A transgenic mice model of retinopathy of cblG-type inherited disorder of one-carbon metabolism highlights epigenome-wide alterations related to cone photoreceptor cells development and retinal metabolism.

BACKGROUND: MTR gene encodes the cytoplasmic enzyme methionine synthase, which plays a pivotal role in the methionine cycle of one-carbon metabolism. This cycle holds a significant importance in generating S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH), the respective universal methyl donor and end-product of epigenetic transmethylation reactions. cblG type of inherited disorders of vitamin B12 metabolism due to mutations in MTR gene exhibits a wide spectrum of symptoms, including a retinopathy unresponsive to conventional therapies. METHODS: To unveil the underlying epigenetic pathological mechanisms, we conducted a comprehensive study of epigenomic-wide alterations of DNA methylation by NGS of bisulfited retinal DNA in an original murine model with conditional Mtr deletion in retinal tissue. Our focus was on postnatal day 21, a critical developmental juncture for ocular structure refinement and functional maturation. RESULTS: We observed delayed eye opening and impaired visual acuity and alterations in the one-carbon metabolomic profile, with a notable dramatic decline in SAM/SAH ratio predicted to impair DNA methylation. This metabolic disruption led to epigenome-wide changes in genes involved in eye development, synaptic plasticity, and retinoid metabolism, including promoter hypermethylation of Rarα, a regulator of Lrat expression. Consistently, we observed a decline in cone photoreceptor cells and reduced expression of Lrat, Rpe65, and Rdh5, three pivotal genes of eye retinoid metabolism. CONCLUSION: We introduced an original in vivo model for studying cblG retinopathy, which highlighted the pivotal role of altered DNA methylation in eye development, cone differentiation, and retinoid metabolism. This model can be used for preclinical studies of novel therapeutic targets.

Intravitreal Injection of Bevacizumab for the Prevention of Postoperative Proliferative Vitreoretinopathy in High-Risk Patients Selected by Laser Flare Photometry.

INTRODUCTION: To evaluate the effect of an intravitreal injection of bevacizumab at the time of rhegmatogenous retinal detachment (RRD) surgery, on postoperative proliferative vitreoretinopathy (PVR) in high-risk patients selected by laser flare photometry. METHODS: This single-center observational retrospective cohort study included 137 consecutive patients who underwent pars plana vitrectomy and gas tamponade for primary RRD with increased aqueous flare between July 2016 and June 2021. From June 2019, an intravitreal injection of bevacizumab was administered as an adjunct to RRD repair. Patients who underwent surgery before this time and who did not receive intravitreal bevacizumab served as controls. The main outcome was the rate of retinal redetachment due to PVR. RESULTS: The median flare value was 22.0 (16.5-36.5) pc/ms in the control group and 28.2 (19.7-41.0) pc/ms in the bevacizumab group (p = 0.063). Eyes treated with bevacizumab were more likely to have macula-off RRD (p = 0.003), grade B PVR (p = 0.038), and worse visual acuity (p = 0.004) than controls. The rate of PVR redetachment was significantly lower in the bevacizumab group (11.1%) than in the control (30.1%) (p = 0.012). This difference was more pronounced after adjusting for potential confounding factors (p = 0.005); the risk of developing PVR was 4.5-fold higher in controls (95% CI, 1.6-12.8). After adjustment, the final median visual acuity was also significantly higher in eyes treated with bevacizumab (p = 0.025). CONCLUSION: This pilot study provides preliminary evidence that bevacizumab may reduce the risk of PVR-related recurrent RRD and improve visual outcomes in high-risk patients selected by laser flare photometry.

Surgery, Tissue Plasminogen Activator, Antiangiogenic Agents, and Age-Related Macular Degeneration Study: A Randomized Controlled Trial for Submacular Hemorrhage Secondary to Age-Related Macular Degeneration.

PURPOSE: To compare the efficacy and the safety of submacular hemorrhage (SMH) management using either surgical pars plana vitrectomy (PPV) or pneumatic displacement (PD) with tissue plasminogen activator (tPA) and vascular endothelial growth factor (VEGF) inhibitor added to each arm. DESIGN: Randomized, open-label, multicenter superiority study. PARTICIPANTS: Ninety patients with neovascular age-related macular degeneration (nAMD) 50 years of age or older with recent SMH (≤ 14 days) of more than 2 optic disc areas and predominantly overlying the retinal pigment epithelium. METHODS: Patients were assigned randomly to surgery (PPV, subretinal tPA [maximum, 0.5 ml/50 µg], and 20% sulfur hexafluoride [SF6] tamponade) or PD (0.05 ml intravitreal tPA [50 µg] and 0.3 ml intravitreal pure SF6). Both groups were asked to maintain a head upright position with the face forward at 45° for 3 days after intervention and received 0.5 mg intravitreal ranibizumab at the end of the intervention, at months 1 and 2, as the loading phase, and then on a pro re nata regimen during a 6-month follow-up. MAIN OUTCOME MEASURES: The primary efficacy endpoint was mean best-corrected visual acuity (VA) change at month 3. The secondary endpoints were mean VA change at month 6, 25-item National Eye Institute Visual Function Questionnaire composite score value at months 3 and 6, number of anti-VEGF injections, and complications during the 6-month follow-up. RESULTS: Of the 90 patients randomized, 78 patients (86.7%) completed the 3-month efficacy endpoint visit. The mean VA change from baseline to month 3 in the surgery group (+16.8 letters [95% confidence interval (CI), 8.7-24.9 letters]) was not significantly superior to that in the PD group (+16.4 letters [95% CI, 7.1-25.7 letters]; adjusted difference ß, 1.9 [-11.0; 14.9]; P = 0.767). Both groups achieved similar secondary outcomes at month 6. No unexpected ocular safety concerns were observed in either group. CONCLUSIONS: Surgery did not yield superior visual gain nor additional benefit for SMH secondary to nAMD compared with PD at 3 months, with intravitreal anti-VEGF added to each arm. Both treatment strategies lead to a clinical improvement of VA without safety concerns for SMH over 6 months. Both design and results of the trial cannot be used to establish equivalence between treatments. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Dissociated Optic Nerve Fiber Layer Appearance after Macular Hole Surgery: A Randomized Controlled Trial Comparing the Temporal Inverted Internal Limiting Membrane Flap Technique with Conventional Peeling.

PURPOSE: To evaluate the effect of the temporal inverted internal limiting membrane (ILM) flap technique compared with that of conventional ILM peeling on the extent of the dissociated optic nerve fiber layer (DONFL) and retinal sensitivity in patients undergoing macular hole (MH) surgery. DESIGN: Single-center, prospective, open-label, randomized controlled clinical trial. PARTICIPANTS: Patients requiring vitrectomy for MHs sized > 250 µm. METHODS: Patients were randomly assigned (1:1) to 1 of the following 2 groups: (1) the control group undergoing standard ILM peeling and (2) the experimental group (flap group) undergoing the temporal inverted ILM flap technique. MAIN OUTCOME MEASURES: The primary outcome measure was the total DONFL score at 3 months after surgery. Important secondary outcomes were microperimetry results, primary MH closure rate, external limiting membrane (ELM) and ellipsoid zone (EZ) recovery rates, and best-corrected visual acuity (BCVA). RESULTS: Sixty-five patients were recruited between February 2018 and July 2020; primary outcome data were available for 60 patients. The median DONFL score was 7.0 (3.0-12.5) in the control group and 5.0 (1.5-8.5) in the flap group at 3 months after surgery (P = 0.145). The focal depressions characteristic of the DONFL were limited to the temporal side of the fovea in the flap group, whereas they were found all around the fovea in the control group on spectral-domain OCT images. The MH closure rate (P = 1), EZ and ELM recovery rates (P = 0.252), and BCVA (P = 0.450) were similar between the 2 groups. The 3-month overall median retinal sensitivity (MRS) (P = 0.142) and MRS improvement (P = 0.916) in the control group were comparable with those observed in the flap group. In addition, there was no significant difference between the 2 techniques when considering the temporal area (P = 0.105) or the nasal area (P = 0.468). CONCLUSIONS: The temporal inverted ILM flap technique reduced the extent of the DONFL by preserving the nasal part of the fovea. However, the overall DONFL score was similar between the 2 techniques. In addition, the MRS and BCVA did not differ from those obtained after complete ILM peeling. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Efficacy of the DRL orthokeratology lens in slowing axial elongation in French children.

Background: This study aims to assess and compare the impact of Orthokeratology Double Reservoir Lens (DRL) versus Single Vision Lenses (SVL) on axial elongation and anterior chamber biometric parameters in myopic children over a 6- and 12-month treatment period in France. Methods: A retrospective study involving 48 patients aged 7 to 17 years, who underwent either orthokeratology treatment or single-vision spectacle correction, was conducted. Changes in refractive error, axial length, and anterior chamber depth were examined. Results: Twenty-five patients comprised the Orthokeratology (OK) group, while twenty-three were in the control group (single-vision spectacle group). Significant increases in mean axial length were observed over time in both the control (0.12 ± 0.13 mm and 0.20 ± 0.17 mm after 6 and 12 months, respectively; F (2,28.9) = 27.68, p < 0.001) and OK groups (0.02 ± 0.07 mm and 0.06 ± 0.13 mm after 6 and 12 months, respectively; F (2,29.1) = 5.30, p = 0.023). No statistically significant differences in axial length were found between male and female children (p > 0.620). Age-specific analysis revealed no significant axial elongation after 12 months in the 14-17 years group in the OK group. Anterior biometric data analysis at 6 and 12 months showed statistical significance only for the DRL group. Conclusion: Orthokeratology resulted in an 86 and 70% reduction in axial elongation after 6 and 12 months of lens wear, respectively, compared to the single-vision spectacles group. Myopia progression was more pronounced in younger children, underscoring the importance of initiating myopia control strategies at early ages.

Bipolar disorders and retinal electrophysiological markers (BiMAR): Study protocol for a comparison of electroretinogram measurements between subjects with bipolar disorder and a healthy control group.

Background: Bipolar disorders (BD) is a common, chronic and disabling psychiatric condition. In addition to being characterized by significant clinical heterogeneity, notable disturbances of sleep and cognitive function are frequently observed in all phases of the disease. Currently, there is no readily available biomarker in current clinical practice to help diagnose or predict the disease course. Thus, identification of biomarkers in BD is today a major challenge. In this context, the study of electrophysiological biomarkers based on electroretinogram (ERG) measurements in BD seems highly promising. The BiMAR study aims to compare electrophysiological data measured with ERG between a group of euthymic patients with BD and a group of healthy control subjects. Secondarily, we will also describe the existing potential relationship between clinical, sleep and neuropsychological phenotypes of patients and electrophysiological data. Methods: The BiMAR study is a comparative and monocentric study carried out at the Expert Center for BD in Nancy, France. In total, 70 euthymic adult patients with BD and 70 healthy control subjects will be recruited. Electrophysiological recordings with ERG and electroencephalogram (EEG) will be performed with a virtual reality headset after a standardized clinical evaluation to all participants. Then, an actigraphic monitoring of 21 consecutive days will be carried out. At the end of this period a neuropsychological evaluation will be performed during a second visit. The primary outcome will be electrophysiological measurements with ERG flash and pattern. Secondary outcomes will be EEG data, sleep settings, clinical and neuropsychological assessments. For patients only, a complementary ancillary study, carried out at the University Hospital of Nancy, will be proposed to assess the retinal structure and microvascularization using Optical Coherence Tomography. Recruitment started in January 2022 and will continue until the end of July 2023. Discussion: The BiMAR study will contribute to identifying candidate ERG electrophysiological markers for helping the diagnosis of BD and identify subgroups of patients with different clinical profiles. Eventually, this would allow earlier diagnosis and personalized therapeutic interventions. Clinical trial registration: The study is registered at Clinicaltrials.gov, NCT05161546, on 17 December 2021 (https://clinicaltrials.gov/ct2/show/NCT05161546).

Visual electrophysiology and neuropsychology in bipolar disorders: A review on current state and perspectives.

Bipolar disorder is a lifelong condition. Today, there is a urgent need to find indicators of the disease. Specifically, they could be useful to improve the diagnosis and the early detection, the prognosis, to estimate the treatment response and to create homogeneous subgroups of patients based on similar pathophysiological mechanisms. Here, we assume that visual electrophysiology in combination with a neuropsychological assessment can give additional data to routine practice, especially to precise specific damages and pathophysiological characteristics of these patients. Visual electrophysiology is characterized by an electroretinogram and the delivery of visual evoked potentials, which measure retinal and visual cortical neuronal functioning in response to visual stimulations. This review highlights the interest of visual electrophysiology and neuropsychology performed in isolation and to present the benefits of combining these measures. We will review the results based on these measures in patients with bipolar disorders. Finally, we argue for the use of innovative techniques such as signal processing and artificial intelligence techniques for routine care and precision medicine in bipolar disorders.

Association of Microvasculature Changes with Visual Outcomes after Successful Retinal Detachment Surgery.

PURPOSE: To evaluate macular microvascular changes and their correlation with visual outcomes after rhegmatogenous retinal detachment (RRD) surgery. DESIGN: Retrospective case series. PARTICIPANTS: The study included 74 eyes successfully operated for RRD. METHODS: The foveal avascular zone area in the superficial capillary plexus, the vessel density (VD) in the superficial capillary plexus, vessel density deep capillary plexus (VD DCP), and choriocapillary plexus were evaluated using octangiography at 1 and 6 months postoperatively. The fellow eyes were used as controls for comparison. MAIN OUTCOME MEASURES: The correlation between octangiography parameters and postoperative best-corrected visual acuity (BCVA) was assessed using a hybrid linear mixed model. We also analyzed the relationship between octangiography parameters and the integrity of the external limiting membrane (ELM) and ellipsoid zone (EZ) of photoreceptors. RESULTS: The median VD DCP was significantly decreased in RRD eyes at 1 month (P = 0.019), but gradually improved over time to reach the value of the fellow eyes at 6 months (P = 1). There was no significant difference between the 2 groups in median foveal avascular zone area, superficial capillary plexus, and choriocapillary plexus (P = 0.579, P = 0.618, P = 0.068 and P = 0.819, P = 1, and P = 1, respectively) at both 1 and 6 months postoperatively. Postoperative BCVA was positively correlated with VD DCP (P = 0.009) in multivariate analysis. Eyes with low 1-month VD DCP tended to have worse final BCVA (P = 0.067). There was no correlation between VD DCP and ELM and/or EZ integrity at both 1 (P = 0.156) and 6 months postoperatively (P = 0.161). Eyes with intact ELM and EZ at 6 months, however, had significantly higher 1-month VD DCP than those with disrupted ELM and/or EZ (P = 0.027). CONCLUSION: The VD DCP was affected in RRD eyes as well as strongly associated with postoperative BCVA and the restoration of photoreceptor layers. It might thus serve as a predictor for visual recovery following successful RRD surgery.

Hypoxia Inhibits Subretinal Inflammation Resolution Thrombospondin-1 Dependently.

Hypoxia is potentially one of the essential triggers in the pathogenesis of wet age-related macular degeneration (wetAMD), characterized by choroidal neovascularization (CNV) which is driven by the accumulation of subretinal mononuclear phagocytes (MP) that include monocyte-derived cells. Here we show that systemic hypoxia (10% O2) increased subretinal MP infiltration and inhibited inflammation resolution after laser-induced subretinal injury in vivo. Accordingly, hypoxic (2% O2) human monocytes (Mo) resisted elimination by RPE cells in co-culture. In Mos from hypoxic mice, Thrombospondin 1 mRNA (Thbs1) was most downregulated compared to normoxic animals and hypoxia repressed Thbs-1 expression in human monocytes in vitro. Hypoxic ambient air inhibited MP clearance during the resolution phase of laser-injury in wildtype animals, but had no effect on the exaggerated subretinal MP infiltration observed in normoxic Thbs1-/--mice. Recombinant Thrombospondin 1 protein (TSP-1) completely reversed the pathogenic effect of hypoxia in Thbs1-/--mice, and accelerated inflammation resolution and inhibited CNV in wildtype mice. Together, our results demonstrate that systemic hypoxia disturbs TSP-1-dependent subretinal immune suppression and promotes pathogenic subretinal inflammation and can be therapeutically countered by local recombinant TSP-1.

Prevalence and predictive factors for posterior vitreous attachment in eyes undergoing epiretinal membrane surgery.

BACKGROUND: To report the prevalence of posterior vitreous attachment (PVA) in patients with idiopathic epiretinal membrane (iERM) and to determine associated preoperative predictive factors. METHODS: Retrospective observational case series of 408 eyes who underwent surgery for iERM without vitreomacular traction. The status of the posterior hyaloid was assessed intraoperatively. Predictive factors were analysed using univariate and multivariate logistic regression. We also evaluated the effect of PVA on the anatomical and functional outcomes of surgery. RESULTS: Eighty-two (20.1%) eyes were found to have an undetached posterior hyaloid during vitrectomy. In multivariate analysis, axial length (AL) and lens status were strongly associated with the posterior vitreous status (p = 0.031 and p = 0.048). The odds of having a PVA decreased by a factor 0.81 per mm of AL (95% CI, 0.66-1.00). Phakic eyes had a 2.88-fold increased risk of exhibiting PVA compared to those with previous cataract extraction (95% CI, 1.10-7.52). The presence of PVA did not have any effect on postoperative anatomical and functional outcomes. In contrast, we found that eyes with shorter axial length, low preoperative visual acuity and disruption of the ellipsoid zone exhibited worse visual recovery (p = 0.006, p < 0.001 and p = 0.037). CONCLUSION: PVA was observed in 20.1% of eyes undergoing vitrectomy for iERM. Shorter AL and phakic status were strong predictive factors of PVA in those eyes. However, the morphological features and the surgical prognosis of iERMs with PVA did not differ from those with posterior vitreous detachment.

Ocular manifestations in patients with inborn errors of intracellular cobalamin metabolism: a systematic review.

Inherited disorders of cobalamin (cbl) metabolism (cblA-J) result in accumulation of methylmalonic acid (MMA) and/or homocystinuria (HCU). Clinical presentation includes ophthalmological manifestations related to retina, optic nerve and posterior visual alterations, mainly reported in cblC and sporadically in other cbl inborn errors.We searched MEDLINE EMBASE and Cochrane Library, and analyzed articles reporting ocular manifestations in cbl inborn errors. Out of 166 studies a total of 52 studies reporting 163 cbl and 24 mut cases were included. Ocular manifestations were found in all cbl defects except for cblB and cblD-MMA; cblC was the most frequent disorder affecting 137 (84.0%) patients. The c.271dupA was the most common pathogenic variant, accounting for 70/105 (66.7%) cases. One hundred and thirty-seven out of 154 (88.9%) patients presented with early-onset disease (0-12 months). Nystagmus and strabismus were observed in all groups with the exception of MMA patients while maculopathy and peripheral retinal degeneration were almost exclusively found in MMA-HCU patients. Optic nerve damage ranging from mild temporal disc pallor to complete atrophy was prevalent in MMA-HCU.and MMA groups. Nystagmus was frequent in early-onset patients. Retinal and macular degeneration worsened despite early treatment and stabilized systemic function in these patients. The functional prognosis remains poor with final visual acuity < 20/200 in 55.6% (25/45) of cases. In conclusion, the spectrum of eye disease in Cbl patients depends on metabolic severity and age of onset. The development of visual manifestations over time despite early metabolic treatment point out the need for specific innovative therapies.

Effect of Duration of Silicone Oil Tamponade on Retinal Structure after Rhegmatogenous Retinal Detachment Surgery.

PURPOSE: The aim of the study was to investigate the effect of tamponade duration on retinal changes induced by silicone oil (SO) in patients who underwent successful rhegmatogenous retinal detachment (RRD) surgery. METHODS: Retrospective comparative case series of 68 patients who underwent SO tamponade for RRD. Patients were divided into 2 groups based on timing of SO removal: <6 months (group 1, n = 34) versus ≥6 months (group 2, n = 34). The main outcome measure was the change in central macular, inner, and outer retinal layer thickness (CMT, IRLT, and ORLT) before and after SO removal (SOR). RESULTS: The median tamponade duration was 4 [Clin Ophthalmol. 2016;10:471-6, Zhonghua Yan Ke Za Zhi. 1997 Jan;33(1):39-41] months in group 1 and 8 [Arch Ophthalmol. 1994 Jun;112(6):778-85, Retina. 2004 Dec;24(6):871-7] months in group 2 (p < 0.001). The mean CMT significantly increased from 245.3 ± 22.2 µm and 238.8 ± 41.6 µm under SO to 281.3 ± 60.2 µm and 259.0 ± 43.5 µm after SOR in group 1 (p = 0.009) and in group 2 (p = 0.007), respectively. Automated segmentation measurement revealed a significant increase in mean IRLT (p = 0.014 and p = 0.013) but no change in mean ORLT (p = 0.080 and p = 0.257) in both groups. After adjustment, there was no difference between the 2 groups in terms of mean final CMT, IRLT, and ORLT and mean retinal thickness changes after SOR. There was also no correlation between the tamponade duration and macular microstructural changes or visual recovery. CONCLUSION: SO tamponade causes a thinning of all retinal layers, mainly affecting the inner retinal layer. However, these changes resolved following SO extraction and were not affected by longer tamponade duration.

Ophthalmologic manifestations in patients with antiphospholipid antibodies: Beware of iatrogenic complications.

BACKGROUND: Antiphospholipid syndrome (APS) is characterized by several clinical manifestations such as venous and arterial thrombosis associated with persistent antiphospholipid antibodies (aPL). Several studies confirmed that retinal vein occlusion was the most common APS ocular manifestation. The purpose of this study was to identify ophthalmologic manifestations in a homogeneous cohort of well-defined persistently aPL-positive patients and to determine variables associated with these manifestations. METHODS: APL-positive patients were selected from two research programs. All ophthalmologic manifestations including those related to APS were recorded. RESULTS: A total of 117 patients were included and 10 of them had APS-related ophthalmologic manifestations (glaucoma, hydroxychloroquine-related maculopathy, anterior acute uveitis, anterior ischemic optic neuropathy). Systemic Lupus Erythematosus (SLE) (OR = 3.4[95%CI; 0.9-12.7), corticosteroids (OR = 9.0 [95%CI; 2.2-37.7]) and aPL-related nephropathy (OR = 7.1 [95%CI; 1.7-30.0]) were significatively associated with the risk of APS-related ophthalmologic manifestations. CONCLUSION: Most of ocular manifestations in this study were iatrogenic related to corticosteroids or hydroxychloroquine. Patients with SLE, small vessel thrombosis in general, or with aPL-related nephropathy in particular, seemed at higher risk to develop APS-related ophthalmologic manifestations thus deserving adequate monitoring.

[Behçet's disease : Description and analysis of a French single-center retrospective study of 51 patients]. / Maladie de Behçet : description et analyse d'une série rétrospective monocentrique française de 51 patients.

PURPOSE: To evaluate if the presence of uveitis in Behçet's disease (BD) is associated with a particular clinical phenotype and to analyze the prognostic impact of a missed diagnosis of BD at the time the uveitis is diagnosed. MATERIEL AND METHODS: Ophthalmologic and systemic clinical features of 51 patients with BD were recorded retrospectively. We compared the clinical phenotype of patients with ocular manifestations with those without ocular manifestations. The patients were divided into two groups depending on the progression of their visual acuity: "decreased visual acuity" versus "stable or improved visual acuity." RESULTS: In the group of patients with ocular involvement, there was a mean 2.3 systemic manifestations, vs. 3.2 in the group without ocular manifestations (P=0.004). When BD was diagnosed prior to the onset of uveitis, we counted fewer patients in the "decreased visual acuity" group in comparison with the patients who had no prior diagnosis of BD at the onset of the uveitis (91.3% in the "decreased visual acuity" group, P=0.04). The time before initiation of immunosuppressive treatment or a biological agent was shorter for these patients (4.4 vs. 39.3 months, P=0.007). CONCLUSION: It appears that different phenotypes exist according to whether or not the BD patient has ocular involvement. Moreover, the visual prognosis is better if the uveitis occurs in patients who have already been diagnosed with BD, due to earlier initiation of immunosuppressive therapy.

OUTCOMES OF COMBINED PHACOEMULSIFICATION AND PARS PLANA VITRECTOMY FOR RHEGMATOGENOUS RETINAL DETACHMENT: A Comparative Study.

PURPOSE: To evaluate and to compare the anatomical and functional results of phacovitrectomy and pars plana vitrectomy (PPV) alone for phakic rhegmatogenous retinal detachment. METHODS: Retrospective, comparative case series of 266 phakic eyes that underwent either combined phacovitrectomy or PPV alone for primary retinal detachment. The primary anatomical success rate, the final best-corrected visual acuity, and the refractive outcomes were analyzed. RESULTS: One hundred and twenty-seven eyes were included in the combined group and 139 in the PPV group. The primary anatomical success rate was 84.3% in the combined group and 89.2% in the PPV group (P = 0.311). One hundred and nine (78.4%) eyes of the PPV group required cataract removal for visual rehabilitation during the follow-up period. There was no significant difference between the two groups in terms of the mean final best-corrected visual acuity (P = 0.185) and mean visual changes (P = 0.470). Overall, combined cataract extraction resulted in a significant myopic shift compared with delayed cataract surgery (P = 0.047). CONCLUSION: Combined phacoemulsification and PPV is a safe and effective procedure to treat retinal detachment. The anatomical and functional results were comparable with those obtained with PPV and delayed cataract surgery. However, the refractive outcomes were less favorable and shifted toward myopia, especially in macula-off cases.

EyeSi Surgical Simulator: validation of a proficiency-based test for assessment of vitreoretinal surgical skills.

PURPOSE: To develop and investigate an evidence-based performance test for assessment of vitreoretinal surgical skills on the EyeSi Surgical Simulator. METHODS: Ten junior residents without any surgical experience, eight senior residents with prior experience in cataract surgery and five vitreoretinal surgeons were included in the study. The test consisted of seven modules and was completed twice by all groups during a single session. Validity evidence was evaluated using Messick's validity framework. Senior residents completed four additional test sessions and were retested 3 months after to assess skill acquisition and retention. RESULTS: Content was aligned with vitreoretinal surgical skills as evaluated by expert surgeons. Response process was ensured through standardized instruction and data collection. The test showed satisfactory internal consistency with Cronbach's α = 0.76 (internal structure) and significant discriminative ability between the residents and the experienced surgeons (relation to other variables). A pass/fail level was determined at 596 using the contrasting groups' method. Consequences of applying this standard resulted in no false positive and no false negative. Senior residents significantly improved their simulator skills over time, reaching a plateau at the fifth iteration and equalling expert performance (p = 0.420). This level of competency was retained during the post-3-month retention testing (p = 0.062). CONCLUSION: We established a performance test with solid evidence for assessment of vitreoretinal surgical skills on the EyeSi Simulator and determined a benchmark criterion that may be used for future implementation of proficiency-based training for novices.

Insulin inhibits inflammation-induced cone death in retinal detachment.

BACKGROUND: Rhegmatogenous retinal detachment (RD) involving the macula is a major cause of visual impairment despite high surgical success rate, mainly because of cone death. RD causes the infiltration of activated immune cells, but it is not clear whether and how infiltrating inflammatory cells contribute to cone cell loss. METHODS: Vitreous samples from patients with RD and from control patients with macular hole were analyzed to characterize the inflammatory response to RD. A mouse model of RD and retinal explants culture were then used to explore the mechanisms leading to cone death. RESULTS: Analysis of vitreous samples confirms that RD induces a marked inflammatory response with increased cytokine and chemokine expression in humans, which is closely mimicked by experimental murine RD. In this model, we corroborate that myeloid cells and T-lymphocytes contribute to cone loss, as the inhibition of their accumulation by Thrombospondin 1 (TSP1) increased cone survival. Using monocyte/retinal co-cultures and TSP1 treatment in RD, we demonstrate that immune cell infiltration downregulates rod-derived cone viability factor (RdCVF), which physiologically regulates glucose uptake in cones. Insulin and the insulin sensitizers rosiglitazone and metformin prevent in part the RD-induced cone loss in vivo, despite the persistence of inflammation CONCLUSION: Our results describe a new mechanism by which inflammation induces cone death in RD, likely through cone starvation due to the downregulation of RdCVF that could be reversed by insulin. Therapeutic inhibition of inflammation and stimulation of glucose availability in cones by insulin signaling might prevent RD-associated cone death until the RD can be surgically repaired and improve visual outcome after RD. TRIAL REGISTRATION: ClinicalTrials.gov NCT03318588.

The 10q26 Risk Haplotype of Age-Related Macular Degeneration Aggravates Subretinal Inflammation by Impairing Monocyte Elimination.

A minor haplotype of the 10q26 locus conveys the strongest genetic risk for age-related macular degeneration (AMD). Here, we examined the mechanisms underlying this susceptibility. We found that monocytes from homozygous carriers of the 10q26 AMD-risk haplotype expressed high amounts of the serine peptidase HTRA1, and HTRA1 located to mononuclear phagocytes (MPs) in eyes of non-carriers with AMD. HTRA1 induced the persistence of monocytes in the subretinal space and exacerbated pathogenic inflammation by hydrolyzing thrombospondin 1 (TSP1), which separated the two CD47-binding sites within TSP1 that are necessary for efficient CD47 activation. This HTRA1-induced inhibition of CD47 signaling induced the expression of pro-inflammatory osteopontin (OPN). OPN expression increased in early monocyte-derived macrophages in 10q26 risk carriers. In models of subretinal inflammation and AMD, OPN deletion or pharmacological inhibition reversed HTRA1-induced pathogenic MP persistence. Our findings argue for the therapeutic potential of CD47 agonists and OPN inhibitors for the treatment of AMD.

Prevalence and risk factors for outer retinal layer damage after macula-off retinal detachment.

PURPOSE: To report the prevalence of outer retinal layer (ORL) damage after macula-off rhegmatogenous retinal detachment (RRD) surgery and to determine its associated preoperative risk factors. METHODS: 253 eyes successfully operated for macula-off RRD were included in the study. The integrity of the external limiting membrane (ELM), ellipsoid zone (EZ) and cone interdigitation zone (CIZ) of the photoreceptors was assessed at 1 month and 6 months using spectral-domain optical coherence tomography. Risk factors were analysed using univariate and multivariate logistic regression. The correlation between ORL integrity and visual outcomes was also evaluated. RESULTS: CIZ, EZ and ELM defects were found in, respectively, 198 (93.4%) eyes, 100 (47.2%) eyes, 64 (30.2%) eyes at 1 month and in 160 (63.2%) eyes, 44 (17.4%) eyes and 18 (7.1%) eyes at 6 months. In multivariate analysis, duration of macular detachment was the only factor associated with ORL damage at 6 months (p=0.007). Best-corrected visual acuity significantly improved from 0.5±0.3 at 1 month to 0.3±0.3 logarithm of minimal angle of resolution at 6 months (p<0.001) and was strongly correlated with the number of affected bands (p<0.001). CONCLUSION: Prevalence of outer retinal band defects substantially decreased through the study period, confirming the ability of photoreceptors to recover over time. However, shorter interval to surgery and better visual outcomes were significantly associated with fewer defects within the ORL at 6 months. These findings suggest that earlier surgery may limit RRD-associated photoreceptor degeneration and improve the patient's visual prognosis.