatment outcomes of optic disc pit maculopathy over two decades.

AIM: To study the long-term outcomes of optic disc pit maculopathy. METHODS: Electronic medical records of 154 patients with optic disc pit were reviewed and 50 patients with optic disc pit maculopathy who met the study criteria were included in the study. Demographic profile of patients, along with clinical characteristics, optical coherence tomography (OCT) features and change in best-corrected visual acuity (BCVA) was recorded. Patients were treated either by observation, barrage laser alone or pars plana vitrectomy (PPV) with optional additional surgical procedures. The primary outcome measures were the change in BCVA and resolution of fluid on OCT. RESULTS: The mean age of patients was 29.96 years (3-62 years) with a follow-up of 27.16 months. The mean baseline BCVA in observation, laser and vitrectomy group was log MAR 0.94, 0.76 and 0.87 and final BCVA was log MAR 0.9, 0.67 and 0.46, respectively. There was a statistically significant improvement in the final BCVA and reduction in subretinal fluid with resolution of the schisis cavity in vitrectomy group than in other groups. On regression analysis significant association was found between final BCVA with baseline BCVA (R 2 = 0.815, p = 0.002), use of C3 F8 endotempanode (p = 0.004) ILM peeling (p = 0.012) and use of triamcinolone (TA; p = 0.003). No significant association was found with juxtapapillary endolaser (p = 0.062). CONCLUSIONS: In patients with disc pit maculopathy, PPV lead to better functional and anatomical outcomes as compared to laser or observation alone. Use of surgical adjuvants like ILM peeling, TA and C3F8 tamponade improved the outcomes, unlike juxtapapillary endolaser treatment.

Heads-up Digitally Assisted Surgical Viewing with Intraoperative Optical Coherence Tomography for Myopic Schisis Repair.

PURPOSE: To describe the surgical approach with a screen-based heads-up, three-dimensional (3-D) digital viewing with intraoperative optical coherence tomography (I-OCT) for the successful repair of a myopic macular schisis (MMS) case. CASE REPORT: A 62-year-old woman with vision loss in the left eye was scheduled for pars plana vitrectomy (PPV) and MMS repair. Surgery was performed using the NGENUITYⓇ system for surgical viewing, and foveal-sparing internal limiting membrane (fs-ILM) peeling was performed without gas tamponade, after confirming the absence of iatrogenic macular hole with I-OCT. There were no intraoperative or postoperative complications. Visual acuity improved to 20/40 and the subfoveal macular thickness improved from 706 µm (preoperative) to 221 µm after seven months of follow-up. CONCLUSION: Heads-up digitally assisted viewing technology with I-OCT may be useful or preferred for patients requiring vitreoretinal surgery in the setting of MMS.

A novel mutation in the RS1 gene in a Chinese family with X-linked congenital retinoschisis.

The purpose of the present study was to assess the clinical characteristics of X-linked retinoschisis (XLRS) in a Chinese family over a 7-year period with the aim of identifying possible genetic mutations associated with this disease. A total of 2 male siblings from a family with XLRS were followed up for 7 years and the best-corrected visual acuity and data obtained using slit-lamp microscopy, indirect ophthalmoscopy, fundus photography, spectral domain-optical coherence tomography (OCT), fundus autofluorescence and fundus fluorescence (FFA) and multifocal electroretinograms (ERG) were examined. The coding regions of the retinoschisin 1 (RS1) gene were amplified by PCR and sequenced directly. The proband exhibited blurred vision at 12 years old and was indicated to exhibit a typical phenotype of XLRS at 30 years old. The elder brother exhibited blurred vision at 11 years old and was diagnosed with XLRS at 33 years old. There was no change in the best-corrected visual acuities in the two patients over the 7 years. The OCT results suggested that there were intraretinal cysts and macular atrophy in the eyes of the older sibling, whilst a 'spoke-wheel' pattern was present in the macula of the younger sibling. In addition, OCT examination revealed foveal schisis. FFA analysis indicated a hyperfluorescent signal in the central macula. Multifocal ERG recordings indicated that responses were markedly reduced in the central and outer rings bilaterally. The central retinal thickness of the younger sibling increased but the central retinal thickness of the older sibling was not changed during the 7 years. Sequencing analysis revealed that the mutation was c.366G>A (p.Trp122*) in exon 5 of Xp22.1. Gene mutation analysis indicated that the affected male siblings harbored a Trp122* (c.366G>A) mutation, while the patients' mother was demonstrated to be a heterozygous carrier of the pathogenic mutation. To conclude, the present study discovered a novel XLRS mutation in a Chinese family, where the Trp122* mutation caused a significant change in the function of the RS1 protein. Over the 7 years of observation, although the vision was not significantly impaired in the two patients examined, the central retinal thickness of the younger sibling increased but the central retinal thickness of the older sibling was not altered.

Optic pit-like maculopathy in a patient without any detectable disc anomalies.

Macular schisis is the splitting of the inner retinal layers at macula, with or without associated detachment. The acquired form of macular schisis is frequently associated with optic disc pit maculopathy, although it could be accompanied by several conditions such as tractional maculopathies, cystoid macular edema, veno-occlusive disease, and shaken baby syndrome. However, a small number of cases of retinoschisis without optic disc pit have been reported elsewhere. Here, we present a patient with acquired macular schisis without high myopia and optic disc abnormality in funduscopic examination and imaging. Macular optical coherence tomography of her left eye revealed schisis of the inner and outer retinal layers and subretinal fluid and choroidal thickness of 426 µm (pachychoroid). Although the optic disc of this patient appeared normal, the probable presumption is that small junctions existed between the macular neuroretinal tissue and the vitreous cavity. Further studies are required to survey the other probable mechanisms of retinoschisis without optic pit with more subjects.

Evolution of macular hole in enhanced S-cone syndrome.

PURPOSE: To describe the stages of development and natural course of a full-thickness macular hole (FTMH) in a patient with enhanced S-cone syndrome (ESCS). METHODS: This study reported the serial ophthalmologic examinations and macular spectral-domain optical coherence tomography (SD-OCT) imaging over a period of 6 years in a 29-year-old man with ESCS confirmed by electroretinography (ERG) and NR2E3 molecular genetic analysis. RESULTS: At presentation, patient had night blindness and visual acuity (VA) of 20/300 in the right eye (OD) and 20/100 in the left eye (OS). Examination showed bilateral retinal midperipheral pigmentary deposits and a macular schisis in OD. Electroretinography and NR2E3 genetic analysis confirmed ESCS. A year later, a lamellar MH (LMH) appeared at the fovea in OD. SD-OCT confirmed it as inner retinal layer LMH with outer retinal preservation and displayed, on the temporal side of the LMH, prominent splitting between the inner and outer retinal layers. At 2 years, a focal defect in the ellipsoid zone appeared on SD-OCT, followed by split in the outer retinal layer creating a progressively expanding outer LMH. The latter had rolled edges which then fused with the inner LMH margins creating a single full-thickness FTMH. Over the next 4 years, enlargement of the FTMH with increased adjacent retinal splitting continued. No visible vitreous abnormalities or vitreoretinal traction forces were identified at any stage during follow-up. VA OD remained unchanged. CONCLUSION: This case illustrates that the clinical evolution of FTMH in ESCS may be progressive and likely involves degeneration and intraretinal, rather than vitreoretinal, traction. This should be kept in mind when considering surgical intervention in these cases.

Dome-shaped macula-Review of literature.

Dome-shaped macula is a convex retinochoroidal elevation within the region of a posterior staphyloma seen commonly in high myopia on optical coherence tomography. With growing awareness of the condition facilitated by inclusion of optical coherence tomography in routine retinal practice, coupled with evolution of enhanced depth optical coherence tomography imaging, multiple studies have attempted to shed light on pathogenesis of this complex pathology, its clinical implications, and treatment of associated complications such as serous macular detachment and choroidal neovascularization with variable success. Our review aims to assimilate, scrutinize, and discuss the available literature for a comprehensive insight into dome-shaped macula.

Long-Term Outcome of Epiretinal Membrane Surgery in Patients with Internal Limiting Membrane Dehiscence.

PURPOSE: To identify the effect of internal limiting membrane (ILM) dehiscence on surgical outcomes in eyes that have undergone epiretinal membrane (ERM) removal. METHODS: Consecutive eyes with performed vitrectomy for ERM removal were included. Subjects were divided into two groups: patients with ILM dehiscence (group 1) and without ILM dehiscence (group 2). The best-corrected visual acuity (BCVA) and retinal layer thickness before and after surgery were compared between the two groups. RESULTS: A total of 86 eyes were enrolled. Forty-six eyes (53.5%) showed ILM dehiscence before surgery. The baseline BCVAs were 0.46 ± 0.29 and 0.45 ± 0.25 in groups 1 and 2, respectively (p = 0.801). The BCVAs at 3, 6, and 12 months after surgery differed significantly between the two groups. The subfoveal thickness and inner retinal layer thickness (IRLT) of group 1 vs. 2 were 507.4 ± 80.0 vs. 417.6 ± 63.6 µm, and 270.2 ± 74.3 vs. 182.6 ± 60.4 µm, respectively (both p < 0.001). These differences between the groups remained significant until 12 months after surgery. In multivariate analyses, the location of ILM dehiscence (B = -0.105, p = 0.034) and final IRLT (B = 0.001, p = 0.046) were significant factors affecting the final BCVA. CONCLUSIONS: ILM dehiscence is a relatively common finding and associated with preoperative and postoperative increased IRLT, which results in worse surgical outcomes compared to the absence of ILM dehiscence in patients with ERM. Additionally, the final BCVA was significantly affected by its location and final IRLT in patients with ILM dehiscence.

Dramatic response to topical dorzolamide in X-linked retinoschisis.

Macular involvement is commonly seen in cases with X-linked retinoschisis (XLRS) which includes foveal schisis and cystic maculopathy. Although no definitive treatment has been described, the use of topical 2% dorzolamide hydrochloride in such cases has shown varied response. We herein report a case of XLRS with foveal schisis showing good response to topical dorzolamide. This case highlights the importance of topical dorzolamide in a patient with XLRS.