Pars Plana Vitrectomy in Progressive Stellate Non-Hereditary Idiopathic Foveomacular Retinoschisis (SNIFR): Surgical Outcomes and Considerations for Pathophysiology

Pars Plana Vitrectomy in Progressive Stellate Non-Hereditary Idiopathic Foveomacular Retinoschisis (SNIFR): Surgical Outcomes and Considerations for Pathophysiology | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Pars Plana Vitrectomy in Progressive Stellate Non-Hereditary Idiopathic Foveomacular Retinoschisis (SNIFR): Surgical Outcomes and Considerations for Pathophysiology Omar Moinuddin, Remo Moraes, Beatriz Moraes, Eduardo Cunha de Souza, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7153161/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 7 You are reading this latest preprint version Abstract Background To report the clinical course and outcomes of a surgical approach for progressive stellate non-hereditary idiopathic foveomacular retinoschisis (SNIFR) using pars plana vitrectomy (PPV). Methods Multi-center, consecutive, interventional case series. Patients with a diagnosis of SNIFR presenting with progressive loss of vision between January 1, 2017 and January 1, 2023. Evaluation of ophthalmologic findings and multimodal ocular imaging at the time of diagnosis, surgical procedure, and of visual and anatomic outcomes postoperatively. The main outcome measures evaluated include best corrected visual acuity (BCVA), central macular thickness (CMT), and findings on optical coherence tomography (OCT). Results Seven patients diagnosed with SNIFR were included. Median age in years at the time of diagnosis was 64 (range, 46–77). Four patients were female, and three were male. Genetic testing for mutations in retinoschisin 1 (RS1) and for other inherited conditions associated with foveomacular retinoschisis was negative. All patients demonstrated progressive retinoschisis, as well as worsening vision loss and metamorphopsia when managed conservatively. PPV was performed and revealed anomalously broad and dense adherence of the posterior hyaloid in all eyes. The internal limiting membrane (ILM) was peeled in all but one case. All eyes demonstrated postoperative resolution of retinoschisis and subretinal fluid, with corresponding improvements in both BCVA and subjective central visual distortion up to six months after surgery. Conclusion PPV is an effective surgical intervention resulting in anatomic resolution of retinoschisis and improved functional vision in eyes with progressive SNIFR. Foveomacular schisis retinoschisis idiopathic pars plana vitrectomy hyaloid internal limiting membrane membrane peel macular thickness Figures Figure 1 Figure 2 Background Initially described in 2014, stellate nonhereditary idiopathic foveomacular retinoschisis (SNIFR) is a distinct clinical entity characterized by a stellate pattern of foveomacular schisis in the absence of identifiable inherited or acquired causes.¹ As a diagnosis of exclusion, SNIFR is established only after thorough investigation to rule out other known etiologies of foveomacular retinoschisis. These include congenital X-linked retinoschisis (CXLRS), enhanced S-cone syndrome (ESCS), Goldmann-Favre syndrome (GFS), myotonic dystrophy, structural anomalies of the optic disc, glaucoma, myopic traction maculopathy, and exposure to niacin and taxane derived medications. 2 , 3 The disease is classically indolent, with a vast majority of patients preserving a best-corrected visual acuity (BCVA) of 20/40 or better. However, a subset of eyes develop significant vision loss due to progressive schisis of the outer plexiform (OPL) and outer nuclear layer (ONL) as well as the accumulation of subfoveal fluid. 4 – 7 As with its pathophysiology, the management of SNIFR remains poorly understood and current treatment options are not well defined in the literature. Moreover, consensus on which eyes to treat and when to intervene is lacking. Herein, we present a multi-center series evaluating the clinical course, surgical management, and outcomes of patients with progressive SNIFR managed using pars plana vitrectomy (PPV). To the best of our knowledge, this study represents the largest case series and longest documented follow-up of eyes with SNIFR undergoing surgical treatment reported to date. We further present a comprehensive characterization of the disease and surgical technique, as well as an updated review of the literature on the pathophysiology and modern management. Methods Research conducted was in compliance with the Health Insurance Portability and Accountability ACT (HIPAA) and the Declaration of Helsinki, while abiding to all regional, national, and international laws of the institutions involved in this study. Informed patient consent was obtained for genetic testing, and every effort was made by the investigators to protect the rights of patients and their respective families during the course of this investigation. This study is in concordance with the tenets of the ethics committee of each contributing center, and was approved by the Western Institutional Review Board. In each case, a diagnosis of SNIFR was made based on a combination of clinical history, ophthalmoscopy, review of multimodal ocular imaging, axial length measurement, and genetic testing to rule out inherited conditions associated with foveomacular retinoschisis. Patients presenting between January 1, 2017 and January 1, 2023 were selectively included in this investigation. Collected data included age, anatomic sex, past medical and family history, results of genetic testing and pedigree analysis, findings on ophthalmologic examination and operative reports, treatment outcomes, and analyses of ocular imaging. Results A total of seven patients were included in this study, of which three (42.9%) were males and four (57.1%) were females. All cases were unilateral. The median length of follow-up was 24 months, (range 18–68 months) for the cohort (Table 1 ). In each case the diagnosis of SNIFR was made in a comprehensive manner based on a review of presenting history, ophthalmologic examination, infrared imaging (IR), spectral domain optical coherence tomography (OCT), fluorescein angiography (FA), and the results of genetic testing. Table 1 Patient Demographics Sex Female, no (%) 4 (57.1%) Male, no (%) 3 (42.9%) Age, years Median, (range) 64, (46–77) Length of follow-up, months Median, (range) 24, (18–68) All eyes exhibited a blunted foveal light reflex with a subtle starburst pattern radiating from the fovea. Careful examination of the retinal periphery with indirect binocular ophthalmoscopy with scleral depression and ocular ultrasound revealed a notable absence of peripheral retinoschisis. Intraocular pressure was within normal limits, and Ishihara color plate testing was unremarkable. Ocular imaging demonstrated alternating areas of spoke-like hyporeflectivity and hyperreflectivity on IR, retinoschisis of the OPL and to a comparatively lesser degree of the ONL on OCT (Fig. 1 ), and no defined hyperfluorescence consistent with staining or leakage on FA. There was no evidence of myopic degeneration, lamellar macular or full thickness macular hole, epiretinal membrane, vitreomacular traction, or optic pit or other structural anomaly of the optic nerve on ophthalmoscopy or imaging. All patients denied experiencing nyctalopia, hemeralopia, constriction of visual field, systemic symptoms of myotonia or muscle weakness, and reported no known family history of CXLRS, ESCS, GFS, myotonic dystrophy, optic neuropathy, or visual impairment from an early age. Genetic testing including for retinoschisin 1 (RS1) was negative. Medical history was unrevealing for malignancy, autoimmune disease, and for current or past use of taxane or niacin based medications. Past ophthalmic history was also unremarkable, with the exception of uncomplicated cataract surgery performed in the affected eye in four patients (57.1%). The median age in years at the time of SNIFR diagnosis was 64 (range, 46–77). Median BCVA at presentation measured 20/50 (range, 20/25 − 20/100). All eyes exhibited significant retinoschisis of the OPL and milder retinoschisis of the ONL, and subfoveal fluid was present in three eyes (42.9%) at initial presentation. Two patients (28.6%) remained asymptomatic and were managed conservatively. Five patients (71.4%) reported symptomatically decreased vision and progressive metamorphopsia, and were treated with topical 2% dorzolamide hydrochloride ophthalmic solution three times daily with no resulting improvement in functional vision. All eyes exhibited progression of retinoschisis over a subsequent period of twelve months. At the time of surgery the median BCVA for the entire cohort declined to 20/70 (range, 20/30 − 20/250), and all patients reported progressively worsening central metamorphopsia. Due to the continued progression of retinoschisis, subretinal fluid, and worsening vision, we opted to perform pars plana vitrectomy (PPV) with elevation and removal of the hyaloid membrane. Written informed consent for surgery was obtained from all patients, and the operations were performed without complication by experienced surgeons at their respective institutions. All surgeons performed 25-gauge PPV, with intravitreal triamcinolone acetonide used to enhance visualization and facilitate mechanical elevation of the posterior hyaloid membrane. Notably, all surgeons observed the posterior hyaloid to demonstrate broad adherence to the retinal surface. Intraoperative findings were consistent across all seven eyes, with anomalous vitreoschisis warranting meticulous dissection of distinct layers of hyaloid and rendering surgical induction of PVD particularly challenging. Following successful lifting of the hyaloid membrane, the residual cortical vitreous was noted to be densely adherent and tightly integrated to the inner retina. Accordingly, careful peeling of the internal limiting membrane (ILM) was performed to further relieve this residual traction exerted by the cortical vitreous in all but one case (Case 2). Brilliant Blue G (Dutch Ophthalmic Research Center, Zuidland, Netherlands) or Indocyanine Green (Akon Pharmaceuticals, Lake Forest, USA) was used in three eyes each to stain and enhance visualization of the ILM, based on individual surgeon’s preference. Similar to the posterior hyaloid, the ILM demonstrated anomalous coherence and posed significant challenges to peeling requiring careful and meticulous dissection. The ILM was ultimately successfully peeled up to near the arcades, corresponding to the broad-based attachment of the posterior hyaloid. A complete fluid-air exchange was performed in all eyes. A dilute gas tamponade was instilled in the six eyes that underwent PPV with subsequent ILM peeling, with sulfur hexafluoride (SF6) used in two eyes and perfluoropropane (C3F8) used in four eyes. Postoperatively all seven eyes demonstrated gradual improvement, and ultimately resolution of retinoschisis over a period of four to six months (Fig. 2 ). Subfoveal fluid resolved in all eyes. OCT demonstrated a significant reduction in central macular thickness (CMT) from a preoperative median of 561µm (range, 493–795µm) to a postoperative median CMT of 240µm (range, 192–307µm). All eyes demonstrated a gradual improvement in vision up to a period of six months following surgery (Table 2 ). At most recent follow-up postoperative vision improved to a median BCVA 20/30 (range, 20/20–20/50), with all patients reporting a marked improvement in the degree of metamorphopsia. All eyes were pseudophakic. Table 2 Clinical Characteristics and Surgical Outcomes Case Age, years Sex Laterality Presenting BCVA Preoperative BCVA Preoperative CMT BCVA Postoperative Month 1 BCVA Postoperative Month 3 BCVA Postoperative Month 6 CMT Postoperative Month 6 Treatment Response 1 74 Male OS 20/50 20/250 602µm 20/125 20/50 20/50 307µm Improved foveomacular schisis, reduced CMT, resolved SRF 2 77 Male OD 20/30 20/60 517µm 20/50 20/30 20/30 240µm Improved foveomacular schisis, reduced CMT 3 62 Female OD 20/70 20/70 557µm 20/80 20/30 20/30 250µm Improved foveomacular schisis, reduced CMT 4 64 Female OS 20/40 20/80 795µm 20/40 20/40 20/40 282µm Improved foveomacular schisis, reduced CMT 5 61 Female OD 20/25 20/30 581µm 20/20 20/20 20/20 239µm Improved foveomacular schisis, reduced CMT 6 66 Female OS 20/50 20/50 493µm 20/20 20/20 20/20 202µm Improved foveomacular schisis, reduced CMT, resolved SRF 7 46 Male OD 20/100 20/100 561 µm 20/80 20/60 20/30 192 µm Improved foveomacular schisis, reduced CMT, resolved SRF Abbreviations: oculus dexter (OD); oculus sinister (OS); best-corrected visual acuity (BCVA); central macular thickness (CMT); subretinal fluid (SRF). Discussion First described by Ober et al in 2014, SNIFR is a rare idiopathic condition characterized by radial spoke-like schisis of the outer retina within the parafovea. 1 SNIFR is a diagnosis of exclusion that occurs in the absence of other acquired or inherited forms of foveomacular schisis, and comprises up to 2% of such cases. 8 The condition is broadly defined as preferential splitting of the HFL along the posterior margin of the OPL, often with comparatively lesser schisis of the ONL. In contrast to CXLRS that is congenital, demonstrates bi-macular involvement, frequently involves the retinal periphery, and assumes an x-linked pattern of inheritance, SNIFR is classically diagnosed in middle aged adults, often unilateral, and typically presents without peripheral retinoschisis. 1 , 2 , 9 Moreover, similar to our findings, the literature demonstrates SNIFR occurs in women more often than in men. 1 , 6 SNIFR is a generally indolent disease process with the majority of patients maintaining vision better than or equal to 20/40. 3,10 Yet, there is a notable number of eyes with significant vision loss and symptomatic metamorphopsia. These eyes tend to demonstrate more extensive stellate retinoschisis of the HFL, often also with involvement of the ONL, and the presence of subretinal fluid. While treatment in such patients is imperative, our current understanding of both the pathophysiology and management of this condition remains obscure, and there exists limited data on the outcomes of eyes with progressive SNIFR. A review of the current literature suggests the development of SNIFR is attributed to continued tractional forces exerted by the posterior hyaloid, 4 , 8 , 11 , 12 particularly on the HFL which lacks the structural support provided by local vessels. 3 , 6 , 13 Indeed, prior studies of retinal ultrastructure have demonstrated the preferential location of retinoschisis in SNIFR aligns with pillars of avascular tissue made up of muller cells and photoreceptor axons within the HFL. 3 , 14 , 15 This pattern of stellate retinoschisis localized to the avascular HFL is reaffirmed by studies of OCT and OCT-angiography in eyes with SNIFR demonstrating overlap of schisis cavities with areas of attenuated vascular signal. 6 , 13 More recent research further demonstrates the role of posterior hyaloidal traction in this condition. In the largest reported cohort of SNIFR to date, Bloch et al documented incomplete separation of the posterior hyaloid in 86% of affected eyes compared to 42% in unaffected fellow eyes. Hyaloidal attachment in these eyes was observed to be anomalously broad, with several eyes exhibiting retinoschisis spanning contiguously from the fovea to the limits of the macular cube scan on OCT. 8 Coinciding with our described intraoperative observations, Feo et al more recently described the use of multimodal ocular imaging to demonstrate the anomalously broad posterior vitreoretinal adhesion in eyes with SNIFR. 16 In addition to foveomacular schisis and subfoveal fluid as observed in three eyes in this present series, the investigators also reported the presence of severe mid-peripheral vitreoretinal traction and resulting microangiopathy. They accordingly coined the term “Central Anomalous Retinoschisis with Mid-Peripheral Traction' (CARPET)” to describe this constellation of features, and concluded these findings characterize a more severe variant of SNIFR. 16 While prominent mid-peripheral retinoschisis and associated microangiopathy were not observed in the cases of progressive SNIFR described herein, future studies incorporating preoperative screening with ultra-widefield OCT and intraoperative OCT may reveal subtle manifestations of these features and further elucidate their clinical and prognostic relevance. The role of anomalous traction from the posterior hyaloid in the pathophysiology of this condition is further substantiated by reports of spontaneously resolving foveomacular schisis and improved vision following release of vitreomacular adhesion in SNIFR eyes. Nogueira et al initially reported this observation in a 67-year-old woman with SNIFR exhibiting complete resorption of fluid and resolution of foveomacular schisis six months following release of VMA. 11 Liu et al reported a similar case of asymmetric SNIFR in which one eye exhibited resolution of central macular schisis and improved vision six months after spontaneous resolution of VMA, while the fellow eye with persistently worsening disease exhibited resolution of schisis and improved vision only after vitrectomy surgery to elevate the posterior hyaloid. 12 Moraes et al first described a surgical approach to SNIFR using PPV with ILM peeling and gas tamponade, and reported gradual regression of schisis cavities and macular thickness, resorption of subretinal fluid, and reapproximation of the outer retinal layers on OCT occurring up to twelve months after surgery. 4 Feo et al similarly performed PPV and mechanical lifting of the posterior hyaloid in a patient with CARPET and observed the progressive resolution of SNIFR and resorption of subfoveal fluid, along with corresponding improvement in BCVA from 20/200 to 20/25 over a period of twelve months. In contrast, two other eyes in this series did not undergo surgery and experienced worsening central inner and middle retinoschisis, subfoveal detachment, and ultimately worsening of functional vision. 16 Non-surgical treatments for eyes with vision loss due to SNIFR have been shown to be comparatively less effective. Ajlan et al initially noted temporary improvement in macular thickness with the use of topical carbonic anhydrase inhibitor (CAI) therapy, but reported recalcitrant schisis and vision loss when the medication was discontinued. 7 Schildroth et al subsequently reported using topical CAI in three eyes with SNIFR of varying severities of retinoschisis, and noted no improvement in vision or anatomy despite up to 19 months of treatment. 6 Treatment with intravitreal anti-vascular endothelial growth factor has also been proposed, particularly in eyes with co-morbid neovascular age-related macular degeneration. However, these studies predictably demonstrated regression of choroidal neovascularization and exudation, but with otherwise unaltered and persistent retinoschisis. 5 , 6 In our cohort, all eyes were initially managed with observation alone. Topical CAI therapy was trialed in four patients experiencing progressive vision loss and metamorphopsia, but no improvement was observed and all eyes experienced worsening foveomacular schisis. Given the worsening retinoschisis and continued decline in vision with conservative medical management, we imperatively escalated treatment to a surgical approach with PPV. The use of IVTA enhanced visibility of the vitreous to facilitate elevation of the posterior hyaloid and revealed a significant presence of vitreoschisis. Remnant cortical vitreous densely adherent to the ILM was observed. Moreover, this observation is supported by ultrastructural analysis of dissected retina that has shown cortical gel frequently remains attached to the ILM after both surgically induced and spontaneous posterior vitreous detachment, and that eyes with vitreomacular pathology exhibit comparatively more severe fibrocellular proliferation at the vitreoretinal interface. 17 – 19 Accordingly, the ILM was subsequently peeled in six of the seven eyes (85.7%) to ensure complete removal of the posterior vitreous. We further theorize membrane peeling eliminates potential contributive tangential traction from stiffening of the ILM in cases of more advanced SNIFR, as is well established in other progressive disorders of the vitreomacular interface. 20 , 21 All eyes demonstrated progressive improvement in retinoschisis and resolution of subretinal fluid, with a median improvement in CMT of 307µm (range, 277–513um). All patients demonstrated significant improvement in BCVA and reported a reduction in central metamorphopsia up to six months following the operation. In eyes with progressive SNIFR warranting surgical intervention, we observe recovery of functional vision following resolution of retinoschisis and subretinal fluid. Both Moraes et al and Feo et al similarly observed this temporal relationship in which anatomic reconstitution precedes visual improvement postoperatively. 4 , 16 Furthermore, this observed delay between anatomic and visual improvement remains consistent with our surgical experience managing other more conventional macular diseases with well-established pathophysiology attributed to an anomalous hyaloidal-macular interface such as full-thickness macular hole. The slow but complete resolution of retinoschisis after the release of the traction through pars plana vitrectomy seems interesting and puzzling. Similar outcome cannot be achieved in XL-retinoschisis. One would wonder about the role of Retinoschisin protein and its ability to reconstruct the retina. One would expect the release of traction to stop the progression of retinoschisis and recovery of foveal anatomy to baseline SNIFR, prior to the progression with vision loss and metamorphopsia. The lack of absence of the protein may explain the complete resolution of retinoschisis, as the retina is able to reconstruct internally. Limitations to this study include the rarity of this condition, the retrospective nature of the investigation, small sample size, and the non-randomized selection of patients. Genetic testing was limited only to patients, and did not include family members. Furthermore, operative technique was not standardized among the various surgeons. Conclusions In summary, we report a retrospective interventional case series of seven patients with progressive SNIFR who were managed with surgical intervention using PPV. We report consistent intraoperative findings of anomalously broad and dense adherence of the posterior hyaloid, as well as significant vitreoschisis across all eyes. We further describe a surgical approach using PPV to mechanically elevate the posterior hyaloid, and with careful consideration given to peeling the ILM to further relieve traction exerted by remnant cortical vitreous and stiffened ILM that may exist in eyes with more advanced progressive SNIFR. We demonstrate successful resolution of retinoschisis and significant improvement in functional vision occurring up to six months following surgery in all cases. We further provide an updated review of the current literature to describe the pathophysiology of this rare condition, which is based on anomalous hyaloidal traction resulting in retinoschisis of the fragile HFL/OPL that is inherently devoid of structural support from local retinal vasculature. The consistent intraoperative findings and favorable outcomes reported by multiple surgeons lend further evidence to support this pathophysiology, and to establish an evidence-based management approach for eyes with vision loss due to progressive SNIFR. The experience in this multi-center series confirms that small gauge vitrectomy is a safe, targeted, and effective treatment option for this rare yet potentially progressive and sight-threatening condition. Abbreviations SNIFR – Stellate Nonhereditary Idiopathic Foveomacular Retinoschisis BCVA – Best-Corrected Visual Acuity OPL – Outer Plexiform Layer ONL – Outer Nuclear Layer PPV – Pars Plana Vitrectomy HIPAA – Health Insurance Portability and Accountability Act CXLRS – Congenital X-linked Retinoschisis ESCS – Enhanced S-Cone Syndrome GFS – Goldmann-Favre Syndrome IR – Infrared Imaging OCT – Optical Coherence Tomography FA – Fluorescein Angiography ILM – Internal Limiting Membrane SF₆ – Sulfur Hexafluoride C₃F₈ – Perfluoropropane CMT – Central Macular Thickness HFL – Henle Fiber Layer CARPET – Central Anomalous Retinoschisis with Mid-Peripheral Traction VMA – Vitreomacular Adhesion IVTA – Intravitreal Triamcinolone Acetonide CAI – Carbonic Anhydrase Inhibitor Declarations Ethics approval and consent to participate: Approved by the ethics committee/institutional review board at Oakland University William Beaumont School of Medicine, Rochester, Michigan. Consent for Publication: Written informed consent for research and publication was obtained from all patients. Availability of data and materials: All data generated and analyzed during this investigation are included in this published article. Competing interests: The authors declare that they have no competing interests. Funding: The authors declare no funding was received for this investigation. Authors Contributions: [ OM, THM, AMBC ] contributed to study conception , design, and supervision of research. [ OM, RTM, BKM, ECS, OMJ, ND, HPJ, ACJ, AMBC, THM ] contributed to performing or assisting in surgical procedures, data collection, and review of imaging findings. [ OM, AMBC, THM ] contributed to statistical analysis. [ OM, RTM, BKM, ECS, OMJ, ND, HPJ, ACJ, AMBC, THM ] contributed to drafting and critical revision of the manuscript. Acknowledgements: Not applicable. References Ober MD, Freund KB, Shah M et al. Stellate nonhereditary idiopathic foveomacular retinoschisis. Ophthalmology. 2014;121:1406–13. Light JG, Pyfer MS, Salabati M et al. Stellate nonhereditary idiopathic foveomacular retinoschisis and an approach to the differential diagnosis of macular star. Curr Opin Ophthalmol. 2022;33:157–66. Fragiotta S, Leong BCS, Kaden TR et al. A proposed mechanism influencing structural patterns in X-linked retinoschisis and stellate nonhereditary idiopathic foveomacular retinoschisis. EYE. 2019;33:724–8. Moraes BRM, Ferreira BFA, Nogueira TM et al. Vitrectomy for stellate nonhereditary idiopathic foveomacular retinoschisis associated with outer retinal layer defect. Retin Cases Brief Rep. 2022;16:289–92. Casalino G, Upendran M, Bandello F, Chakravarthy U. Stellate nonhereditary idiopathic foveomacular retinoschisis concomitant to exudative maculopathies. EYE. 2016;30:754–7. Schildroth KR, Mititelu M, Etheridge T et al. Stellate nonhereditary idiopathic foveomacular retinoschisis: Novel findings and optical coherence tomography angiography analysis. Retin Cases Brief Rep. 2023;17:165–9. Ajlan RS, Hammamji KS. Stellate nonhereditary idiopathic foveomacular retinoschisis. Retin Cases Brief Rep . 2017; Publish Ahead of Print :364–366. Bloch E, Flores-Sánchez B, Georgiadis O et al. An association between stellate nonhereditary idiopathic foveomacular retinoschisis, peripheral retinoschisis, and posterior hyaloid attachment. Retina. 2021;41:2361–9. Rao P, Dedania VS, Drenser KA. Congenital X-linked retinoschisis: An updated clinical review. Asia Pac J Ophthalmol (Phila). 2018;7:169–75. Javaheri M, Sadda SR. Atypical peripapillary inner retinoschisis in stellate nonhereditary idiopathic foveomacular retinoschisis. Retin Cases Brief Rep. 2017;12 Suppl 1:S92–7. Machado Nogueira T, de Souza Costa D, Isenberg J, Rezende FA. Stellate nonhereditary idiopathic foveomacular retinoschisis resolution after vitreomacular adhesion release. Am J Ophthalmol Case Rep. 2021;23:101153. Liu J, Wang Y, Wang L. Stellate nonheritable idiopathic foveomacular retinoschisis in juveniles: case report. BMC Ophthalmol. 2023;23:389. Montano M, Alfaro DV, Quiroz-Reyes MA et al. Stellate unilateral nonhereditary idiopathic foveomacular retinoschisis: A multimodal imaging analysis and case report. Retin Cases Brief Rep. 2022;16:439–43. Campbell JP, Zhang M, Hwang TS et al. Detailed vascular anatomy of the human retina by projection-resolved optical coherence tomography angiography. Sci Rep . 2017; 7 . Mrejen S, Gallego-Pinazo R, Freund KB, Paques M. Recognition of Henle’s fiber layer on OCT images. Ophthalmology. 2013;120:e32–31. Feo A, Govetto A, Ramtohul P et al. Stellate nonhereditary idiopathic foveomacular retinoschisis and Central Anomalous Retinoschisis with mid-PEripheral Traction (CARPET). Ophthalmol Retina . 2025. Schumann RG, Schaumberger MM, Rohleder M et al. Ultrastructure of the vitreomacular interface in full-thickness idiopathic macular holes: a consecutive analysis of 100 cases. Am J Ophthalmol. 2006;141:1112–9. Gandorfer A, Rohleder M, Kampik A. Epiretinal pathology of vitreomacular traction syndrome. Br J Ophthalmol. 2002;86:902–9. Kishi S, Demaria C, Shimizu K. Vitreous cortex remnants at the fovea after spontaneous vitreous detachment. Int Ophthalmol. 1986;9:253–60. Takano M, Kishi S. Foveal retinoschisis and retinal detachment in severely myopic eyes with posterior staphyloma. Am J Ophthalmol. 1999;128:472–6. Morescalchi F, Costagliola C, Gambicorti E et al. Controversies over the role of internal limiting membrane peeling during vitrectomy in macular hole surgery. Surv Ophthalmol. 2017;62:58–69. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 24 Sep, 2025 Reviews received at journal 30 Jul, 2025 Reviewers agreed at journal 25 Jul, 2025 Reviewers invited by journal 23 Jul, 2025 Editor assigned by journal 22 Jul, 2025 Submission checks completed at journal 18 Jul, 2025 First submitted to journal 17 Jul, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7153161","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":490334136,"identity":"26e3f9b3-ac8d-4f83-851d-7c415fdf7b94","order_by":0,"name":"Omar Moinuddin","email":"","orcid":"","institution":"Associated Retinal Consultants","correspondingAuthor":false,"prefix":"","firstName":"Omar","middleName":"","lastName":"Moinuddin","suffix":""},{"id":490334137,"identity":"38ba336b-5ade-474f-88cb-66f1fad0dbaa","order_by":1,"name":"Remo Moraes","email":"","orcid":"","institution":"Brazilian Institute of Ophthalmology","correspondingAuthor":false,"prefix":"","firstName":"Remo","middleName":"","lastName":"Moraes","suffix":""},{"id":490334138,"identity":"f79f21bb-1379-4d72-8385-2fa3a7b8b5d9","order_by":2,"name":"Beatriz Moraes","email":"","orcid":"","institution":"Brazilian Institute of Ophthalmology","correspondingAuthor":false,"prefix":"","firstName":"Beatriz","middleName":"","lastName":"Moraes","suffix":""},{"id":490334139,"identity":"31efe41a-a3bf-4d1e-9e27-52337cd5abaa","order_by":3,"name":"Eduardo Cunha de Souza","email":"","orcid":"","institution":"São José do Rio Preto Medical School","correspondingAuthor":false,"prefix":"","firstName":"Eduardo","middleName":"Cunha","lastName":"de Souza","suffix":""},{"id":490334140,"identity":"4ea97020-afee-4477-b24b-b1835eeae6f1","order_by":4,"name":"Octaviano Magalhaes Junior","email":"","orcid":"","institution":"Universidade Federal de São Paulo","correspondingAuthor":false,"prefix":"","firstName":"Octaviano","middleName":"Magalhaes","lastName":"Junior","suffix":""},{"id":490334141,"identity":"5c0edc2c-5c70-44a0-9182-42de0abc0861","order_by":5,"name":"Nadyr Damasceno","email":"","orcid":"","institution":"Hospital Naval Marcilio Dias","correspondingAuthor":false,"prefix":"","firstName":"Nadyr","middleName":"","lastName":"Damasceno","suffix":""},{"id":490334142,"identity":"9dfce8f4-c7dd-43f4-9fdb-ed43164ed0fc","order_by":6,"name":"Hélio Primiano Júnior","email":"","orcid":"","institution":"Universidade Estadual de São Paulo","correspondingAuthor":false,"prefix":"","firstName":"Hélio","middleName":"Primiano","lastName":"Júnior","suffix":""},{"id":490334143,"identity":"2080598e-b860-4064-9b4a-9257da0aabcb","order_by":7,"name":"Antonio Capone Jr.","email":"","orcid":"","institution":"Associated Retinal Consultants","correspondingAuthor":false,"prefix":"","firstName":"Antonio","middleName":"","lastName":"Capone","suffix":"Jr."},{"id":490334144,"identity":"786cf755-52a2-48a0-8646-9895966f78a2","order_by":8,"name":"Antonio Marcelo Casella","email":"","orcid":"","institution":"Universidade Estadual de Londrina","correspondingAuthor":false,"prefix":"","firstName":"Antonio","middleName":"Marcelo","lastName":"Casella","suffix":""},{"id":490334145,"identity":"2e412234-d93d-4d26-a05d-4062e71030f7","order_by":9,"name":"Tamer Mahmoud","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAxUlEQVRIiWNgGAWjYDACCQYGZjDjeAOUQQjwwLWcOUCylhsJRGqxl+5O/FyYY5PYd/ON4eeCChsG/vbuBPy2yJzdLD1zW1rizNs5xtIzzqQxSJw5u4GAw3I3SPNuO5y44XaOgTRv22EGA6AIIS2bf4O13Dxj/JtYLdsgttzgMSPSlhu526x5t6UZzzyTVmbNcyaNh6Bf2Gfkbr7Nu81Gtu/44c23eSps5Pjbe/FrQQIcBmBriVUOtvABKapHwSgYBaNgBAEA51FICeRxrfQAAAAASUVORK5CYII=","orcid":"","institution":"Associated Retinal Consultants","correspondingAuthor":true,"prefix":"","firstName":"Tamer","middleName":"","lastName":"Mahmoud","suffix":""}],"badges":[],"createdAt":"2025-07-18 02:38:23","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7153161/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7153161/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":87731841,"identity":"5cba21c3-f1aa-4e88-aaa8-ae99b06df76f","added_by":"auto","created_at":"2025-07-28 11:46:33","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":841734,"visible":true,"origin":"","legend":"\u003cp\u003eMultimodal imaging of patient 4. \u003cstrong\u003eA.\u003c/strong\u003e Color fundus photography at presentation. Spoke-like radial cysts with a stellate appearance of the macula are noted (inset). An anomalous temporal vitreoretinal adhesion can be noted temporal to the macula. \u003cstrong\u003eB, C. \u003c/strong\u003eOCT at presentation. The outer plexiform layer schisis with cystoid spaces in the foveal area, and a temporal inner nuclear layer splitting with an anomalous vitreous adhesion are observed. \u003cstrong\u003eD. \u003c/strong\u003eSix-month postoperative color fundus photography. \u003cstrong\u003eE.\u003c/strong\u003e Six-month postoperative OCT. Foveomacular retinoschisis is resolved.\u003c/p\u003e","description":"","filename":"figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7153161/v1/544668af06b0c73250995eb8.jpg"},{"id":87731844,"identity":"829f818c-9866-4b8d-90d5-8dd0fe42cd4a","added_by":"auto","created_at":"2025-07-28 11:46:33","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":2814521,"visible":true,"origin":"","legend":"\u003cp\u003eOCT imaging of patient 3. \u003cstrong\u003eA, B. \u003c/strong\u003ePreoperative. The outer plexiform layer schisis with cystoid spaces in the foveal area, and a temporal inner nuclear layer splitting with an anomalous vitreous adherence near the superior temporal arcade are observed. \u003cstrong\u003eC. \u003c/strong\u003eOne month surgery, improving intraretinal schisis. \u003cstrong\u003eD.\u003c/strong\u003e Six months after surgery, foveomacular retinoschisis is resolved.\u003c/p\u003e","description":"","filename":"figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7153161/v1/e86170d4c4a4edb424e13ad8.jpg"},{"id":87733448,"identity":"05b378c3-7786-44e3-b3da-c3a7971232fb","added_by":"auto","created_at":"2025-07-28 12:02:35","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":4424637,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7153161/v1/1ac62cb5-4579-4dc0-b186-bb97bb6fbf81.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Pars Plana Vitrectomy in Progressive Stellate Non-Hereditary Idiopathic Foveomacular Retinoschisis (SNIFR): Surgical Outcomes and Considerations for Pathophysiology","fulltext":[{"header":"Background","content":"\u003cp\u003eInitially described in 2014, stellate nonhereditary idiopathic foveomacular retinoschisis (SNIFR) is a distinct clinical entity characterized by a stellate pattern of foveomacular schisis in the absence of identifiable inherited or acquired causes.¹ As a diagnosis of exclusion, SNIFR is established only after thorough investigation to rule out other known etiologies of foveomacular retinoschisis. These include congenital X-linked retinoschisis (CXLRS), enhanced S-cone syndrome (ESCS), Goldmann-Favre syndrome (GFS), myotonic dystrophy, structural anomalies of the optic disc, glaucoma, myopic traction maculopathy, and exposure to niacin and taxane derived medications.\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e,\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eThe disease is classically indolent, with a vast majority of patients preserving a best-corrected visual acuity (BCVA) of 20/40 or better. However, a subset of eyes develop significant vision loss due to progressive schisis of the outer plexiform (OPL) and outer nuclear layer (ONL) as well as the accumulation of subfoveal fluid.\u003csup\u003e\u003cspan additionalcitationids=\"CR5 CR6\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e–\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e As with its pathophysiology, the management of SNIFR remains poorly understood and current treatment options are not well defined in the literature. Moreover, consensus on which eyes to treat and when to intervene is lacking.\u003c/p\u003e\u003cp\u003eHerein, we present a multi-center series evaluating the clinical course, surgical management, and outcomes of patients with progressive SNIFR managed using pars plana vitrectomy (PPV). To the best of our knowledge, this study represents the largest case series and longest documented follow-up of eyes with SNIFR undergoing surgical treatment reported to date. We further present a comprehensive characterization of the disease and surgical technique, as well as an updated review of the literature on the pathophysiology and modern management.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eResearch conducted was in compliance with the Health Insurance Portability and Accountability ACT (HIPAA) and the Declaration of Helsinki, while abiding to all regional, national, and international laws of the institutions involved in this study. Informed patient consent was obtained for genetic testing, and every effort was made by the investigators to protect the rights of patients and their respective families during the course of this investigation. This study is in concordance with the tenets of the ethics committee of each contributing center, and was approved by the Western Institutional Review Board.\u003c/p\u003e\u003cp\u003eIn each case, a diagnosis of SNIFR was made based on a combination of clinical history, ophthalmoscopy, review of multimodal ocular imaging, axial length measurement, and genetic testing to rule out inherited conditions associated with foveomacular retinoschisis. Patients presenting between January 1, 2017 and January 1, 2023 were selectively included in this investigation. Collected data included age, anatomic sex, past medical and family history, results of genetic testing and pedigree analysis, findings on ophthalmologic examination and operative reports, treatment outcomes, and analyses of ocular imaging.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eA total of seven patients were included in this study, of which three (42.9%) were males and four (57.1%) were females. All cases were unilateral. The median length of follow-up was 24 months, (range 18\u0026ndash;68 months) for the cohort (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). In each case the diagnosis of SNIFR was made in a comprehensive manner based on a review of presenting history, ophthalmologic examination, infrared imaging (IR), spectral domain optical coherence tomography (OCT), fluorescein angiography (FA), and the results of genetic testing.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003ePatient Demographics\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"2\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eSex\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFemale, no (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4 (57.1%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMale, no (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3 (42.9%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003e\u003cb\u003eAge, years\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMedian, (range)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e64, (46\u0026ndash;77)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003e\u003cb\u003eLength of follow-up, months\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMedian, (range)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e24, (18\u0026ndash;68)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eAll eyes exhibited a blunted foveal light reflex with a subtle starburst pattern radiating from the fovea. Careful examination of the retinal periphery with indirect binocular ophthalmoscopy with scleral depression and ocular ultrasound revealed a notable absence of peripheral retinoschisis. Intraocular pressure was within normal limits, and Ishihara color plate testing was unremarkable. Ocular imaging demonstrated alternating areas of spoke-like hyporeflectivity and hyperreflectivity on IR, retinoschisis of the OPL and to a comparatively lesser degree of the ONL on OCT (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e), and no defined hyperfluorescence consistent with staining or leakage on FA. There was no evidence of myopic degeneration, lamellar macular or full thickness macular hole, epiretinal membrane, vitreomacular traction, or optic pit or other structural anomaly of the optic nerve on ophthalmoscopy or imaging.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eAll patients denied experiencing nyctalopia, hemeralopia, constriction of visual field, systemic symptoms of myotonia or muscle weakness, and reported no known family history of CXLRS, ESCS, GFS, myotonic dystrophy, optic neuropathy, or visual impairment from an early age. Genetic testing including for retinoschisin 1 (RS1) was negative. Medical history was unrevealing for malignancy, autoimmune disease, and for current or past use of taxane or niacin based medications. Past ophthalmic history was also unremarkable, with the exception of uncomplicated cataract surgery performed in the affected eye in four patients (57.1%).\u003c/p\u003e\u003cp\u003eThe median age in years at the time of SNIFR diagnosis was 64 (range, 46\u0026ndash;77). Median BCVA at presentation measured 20/50 (range, 20/25\u0026thinsp;\u0026minus;\u0026thinsp;20/100). All eyes exhibited significant retinoschisis of the OPL and milder retinoschisis of the ONL, and subfoveal fluid was present in three eyes (42.9%) at initial presentation. Two patients (28.6%) remained asymptomatic and were managed conservatively. Five patients (71.4%) reported symptomatically decreased vision and progressive metamorphopsia, and were treated with topical 2% dorzolamide hydrochloride ophthalmic solution three times daily with no resulting improvement in functional vision. All eyes exhibited progression of retinoschisis over a subsequent period of twelve months. At the time of surgery the median BCVA for the entire cohort declined to 20/70 (range, 20/30\u0026thinsp;\u0026minus;\u0026thinsp;20/250), and all patients reported progressively worsening central metamorphopsia. Due to the continued progression of retinoschisis, subretinal fluid, and worsening vision, we opted to perform pars plana vitrectomy (PPV) with elevation and removal of the hyaloid membrane. Written informed consent for surgery was obtained from all patients, and the operations were performed without complication by experienced surgeons at their respective institutions.\u003c/p\u003e\u003cp\u003eAll surgeons performed 25-gauge PPV, with intravitreal triamcinolone acetonide used to enhance visualization and facilitate mechanical elevation of the posterior hyaloid membrane. Notably, all surgeons observed the posterior hyaloid to demonstrate broad adherence to the retinal surface. Intraoperative findings were consistent across all seven eyes, with anomalous vitreoschisis warranting meticulous dissection of distinct layers of hyaloid and rendering surgical induction of PVD particularly challenging. Following successful lifting of the hyaloid membrane, the residual cortical vitreous was noted to be densely adherent and tightly integrated to the inner retina. Accordingly, careful peeling of the internal limiting membrane (ILM) was performed to further relieve this residual traction exerted by the cortical vitreous in all but one case (Case 2).\u003c/p\u003e\u003cp\u003eBrilliant Blue G (Dutch Ophthalmic Research Center, Zuidland, Netherlands) or Indocyanine Green (Akon Pharmaceuticals, Lake Forest, USA) was used in three eyes each to stain and enhance visualization of the ILM, based on individual surgeon\u0026rsquo;s preference. Similar to the posterior hyaloid, the ILM demonstrated anomalous coherence and posed significant challenges to peeling requiring careful and meticulous dissection. The ILM was ultimately successfully peeled up to near the arcades, corresponding to the broad-based attachment of the posterior hyaloid. A complete fluid-air exchange was performed in all eyes. A dilute gas tamponade was instilled in the six eyes that underwent PPV with subsequent ILM peeling, with sulfur hexafluoride (SF6) used in two eyes and perfluoropropane (C3F8) used in four eyes.\u003c/p\u003e\u003cp\u003ePostoperatively all seven eyes demonstrated gradual improvement, and ultimately resolution of retinoschisis over a period of four to six months (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Subfoveal fluid resolved in all eyes. OCT demonstrated a significant reduction in central macular thickness (CMT) from a preoperative median of 561\u0026micro;m (range, 493\u0026ndash;795\u0026micro;m) to a postoperative median CMT of 240\u0026micro;m (range, 192\u0026ndash;307\u0026micro;m). All eyes demonstrated a gradual improvement in vision up to a period of six months following surgery (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). At most recent follow-up postoperative vision improved to a median BCVA 20/30 (range, 20/20\u0026ndash;20/50), with all patients reporting a marked improvement in the degree of metamorphopsia. All eyes were pseudophakic.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eClinical Characteristics and Surgical Outcomes\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"12\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c12\" colnum=\"12\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCase\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAge, years\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eSex\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eLaterality\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003ePresenting BCVA\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003ePreoperative BCVA\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003ePreoperative CMT\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e\u003cp\u003eBCVA Postoperative Month 1\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003eBCVA Postoperative Month 3\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c10\"\u003e\u003cp\u003eBCVA Postoperative Month 6\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c11\"\u003e\u003cp\u003eCMT Postoperative Month 6\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c12\"\u003e\u003cp\u003eTreatment Response\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e74\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eMale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eOS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e20/50\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e20/250\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e602\u0026micro;m\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e20/125\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e20/50\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e20/50\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e307\u0026micro;m\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003eImproved foveomacular schisis, reduced CMT, resolved SRF\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e77\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eMale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eOD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e20/30\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e20/60\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e517\u0026micro;m\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e20/50\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e20/30\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e20/30\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e240\u0026micro;m\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003eImproved foveomacular schisis, reduced CMT\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e62\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eFemale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eOD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e20/70\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e20/70\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e557\u0026micro;m\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e20/80\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e20/30\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e20/30\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e250\u0026micro;m\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003eImproved foveomacular schisis, reduced CMT\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e64\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eFemale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eOS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e20/40\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e20/80\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e795\u0026micro;m\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e20/40\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e20/40\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e20/40\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e282\u0026micro;m\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003eImproved foveomacular schisis, reduced CMT\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e61\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eFemale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eOD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e20/25\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e20/30\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e581\u0026micro;m\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e20/20\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e20/20\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e20/20\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e239\u0026micro;m\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003eImproved foveomacular schisis, reduced CMT\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e66\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eFemale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eOS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e20/50\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e20/50\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e493\u0026micro;m\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e20/20\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e20/20\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e20/20\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e202\u0026micro;m\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003eImproved foveomacular schisis, reduced CMT, resolved SRF\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e46\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eMale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eOD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e20/100\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e20/100\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e561 \u0026micro;m\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e20/80\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e20/60\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e20/30\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e192 \u0026micro;m\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003eImproved foveomacular schisis, reduced CMT, resolved SRF\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"12\"\u003e\u003cem\u003eAbbreviations: oculus dexter (OD); oculus sinister (OS); best-corrected visual acuity (BCVA); central macular thickness (CMT); subretinal fluid (SRF).\u003c/em\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eFirst described by Ober et al in 2014, SNIFR is a rare idiopathic condition characterized by radial spoke-like schisis of the outer retina within the parafovea.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e SNIFR is a diagnosis of exclusion that occurs in the absence of other acquired or inherited forms of foveomacular schisis, and comprises up to 2% of such cases.\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e The condition is broadly defined as preferential splitting of the HFL along the posterior margin of the OPL, often with comparatively lesser schisis of the ONL. In contrast to CXLRS that is congenital, demonstrates bi-macular involvement, frequently involves the retinal periphery, and assumes an x-linked pattern of inheritance, SNIFR is classically diagnosed in middle aged adults, often unilateral, and typically presents without peripheral retinoschisis.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e,\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e,\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e Moreover, similar to our findings, the literature demonstrates SNIFR occurs in women more often than in men.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e,\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eSNIFR is a generally indolent disease process with the majority of patients maintaining vision better than or equal to 20/40.\u003csup\u003e3,10\u003c/sup\u003e Yet, there is a notable number of eyes with significant vision loss and symptomatic metamorphopsia. These eyes tend to demonstrate more extensive stellate retinoschisis of the HFL, often also with involvement of the ONL, and the presence of subretinal fluid. While treatment in such patients is imperative, our current understanding of both the pathophysiology and management of this condition remains obscure, and there exists limited data on the outcomes of eyes with progressive SNIFR.\u003c/p\u003e\u003cp\u003eA review of the current literature suggests the development of SNIFR is attributed to continued tractional forces exerted by the posterior hyaloid,\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e,\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e,\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e,\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e particularly on the HFL which lacks the structural support provided by local vessels.\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e,\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e,\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e Indeed, prior studies of retinal ultrastructure have demonstrated the preferential location of retinoschisis in SNIFR aligns with pillars of avascular tissue made up of muller cells and photoreceptor axons within the HFL.\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e,\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e,\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e This pattern of stellate retinoschisis localized to the avascular HFL is reaffirmed by studies of OCT and OCT-angiography in eyes with SNIFR demonstrating overlap of schisis cavities with areas of attenuated vascular signal.\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e,\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e More recent research further demonstrates the role of posterior hyaloidal traction in this condition. In the largest reported cohort of SNIFR to date, Bloch et al documented incomplete separation of the posterior hyaloid in 86% of affected eyes compared to 42% in unaffected fellow eyes. Hyaloidal attachment in these eyes was observed to be anomalously broad, with several eyes exhibiting retinoschisis spanning contiguously from the fovea to the limits of the macular cube scan on OCT.\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eCoinciding with our described intraoperative observations, Feo et al more recently described the use of multimodal ocular imaging to demonstrate the anomalously broad posterior vitreoretinal adhesion in eyes with SNIFR.\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e In addition to foveomacular schisis and subfoveal fluid as observed in three eyes in this present series, the investigators also reported the presence of severe mid-peripheral vitreoretinal traction and resulting microangiopathy. They accordingly coined the term \u0026ldquo;Central Anomalous Retinoschisis with Mid-Peripheral Traction' (CARPET)\u0026rdquo; to describe this constellation of features, and concluded these findings characterize a more severe variant of SNIFR.\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e While prominent mid-peripheral retinoschisis and associated microangiopathy were not observed in the cases of progressive SNIFR described herein, future studies incorporating preoperative screening with ultra-widefield OCT and intraoperative OCT may reveal subtle manifestations of these features and further elucidate their clinical and prognostic relevance.\u003c/p\u003e\u003c/p\u003e\u003cp\u003eThe role of anomalous traction from the posterior hyaloid in the pathophysiology of this condition is further substantiated by reports of spontaneously resolving foveomacular schisis and improved vision following release of vitreomacular adhesion in SNIFR eyes. Nogueira et al initially reported this observation in a 67-year-old woman with SNIFR exhibiting complete resorption of fluid and resolution of foveomacular schisis six months following release of VMA.\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e Liu et al reported a similar case of asymmetric SNIFR in which one eye exhibited resolution of central macular schisis and improved vision six months after spontaneous resolution of VMA, while the fellow eye with persistently worsening disease exhibited resolution of schisis and improved vision only after vitrectomy surgery to elevate the posterior hyaloid.\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e Moraes et al first described a surgical approach to SNIFR using PPV with ILM peeling and gas tamponade, and reported gradual regression of schisis cavities and macular thickness, resorption of subretinal fluid, and reapproximation of the outer retinal layers on OCT occurring up to twelve months after surgery.\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e Feo et al similarly performed PPV and mechanical lifting of the posterior hyaloid in a patient with CARPET and observed the progressive resolution of SNIFR and resorption of subfoveal fluid, along with corresponding improvement in BCVA from 20/200 to 20/25 over a period of twelve months. In contrast, two other eyes in this series did not undergo surgery and experienced worsening central inner and middle retinoschisis, subfoveal detachment, and ultimately worsening of functional vision.\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eNon-surgical treatments for eyes with vision loss due to SNIFR have been shown to be comparatively less effective. Ajlan et al initially noted temporary improvement in macular thickness with the use of topical carbonic anhydrase inhibitor (CAI) therapy, but reported recalcitrant schisis and vision loss when the medication was discontinued.\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e Schildroth et al subsequently reported using topical CAI in three eyes with SNIFR of varying severities of retinoschisis, and noted no improvement in vision or anatomy despite up to 19 months of treatment.\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e Treatment with intravitreal anti-vascular endothelial growth factor has also been proposed, particularly in eyes with co-morbid neovascular age-related macular degeneration. However, these studies predictably demonstrated regression of choroidal neovascularization and exudation, but with otherwise unaltered and persistent retinoschisis.\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e,\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e In our cohort, all eyes were initially managed with observation alone. Topical CAI therapy was trialed in four patients experiencing progressive vision loss and metamorphopsia, but no improvement was observed and all eyes experienced worsening foveomacular schisis.\u003c/p\u003e\u003cp\u003eGiven the worsening retinoschisis and continued decline in vision with conservative medical management, we imperatively escalated treatment to a surgical approach with PPV. The use of IVTA enhanced visibility of the vitreous to facilitate elevation of the posterior hyaloid and revealed a significant presence of vitreoschisis. Remnant cortical vitreous densely adherent to the ILM was observed. Moreover, this observation is supported by ultrastructural analysis of dissected retina that has shown cortical gel frequently remains attached to the ILM after both surgically induced and spontaneous posterior vitreous detachment, and that eyes with vitreomacular pathology exhibit comparatively more severe fibrocellular proliferation at the vitreoretinal interface.\u003csup\u003e\u003cspan additionalcitationids=\"CR18\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e Accordingly, the ILM was subsequently peeled in six of the seven eyes (85.7%) to ensure complete removal of the posterior vitreous. We further theorize membrane peeling eliminates potential contributive tangential traction from stiffening of the ILM in cases of more advanced SNIFR, as is well established in other progressive disorders of the vitreomacular interface.\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e,\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e All eyes demonstrated progressive improvement in retinoschisis and resolution of subretinal fluid, with a median improvement in CMT of 307\u0026micro;m (range, 277\u0026ndash;513um). All patients demonstrated significant improvement in BCVA and reported a reduction in central metamorphopsia up to six months following the operation. In eyes with progressive SNIFR warranting surgical intervention, we observe recovery of functional vision following resolution of retinoschisis and subretinal fluid. Both Moraes et al and Feo et al similarly observed this temporal relationship in which anatomic reconstitution precedes visual improvement postoperatively.\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e,\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e Furthermore, this observed delay between anatomic and visual improvement remains consistent with our surgical experience managing other more conventional macular diseases with well-established pathophysiology attributed to an anomalous hyaloidal-macular interface such as full-thickness macular hole.\u003c/p\u003e\u003cp\u003eThe slow but complete resolution of retinoschisis after the release of the traction through pars plana vitrectomy seems interesting and puzzling. Similar outcome cannot be achieved in XL-retinoschisis. One would wonder about the role of Retinoschisin protein and its ability to reconstruct the retina. One would expect the release of traction to stop the progression of retinoschisis and recovery of foveal anatomy to baseline SNIFR, prior to the progression with vision loss and metamorphopsia. The lack of absence of the protein may explain the complete resolution of retinoschisis, as the retina is able to reconstruct internally.\u003c/p\u003e\u003cp\u003eLimitations to this study include the rarity of this condition, the retrospective nature of the investigation, small sample size, and the non-randomized selection of patients. Genetic testing was limited only to patients, and did not include family members. Furthermore, operative technique was not standardized among the various surgeons.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eIn summary, we report a retrospective interventional case series of seven patients with progressive SNIFR who were managed with surgical intervention using PPV. We report consistent intraoperative findings of anomalously broad and dense adherence of the posterior hyaloid, as well as significant vitreoschisis across all eyes. We further describe a surgical approach using PPV to mechanically elevate the posterior hyaloid, and with careful consideration given to peeling the ILM to further relieve traction exerted by remnant cortical vitreous and stiffened ILM that may exist in eyes with more advanced progressive SNIFR.\u003c/p\u003e\u003cp\u003eWe demonstrate successful resolution of retinoschisis and significant improvement in functional vision occurring up to six months following surgery in all cases.\u003c/p\u003e\u003cp\u003eWe further provide an updated review of the current literature to describe the pathophysiology of this rare condition, which is based on anomalous hyaloidal traction resulting in retinoschisis of the fragile HFL/OPL that is inherently devoid of structural support from local retinal vasculature. The consistent intraoperative findings and favorable outcomes reported by multiple surgeons lend further evidence to support this pathophysiology, and to establish an evidence-based management approach for eyes with vision loss due to progressive SNIFR. The experience in this multi-center series confirms that small gauge vitrectomy is a safe, targeted, and effective treatment option for this rare yet potentially progressive and sight-threatening condition.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eSNIFR – Stellate Nonhereditary Idiopathic Foveomacular Retinoschisis\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;BCVA – Best-Corrected Visual Acuity\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;OPL – Outer Plexiform Layer\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;ONL – Outer Nuclear Layer\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;PPV – Pars Plana Vitrectomy\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;HIPAA – Health Insurance Portability and Accountability Act\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;CXLRS – Congenital X-linked Retinoschisis\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;ESCS – Enhanced S-Cone Syndrome\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;GFS – Goldmann-Favre Syndrome\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;IR – Infrared Imaging\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;OCT – Optical Coherence Tomography\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;FA – Fluorescein Angiography\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;ILM – Internal Limiting Membrane\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;SF₆\u0026nbsp;– Sulfur Hexafluoride\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;C₃F₈\u0026nbsp;– Perfluoropropane\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;CMT – Central Macular Thickness\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;HFL – Henle Fiber Layer\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;CARPET – Central Anomalous Retinoschisis with Mid-Peripheral Traction\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;VMA – Vitreomacular Adhesion\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;IVTA – Intravitreal Triamcinolone Acetonide\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;CAI – Carbonic Anhydrase Inhibitor\u003c/p\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate:\u003c/strong\u003e Approved by the ethics committee/institutional review board at Oakland University William Beaumont School of Medicine, Rochester, Michigan.\u003c/p\u003e\n\u003cp\u003eConsent for Publication: Written informed consent for research and publication was obtained from all patients.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials:\u003c/strong\u003e All data generated and analyzed during this investigation are included in this published article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests:\u003c/strong\u003e The authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e The authors declare no funding was received for this investigation.\u003c/p\u003e\n\u003cp\u003eAuthors Contributions:\u003cstrong\u003e\u0026nbsp;[\u003c/strong\u003e\u003c/strong\u003e\u003cstrong\u003eOM, THM, AMBC\u003c/strong\u003e\u003cstrong\u003e] contributed to study conception\u003c/strong\u003e\u003cstrong\u003e, design, and supervision of research.\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e[\u003c/strong\u003e\u003cstrong\u003eOM, RTM, BKM, ECS, OMJ, ND, HPJ, ACJ, AMBC, THM\u003c/strong\u003e\u003cstrong\u003e] contributed to\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eperforming or assisting in surgical procedures, data collection, and review of imaging findings.\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e[\u003c/strong\u003e\u003cstrong\u003eOM, AMBC, THM\u003c/strong\u003e\u003cstrong\u003e] contributed to\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003estatistical analysis.\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e[\u003c/strong\u003e\u003cstrong\u003eOM, RTM, BKM, ECS, OMJ, ND, HPJ, ACJ, AMBC, THM\u003c/strong\u003e\u003cstrong\u003e]\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003econtributed to drafting and critical revision of the manuscript.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements: Not applicable.\u003c/strong\u003e\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eOber MD, Freund KB, Shah M et al. Stellate nonhereditary idiopathic foveomacular retinoschisis. Ophthalmology. 2014;121:1406\u0026ndash;13.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLight JG, Pyfer MS, Salabati M et al. Stellate nonhereditary idiopathic foveomacular retinoschisis and an approach to the differential diagnosis of macular star. Curr Opin Ophthalmol. 2022;33:157\u0026ndash;66.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eFragiotta S, Leong BCS, Kaden TR et al. A proposed mechanism influencing structural patterns in X-linked retinoschisis and stellate nonhereditary idiopathic foveomacular retinoschisis. EYE. 2019;33:724\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMoraes BRM, Ferreira BFA, Nogueira TM et al. Vitrectomy for stellate nonhereditary idiopathic foveomacular retinoschisis associated with outer retinal layer defect. Retin Cases Brief Rep. 2022;16:289\u0026ndash;92.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eCasalino G, Upendran M, Bandello F, Chakravarthy U. Stellate nonhereditary idiopathic foveomacular retinoschisis concomitant to exudative maculopathies. EYE. 2016;30:754\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSchildroth KR, Mititelu M, Etheridge T et al. Stellate nonhereditary idiopathic foveomacular retinoschisis: Novel findings and optical coherence tomography angiography analysis. Retin Cases Brief Rep. 2023;17:165\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAjlan RS, Hammamji KS. Stellate nonhereditary idiopathic foveomacular retinoschisis. \u003cem\u003eRetin Cases Brief Rep\u003c/em\u003e. 2017;\u003cem\u003ePublish Ahead of Print\u003c/em\u003e:364\u0026ndash;366.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBloch E, Flores-S\u0026aacute;nchez B, Georgiadis O et al. An association between stellate nonhereditary idiopathic foveomacular retinoschisis, peripheral retinoschisis, and posterior hyaloid attachment. Retina. 2021;41:2361\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRao P, Dedania VS, Drenser KA. Congenital X-linked retinoschisis: An updated clinical review. Asia Pac J Ophthalmol (Phila). 2018;7:169\u0026ndash;75.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eJavaheri M, Sadda SR. Atypical peripapillary inner retinoschisis in stellate nonhereditary idiopathic foveomacular retinoschisis. Retin Cases Brief Rep. 2017;12 Suppl 1:S92\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMachado Nogueira T, de Souza Costa D, Isenberg J, Rezende FA. Stellate nonhereditary idiopathic foveomacular retinoschisis resolution after vitreomacular adhesion release. Am J Ophthalmol Case Rep. 2021;23:101153.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLiu J, Wang Y, Wang L. Stellate nonheritable idiopathic foveomacular retinoschisis in juveniles: case report. BMC Ophthalmol. 2023;23:389.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMontano M, Alfaro DV, Quiroz-Reyes MA et al. Stellate unilateral nonhereditary idiopathic foveomacular retinoschisis: A multimodal imaging analysis and case report. Retin Cases Brief Rep. 2022;16:439\u0026ndash;43.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eCampbell JP, Zhang M, Hwang TS et al. Detailed vascular anatomy of the human retina by projection-resolved optical coherence tomography angiography. \u003cem\u003eSci Rep\u003c/em\u003e. 2017;\u003cem\u003e7\u003c/em\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMrejen S, Gallego-Pinazo R, Freund KB, Paques M. Recognition of Henle\u0026rsquo;s fiber layer on OCT images. Ophthalmology. 2013;120:e32\u0026ndash;31.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eFeo A, Govetto A, Ramtohul P et al. Stellate nonhereditary idiopathic foveomacular retinoschisis and Central Anomalous Retinoschisis with mid-PEripheral Traction (CARPET). \u003cem\u003eOphthalmol Retina\u003c/em\u003e. 2025.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSchumann RG, Schaumberger MM, Rohleder M et al. Ultrastructure of the vitreomacular interface in full-thickness idiopathic macular holes: a consecutive analysis of 100 cases. Am J Ophthalmol. 2006;141:1112\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGandorfer A, Rohleder M, Kampik A. Epiretinal pathology of vitreomacular traction syndrome. Br J Ophthalmol. 2002;86:902\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKishi S, Demaria C, Shimizu K. Vitreous cortex remnants at the fovea after spontaneous vitreous detachment. Int Ophthalmol. 1986;9:253\u0026ndash;60.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTakano M, Kishi S. Foveal retinoschisis and retinal detachment in severely myopic eyes with posterior staphyloma. Am J Ophthalmol. 1999;128:472\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMorescalchi F, Costagliola C, Gambicorti E et al. Controversies over the role of internal limiting membrane peeling during vitrectomy in macular hole surgery. Surv Ophthalmol. 2017;62:58\u0026ndash;69.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"international-journal-of-retina-and-vitreous","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"IJRV","sideBox":"Learn more about [International Journal of Retina and Vitreous](https://jneurodevdisorders.biomedcentral.com/)","snPcode":"40942","submissionUrl":"https://submission.nature.com/new-submission/40942/3","title":"International Journal of Retina and Vitreous","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Foveomacular schisis, retinoschisis, idiopathic, pars plana vitrectomy, hyaloid, internal limiting membrane, membrane peel, macular thickness","lastPublishedDoi":"10.21203/rs.3.rs-7153161/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7153161/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cb\u003eBackground\u003c/b\u003e\u003c/p\u003e\u003cp\u003eTo report the clinical course and outcomes of a surgical approach for progressive stellate non-hereditary idiopathic foveomacular retinoschisis (SNIFR) using pars plana vitrectomy (PPV).\u003c/p\u003e\u003cp\u003e\u003cb\u003eMethods\u003c/b\u003e\u003c/p\u003e\u003cp\u003eMulti-center, consecutive, interventional case series. Patients with a diagnosis of SNIFR presenting with progressive loss of vision between January 1, 2017 and January 1, 2023. Evaluation of ophthalmologic findings and multimodal ocular imaging at the time of diagnosis, surgical procedure, and of visual and anatomic outcomes postoperatively. The main outcome measures evaluated include best corrected visual acuity (BCVA), central macular thickness (CMT), and findings on optical coherence tomography (OCT).\u003c/p\u003e\u003cp\u003e\u003cb\u003eResults\u003c/b\u003e\u003c/p\u003e\u003cp\u003eSeven patients diagnosed with SNIFR were included. Median age in years at the time of diagnosis was 64 (range, 46\u0026ndash;77). Four patients were female, and three were male. Genetic testing for mutations in retinoschisin 1 (RS1) and for other inherited conditions associated with foveomacular retinoschisis was negative. All patients demonstrated progressive retinoschisis, as well as worsening vision loss and metamorphopsia when managed conservatively. PPV was performed and revealed anomalously broad and dense adherence of the posterior hyaloid in all eyes. The internal limiting membrane (ILM) was peeled in all but one case. All eyes demonstrated postoperative resolution of retinoschisis and subretinal fluid, with corresponding improvements in both BCVA and subjective central visual distortion up to six months after surgery.\u003c/p\u003e\u003cp\u003e\u003cb\u003eConclusion\u003c/b\u003e\u003c/p\u003e\u003cp\u003ePPV is an effective surgical intervention resulting in anatomic resolution of retinoschisis and improved functional vision in eyes with progressive SNIFR.\u003c/p\u003e","manuscriptTitle":"Pars Plana Vitrectomy in Progressive Stellate Non-Hereditary Idiopathic Foveomacular Retinoschisis (SNIFR): Surgical Outcomes and Considerations for Pathophysiology","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-07-28 11:46:29","doi":"10.21203/rs.3.rs-7153161/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-09-24T20:57:13+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-07-30T12:05:33+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"206359071725047466614471089322488911321","date":"2025-07-25T08:31:51+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-07-23T12:31:17+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-07-23T02:11:13+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-07-19T03:36:42+00:00","index":"","fulltext":""},{"type":"submitted","content":"International Journal of Retina and Vitreous","date":"2025-07-18T02:33:14+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"international-journal-of-retina-and-vitreous","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"IJRV","sideBox":"Learn more about [International Journal of Retina and Vitreous](https://jneurodevdisorders.biomedcentral.com/)","snPcode":"40942","submissionUrl":"https://submission.nature.com/new-submission/40942/3","title":"International Journal of Retina and Vitreous","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"bd040dae-91cd-403a-aab3-83cef1da98bc","owner":[],"postedDate":"July 28th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2025-10-01T00:53:15+00:00","versionOfRecord":[],"versionCreatedAt":"2025-07-28 11:46:29","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7153161","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7153161","identity":"rs-7153161","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}