Untargeted Multiomics Approach Coupling Lipidomics and Metabolomics Profiling Reveals New Insights in Diabetic Retinopathy.

Diabetic retinopathy (DR) is a microvascular complication of diabetes mellitus (DM) which is the main cause of vision loss in the working-age population. Currently known risk factors such as age, disease duration, and hemoglobin A1c lack sufficient efficiency to distinguish patients with early stages of DR. A total of 194 plasma samples were collected from patients with type 2 DM and DR (moderate to proliferative (PDR) or control (no or mild DR) matched for age, gender, diabetes duration, HbA1c, and hypertension. Untargeted lipidomic and metabolomic approaches were performed. Partial-least square methods were used to analyze the datasets. Levels of 69 metabolites and 85 lipid species were found to be significantly different in the plasma of DR patients versus controls. Metabolite set enrichment analysis indicated that pathways such as metabolism of branched-chain amino acids (methylglutaryl carnitine p = 0.004), the kynurenine pathway (tryptophan p < 0.001), and microbiota metabolism (p-Cresol sulfate p = 0.004) were among the most enriched deregulated pathways in the DR group. Moreover, Glucose-6-phosphate (p = 0.001) and N-methyl-glutamate (p < 0.001) were upregulated in DR. Subgroup analyses identified a specific signature associated with PDR, macular oedema, and DR associated with chronic kidney disease. Phosphatidylcholines (PCs) were dysregulated, with an increase of alkyl-PCs (PC O-42:5 p < 0.001) in DR, while non-ether PCs (PC 14:0-16:1, p < 0.001; PC 18:2-14:0, p < 0.001) were decreased in the DR group. Through an unbiased multiomics approach, we identified metabolites and lipid species that interestingly discriminate patients with or without DR. These features could be a research basis to identify new potential plasma biomarkers to promote 3P medicine.

Paracentral Acute Middle Maculopathy as a Specific Sign of Arteritic Anterior Ischemic Optic Neuropathy.

PURPOSE: The purpose of this study is to assess the diagnostic accuracy of paracentral acute middle maculopathy (PAMM) in the setting of anterior ischemic optic neuropathy (AION) to distinguish arteritic (A-AION) from nonarteritic (NA-AION) type. DESIGN: Retrospective cross-sectional diagnostic evaluation. METHODS: PAMM was evaluated by 3 physicians blinded to diagnosis using macular spectral-domain optical coherence tomography. We studied 45 patients with AION. Of those, 28 had NA-AION and 17 had A-AION. The study was conducted in the Department of Ophthalmology at the Hospital of Marseille-Assistance Publique, France, from January 1, 2018, to March 31, 2022. RESULTS: PAMM were only found in the A-AION group (N = 4) (P = .0143). As a distinctive sign of A-AION, we found a specificity of 100% (95% IC, 88.06%-100%) and a positive predictive value of 100%. In contrast, sensitivity and negative predictive value were lower, 19.1% (95% IC, 5.5-42.0) and 63.0% (95% CI, 58.1-67.7), respectively. CONCLUSIONS: The PAMM finding is highly specific for A-AION in the setting of AION. According to our results, macular spectral-domain optical coherence tomography looking for PAMM should be performed with any patient presenting with AION.

COMPARISON OF PRIMARY AND SECONDARY FORMS OF MULTIPLE EVANESCENT WHITE DOT SYNDROME.

PURPOSE: The aim of this study was to compare primary versus secondary forms of multiple evanescent white dot syndrome (MEWDS) at T0 (baseline) and T1 (1-4 months after the onset of symptoms). METHODS: A total of 101 eyes in 100 patients were included in a multicentric retrospective study. RESULTS: Secondary MEWDS was defined as MEWDS associated with underlying chorioretinal inflammatory pathologies, mainly multifocal choroiditis and punctuate inner choroidopathy. Patients with secondary MEWDS were older (P = 0.011). The proportion of women (P = 0.8), spherical equivalent (P = 0.3), and best-corrected visual acuity at T0 (P = 0.2) were not significantly different between the two groups. The area of MEWDS lesions on late-phase indocyanine green angiography was significantly smaller in secondary MEWDS (P = 0.001) and less symmetrical with respect to both horizontal (P = 0.003) and vertical (P = 0.004) axis. At T0, neither the clinical (P = 0.5) nor the multimodal imaging (P = 0.2) inflammation scores were significantly different between the groups. At T1, the multimodal imaging inflammation score was higher in secondary MEWDS (P = 0.021). CONCLUSION: In secondary MEWDS, outer retinal lesions are less extensive and located close to preexisting chorioretinal lesions. Mild signs of intraocular inflammation on multimodal imaging are more frequent in secondary MEWDS during recovery. These findings suggest that chorioretinal inflammation may trigger secondary MEWDS.

Evolution of Quantitative Optical Coherence Tomography Angiography Markers with Glycemic Control: A Pilot Study.

Aim: We aimed to analyze changes in retinal microvascularization with intensive reduction of glycated hemoglobin A1c (HbA1c) in patients with poorly controlled diabetes using quantitative optical coherence tomography angiography (OCT-A) metrics. Method: This was a retrospective observational study in patients with uncontrolled diabetes admitted to the hospital for glycemic control. A second set of 15 healthy volunteers was included to serve as a control group. OCT-A was performed at inclusion and at 3 months to measure foveal avascular zone area (FAZA), vessel density (VD) of the superficial capillary plexus (SCP) and deep capillary plexus (DCP), acircularity index (AI), and fractal dimension (FD). Results: This analysis included 35 patients (35 eyes): 28 type-2 diabetics and 7 type-1 diabetics. Mean HbA1c was 13.1 ± 2.0% at inclusion and 7.0 ± 1.5% at 3 months. In the short period from inclusion to 3 months post-inclusion, patients showed significant decrease in VD−DCP (28.8% vs. 27.8%; p = 0.014), a significant increase in FAZA (0.300 mm2 vs. 0.310 mm2; p < 0.001), and a significant increase in AI (1.31 vs. 1.34; p < 0.01). Multivariate analysis found an increase in FAZA was correlated with baseline HbA1c level and age (R2 = 0.330), and a decrease in VD-DCP was correlated with HbA1c decrease and diabetes duration (R2 = 0.286). Conclusions: Rapid glycemic control in patients with uncontrolled diabetes led to possible short-term microvascular damage that correlated to both initial and decreased HbA1c.

Comparative Effectiveness of Intravitreal Anti-Vascular Endothelial Growth Factor Therapies for Managing Neovascular Age-Related Macular Degeneration: A Meta-Analysis.

Intravitreal injections (IVI) of anti-vascular endothelial growth factor (anti-VEGF) have become the standard of care for age-related macular degeneration (AMD). Although most pivotal trials have used monthly injections, alternative strategies that enable the injections to be administered on a more flexible schedule, including pro re nata (PRN) and treat-and-extend (T&E) regimens, are being applied more frequently. This review sought to provide further scientific evidence about the visual outcomes and treatment burden among the currently available anti-VEGF agents and regimens, including aflibercept, ranibizumab, abicipar and brolucizumab. To this end, a systematic review of published randomized studies was conducted from the MEDLINE and EMBASE databases and the Cochrane library, and a meta-analysis was applied to the obtained data using single-means modeling to compare the efficacy and maintenance among the different available treatments and regimens at Years 1 and 2. Quality analysis identified the best-informed data for modeling purposes. Overall, 47 relevant publications were retrieved for the analysis. Superior efficacy, meaning that there were observed improvements in visual acuity (VA) and central retinal thickness (CRT), occurred with monthly versus PRN regimens, yet a higher IVI number was also observed. Conversely, the T&E regimens displayed similar efficacy to the monthly regimens, but with a reduced IVI number. Aflibercept T&E exhibited similar efficacy to ranibizumab T&E, but with significantly lower IVI numbers at both Year 1 (p < 0.0001) and Year 2 (p = 0.0011). Though all of the regimens resulted in maintained efficacy between Years 1 and 2, the required IVI number varied. The retrieved data did not enable other regimens or newer anti-VEGF agents such as brolucizumab to be compared. In conclusion, the T&E regimens were shown to be the most efficient, optimizing durable effectiveness whilst minimizing the IVI number in newly diagnosed exudative AMD, with aflibercept requiring the lowest IVI number.

CLINICAL FEATURES OF RETINAL METASTASES: New Cases Integrated in a Systematic Review of the Literature.

PURPOSE: To report a cohort of patients diagnosed with retinal metastases (RM), and to integrate these new cases in a systematic review of the literature, analyzing the clinical features and prognosis factors of patients with RM. METHODS: We conducted a retrospective multicenter study including patients with RM. We also performed a full literature review of all published cases with a diagnosis of RM. RESULTS: A total of six new cases were described on multimodal imaging. By combining the data from the literature and from our patients, we report the characteristics of a total of 69 patients. The most frequent primary tumor sites were cutaneous melanoma (36%), lung (23%), gastrointestinal tract (17%), and breast (12%). Multimodal imaging highlighted specific characteristics of RM. Fluorescein and indocyanine green angiography revealed early hypofluorescence followed by progressive filling of intrinsic dilated vessels. Optical coherence tomography demonstrated a hyperreflective intraretinal mass in all cases with or without subretinal fluid, hyperreflective intraretinal dots, or intraretinal fluid. Ultrasonography revealed a medium-high reflective dome-shaped tumor. Fifty-nine percent of the patients died during the follow-up with a mean survival time of 8.8 ± 8.7 months. CONCLUSION: We described here the clinical spectrum of RM and highlighted specific features of the disease.

Bilateral acute retinal necrosis with encephalitis in a premature infant.

INTRODUCTION: Neonatal herpes infections can be extremely severe and their early recognition allows for appropriate management and increases the child's chances of survival. CASE DESCRIPTION: We report the case of a premature infant born by vaginal delivery and transferred to intensive care after neonatal misadaptation. Examination of the fundus revealed lesions of acute bilateral retinal necrosis, strongly suggesting a herpetic etiology. CONCLUSIONS: This case highlights the clinical benefit of an ophthalmologic exam in newborns with equivocal brain lesions. Herein, the fundus examination allowed for high suspicion of herpes virus infection.

Costs comparison of treating diabetic macular edema with aflibercept, ranibizumab or dexamethasone at 1 year in France (INVICOST study).

PURPOSE: INVICOST, a medico-economic analysis, compared costs of managing treatment-naive patients with diabetic macular edema (DME) receiving intravitreal injections (IVIs) of aflibercept (AFL), dexamethasone implant (DXI) or ranibizumab (RAN) over 1 year. METHODS: Healthcare resource use and associated costs were estimated using individual patient data from INVICTUS, a prospective, open-label, monocentric study. Healthcare costs comprised direct medical costs such as drug acquisition and administration, consultations and ophthalmological procedures. Costs were assessed from the French National Health Insurance perspective using published national tariffs expressed in 2019 euros. RESULTS: Of the 60 treated eyes, 48 had no treatment switch; 14 received AFL, 19 received DXI and 15 received RAN. AFL-treated eyes received an average of 6.5 IVIs, DXI-treated patients received 2 IVIs and RAN-treated received 6.8 IVIs. All treated eyes received an initial prescription for adjunctive ocular medications and 349 follow-up procedures were performed including an average of 3.9 optical coherence tomography and 3.2 retinography procedures per eye. Average total direct cost of per-eye treatment was €4516 (€1128-€8257). Average cost was €5782 for eyes treated with AFL, €2779 with DXI and €5536 with RAN. Drug therapy was the cost driver: €4394 (76%) for AFL, €1915 for DXI (69%) and €4268 (77%) for RAN. CONCLUSION: The difference in total treatment cost is largely explained by the significantly lower frequency of IVI and annual cost of therapy with DXI, compared with AFL and RAN. INVICOST is the first study comparing treatment costs with AFL, DXI and RAN in France in current clinical practice.

Aflibercept in real-life for the treatment of age-related macular degeneration using a treat and extend protocol: The Armada study.

PURPOSE: To report the visual and anatomic outcomes in treatment-naïve neovascular age-related macular degeneration (nAMD) patients treated with aflibercept under a standardized Treat and Extend (T&E) protocol for up to 3 years of follow-up in "real-life" practice. METHODS: This retrospective, observational, multicenter study included patients with treatment-naïve nAMD and at least 12 months of follow-up. T&E regimen adjustment was initiated after loading phase. At each visit best-corrected visual acuity (BCVA) and optical coherence tomography parameters were performed. RESULTS: One hundred and thirty-six eyes of 115patients had at least 1 year of follow-up with 114 and 82 eyes completing at least 2 and 3 years of follow-up, respectively (mean follow-up duration: 2.7 ± 1.3 years). Mean age was 78.6 ± 8.6 years old and 52% were women. Mean BCVA increased from 60.6 ± 18.7 letters at diagnosis to 66.9 ± 16.2 letters at 1 year (+6.3 letters, p = 0.003) and remained stable throughout the follow-up period (63.1 ± 20.3 letters (+2.5, p = 0.1) and 64.0 ± 20.1 letters (+3.4, p = 0.27) at 2 and 3 years, respectively). The mean central retinal thickness decreased significantly from 358.2 ± 87.9 µm at baseline to 302 ± 71.7 µm at 12 months and maintained stable after 36 months of follow-up (297.1 ± 76 µm, p < 0.0001). Mean number of injections was 6.6 ± 2.2, 4.8 ± 1.9, and 5.6 ± 1.7 at 1, 2, and 3 years, respectively. Mean cumulative number of 16.4 ± 5.6 injections after 3 years. Mean treatment interval was 6.8 ± 2.5 weeks at 1 year. Eight-week and 12-week treatment interval were achieved in 59.5% and 19.1%, 65.8%, and 36.8% and 69.5% and 41.5% at 1, 2, and 3 years, respectively. CONCLUSIONS: Our study demonstrated that intravitreal injections of aflibercept initiated under a standardized T&E for patients with treatment-naïve nAMD allow for significant visual improvement at 12 months, which was maintained over a 3-year follow-up period.

ULTRAWIDEFIELD PSEUDOCOLOR RETINAL IMAGING VERSUS REAL-COLOR FUNDUS PHOTOGRAPHY FOR DETECTION OF INTRARETINAL PIGMENT MIGRATION IN AGE-RELATED MACULAR DEGENERATION.

PURPOSE: To compare pseudocolor Optos ultrawidefield (UWF) retinal images with conventional real-color fundus photography (CFP) for detecting macular hyperpigmentary changes in intermediate age-related macular degeneration. METHODS: This retrospective study included 50 patients diagnosed with intermediate age-related macular degeneration. All patients underwent Optos imaging and CFP. The overall accuracy to visualize hyperpigmentation and its morphologic features was graded by two independent readers using a standardized grid. Structural and en face optical coherence tomography images were correlated with UWF and CFP images to determine spatial correspondence of pigment clumping on fundus images and hyperreflective foci on optical coherence tomography. RESULTS: One hundred eyes of 50 patients had hyperpigmentary changes on funduscopic examination and were included. The intragraders and intergraders agreements were high for all measurements (P < 0.001). At least one hyperpigmentary changes within the standardized grid was detected in 93% using CFP and 100% using UWF camera (P = 0.02). The total area of hyperpigmentation measured on UWF images was significantly higher than on CFP images (P < 0.001). There was a significant correlation between the presence of hyperpigmentary changes on both CFP and UWF images and hyperreflective foci on structural optical coherence tomography (P < 0.001). CONCLUSION: Ultrawidefield fundus images allow high detection and accurate quantification of macular hyperpigmentary changes in intermediate age-related macular degeneration compared with conventional CFP.

INVICTUS: Intravitreal anti-VEGF and dexamethasone implant comparison for the treatment of diabetic macular edema: A 12 months follow-up study.

PURPOSE: To compare the efficacy of intravitreal injections (IVI) of ranibizumab (Lucentis®, Novartis, Basel, Switzerland; RAN), aflibercept (Eylea®, Bayer, Leverkusen, Germany; AFL) and dexamethasone implant (Ozurdex®, Allergan, Irvine, California; DXI) in the treatment of naive diabetic macular oedema (DME) during a 12-month follow-up, in real life. METHODS: Nineteen eyes treated with RAN, 20 with AFL and 21 with DXI were analysed from inclusion up to 12 months (M12) with intermediate analysis at M6. Best corrected visual acuity (BCVA), fundus and central retinal thickness (CRT) using spectral-domain optical coherence tomography (SD-OCT; Spectralis/HRA, Heidelberg Engineering, Germany) were performed at inclusion, M3, M6 and M12. RESULTS: BCVA improved until 67.9 letters ±13.3 SD (+5.5 letters) at M6 and 69.6 letters ±12 SD (+7.2 letters) at 12 months for RAN group (p = 0.036). For the AFL group it improved until 63.6 letters ±15.2 SD (+6.6 letters) at M6 and 67.5 letters ±12.2 SD (+8.5 letters) at 12 months (p = 0.014). Lastly DXI group improved by 66.9 letters ±15.1 SD (+7.9 letters) at M6 and 68.4 letters ±11.2 SD (+9.4 letters) at 12 months (p = 0.0023). CRT decreased by 124.4 µm at M6 and 99.3 µm at M12 in RAN group, 144.3 µm and 101.5 µm in AFL group and finally 95.6 µm and 162.7 µm in DXI group. CONCLUSION: In summary, these three drugs provide an efficient treatment option with an acceptable benefit-risk ratio for the treatment of naive patients with DME, whether on BCVA or CRT on the first year of treatment.

Covid-19-Associated Retinopathy: A Case Report.

A 53-year-old man presented with acute loss of vision, negative scotoma and dyschromatopsia in his left eye. He reported contact with people with severe respiratory syndrome - coronavirus-2 (SARS-CoV-2) 8 days prior symptoms. Funduscopic examination revealed several retinal hemorrhages. Spectral-domain optical coherence tomography showed lesions consistent with acute macular neuroretinopathy and paracentral acute middle maculopathy. Quickly after his presentation, SARSCov-2 was confirmed by chest computed tomography-scan and RT-PCR in this patient. Thrombotic complications associated with Covid-19 infection have high incidence and may involve the retina. We described a case of retinal involvement associated with Covid-19 infection. PRÉCIS: Funduscopic examination revealed retinal hemorrhages in a man with loss of vision. Optical coherence tomography showed an acute macular neuroretinopathy and paracentral acute middle maculopathy. Coronavirus disease was confirmed by chest computed tomography-scan and RT-PCR.