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Enrico Peiretti,1 Chiara Ascardi,2 Francesco Bandello,3 Francesco Boscia,4 Monica Varano,5 Marta Bartezaghi,2 Lorenzo De Santi,2 Giovanni Staurenghi6 1Clinica Oculistica, San Giovanni di Dio Hospital, Azienda Ospedaliera, Universitaria di Cagliari, Cagliari, Italy; 2Novartis Farma S.p.A, Milan, Italy; 3Department of Ophthalmology, San Raffaele Scientific Institute, Vita-Salute University, Milan, Italy; 4Department of Medical Science, Neuroscience and Sense Organs, Eye Clinic, University of Bari, Azienda Ospedaliero-Universitaria Policlinico Bari, Bari, Italy; 5IRCCS G.B. Bietti Foundation, Rome, Italy; 6Eye Clinic, Department of Biomedical and Clinical Sciences, Luigi Sacco Hospital, University of Milan, Milan, ItalyCorrespondence: Enrico Peiretti, Head of the Retina Unit, Eye Clinic, University of Cagliari, Via Ospedale 48, Cagliari, 09100, Italy, Email enripei@hotmail.comPurpose: Limited data is available on treatment satisfaction with the management of wet age-related macular degeneration (wAMD) among patients in Italy. In this cross-sectional real-world study, treatment satisfaction with anti-vascular endothelial growth factor (anti-VEGFs) was assessed in patients with wAMD in Italy.Patients and Methods: This was a non-interventional, cross-sectional survey involving patients with wAMD receiving anti-VEGFs. The survey was administered through a virtual assistant via phone. Patients’ treatment satisfaction was assessed using a newly developed Novartis Tailored Treatment Satisfaction Questionnaire (NVS TTSQ) and the validated Macular Disease Treatment Satisfaction Questionnaire (MacTSQ).Results: Overall, 154 evaluable patients were enrolled in 5 centers across Italy. The mean (SD) age of the patients was 76.8 years (7.01). Overall treatment satisfaction score assessed by NVS TTSQ was 40.50 (7.11), with a mean of 9.97 (1.84) on the information domain and 22.98 (4.57) on the unmet need domain. Patients were satisfied with diagnosis communication (4.99 [1.30]), information provided on treatment administration (4.58 [1.49], range 0– 6), the waiting room (4.40 [1.43]), and management of visits and injections at the center (5.14 [1.12]), general management of maculopathy at the center (5.22 [1.01]). Patients were not satisfied with their independence in terms of disease management (2.56 [2.45]); they would like additional information about the disease (5.38 [1.03]) and to discuss the injection procedures (4.02 [1.94]) with already-treated patients. The overall treatment satisfaction score on MacTSQ scale was 55.84 (10.13).Conclusion: Patients with wAMD are satisfied with the overall management of their disease in Italy. However, patients would like to have more information on prognosis and management of the disease.Keywords: anti-VEGF, patient-reported outcomes, real-world study, treatment satisfaction, treatment satisfaction questionnaire, wAMD

Domenico Grosso, Enrico Borrelli, Riccardo Sacconi, Francesco Bandello, Giuseppe Querques Department of Ophthalmology, San Raffaele University Hospital, Milan, ItalyCorrespondence: Giuseppe QuerquesDepartment of Ophthalmology, University Vita-Salute San Raffaele, Via Olgettina 60, Milan, ItalyTel +390226432648Fax +390226433643Email giuseppe.querques@hotmail.itAbstract: Chorioretinal folds (CRFs) are undulations of the choroid and overlying Bruch’s membrane, retinal pigment epithelium and neurosensory retina. CRFs represent a clinical sign that is mandatory to investigate assuming their association with several ocular and extra-ocular disorders. Recent advances in retinal imaging have improved the characterization of CRFs. More importantly, retinal imaging may be useful to detect ocular complications secondary to chronic CRFs, including the development of choroidal neovascularization.Keywords: chorioretinal folds, maculopathy, choroid, retina

Riccardo Sacconi,1,* Corrado Campochiaro,2,* Alessandro Rabiolo,1,* Alessandro Marchese,1 Alessandro Tomelleri,2 Livia Tomasso,1 Maria Vittoria Cicinelli,1 Lea Querques,1 Francesco Bandello,1 Lorenzo Dagna,2,* Giuseppe Querques1,* 1Department of Ophthalmology, University Vita-Salute, IRCCS San Raffaele Scientific Institute, Milan, Italy; 2Unit of Immunology, Rheumatology, Allergy and Rare Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy*These authors contributed equally to this workCorrespondence: Giuseppe QuerquesDepartment of Ophthalmology, University Vita-Salute, IRCCS San Raffaele Scientific Institute, Via Olgettina 60, Milan 20132, ItalyTel +39 0226432648Fax +39 0226433643Email giuseppe.querques@hotmail.itPurpose: To analyze the subclinical intraocular involvement using multimodal imaging approach in patients affected by Erdheim-Chester disease (ECD) without ocular symptoms.Patients and Methods: In this prospective cross-sectional study, 18 eyes of 9 consecutive patients with ECD were enrolled. Each patient underwent comprehensive ocular examination and extensive multimodal chorioretinal imaging.Results: None of the patients presented any evidence of chorioretinal localization of disease using multimodal imaging. One patient exhibited a choroidal nevus complicated by active polypoidal choroidal neovascularization. Subretinal hyperreflective material was seen in three eyes, mainly resembling acquired vitelliform lesion. One patient had an isolated intraretinal hemorrhage. Most patients exhibited peripheral vascular abnormalities (ie, microaneurysms, peripheral vascular leakage). Fundus autofluorescence showed faint hyperautofluorescence in eleven eyes.Conclusion: Intraocular involvement is an extremely rare event of an extremely rare disease. In patients affected by ECD without ocular symptoms, advance multimodal imaging examinations did not show signs of subclinical chorioretinal involvement related to the disease.Keywords: Erdheim-Chester disease, histiocytosis, fluorescein angiography, indocyanine green angiography, optical coherence tomography

Maria Brambati, Enrico Borrelli, Riccardo Sacconi, Francesco Bandello, Giuseppe Querques Ophthalmology Department, San Raffaele University Hospital, Milan, ItalyCorrespondence: Giuseppe QuerquesDepartment of Ophthalmology, University Vita-Salute San Raffaele, Via Olgettina 60, Milan, ItalyTel +390226432648Fax +390226433643Email giuseppe.querques@hotmail.itAbstract: Choroideremia (CHM) is an X-linked chorioretinal dystrophy characterized by progressive degeneration of the choroid, retinal pigment epithelium and retina. This disease is caused by mutations in the X-linked CHM gene encoding a Ras-related GTPase Rab escort protein (REP)-1, which is extremely important for the retinal function. Clinically, male-affected patients have a progressive reduction in visual acuity. This disease is formally considered incurable, although new promising treatments have been recently introduced. In this article, a review of the salient pathogenetic features of choroideremia, essential for the proper interpretation of therapeutic approaches, is followed by a discussion of the fundamental clinical features of this hereditary disease. Finally, relevant new therapeutic approaches in this disease will be discussed, including gene therapy, stem cells, small molecules, and retinal prosthesis.Keywords: choroideremia, heredodystrophies, gene, therapy, clinical trials, stem cells, gene therapy, small molecules, retinal prosthesis

Maria Vittoria Cicinelli, Marco Battista, Vincenzo Starace, Maurizio Battaglia Parodi, Francesco Bandello Department of Ophthalmology, University Vita-Salute, IRCCS Ospedale San Raffaele, Milan, ItalyCorrespondence: Maria Vittoria CicinelliDepartment of Ophthalmology, San Raffaele Vita-Salute University, Via Olgettina, 60, Milano 20132, ItalyTel +39 02 26432648Fax +39 02 26483643Email cicinelli.mariavittoria@hsr.itAbstract: Stargardt disease (STGD1) represents one of the major common causes of inherited irreversible visual loss. Due to its high phenotypic and genotypic heterogeneity, STGD1 is a complex disease to understand. Non-invasive imaging, biochemical, and genetic advances have led to substantial improvements in unveiling the disease processes and novel promising therapeutic landscapes have been proposed. This review recapitulates the modalities for monitoring patients with STGD1 and the therapeutic options currently under investigation for the different stages of the disease.Keywords: Stargardt disease, inherited retinal dystrophy, multimodal imaging, optical coherence tomography, gene therapy

Lorenzo Iuliano,1 Giovanni Fogliato,1 Francesca Gorgoni,2 Eleonora Corbelli,1 Francesco Bandello,1 Marco Codenotti11Ospedale San Raffaele Scientific Institute, Vita-Salute University, Milan, Italy; 2Ospedali Riuniti di Ancona, Università Politecnica Delle Marche, Ancona, ItalyAbstract: This review aims to give to the reader an overview selectively oriented on safety and efficacy of surgery, providing concise and direct answers about crucial questions of trainees and experts. Surgery for idiopathic epiretinal membrane (ERM) is a safe and effective procedure that can achieve long-term stable postoperative visual and anatomical improvement, with an overall low recurrence and complication rate. Young patients, with a short onset of symptoms and with better initial visual acuity achieve higher levels of visual outcome. The preoperative degree of metamorphopsia is the prognostic factor for their postoperative degree. Successful results may be obtained in eyes with specific optical coherence tomography criteria, such as thin ganglion cell layers, thin internal plexiform layer, longer photoreceptors outer segment, regular ellipsoid zone and cone outer segment tips line, and without ectopic inner foveal layer. Internal limiting membrane peeling demonstrates positive anatomical and functional outcomes, but final positions about its safety remain controversial.Keywords: idiopathic epiretinal membrane, outcome, safety, efficacy, prognostic factor

Ashish Sharma,1 Prahalad Reddy,1 Baruch D Kuppermann,2 Bandello Francesco,3 Anat Lowenstein41Department of Vitreoretina, Lotus Eye Hospital and Institute, Coimbatore, Tamil Nadu, India; 2Department of Ophthalmology, Gavin Herbert Eye Institute, University of California, Irvine, CA, USA; 3Department of Ophthalmology, Scientific Institute San Raffaele, University Vita-Salute, Milano, Italy; 4Division of Ophthalmology, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel Abstract: Retinal disease management has witnessed remarkable advances in posterior segment pharmacotherapy with the development of anti-VEGF molecules such as Lucentis® (ranibizumab), Eylea® (aflibercept), and off-label bevacizumab (Avastin). The US patents for ranibizumab and aflibercept will expire in 2020 (though Regeneron has indicated that it might attempt to extend its US patent to June 2023 with additional patent claims), and their European patents will expire in 2022 and 2025. Aflibercept comes off patent in 2022 in People’s Republic of China and Japan. As soon as each patent expires, biosimilar molecules could potentially come in the mainstream clinical practice as a more cost-efficient choice in the form of generic biosimilars. It is difficult to predict how significant this shift would be in terms of more cost-effective clinical management and how it will impact the care in developed and developing world. It is important for clinicians to have a clear understanding about ophthalmic biosimilars before the industry brings these molecules to the mainstream clinical use globally.Keywords: biosimilar, Razumab®, Lucentis®, Eylea®, ophthalmology

Alessandro Rabiolo,1 Riccardo Sacconi,1,2 Maria Vittoria Cicinelli,1 Lea Querques,1,3 Francesco Bandello,1 Giuseppe Querques1 1Department of Ophthalmology, University Vita-Salute, IRCCS San Raffaele, Milan, 2Eye Clinic, Department of Neurological and Movement Sciences, University of Verona, Verona, 3G. B. Bietti Foundation-IRCCS, Rome, Italy Abstract: Age-related macular degeneration (AMD) is a leading cause of vision loss in patients >50 years old. The hallmark of the disease is represented by the accumulation of extracellular material between retinal pigment epithelium and the inner collagenous layer of Bruch’s membrane, called drusen. Although identified almost 30 years ago, reticular pseudodrusen (RPD) have been recently recognized as a distinctive phenotype. Unlike drusen, they are located in the subretinal space. RPD are strongly associated with late AMD, especially geographic atrophy, type 2 and 3 choroidal neovascularization, which, in turn, are less common in typical AMD. RPD identification is not straightforward at fundus examination, and their identification should employ at least 2 different imaging modalities. In this narrative review, we embrace all aspects of RPD, including history, epidemiology, histology, imaging, functional test, natural history and therapy. Keywords: age-related macular degeneration, choroidal neovascularization, geographic atrophy, reticular macular degeneration, reticular drusen, reticular macular disease, reticular pseudodrusen, subretinal drusenoid deposit

Alessandro Rabiolo,1 Mariacristina Parravano,2 Lea Querques,1,2 Maria Vittoria Cicinelli,1 Adriano Carnevali,1,3 Riccardo Sacconi,1,4 Teresa Centoducati,1 Stela Vujosevic,5 Francesco Bandello,1 Giuseppe Querques1 1Department of Ophthalmology, University Vita-Salute, Scientific Institute San Raffaele, Milan, 2G. B. Bietti Foundation – IRCCS, Rome, 3Department of Ophthalmology, University of “Magna Graecia,” Catanzaro, 4Department of Neurological and Movement Sciences, University of Verona, Verona, 5Department of Neuroscience, Ophthalmology Clinic, University of Padova, Padova, Italy Abstract: Fluorescein angiography (FA) is a useful examination in patients suffering from diabetic retinopathy (DR). Traditional angiograms explore 30°–50° of the retina at once; however, visualization of peripheral retina is fundamental in order to assess nonperfused areas, vascular leakage, microvascular abnormalities, and neovascularizations. In order to expand the field of view, wide-field and ultra-wide-field imaging has been developed allowing to image up to 200° of retinal surface in one single shot. The aim of this narrative review was to provide an overview of the role of the most recent technique of ultra-wide-field fluorescein angiography in DR. Keywords: ischemic index, targeted retinal photocoagulation, diabetic macular edema, diabetic macular ischemia, peripheral vessel leakage, capillary nonperfusion

This study aimed to determine the retest variability of quantitative fundus autofluorescence (QAF) in patients with and without age-related macular degeneration (AMD) and evaluate the predictive value of patient reliability indices on retest reliability. A total of 132 eyes from 68 patients were examined, including healthy individuals and those with various stages of AMD. Duplicate QAF imaging was conducted at baseline and 2 weeks later across six study sites. Intraclass correlation (ICC) analysis was used to evaluate the consistency of imaging, and mean opinion scores (MOS) of image quality were generated by two researchers. The contribution of MOS and other factors to retest variation was assessed using mixed-effect linear models. Additionally, a Random Forest Regressor was trained to evaluate the extent to which manual image grading of image quality could be replaced by automated assessment (inferred MOS). The results showed that ICC values were high for all QAF images, with slightly lower values in AMD-affected eyes. The average inter-day ICC was found to be 0.77 for QAF segments within the QAF8 ring and 0.74 for peripheral segments. Image quality was predicted with a mean absolute error of 0.27 on a 5-point scale, and of all evaluated reliability indices, MOS/inferred MOS proved most important. The findings suggest that QAF allows for reliable testing of autofluorescence levels at the posterior pole in patients with AMD in a multicenter, multioperator setting. Patient reliability indices could serve as eligibility criteria for clinical trials, helping identify patients with adequate retest reliability. [ABSTRACT FROM AUTHOR]

Pravin U Dugel,1,2 Francesco Bandello,3 Anat Loewenstein4 1Retinal Consultants of Arizona, Phoenix, AZ, 2Department of Ophthalmology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; 3Department of Ophthalmology, University Vita-Salute Scientific Institute San Raffaele, Milan, Italy; 4Department of Ophthalmology, Tel Aviv Medical Center and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel Abstract: Diabetic macular edema (DME) resembles a chronic, low-grade inflammatory reaction, and is characterized by blood–retinal barrier (BRB) breakdown and retinal capillary leakage. Corticosteroids are of therapeutic benefit because of their anti-inflammatory, antiangiogenic, and BRB-stabilizing properties. Delivery modes include periocular and intravitreal (via pars plana) injection. To offset the short intravitreal half-life of corticosteroid solutions (~3 hours) and the need for frequent intravitreal injections, sustained-release intravitreal corticosteroid implants have been developed. Dexamethasone intravitreal implant provides retinal drug delivery for ≤6 months and recently has been approved for use in the treatment of DME. Pooled findings (n=1,048) from two large-scale, randomized Phase III trials indicated that dexamethasone intravitreal implant (0.35 mg and 0.7 mg) administered at ≥6-month intervals produced sustained improvements in best-corrected visual acuity (BCVA) and macular edema. Significantly more patients showed a ≥15-letter gain in BCVA at 3 years with dexamethasone intravitreal implant 0.35 mg and 0.7 mg than with sham injection (18.4% and 22.2% vs 12.0%). Anatomical assessments showed rapid and sustained reductions in macular edema and slowing of retinopathy progression. Phase II study findings suggest that dexamethasone intravitreal implant is effective in focal, cystoid, and diffuse DME, in vitrectomized eyes, and in combination with laser therapy. Ocular complications of dexamethasone intravitreal implant in Phase III trials included cataract-related events (66.0% in phakic patients), intraocular pressure elevation ≥25 mmHg (29.7%), conjunctival hemorrhage (23.5%), vitreous hemorrhage (10.0%), macular fibrosis (8.3%), conjunctival hyperemia (7.2%), eye pain (6.1%), vitreous detachment (5.8%), and dry eye (5.8%); injection-related complications (eg, retinal tear/detachment, vitreous loss, endophthalmitis) were infrequent (

Chiara Ancona, Monica Stoppani, Veronica Odazio, Carlo La Spina, Giulia Corradetti, Francesco Bandello Department of Ophthalmology, University Vita-Salute, Scientific Institute San Raffaele, Milano, Italy Purpose: To compare four stereo tests (Lang I, Lang II, Titmus, and TNO) and assess their effectiveness. The main focus of this study is to identify the most useful stereo test as a challenging tool in the screening of strabismus. Patients and methods: A total of 143 Caucasian subjects, 74 males (52%) and 69 females (48%), aged between 4 years and 78 years (mean age 19.09±15.12 years) were examined at our Strabismus Service (Scientific Institute San Raffaele Hospital, Milan, Italy) and included in this observational cross-sectional study. Subjects recruited in this study were either affected by strabismus, including microstrabismic patients, or healthy volunteers. Subjects affected by ophthalmological diseases, other than strabismus, were excluded. All patients underwent both ophthalmological and orthoptic examination, including stereo tests, Hirschberg Corneal Light Reflex Test, Worth Four-Dot Test, the 4 Prism Diopter Base-Out Test, Cover Testing, ­Bruckner Test, visual acuity, automated refraction under 1% tropicamide cycloplegia and thereafter, posterior pole evaluation. Results: All data were processed using the IBM SPSS Statistics, Version 2.0, to perform all statistical calculations. The main finding of this study is that Lang I stereo test achieved the highest sensitivity (89.8%) and specificity (95.2%) in detecting strabismus, including microstrabismus as well, compared to all the other stereoacuity tests. Furthermore, Lang I is the stereo test with the highest positive predictive value and negative predictive value, both greater than 90%. Conclusion: The stereo test with the highest sensitivity, specificity, positive predictive value, and negative predictive value is Lang I. These results suggest its applicability as a screening test for strabismus in people older than 4 years. Keywords: stereo tests, screening, strabismus, Lang I

Francesco Bandello1, Umberto De Benedetto1, Karl Anders Knutsson1, Maurizio Battaglia Parodi1, Maria Lucia Cascavilla1, Pierluigi Iacono21Department of Ophthalmology, University Vita-salute, Scientific Institute San Raffaele, Milan, Italy; 2Fondazione G B Bietti per l’Oftalmologia, IRCCS, Rome, ItalyAbstract: Diabetic macular edema is the major cause of visual acuity impairment in diabetic patients. The exact etiopathogenesis is unknown and, currently, grid/focal retinal laser photocoagulation represents the recommended treatment. It has been demonstrated that vascular endothelial growth factor (VEGF) plays a key role in the pathogenesis of diabetic macular edema by mediating vascular permeability and accumulation of intracellular and extracellular fluid, and thereby represents an appealing candidate as a therapeutic target for the treatment of diabetic macular edema. The advent of intravitreal anti-VEGF drugs has opened up a new era for the management of diabetic macular edema. At present, three anti-VEGF substances are available for routine clinical use, ie, pegaptanib, ranibizumab, and bevacizumab. The aim of this review is to summarize the evidence supporting the use of ranibizumab in clinical practice. Most of the studies analyzed in this review are prospective, controlled clinical trials that have focused on documenting the therapeutic effect of ranibizumab and its safety, providing encouraging results.Keywords: ranibizumab, diabetic macular edema, anti-VEGF, diabetic macular edema

Giuseppe Querques¹, Fernando Onofrio Avellis1,2, Lea Querques1,3, Francesco Bandello³, Eric H Souied¹ ¹Service d'Ophtalmologie, Centre Hospitalier Intercommunal Créteil, Université Paris-Est Créteil, Créteil, France; ²Parma Eye Clinic University Hospital, Università degli Studi di Parma, Parma, Italy; ³Department of Ophthalmology, Università Vita-Salute San Raffaele Milano, Milano, Italy Date of preparation: March 3, 2011 Conflict of interest: None declaredClinical question: Is there any new knowledge about the pathogenesis and treatment of age-related macular degeneration (AMD)?Results: We now understand better the biochemical and pathological pathways involved in the genesis of AMD. Treatment of exudative AMD is based on intravitreal injection of new antivascular endothelial growth factor drugs for which there does not yet exist a unique recognized strategy of administration. No therapies are actually available for atrophic AMD, despite some experimental new pharmacological approaches.Implementation: strategy of administration, safety of intravitreal injectionKeywords: age-related macular degeneration, antivascular endothelial growth factor, choroidal neovascularization, drusen, geographic atrophy

Quantification of the relative ellipsoid zone reflectivity (rEZR) might be a structural surrogate parameter for an early disease progression in the context of age-related macular degeneration (AMD). Within the European multicenter, cross-sectional MACUSTAR study, we have devised an automatic approach to determine the mean rEZR [arbitrary units, AU] at two independent visits in SD-OCT volume scans in study participants. Linear mixed-effects models were applied to analyze the association of AMD stage and AMD associated high-risk features including presence of pigmentary abnormalities, reticular pseudodrusen (RPD), volume of the retinal-pigment-epithelial–drusenoid-complex (RPEDC) with the rEZR. Intra-class correlation coefficients (ICC) were determined for rEZR reliability analysis. Within the overall study cohort (301 participants), we could observe decreased rEZR values (coefficient estimate ± standard error) of − 8.05 ± 2.44 AU (p = 0.0011) in the intermediate and of − 22.35 ± 3.28 AU (p < 0.0001) in the late AMD group. RPD presence was significantly associated with the rEZR in iAMD eyes (− 6.49 ± 3.14 AU; p = 0.0403), while there was a good ICC of 0.846 (95% confidence interval: 0.809; 0.876) in the overall study cohort. This study showed an association of rEZR with increasing disease severity and the presence of iAMD high-risk features. Further studies are necessary to evaluate the rEZR's value as a novel biomarker for AMD and disease progression. [ABSTRACT FROM AUTHOR]