X-Linked Retinoschisis: Deep Phenotyping and Genetic Characterization.

PURPOSE: To examine the genetic and clinical features in children and adults with X-linked retinoschisis (XLRS). DESIGN: Single-center consecutive, retrospective, observational study. PARTICIPANTS: Adults and children with molecularly confirmed XLRS followed up between 1999 and 2020. METHODS: Analysis of genetic, clinical, and retinal imaging findings, including OCT and fundus autofluorescence (FAF), cross-sectionally and longitudinally, was performed. MAIN OUTCOMES MEASURES: RS1, variants, type of variants and phenotype correlations, age of onset, complications rates and types, fundoscopy findings, OCT metrics, FAF patterns, correlations including between best corrected visual acuity (BCVA) and age, and OCT characteristics. RESULTS: One hundred thirty-two male patients were identified harboring 66 retinoschisin 1 variants, with 7 being novel. The mean age at onset was 16.5 years (range, 0-58 years). Seventy-one patients (71/75 [94.7%]) were symptomatic at presentation; all had decreased best-corrected visual acuity (BCVA). Funduscopy findings were symmetric in 104 patients (104/108 [96.3%]), with the most common finding being macular schisis (82.4%), whereas peripheral retinoschisis was present in 38.9% and macular atrophy was present in 11.1%. Twenty patients (18.5%) demonstrated complications (vitreous hemorrhage, retinal detachment, or both). Mean BCVA was 0.65 logarithm of the minimum angle of resolution (logMAR; Snellen equivalent, 20/89) in the right eye and 0.64 logMAR (Snellen equivalent, 20/87) in the left eye. Mean BCVA change over a mean interval of 6.7 years was 0.04 and 0.01 logMAR for right and left eyes, respectively. A normal FAF pattern was identified in 16 of 106 eyes (15.1%); 45 eyes (42.5%) showed a spoke-wheel pattern, 13 eyes (12.3%) showed foveal hyperautofluorescence, and 18 eyes (17.0%) showed a central reduction in signal. In total, 14 patients demonstrated evidence of progression on FAF over time. On OCT, foveoschisis was observed in 172 eyes (172/215 [80%]), parafoveal schisis was observed in 171 eyes (171/215 [79.5%]), and foveal atrophy was observed in 44 eyes (44/215 [20.5%]). Cystoid changes were localized to the inner nuclear layer (172/181 eyes [95%]), the outer nuclear layer (97/181 [53.6%]), and the ganglion cell layer (92/181 [50.8%]). Null variants were associated with worse final BCVA and aforementioned complications. CONCLUSIONS: X-linked retinoschisis is highly phenotypically variable, but with relative foveal and BCVA preservation until late adulthood, allowing more accurate prognostication. The slowly (often minimally) progressive disease course may pose a challenge in identification of early end points for therapeutic trials aimed at altering the kinetics of degeneration.

HUMAN AMNIOTIC MEMBRANE TO TREAT MACULAR HOLES THAT FAILED TO CLOSE, SULFUR HEXAFLUORIDE ENDOTAMPONADE VERSUS AIR ENDOTAMPONADE: A Prospective Comparative Study.

BACKGROUND/PURPOSE: To determinate the efficacy of the human amniotic membrane plugs with sulfur hexafluoride versus human amniotic membrane plug with air as endotamponade to treat macular holes that failed to close after vitrectomy plus internal limiting membrane peeling. Multimodal imaging was focused to evaluate preoperative features and postoperative changes. METHODS: Prospective interventional comparative study. Twenty eyes of 20 patients affected with macular hole that failed to close were divided into 2 groups: 10 eyes received an amniotic membrane plug with 20% sulfur hexafluoride tamponade and 10 eyes received an amniotic membrane plug with air tamponade. All eyes were studied using multimodal advanced diagnostic tools, such as spectral-domain optical coherence tomography, optical coherence tomography angiography, microperimetry, and adaptive optics to investigate the postoperative results. RESULTS: In both groups, all macular holes were found successfully closed after 12 months. Mean preoperative best-corrected visual acuity was 20/400 in the SF6 group and 20/250 in air group. Final mean best-corrected visual acuity was 20/63 in both groups. The superficial capillary plexus, studied using optical coherence tomography angiography, showed a statistically significant difference between the treated and the fellow eyes. Adaptive optics images revealed the presence of a photoreceptor cell mosaic in the area of the amniotic membrane plug. CONCLUSION: The human amniotic membrane combined with air endotamponade demonstrated its effectiveness to seal macular holes that failed to close after vitrectomy plus internal limiting membrane peeling. Advanced multimodal diagnostic imaging helped us to better understand the modifications associated with the use of the amniotic membrane in these cases.

OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY FINDINGS BEFORE AND AFTER VITRECTOMY FOR MACULAR HOLES: Useful or Useless?

PURPOSE: To investigate the vascular remodeling of optical coherence tomography angiography in full-thickness macular hole surgery. METHODS: This retrospective, observational case series included 33 eyes of 33 patients with a full-thickness macular hole who underwent epiretinal membrane removal. Data were collected on best-corrected visual acuity, structural B-scan optical coherence tomography, and optical coherence tomography angiography preoperatively and at 1, 3, and 6 months postoperatively. Optical coherence tomography angiography was used to assess the retinal vascular density (VD) of the superficial vascular plexus and deep vascular plexus (DVP). Vascular density was assessed using the Early Treatment Diabetic Retinopathy Study grid for the whole, inner, and outer grids. RESULTS: A statistically significant correlation was found between the VD (whole, inner, and outer grids) of the superficial vascular plexus alone from baseline to 1-month postoperatively (P < 0.001). Similarly, VD was correlated from baseline to 1, 3, and 6 months postoperatively to the whole (P < 0.0005, F = 23.22), inner (P < 0.0005, F = 28.23), and outer Early Treatment Diabetic Retinopathy Study grids of DVP (P = 0.033, F = 3.49). The best-corrected visual acuity and VD were significantly correlated with the superficial vascular plexus and DVP at baseline and 6 months (P < 0.05, all correlations). The most significant correlation was observed at 6 months between best-corrected visual acuity and DVP in the whole, inner, and outer Early Treatment Diabetic Retinopathy Study grids (P < 0.001). CONCLUSION: Superficial vascular plexus and DVP are affected by full-thickness macular holes, with the most significant effects being on the DVP. Full-thickness macular hole surgery leads to an improvement in the best-corrected visual acuity in many eyes and the restoration of the VD, especially of the DVP.

ATTENUATION OUTER RETINAL BANDS ON OPTICAL COHERENCE TOMOGRAPHY FOLLOWING MACULAR EDEMA: A Possible Manifestation of Photoreceptor Misalignment.

PURPOSE: Macular edema is a common retinal disease which may leave important anatomical and functional sequelaes. Directional fundus imaging consists of comparing on- and off-axis images to reveal angle-dependent reflectance properties of fundus structures, which may be related to misaligned photoreceptors. Here, we analyzed directional optical coherence tomography (OCT) and flood-illumination adaptive optics ophthalmoscopy images to detect evidence of misaligned photoreceptors following macular edema. METHODS: Transversal, observational study. Nine patients having recovered a normal macular profile after macular edema due to retinal vein occlusion were included. For each patient, a reference OCT scan (i.e., with the incident beam normal to the fovea) was acquired, and off-axis scans were then acquired by laterally shifting the entry pupil. In addition, in four of these eyes, directional adaptive optics ophthalmoscopy documented the directional variations of cone metrics. RESULTS: Included patients comprised two women and seven men (age range, 19-76 years). Reference OCT scans showed patchy attenuation of the cone outer segment tips and to a lesser extent of the inner segment/outer segment lines in all, but two eyes; these. Increased intensity of the cone outer segment tips and inner segment/outer segment lines could be observed on off-axis scans. Accordingly, fusion images showed 66% average reduction of the length of cone outer segment tips attenuation. In two cases, although reference scans showed continuity of outer bands, focal attenuation was evidenced in off-axis images. Directional adaptive optics ophthalmoscopy imaging showed a strong directional variability of cone counts in these areas, ranging from near absence to roughly two-third of reference values. In each case, directional variations of cone counts paralleled those of the reflectance of outer bands. CONCLUSION: After macular edema, focal attenuations of the inner segment/outer segment and of the cone outer segment tips lines may be present on OCT. These areas may show a strong directional variability by both OCT and adaptive optics ophthalmoscopy, suggesting that misaligned photoreceptor outer segments contribute to such features. The evaluation of outer retinal damage following macular edema should therefore take into account the optical Stiles-Crawford effect to disambiguate missing from misaligned cones.

IN VIVO OBSERVATION OF RETINAL VASCULAR DEPOSITS USING ADAPTIVE OPTICS IMAGING IN FABRY DISEASE.

PURPOSE: To report a novel finding in patients with Fabry disease, that is, the observation by adaptive optics ophthalmoscopy of intracellular lipidic deposits in retinal vessels. METHODS: Observational two-center case series. Eighteen patients with genetically proven Fabry disease underwent flood-illumination adaptive optics ophthalmoscopy imaging (rtx1; Imagine Eyes, Orsay, France) of retinal vessels. RESULTS: Fourteen patients (78% of all patients; 7 of the 10 women and 7 of the 8 men) showed paravascular punctuate or linear opacities in both eyes. In the least-affected patients, these were seen only in the wall of precapillary arterioles as discrete spots of 5 µm to 10 µm large, whereas in those more severely affected, capillaries and first-order vessels were also involved with diffuse opacification of the wall. These deposits sometime showed a striated pattern, suggesting colocalization with vascular smooth muscle cells. CONCLUSION: Adaptive optics ophthalmoscopy of retinal vessels may be of interest for patients with Fabry disease, providing noninvasive, gradable evaluation of microvascular involvement.

VITRECTOMY WITH INTERNAL LIMITING MEMBRANE PEELING AND AIR TAMPONADE FOR MYOPIC FOVEOSCHISIS.

PURPOSE: To evaluate the functional and anatomical outcomes of 23-gauge or 25-gauge pars plana vitrectomy with internal limiting membrane peeling and air tamponade for the treatment of myopic foveoschisis. METHODS: Retrospective, noncomparative, interventional case series. The records of 29 patients (32 eyes), with myopic foveoschisis who were treated by 23-gauge or 25-gauge 3-port pars plana vitrectomy with internal limiting membrane peeling and air tamponade, were reviewed. At each visit, a complete ophthalmic examination, intraocular pressure, best-corrected visual acuity, and central foveal thickness measured using optical coherence tomography were assessed. RESULTS: Twenty-five eyes of 23 patients (M:F = 4:19) matched the inclusion criteria, whereas 7 eyes of 6 patients were excluded. The mean logarithm of the minimum angle of resolution best-corrected visual acuity (Snellen equivalent) was 0.62 (20/80) (SE: 0.061), and the mean preoperative central foveal thickness was 619.5 µm (SE: 16.38) at baseline. Visual acuity significantly improved of 5 Early Treatment Diabetic Retinopathy Study letters (45 letters) at the 1-month follow-up (P < 0.001), 2 lines (50 Early Treatment Diabetic Retinopathy Study letters) at the 6-month follow-up (P < 0.001), and it reached 55 Early Treatment Diabetic Retinopathy Study letters at the 1-year follow-up visit (P < 0.001). Central foveal thickness decreased to 292.4 µm (SE: 15.93), to 227.3 µm (SE: 14.05), and to 208.8 µm (SE: 12.86), respectively, at the 1-, 6-, and 12-month follow-ups (for each P < 0.001). There were no differences in best-corrected visual acuity or central foveal thickness changes between the foveal detachment group and the nonfoveal detachment group (P > 0.05). CONCLUSION: Small-gauge vitrectomy with internal limiting membrane peeling and air tamponade results in favorable anatomical and functional outcomes for patients affected by myopic macular foveoschisis.

Long-Term Follow-Up of Choroidal Neovascularization due to Angioid Streaks with pro re nata Intravitreal Anti-VEGF Treatment.

PURPOSE: To evaluate the long-term outcomes of intravitreal anti-vascular endothelial growth factor (VEGF) drugs with a pro re nata (PRN) regimen for the treatment of choroidal neovascularization (CNV) secondary to angioid streaks (AS). METHODS: This is a retrospective, multicenter, noncomparative case series of consecutive AS eyes affected by treatment-naïve CNV. A complete ophthalmologic examination was performed every 30-45 days after the loading phase, including fluorescein angiography and/or optical coherence tomography. RESULTS: In all, 52 eyes of 39 patients were treated with intravitreal bevacizumab and/or ranibizumab and followed up for a mean of 33.8 months. The best corrected visual acuity at baseline was 20/40, and it deteriorated by an average of 6.8 ETDRS letters per year (p < 0.001). We performed an average of 5.1, 6.5, and 6.8 injections at the 1-, 2-, and 3-year follow-up, respectively. CONCLUSIONS: Intravitreal anti-VEGF drugs in a PRN regimen with close monitoring appear to slow the progression of CNV in AS, but they do not prevent the affected eyes from progressive visual loss.

Results of intravitreal ranibizumab with a prn regimen in the treatment of extrafoveal and juxtafoveal neovascular membranes in age-related macular degeneration.

PURPOSE: To evaluate the efficacy of intravitreal ranibizumab with a "pro re nata" regimen in the treatment of nonsubfoveal neovascular membranes secondary to age-related macular degeneration. METHODS: Retrospective noncomparative case series. Thirty-one eyes with naive nonsubfoveal neovascularization secondary to age-related macular degeneration were consecutively enrolled and treated with ranibizumab intravitreal injections according to a pro re nata regimen. The follow-up was performed monthly up to 6 months and quarterly up to 2 years (25 patients). Early treatment diabetic retinopathy study best-corrected visual acuity and lesion size analysis with fluorescein angiography were recorded. RESULTS: The mean baseline early treatment diabetic retinopathy study best-corrected visual acuity worsened from 20/40 (0.28 logMAR) at baseline to 20/50 (0.42 logMAR) at 1-year follow-up and 20/60 (0.53 logMAR) at 2-year follow-up. The mean lesions size nearly doubled from baseline at the 2-year follow up (1.19-2.47 mm). Twenty-two patients had one or more recurrences at 1-year follow-up. All 25 patients developed a recurrence at 2 years with 7 cases developing a recurrence by 12 months. Twelve cases progressed to subfoveal lesions by the 24-month visit. CONCLUSION: Other regimens described in the literature might result in a more the satisfactory outcome using more frequent follow-up and more frequent intravitreal injections.

Uveal melanoma: Recent advances in immunotherapy.

Uveal melanoma (UM) is the most common primary intraocular cancer in adults. The incidence in Europe and the United States is 6-7 per million population per year. Although most primary UMs can be successfully treated and locally controlled by irradiation therapy or local tumor resection, up to 50% of UM patients develop metastases that usually involve the liver and are fatal within 1 year. To date, chemotherapy and targeted treatments only obtain minimal responses in patients with metastatic UM, which is still characterized by poor prognosis. No standard therapeutic approaches for its prevention or treatment have been established. The application of immunotherapy agents, such as immune checkpoint inhibitors that are effective in cutaneous melanoma, has shown limited effects in the treatment of ocular disease. This is due to UM's distinct genetics, natural history, and complex interaction with the immune system. Unlike cutaneous melanomas characterized mainly by BRAF or NRAS mutations, UMs are usually triggered by a mutation in GNAQ or GNA11. As a result, more effective immunotherapeutic approaches, such as cancer vaccines, adoptive cell transfer, and other new molecules are currently being studied. In this review, we examine novel immunotherapeutic strategies in clinical and preclinical studies and highlight the latest insight in immunotherapy and the development of tailored treatment of UM.

Innovative Strategies for Drug Delivery to the Ocular Posterior Segment.

Innovative and new drug delivery systems (DDSs) have recently been developed to vehicle treatments and drugs to the ocular posterior segment and the retina. New formulations and technological developments, such as nanotechnology, novel matrices, and non-traditional treatment strategies, open new perspectives in this field. The aim of this mini-review is to highlight promising strategies reported in the current literature based on innovative routes to overcome the anatomical and physiological barriers of the vitreoretinal structures. The paper also describes the challenges in finding appropriate and pertinent treatments that provide safety and efficacy and the problems related to patient compliance, acceptability, effectiveness, and sustained drug delivery. The clinical application of these experimental approaches can help pave the way for standardizing the use of DDSs in developing enhanced treatment strategies and personalized therapeutic options for ocular pathologies.

Recent Advances of Adipose-Tissue-Derived Mesenchymal Stem Cell-Based Therapy for Retinal Diseases.

With the rapid development of stem cell research in modern times, stem cell-based therapy has opened a new era of tissue regeneration, becoming one of the most promising strategies for currently untreatable retinal diseases. Among the various sources of stem cells, adipose tissue-derived mesenchymal stem cells (ADSCs) have emerged as a promising therapeutic modality due to their characteristics and multiple functions, which include immunoregulation, anti-apoptosis of neurons, cytokine and growth factor secretion, and antioxidative activities. Studies have shown that ADSCs can facilitate the replacement of dying cells, promote tissue remodeling and regeneration, and support the survival and growth of retinal cells. Recent studies in this field have provided numerous experiments using different preclinical models. The aim of our review is to provide an overview of the therapeutic strategies, modern-day clinical trials, experimental models, and potential clinical use of this fascinating class of cells in addressing retinal disorders and diseases.

Recent Developments in Gene Therapy for Neovascular Age-Related Macular Degeneration: A Review.

Age-related macular degeneration (AMD) is a complex and multifactorial disease and a leading cause of irreversible blindness in the elderly population. The anti-vascular endothelial growth factor (anti-VEGF) therapy has revolutionized the management and prognosis of neovascular AMD (nAMD) and is currently the standard of care for this disease. However, patients are required to receive repeated injections, imposing substantial social and economic burdens. The implementation of gene therapy methods to achieve sustained delivery of various therapeutic proteins holds the promise of a single treatment that could ameliorate the treatment challenges associated with chronic intravitreal therapy, and potentially improve visual outcomes. Several early-phase trials are currently underway, evaluating the safety and efficacy of gene therapy for nAMD; however, areas of controversy persist, including the therapeutic target, route of administration, and potential safety issues. In this review, we assess the evolution of gene therapy for nAMD and summarize several preclinical and early-stage clinical trials, exploring challenges and future directions.

Optical Coherence Tomography-Based Choroidal Structural Analysis and Vascularity Index in Best Vitelliform Macular Dystrophy.

INTRODUCTION: This study investigated choroidal structural changes on optical coherence tomography (OCT) using choroidal vascularity index (CVI) and choroidal thickness (CT) in patients with Best vitelliform macular dystrophy (BVMD). METHODS: This retrospective case control study included 78 patients with BVMD of different clinical stages and 242 age- and gender-matched healthy controls. Subfoveal OCT scans were analysed. Total choroidal area (TCA), luminal area (LA) and CT were measured after image segmentation and binarization. CVI, a novel marker for choroidal angioarchitecture, was defined as the ratio of LA to TCA. CVI and CT were compared between BVMD and control group, as well as among the BVMD subgroups. RESULTS: Mean CVI was lower in eyes with BVMD (65.0 ± 3.5%) compared to that in control eyes (67.5 ± 3.9%) and this was statistically significant (p < 0.0001). There was no significant difference in subfoveal CT between BVMD (302.88 ± 81.68 µm) and control (309.31 ± 65.46 µm) eyes (p = 0.4799). In the subgroup analysis, all stages of BVMD showed lower CVI compared to control while SFCT remained similar. Within the BVMD subgroups, CVI and subfoveal CT did not differ significantly and both were not shown to be associated with visual acuity. CONCLUSION: Decreased CVI was shown in eyes with BVMD compared to control eyes, while no significant difference in subfoveal CT was seen. CVI may be helpful in the understanding of choroidal pathology in BVMD.

Adaptive Optics Imaging in Patients Affected by Pseudoxanthoma Elasticum.

PURPOSE: To describe the retinal findings of patients affected by pseudoxanthoma elasticum (PXE) using a multimodal imaging approach including flood-illumination adaptive optics ophthalmoscopy (AO). DESIGN: Retrospective case series. MATERIALS AND METHODS: Patients affected by PXE were retrospectively studied. Clinical data, color, infrared and autofluorescence fundus imaging, optical coherence tomographic scans, and AO examinations were collected. Furthermore, the photoreceptor count was assessed. PXE diagnosis was confirmed by a positive skin biopsy and/or genetic testing. RESULTS: Twenty-one eyes of 18 patients (11 females and 7 males) were included in the study. In 3 patients, both eyes were studied. The mean age at examination was 37.7 ± 16.4 years (range 14-66) and the mean best-corrected visual acuity (BCVA) was 0.1 ± 0.2 logMAR (range 0-1). We identified 3 types of angioid streaks (AS) using AO: "crack," "band," and "hypopigmented." The first 2 were very similar and they differed in size; the third type showed specific clinical features. Comet lesions appeared as hyper-reflective round lesions on AO imaging. In all eyes, the cone mosaic appeared reduced inside the streaks compared to the neighboring areas (13,532.8 ± 1,366.5 cones/mm2 vs 16,817.1 ± 1,263.0 cones/mm2 respectively). CONCLUSION: Using AO imaging in PXE-related retinopathy, we were able to observe the presence of the photoreceptors within the angioid streaks, differentiate 3 types of angioid streaks, based on size and reflective features, and identify the very small crystalline bodies not identifiable using other retinal imaging techniques.

Combining cataract surgery with 25-gauge high-speed pars plana vitrectomy: A prospective study.

PURPOSE: To compare visual outcome and postoperative complications of combined 25-gauge pars plana vitrectomy and phacoemulsification with vitrectomy alone surgery in patients with epiretinal membrane and macular hole. METHODS: A total of 110 eyes (73 eyes with epiretinal membrane and 37 eyes with macular hole) were enrolled in this prospective study. The eyes were divided into two groups: Group A included 55 eyes which underwent phacovitrectomy at the same time and Group B included 55 eyes which underwent vitrectomy alone. Follow-up visits were at 1, 3, and 6 months. RESULTS: The best-corrected visual acuity correlation by analysis of variance measurement showed statistically non-significant differences between the two groups (p = 0.32). The post hoc analysis from baseline, 1°, 2°, and 3° follow-ups was not statistically significant (p > 0.05). The most common postoperative complication was cystoid macular edema that has been detected in 11 patients (10%) (seven eyes in Group A and four eyes in Group B): 2 patients (1.8%) developed a chronic macular edema. Intraocular hypertension occurred in five eyes (4.5%) (three in Group A and two in Group B). Four eyes (3.6%) underwent another surgical procedure for a persistent macular hole (two in Group A and two in Group B). The intraocular lens repositioning was performed one day after surgery in three eyes (2.7%) (Group A). The mean preoperative visual acuity was not different between the two groups (p = 0.80). CONCLUSION: No significative differences between combined surgery and vitrectomy alone have been detected, in terms of postoperative complications and visual outcome.

The Role of OCT Angiography in the Assessment of Epiretinal Macular Membrane.

BACKGROUND: The aim of this observational study is to assess pre- and postoperative retinochoroidal vascular changes in patients undergoing epiretinal macular membrane (ERM) surgery by using optical coherence tomography angiography (OCTA). MATERIALS AND METHODS: 23 eyes affected by ERM and those which underwent phacovitrectomy associated with ERM peeling were enrolled. They were evaluated using structural OCT and OCTA before surgery and at 1, 3, and 6 months postoperatively. RESULTS: We found a statistically significant (p < 0.05) increase in the superficial capillary plexus vessel density (VD) from baseline to the 6-month follow-up. We observed a large increase in both the perfusion density (PD) and the VD of the deep capillary plexus between baseline and the 6-month follow-up (p < 0.001). A significant decrease in the VD and PD of the choriocapillaris (CC) from baseline to the 1st month and a significant increase in CC perfusion density at the 6-month follow-up compared to the preoperative value were revealed. The FAZ area and perimeter after surgery significantly increased during the follow-up (p < 0.001) at baseline retinal and choroidal plexi with a lower PD or VD correlated with worse visual acuity (p < 0.05 for all plexi). At baseline and at the 1-month follow-up, a significant correlation was found with the FAZ area and the FAZ perimeter: a smaller FAZ area or a smaller FAZ perimeter was correlated to a lower visual acuity. Before surgery, negative correlations (p < 0.05) were found between the Govetto ERM stages and perfusion density of the SCP and the DCP and between the Govetto stages and vessel density of the DCP. CONCLUSIONS: In our study, OCTA detected vascular alterations induced by the presence of the ERM, allowing several correlations with functional data. In these patients, OCTA may be useful to add new potential surgical prognostic factors.