Medical hypothesis discovery and innovation in ophthalmology

Background: Cystoid macular edema (CME), a common complication of branch retinal vein occlusion (BRVO), is associated with a significant vision loss. Anti-vascular endothelial growth factor (anti-VEGF) therapy is the gold standard of treatment, while grid macular photocoagulation has also been used as an adjuvant in patients with CME secondary to BRVO. More recent efforts were successful with the use of intravitreal triamcinolone acetonide. We proposed a concurrent use of intravitreal triamcinolone acetonide and intravitreal bevacizumab in the treatment of CME secondary to BRVO.
Case presentation: We described an 82-year-old female with a BRVO in the right eye who developed associated CME. Repeated injections of intravitreal bevacizumab and modified grid macular laser treatment were ineffective. A concurrent treatment with intravitreal bevacizumab and triamcinolone acetonide resulted in complete and dramatic resolution of CME with a favorable visual outcome. Optical Coherence Tomography (OCT) demonstrated a significant decrease in central subfield thickness (CST) from 764 micrometers to 253micrometers, without any post-procedure complications or recurrence of macular edema with complete recovery of visual acuity at 6-month follow-up.
Conclusion: Early concurrent treatment with intravitreal anti-VEGF therapy (e.g. intravitreal bevacizumab) and intravitreal triamcinolone acetonide is likely to be more effective than intravitreal anti-VEGF agents alone or grid macular photocoagulation in the management of CME associated with BRVO.

Background: The novel coronavirus pneumonia has attracted considerable attention from the international community. With the spread of outbreaks around the world, the WHO characterized COVID-19 as a pandemic.
Methods: Relevant studies in PubMed were searched from January 1, 2020 to April 12, 2020, using the following search strategy: (“novel coronavirus pneumonia” OR “severe acute respiratory syndrome coronavirus 2” OR “coronavirus disease 2019” OR “COVID-19” OR “novel coronavirus neumonia”) AND (“ophthalmology” OR “ophthalmologist” OR “eye” OR “conjunctiva” OR “conjunctivitis” OR “corneal” OR “keratitis”).
Results: SARS-CoV-2 can spread through aerosol and is detected in tears of patients with COVID-19 infection. Notably, some infected patients had conjunctivitis, and conjunctivitis was the first symptom in some patients later diagnosed to have COVID-19 infection. This would increase the risk for ophthalmologists through inpatient consultations or regular clinical practice. When dealing with seemingly regular ophthalmic patients, the vigilance of ophthalmologists and associated staff tends to be reduced.
Conclusion: Ophthalmologists must continuously update their knowledge regarding COVID-19 and take effective measures to prevent COVID-19 transmission.

Background: Refractive surgery (RS) for myopia has made a very big progress regarding its safety and predictability of the outcome. Still, a small percentage of operations require retreatment. Therefore, both legally and ethically, patients should be informed that sometimes a corrective RS may be required. We addressed this issue using Neural Networks (NN) in RS for myopia. This was a recently developed validation study of a NN. 
Methods: We anonymously searched the Ophthalmica Institute of Ophthalmology and Microsurgery database for patients who underwent RS with PRK, LASEK, Epi-LASIK or LASIK between 2010 and 2018. We used a total of 13 factors related to RS. Data was divided into four sets of successful RS outcomes used for training the NN, successful RS outcomes used for testing the NN performance, RS outcomes that required retreatment used for training the NN and RS outcomes that required retreatment used for testing the NN performance. We created eight independent Learning Vector Quantization (LVQ) networks, each one responding to a specific query with 0 (for the retreat class) or 1 (for the correct class). The results of the 8 LVQs were then averaged so we could obtain a best estimate of the NN performance. Finally, a voting procedure was used to reach to a conclusion.
Results: There was a statistically significant agreement (Cohen’s Kapp = 0.7658) between the predicted and the actual results regarding the need for retreatment. Our predictions had good sensitivity (0.8836) and specificity (0.9186).
Conclusion: We validated our previously published results and confirmed our expectations for the NN we developed. Our results allow us to be optimistic about the future of NNs in predicting the outcome and, eventually, in planning RS.

Background: Intravitreal vascular endothelial growth factor (VEGF) inhibitors represent the mainstay of neovascular age-related macular degeneration (nAMD) treatment. Although bevacizumab has been the first anti-VEGF used in ophthalmology, it is unlicensed for intraocular use. However, the favourable cost-benefit balance has favoured its widespread use. We aimed to present relevant literature regarding the safety profile and the regulatory issues of intravitreal bevacizumab use.
Methods: In this narrative review we report relevant studies regarding the safety profile of intravitreal bevacizumab. Expert commentary is provided and an overview of the current scenario and possible future directions discussed.
Results: Randomized controlled trials have demonstrated that bevacizumab is not inferior to the licensed anti-VEGF agents showing similar efficacy and safety profiles. However, a significant debate on the regulatory issues of intravitreal bevacizumab used as an off-label first-line treatment in nAMD still persists. Recently, the Regional Health System of Lombardia in Italy decided to only cover the expenses of bevacizumab, forcing clinicians to use bevacizumab as the first choice in the treatment of nAMD. Issues about the practical implications of this decision are discussed.
Conclusion: The use of intravitreal bevacizumab as first-line therapy in nAMD remains controversial. Many differences in the regulatory aspects still persist among the European countries and sometimes within the same countries, like Italy. Of note the clinical scenario will be modified in future by the introduction of newly developed anti-VEGF agents and anti-VEGF biosimilars.

Background: The aim of this study was to evaluate the characteristics of the macular vessel density (VD) and the foveal avascular zone (FAZ) in glaucoma quantitatively using the optical coherence tomography angiography (OCT-A).
Methods: Twenty-five eyes of 13 patients with primary open angle glaucoma (POAG) and 12 eyes of 6 healthy participants were enrolled retrospectively. Functional visual field (VF) and structural Spectral-Domain optical coherence tomography (SD-OCT) Retinal Nerve Fiber Layer Thickness (RNFLT) were assessed in all participants. OCT-A was performed on a fovea centered, 15x10 degrees, macular region. OCT-A scans were processed with MATLAB software and automatically graded to define FAZ parameters. The parafoveal VD in the superficial and deep retinal vascular plexus (SVP and DVP) was analyzed by quadrant and circular segmented zones.
Results: Foveal Avascular Zone -Major Axis Length (p=0.02), Area (p=0.04), Equivalent Diameter (p=0.04) and Perimeter (p=0.04) were significantly larger in glaucoma than the control group. Regarding SVP and DVP, the average macular total VD were lower in glaucoma patients compared to the control group (p<0.01; p<0.01). Additionally, the inner circular region (p=0.04; p<0.01 respectively for SVP and DVP) and all quadrants except for North had a lower VD in glaucoma group compared to the control group. Assessment of the total VD successfully predicted RNFLT (p<0.001) and was significantly associated with the probability of glaucoma (p=0.009).
Conclusion: OCT-A parameters, namely the FAZ morphology and the macular VD, were associated with glaucomatous functional and structural changes. The macular VD showed a considerable diagnostic value. It may be a modern biomarker, representing microvascular network disruption of the macular perfusion in glaucoma.

Background: To identify prognostic preoperative and intraoperative factors for anatomical and visual success of idiopathic macular hole (MH) surgery.
Methods: We conducted a non-randomized, collaborative multicenter study using data of 4207 MH surgery from 140 surgeons. Main study outcomes were anatomical closure and best corrected visual acuity (BCVA) improvement postoperative at 6-12 months.
Results: Information on anatomical success was available for 4138 eyes of 4207 operations. Anatomical closure of MH was achieved in 85.7% (3546 eyes). Closure was higher in smaller MH (stages 1-2 versus stage 3: OR=0.35; stage 2 versus stage 4: OR=0.16, and in MH with shorter duration before the operation (OR=0.94). Macular Holes were more likely to close when dyes were used to facilitate internal limiting membrane (ILM) peeling (odds ratio=1.73 to 3.58). The most important predictors of postoperative BCVA were the preoperative BCVA (estimate=0.39, p<0.001) and closure of the macular hole (estimate=0.34, p<0.001). We observed Larger improvement in BCVA in combined vitrectomy and phacoemulsification (estimate = 0.10) and post cataract surgery in phakic eyes (estimate=0.05). Retinal tears occurred in 5.1% of eyes, and were less with use of trocars (OR= -1.246) and in combined vitrectomy/ phacoemulsification surgery (OR= -0.688).
Conclusion: This international survey confirmed that staining with dyes improves anatomical results but not visual outcomes. After surgery, visual acuity improved during the first year, and final visual acuity was better in both pseudophakic eyes and eyes that underwent cataract surgery during the first year following MH repair.

Background: According to the World Health Organization, myopia is already one of the major causes of vision impairment and blindness. It is predicted to affect almost a half of the world's population within the next years. A lot of researches around the world have been performed on myopia, there is no clear overview of these researchers. In this manuscript, we analyzed the main connections between the most cited researchers, to build a citation network to evaluate the impact of different authors, journals, and subjects in the field of myopia control.
Methods: A search using the keywords Myopia Control was made through the Web of Science. Extracted data were analyzed using CitNetExplorer software obtaining a visual evaluation of the most cited publications. A subnet analysis was made by adding the keywords myopia control AND ("orthokeratology" OR "corneal refractive therapy"), "myopia control" AND ("soft contact lens*" OR "multifocal contact lens"), and "myopia control" AND "atropine". The most important publications of the network and subnetworks were analyzed using the "core" function.
Results: This study showed 228 references that generated 1087 citations across the network. 2013 was the most important year for myopia control, with most publications and citations. Optometry and Vision Science journal has published the most cited papers. Regarding the authors, Walline ranked the first of the most cited articles on myopia control.
Conclusion: This study analyzed the associations between the authors, journals and subjects in myopia control, highlighting the great importance of this area in the recent years. More than 50% of the papers in the network were published after 2013.