Gaps and future of human-centered artificial intelligence in ophthalmology: Future Vision Forum consensus statement.

PURPOSE OF REVIEW: The Future Vision Forum discussed the current state of Human Centered Computing and the future of data collection, curation, and collation in ophthalmology. Although the uptake of electronic health record (EHR) systems and the digitization of healthcare data is encouraging, there are still barriers to implementing a specialty-wide clinical trial database. The article identifies several critical opportunities, including the need for standardization of image metadata and data, the establishment of a centralized trial database, incentives for clinicians and trial sponsors to participate, and resolving ethical concerns surrounding data ownership. FINDINGS: Recommendations to overcome these challenges include the standardization of image metadata using the Digital Imaging and Communications in Medicine (DICOM) guidelines, the establishment of a centralized trial database that uses federated learning (FL), and the use of FL to facilitate cross-institutional collaboration for rare diseases. Forum faculty suggests incentives will accelerate artificial intelligence, digital innovation projects, and data sharing agreements to empower patients to release their data. SUMMARY: A specialty-wide clinical trial database could provide invaluable insights into the natural history of disease, pathophysiology, why trials fail, and improve future clinical trial design. However, overcoming the barriers to implementation will require continued discussion, collaboration, and collective action from stakeholders across the ophthalmology community.

ADVERSE EVENTS OF THE ARGUS II RETINAL PROSTHESIS: Incidence, Causes, and Best Practices for Managing and Preventing Conjunctival Erosion.

PURPOSE: To analyze and provide an overview of the incidence, management, and prevention of conjunctival erosion in Argus II clinical trial subjects and postapproval patients. METHODS: This retrospective analysis followed the results of 274 patients treated with the Argus II Retinal Prosthesis System between June 2007 and November 2017, including 30 subjects from the US and European clinical trials, and 244 patients in the postapproval phase. Results were gathered for incidence of a serious adverse event, incidence of conjunctival erosion, occurrence sites, rates of erosion, and erosion timing. RESULTS: Overall, 60% of subjects in the clinical trial subjects versus 83% of patients in the postapproval phase did not experience device- or surgery-related serious adverse events. In the postapproval phase, conjunctival erosion had an incidence rate of 6.2% over 5 years and 11 months. In 55% of conjunctival erosion cases, erosion occurred in the inferotemporal quadrant, 25% in the superotemporal quadrant, and 20% in both. Sixty percent of the erosion events occurred in the first 15 months after implantation, and 85% within the first 2.5 years. CONCLUSION: Reducing occurrence of conjunctival erosion in patients with the Argus II Retinal Prosthesis requires identification and minimization of risk factors before and during implantation. Implementing inverted sutures at the implant tabs, use of graft material at these locations as well as Mersilene rather than nylon sutures, and accurate Tenon's and conjunctiva closure are recommended for consideration in all patients.

Worldwide Argus II implantation: recommendations to optimize patient outcomes.

BACKGROUND: A position paper based on the collective experiences of Argus II Retinal Prosthesis System investigators to review strategies to optimize outcomes in patients with retinitis pigmentosa undergoing retinal prosthesis implantation. METHODS: Retinal surgeons, device programmers, and rehabilitation specialists from Europe, Canada, Middle East, and the United States were convened to the first international Argus II Investigator Meeting held in Ann Arbor, MI in March 2015. The recommendations from the collective experiences were collected. Factors associated with successful outcomes were determined. RESULTS: Factors leading to successful outcomes begin with appropriate patient selection, expectation counseling, and preoperative retinal assessment. Challenges to surgical implantation include presence of staphyloma and inadequate Tenon's capsule or conjunctiva. Modified surgical technique may reduce risks of complications such as hypotony and conjunctival erosion. Rehabilitation efforts and correlation with validated outcome measures following implantation are critical. CONCLUSIONS: Bringing together Argus II investigators allowed the identification of strategies to optimize patient outcomes. Establishing an on-line collaborative network will foster coordinated research efforts to advance outcome assessment and rehabilitation strategies.

Retinal and nonocular abnormalities in Cyp27a1(-/-)Cyp46a1(-/-) mice with dysfunctional metabolism of cholesterol.

Cholesterol elimination from nonhepatic cells involves metabolism to side-chain oxysterols, which serve as transport forms of cholesterol and bioactive molecules modulating a variety of cellular processes. Cholesterol metabolism is tissue specific, and its significance has not yet been established for the retina, where cytochromes P450 (CYP27A1 and CYP46A1) are the major cholesterol-metabolizing enzymes. We generated Cyp27a1(-/-)Cyp46a1(-/-) mice, which were lean and had normal serum cholesterol and glucose levels. These animals, however, had changes in the retinal vasculature, retina, and several nonocular organs (lungs, liver, and spleen). Changes in the retinal vasculature included structural abnormalities (retinal-choroidal anastomoses, arteriovenous shunts, increased permeability, dilation, nonperfusion, and capillary degeneration) and cholesterol deposition and oxidation in the vascular wall, which also exhibited increased adhesion of leukocytes and activation of the complement pathway. Changes in the retina included increased content of cholesterol and its metabolite, cholestanol, which were focally deposited at the apical and basal sides of the retinal pigment epithelium. Retinal macrophages of Cyp27a1(-/-)Cyp46a1(-/-) mice were activated, and oxidative stress was noted in their photoreceptor inner segments. Our findings demonstrate the importance of retinal cholesterol metabolism for maintenance of the normal retina, and suggest new targets for diseases affecting the retinal vasculature.

SAFETY PROFILE OF OCRIPLASMIN FOR SYMPTOMATIC VITREOMACULAR ADHESION: A Comprehensive Analysis of Premarketing and Postmarketing Experiences.

PURPOSE: After the recent approval of ocriplasmin by the Food and Drug Administration, postmarketing safety concerns have been raised by the vitreoretinal community. The American Society of Retina Specialists Therapeutic Surveillance Committee was commissioned to monitor postmarketing drug-related and device-related adverse events. The purpose of this report is to analyze the postmarketing safety experience in the context of available premarketing safety data. METHODS: Periodic aggregate safety reports consisting of premarketing, or clinical trial, data (n = 999 injections) and postmarketing reports through July 16, 2013 (n = 4,387 injections), were retrospectively analyzed by the TSC. The aggregate data were analyzed to classify adverse events, and the postmarketing safety data for each event type were compared with the premarketing data. RESULTS: Eight categories of adverse events were identified. Acute reduction in visual acuity attributable to either worsening of macular pathology or development of subretinal fluid, electroretinogram changes, dyschromatopsia, retinal tears and detachments, lens subluxation or phacodonesis, impaired pupillary reflex, and retinal vessel findings were reported in both the premarketing and postmarketing experiences. Ellipsoid zone (inner segment/outer segment) findings were only reported in the postmarketing experience. Rates of postmarketing reports were lower than in the premarketing data. Adverse events were generally transient, and characteristics of these adverse events were generally similar between the premarketing and postmarketing experience. CONCLUSION: Postmarket analyses are limited by significant underreporting, and in the case of ocriplasmin as a first in-class drug, they may not have captured safety events that have only more recently been identified. Nonetheless, postmarket analyses can identify the scope of potential safety events based on real-world experiences. Ocriplasmin administration should be guided by an appropriate and informed risk-benefit discussion with the patient. Ongoing active postmarket surveillance by all practitioners will continue to be critical to better understand this safety profile.

Optical Coherence Tomography Classification Systems for Diabetic Macular Edema and Their Associations With Visual Outcome and Treatment Responses - An Updated Review.

ABSTRACT: Optical coherence tomography (OCT) is an invaluable imaging tool in detecting and assessing diabetic macular edema (DME). Over the past decade, there have been different proposed OCT-based classification systems for DME. In this review, we present an update of spectral-domain OCT (SDOCT)-based DME classifications over the past 5 years. In addition, we attempt to summarize the proposed OCT qualitative and quantitative parameters from different classification systems in relation to disease severity, risk of progression, and treatment outcome. Although some OCT-based measurements were found to have prognostic value on visual outcome, there has been a lack of consensus or guidelines on which parameters can be reliably used to predict treatment outcomes. We also summarize recent literatures on the prognostic value of these parameters including quantitative measures such as macular thickness or volume, central subfield thickness or foveal thickness, and qualitative features such as the morphology of the vitreoretinal interface, disorganization of retinal inner layers, ellipsoid zone disruption integrity, and hyperreflec-tive foci. In addition, we discuss that a framework to assess the validity of biomarkers for treatment outcome is essentially important in assessing the prognosis before deciding on treatment in DME. Finally, we echo with other experts on the demand for updating the current diabetic retinal disease classification.

The primary care physician's role in preventing vision loss and blindness in patients with diabetes.

While not trained to specifically diagnose or treat ophthalmic conditions, primary care physicians can play a significant role in the visual health of their patients, specifically those with diabetes. Diabetic retinopathy is a leading cause of vision loss and blindness in the United States and because of its asymptomatic nature, patients often do not seek eye care until they notice changes in their vision. Patients with diabetes look to their physicians for guidance in managing all aspects of the disease, and research has shown people are more likely to have their eyes examined if their physician suggests it. Physicians should discuss visual health with patients and make referrals for annual comprehensive dilated eye examinations. Vision loss and blindness from diabetes can often be prevented through early detection and timely treatment; however, many patients seek eye care at a stage too late for treatment to be effective.

COVID-19: Update on Its Ocular Involvements, and Complications From Its Treatments and Vaccinations.

ABSTRACT: The coronavirus disease 2019 (COVID-19) came under the attention of the international medical community when China first notified the World Health Organization of a pneumonia outbreak of then-unknown etiology in Wuhan in December 2019. Since then, COVID-19 caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has appalled the world by spreading at a pandemic speed. Although ophthalmologists do not directly engage in the clinical care of COVID-19 patients, the ophthalmology community has become aware of the close ties between its practice and the pandemic. Not only are ophthalmologists at heightened risk of SARS-CoV-2 exposure due to their physical proximity with patients in routine ophthalmic examinations, but SARS-CoV-2 possesses ocular tropism resulting in ocular complications beyond the respiratory tract after viral exposure. Furthermore, patients could potentially suffer from adverse ocular effects in the therapeutic process. This review summarized the latest literature to cover the ophthalmic manifestations, effects of treatments, and vaccinations on the eye to aid the frontline clinicians in providing effective ophthalmic care to COVID-19 patients as the pandemic continues to evolve.

Future Vision 2020 and Beyond-5 Critical Trends in Eye Research.

Ophthalmology has been at the forefront of many innovations in basic science and clinical research. The randomized prospective multicenter clinical trial, comparative clinical trials, the bench to beside development of diagnostic and therapeutic devices, the powerful combination of biostatistics and epidemiology, gene therapy, cell-based therapy, stem cell therapy, regenerative medicine, artificial intelligence, and the development of personalized molecular medicine continue to propel us forward. This article summarizes several critical trends in eye research.Innovative translational research continues to bring new solutions to blinding retinal diseases. The discovery of the genetic code presaged a day when the development of molecular tools and understanding of the basis of disease would lead not only to disease management but potentially lifelong cure. After decades of investigation, gene therapy is now a reality for a single autosomal recessive bi-allelic disease, Lebers Congenital Amaurosis. Its success has paved the way for a myriad of conditions once thought to be untreatable. In parallel, the progress to utilize pluripotential stem cells, immunomodulation, computational biology, and continued investigation into the fundamental mechanisms of cell and molecular biology is breathtaking in its rapidity. The next decade is likely to be the most exciting in the history of medicine. It will be essential that research progresses in a meticulously thoughtful, ethical, and collaborative process that safeguards the trust of our work and that of the society we serve.Presented as the International Award Lecture, Asia-Pacific Vitreoretinal Society meeting, November 2019, Shanghai China.

Death tolls of COVID-19: Where come the fallacies and ways to make them more accurate.

The death toll of the coronavirus disease 2019 (COVID-19) sparked much controversy since its advent in December 2019. Underestimation because of under testing and deaths happening outside the hospitals were important causes. Bold revisions of the diagnostic criteria leading to dramatic changes in death tolls by different governments were observed in attempts to generate more accurate estimates. On the other hand, the influence, censorship and manipulation on case and death data from top political leaders of some countries could create important impacts on the death toll. Baseline mortality data of previous years may help make more accurate estimates of the actual death toll. The pitfalls and strategies during such processes could become valuable lessons to leaders and policymakers worldwide as more accurate statistics serve to navigate policies to combat this pandemic in the days and months to come.

COVID-19: Ocular Manifestations and the APAO Prevention Guidelines for Ophthalmic Practices.

The World Health Organization declared the Coronavirus Disease 2019 (COVID-19) caused by Severe Acute Respiratory Syndrome Coronavirus 2 a "Pandemic" on March 11, 2020. As of June 1, 2020, Severe Acute Respiratory Syndrome Coronavirus 2 has infected >6.2 million people and caused >372,000 deaths, including many health care personnel. It is highly infectious and ophthalmologists are at a higher risk of the infection due to a number of reasons including the proximity between doctors and patients during ocular examinations, microaerosols generated by the noncontact tonometer, tears as a potential source of infection, and some COVID-19 cases present with conjunctivitis. This article describes the ocular manifestations of COVID-19 and the APAO guidelines in mitigating the risks of contracting and/or spreading COVID-19 in ophthalmic practices.

COVID-19: Special Precautions in Ophthalmic Practice and FAQs on Personal Protection and Mask Selection.

The Coronavirus Disease 2019 (COVID-19), caused by severe acute respiratory coronavirus-2, was first reported in December 2019. The World Health Organization declared COVID-19 a pandemic on March 11, 2020 and as of April 17, 2020, 210 countries are affected with >2,000,000 infected and 140,000 deaths. The estimated case fatality rate is around 6.7%. We need to step up our infection control measures immediately or else it may be too late to contain or control the spread of COVID-19. In case of local outbreaks, the risk of infection to healthcare workers and patients is high. Ophthalmic practice carries some unique risks and therefore high vigilance and special precautions are needed. We share our protocols and experiences in the prevention of infection in the current COVID-19 outbreak and the previous severe acute respiratory syndrome epidemic in Hong Kong. We also endeavor to answer the key frequently asked questions in areas of the coronaviruses, COVID-19, disease transmission, personal protection, mask selection, and special measures in ophthalmic practices. COVID-19 is highly infectious and could be life-threatening. Using our protocol and measures, we have achieved zero infection in our ophthalmic practices in Hong Kong and China. Preventing spread of COVID-19 is possible and achievable.

Comparison of macular buckling and vitrectomy for the treatment of macular schisis and associated macular detachment in high myopia: a randomized clinical trial.

OBJECTIVE: To compare the efficacy and safety of macular buckling and vitrectomy for myopic traction maculopathy showing macular schisis (MS) and associated macular detachment (MD) but without full-thickness macular hole (FTMH). DESIGN: Prospective, randomized, parallel, open-label study. METHODS: Patients were randomly assigned to either buckling or vitrectomy group. Macular buckling and intravitreal C3F8 gas injection were performed in the buckling group. Small gauge vitrectomy, internal limiting membrane peeling (ILMP) and C3F8 gas tamponade were performed in the vitrectomy group. The patients were followed for 12 months. MAIN OUTCOME MEASURES: Best-corrected visual acuity (BCVA) at 12 months. RESULTS: A total of 85 patients were randomized, 80 eyes were included (41 receiving buckling, 39 received vitrectomy), and 78 patients completed the study. There were less eyes determined as surgical failure and required a second surgery in the buckling group than vitrectomy the group (2.4% versus 18.4%, p = 0.021). After surgery, macular buckling achieved more improvement in BCVA (+21.7 versus +4.5 Early Treatment Diabetic Retinopathy Study (ETDRS) letters, p = 0.002). FTMH development was observed in only 1 (2.4%) eye, after removing of the implant due to recurrent conjunctival erosion, in the buckling group and 10 (26.3%) eyes (seven with-, three without MD) in the vitrectomy group (p < 0.001). More eyes developed cataracts in the vitrectomy group than did in the buckling group (28.9% versus 7.5%, p = 0.014). Macular buckling-associated strabismus (esotropia), binocular diplopia and implant exposure were observed in limited cases. CONCLUSIONS AND RELEVANCE: Macular buckling is superior to vitrectomy with ILM peeling plus gas injection for surgical treatment of MS and associated MD in high myopia.

Anti-vascular endothelial growth factor pharmacotherapy for age-related macular degeneration: a report by the American Academy of Ophthalmology.

OBJECTIVE: To examine the evidence about the safety and efficacy of anti-vascular endothelial growth factor (VEGF) pharmacotherapies for the treatment of neovascular age-related macular degeneration (AMD). DESIGN: Literature searches were conducted in May and October 2007 in PubMed with no date restrictions, limited to articles published in English, and in the Cochrane Central Register of Controlled Trials without a language limitation and yielded 310 citations. The first author reviewed the abstracts of these articles and selected 73 articles of possible clinical relevance for review by the panel. The panel deemed 64 of these articles sufficiently clinically relevant to review in full text and assigned ratings of level of evidence to each of the selected articles with the guidance of the panel methodologists. RESULTS: Eleven studies provided level I evidence for intravitreal pegaptanib and ranibizumab for neovascular AMD; there were no studies rated level I for bevacizumab for neovascular AMD. Five studies were rated as level II, which included studies of ranibizumab and bevacizumab, and the remaining 38 articles retrieved were rated as level III. The studies do not provide information about long-term results or the value (comparative effectiveness) and cost-effectiveness of combined therapies. CONCLUSIONS: Review of the available literature to date suggests that anti-VEGF pharmacotherapy, delivered by intravitreal injection, is a safe and effective treatment for neovascular AMD for up to 2 years. There is level I evidence to support this conclusion for pegaptanib and ranibizumab, but none for bevacizumab at this time.

Optical coherence tomography measurements and analysis methods in optical coherence tomography studies of diabetic macular edema.

OBJECTIVE: To evaluate optical coherence tomography (OCT) measurements and methods of analysis of OCT data in studies of diabetic macular edema (DME). DESIGN: Associations of pairs of OCT variables and results of 3 analysis methods using data from 2 studies of DME. PARTICIPANTS: Two hundred sixty-three subjects from a study of modified Early Treatment of Diabetic Retinopathy Study (mETDRS) versus modified macular grid (MMG) photocoagulation for DME and 96 subjects from a study of diurnal variation of DME. METHODS: Correlations were calculated for pairs of OCT variables at baseline and for changes in the variables over time. Distribution of OCT measurement changes, predictive factors for OCT measurement changes, and treatment group outcomes were compared when 3 measures of change in macular thickness were analyzed: absolute change in retinal thickness, relative change in retinal thickness, and relative change in retinal thickening. MAIN OUTCOME MEASURES: Concordance of results using different OCT variables and analysis methods. RESULTS: Center point thickness correlated highly with central subfield mean thickness (CSMT) at baseline (0.98-0.99). The distributions of changes in CSMT were approximately normally distributed for absolute change in retinal thickness and relative change in retinal thickness, but not for relative change in retinal thickening. Macular thinning in the mETDRS group was significantly greater than in the MMG group when absolute change in retinal thickness was used, but not when relative change in thickness and relative change in thickening were used. Relative change in macular thickening provides unstable data in eyes with mild degrees of baseline thickening, unlike the situation with absolute or relative change in retinal thickness. CONCLUSIONS: Central subfield mean thickness is the preferred OCT measurement for the central macula because of its higher reproducibility and correlation with other measurements of the central macula. Total macular volume may be preferred when the central macula is less important. Absolute change in retinal thickness is the preferred analysis method in studies involving eyes with mild macular thickening. Relative change in thickening may be preferable when retinal thickening is more severe.

Development and surgical removal of an epiretinal membrane in infantile nystagmus syndrome: a new type of oscillopsia.

PURPOSE: To report and discuss a focal oscillopsia in a small area of the visual field produced by, and after the removal of, an epiretinal membrane (ERM) in an individual with infantile nystagmus syndrome (INS) since birth with no associated afferent visual deficits. STUDY DESIGN: A retrospective case report. METHODS: A chart review, including clinical and electrophysiological data. A 74 y/o man with INS and an epiretinal membrane was studied. Detailed studies of the retina post-removal of an epiretinal membrane, with consequent changes in best-corrected visual acuity (BCVA), and subjective oscillopsia compared to INS waveforms. OCT measurements and eye-movement data from digital video and scleral search-coil systems were used. RESULTS: The monocular ERM produced an unexpected focal area of torsional/vertical oscillopsia (noted 1 year prior to the ERM surgery) in the portion of the visual field that corresponded with distortions from the ERM. The remainder of the visual field, corresponding with normal healthy retina was unaffected and stable in all planes. Post-removal, BCVA improved with redevelopment of the foveal pit and focal oscillopsia became less noticeable but remained due to the retinal distortion. CONCLUSIONS: In patients with INS, complete oscillopsia suppression across the visual field requires undistorted vision. If a retinal area of visual distortion develops or results from retinal surgery, a symptomatic island of oscillopsia in one or more planes may result.

Retinal Anatomy and Electrode Array Position in Retinitis Pigmentosa Patients After Argus II Implantation: An International Study.

PURPOSE: To assess the retinal anatomy and array position in Argus II retinal prosthesis recipients. DESIGN: Prospective, noncomparative cohort study. METHODS: Setting: International multicenter study. PATIENTS: Argus II recipients enrolled in the Post-Market Surveillance Studies. PROCEDURES: Spectral-domain optical coherence tomography images collected for the Surveillance Studies (NCT01860092 and NCT01490827) were reviewed. Baseline and postoperative macular thickness, electrode-retina distance (gap), optic disc-array overlap, and preretinal membrane presence were recorded at 1, 3, 6, and 12 months. MAIN OUTCOME MEASURES: Axial retinal thickness and axial gap along the array's long axis (a line between the tack and handle); maximal retinal thickness and maximal gap along a B-scan near the tack, midline, and handle. RESULTS: Thirty-three patients from 16 surgical sites in the United States and Germany were included. Mean axial retinal thickness increased from month 1 through month 12 at each location, but reached statistical significance only at the array midline (P = .007). The rate of maximal thickness increase was highest near the array midline (slope = 6.02, P = .004), compared to the tack (slope = 3.60, P < .001) or the handle (slope = 1.93, P = .368). The mean axial and maximal gaps decreased over the study period, and the mean maximal gap size decrease was significant at midline (P = .032). Optic disc-array overlap was seen in the minority of patients. Preretinal membranes were common before and after implantation. CONCLUSIONS: Progressive macular thickening under the array was common and corresponded to decreased electrode-retina gap over time. By month 12, the array was completely apposed to the macula in approximately half of the eyes.

The eye at altitude.

High altitude retinopathy (HAR) was first described in 1969 as engorgement of retinal veins with occasional papilloedema and vitreous hemorrhage. Since then various studies have attempted to define the incidence, etiology and significance of this phenomenon, usually with small numbers of subjects. Recently studies on relatively large groups of subjects in Nepal, Bolivia and Tibet have confirmed that the retinal vasculature becomes engorged and tortuous in all lowlanders ascending above 2500m. Sometimes this leads to hemorrhages, cotton wool spots and papilloedema, which is the pathological state better known as high altitude retinopathy. These studies have also shown a significant change in both corneal thickness and intraocular pressure at altitude. The retinal blood vessels are the only directly observable vascular system in the human body and also supply some of the most oxygen-demanding tissue, the photoreceptors of the retina. New techniques are being applied in both hypobaric chamber and field expeditions to observe changes in retinal function during conditions of hypobaric hypoxia. This work allows better advice to be given to lowlanders traveling to altitude either if they have pre-existing ocular conditions or if they suffer from visual problems whilst at altitude. This especially applies to the effect of altitude on refractive eye surgery and results of recent studies will be discussed so that physicians can advise their patients using the latest evidence. Retinal hypoxia at sea level accounts for the developed world's largest cause of blindness, diabetic retinopathy. The investigation of retinal response to hypobaric hypoxia in healthy subjects may open new avenues for treatment of this debilitating disease.