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Purpose To review the evidence on the safety and efficacy of current anti-vascular endothelial growth factor (VEGF) and intravitreal corticosteroid pharmacotherapies for the treatment of diabetic macular edema (DME). Methods Literature searches were last conducted on May 13, 2020, in the PubMed database with no date restrictions and limited to articles published in English. The combined searches yielded 230 citations, of which 108 were reviewed in full text. Of these, 31 were deemed appropriate for inclusion in this assessment and were assigned a level of evidence rating by the panel methodologist. Results Only the 21 articles with level I evidence were included in this assessment. Seventeen articles provided level I evidence for 1 or more anti-VEGF pharmacotherapies, including ranibizumab (14), aflibercept (5), and bevacizumab (2) alone or in combination with other treatments for DME. Level I evidence was identified in 7 articles on intravitreal corticosteroid therapy for treatment of DME: triamcinolone (1), dexamethasone (4), and fluocinolone acetonide (2). Conclusions Review of the available literature indicates that intravitreal injections of anti-VEGF agents and corticosteroids are efficacious treatments for DME. Elevated intraocular pressure and cataract progression are important potential complications of corticosteroid therapy. Further evidence is required to assess the comparative efficacy of these therapies. Given the limited high-quality comparative efficacy data, choice of therapy must be individualized for each patient and broad therapeutic access for patients is critical to maximize outcomes.

Purpose To determine classification criteria for tubercular uveitis DESIGN: Machine learning of cases with tubercular uveitis and 14 other uveitides. Methods Cases of non-infectious posterior or panuveitis, and of infectious posterior or panuveitis were collected in an informatics-designed preliminary database, and a final database was constructed of cases achieving supermajority agreement on the diagnosis, using formal consensus techniques. Cases were analyzed by anatomic class, and each class was split into a training set and a validation set. Machine learning using multinomial logistic regression was used on the training set to determine a parsimonious set of criteria that minimized the misclassification rate among the intermediate uveitides. The resulting criteria were evaluated on the validation sets. Results Two hundred seventy-seven cases of tubercular uveitis were evaluated by machine learning against other uveitides. Key criteria for tubercular uveitis were a compatible uveitic syndrome, including: 1) anterior uveitis with iris nodules, 2) serpiginous-like tubercular choroiditis, 3) choroidal nodule (tuberculoma), 4) occlusive retinal vasculitis, and 5) in hosts with evidence of active systemic tuberculosis, multifocal choroiditis; and evidence of tuberculosis, including: 1) histologically- or microbiologically-confirmed infection, 2) positive interferon-Ɣ release assay test, or 3) positive tuberculin skin test. The overall accuracy of the diagnosis of tubercular uveitis versus other uveitides in the validation set was 98.2% (95% CI 96.5, 99.1). The misclassification rates for tubercular uveitis were: training set 3.4%; and validation set 3.6%. Conclusions The criteria for tubercular uveitis had a low misclassification rate and appeared to perform sufficiently well for use in clinical and translational research.

To determine classification criteria for acute retinal necrosis (ARN).Machine learning of cases with ARN and 4 other infectious posterior uveitides / panuveitides.Cases of infectious posterior uveitides / panuveitides were collected in an informatics-designed preliminary database, and a final database was constructed of cases achieving supermajority agreement on diagnosis, using formal consensus techniques. Cases were split into a training set and a validation set. Machine learning using multinomial logistic regression was used on the training set to determine a parsimonious set of criteria that minimized the misclassification rate among the infectious posterior uveitides / panuveitides. The resulting criteria were evaluated on the validation set.Eight hundred three cases of infectious posterior uveitides / panuveitides, including 186 cases of ARN, were evaluated by machine learning. Key criteria for ARN included (1) peripheral necrotizing retinitis and either (2) polymerase chain reaction assay of an intraocular fluid specimen positive for either herpes simplex virus or varicella zoster virus or (3) a characteristic clinical appearance with circumferential or confluent retinitis, retinal vascular sheathing and/or occlusion, and more than minimal vitritis. Overall accuracy for infectious posterior uveitides / panuveitides was 92.1% in the training set and 93.3% (95% confidence interval 88.2, 96.3) in the validation set. The misclassification rates for ARN were 15% in the training set and 11.5% in the validation set.The criteria for ARN had a reasonably low misclassification rate and seemed to perform sufficiently well for use in clinical and translational research.

PURPOSE: To determine classification criteria for cytomegalovirus (CMV) retinitis. DESIGN: Machine learning of cases with CMV retinitis and 4 other infectious posterior/panuveitides. METHODS: Cases of infectious posterior/panuveitides were collected in an informatics-designed preliminary database, and a final database was constructed of cases achieving supermajority agreement on diagnosis, using formal consensus techniques. Cases were split into a training set and a validation set. Machine learning using multinomial logistic regression was used on the training set to determine a parsimonious set of criteria that minimized the misclassification rate among the infectious posterior/panuveitides. The resulting criteria were evaluated on the validation set. RESULTS: Eight hundred three cases of infectious posterior/panuveitides, including 211 cases of CMV retinitis, were evaluated by machine learning. Key criteria for CMV retinitis included: 1) necrotizing retinitis with indistinct borders due to numerous small satellites; 2) evidence of immune compromise; and either 3) a characteristic clinical appearance or 4) positive polymerase chain assay for CMV from an intraocular specimen. Characteristic appearances for CMV retinitis included: 1) wedge-shaped area of retinitis; 2) hemorrhagic retinitis; or 3) granular retinitis. Overall accuracy for infectious posterior/panuveitides was 92.1% in the training set and 93.3% (95% confidence interval 88.2, 96.3) in the validation set. The misclassification rates for CMV retinitis were 6.9% in the training set and 6.3% in the validation set. CONCLUSIONS: The criteria for CMV retinitis had a low misclassification rate and appeared to perform sufficiently well for use in clinical and translational research.

PURPOSE: To determine classification criteria for syphilitic uveitis DESIGN: Machine learning of cases with syphilitic uveitis and 24 other uveitides. METHODS: Cases of anterior, intermediate, posterior, and panuveitides were collected in an informatics-designed preliminary database, and a final database was constructed of cases achieving supermajority agreement on the diagnosis, using formal consensus techniques. Cases were analyzed by anatomic class, and each class was split into a training set and a validation set. Machine learning using multinomial logistic regression was used on the training set to determine a parsimonious set of criteria that minimized the misclassification rate among the different uveitic classes. The resulting criteria were evaluated on the validation set. RESULTS: Two hundred twenty-two cases of syphilitic uveitis were evaluated by machine learning with cases evaluated against other uveitides in the relevant uveitic class. Key criteria for syphilitic uveitis included a compatible uveitic presentation, (1) anterior uveitis, 2) intermediate uveitis, or 3) posterior or panuveitis with retinal, retinal pigment epithelial, or retinal vascular inflammation) and evidence of syphilis infection with a positive treponemal test. The Centers for Disease Control and Prevention reverse screening algorithm for syphilis testing is recommended. The misclassification rates for syphilitic uveitis in the training sets were: anterior uveitides 0%, intermediate uveitides 6.0%, posterior uveitides 0%, panuveitides 0%, and infectious posterior/panuveitides 8.6%. The overall accuracy of the diagnosis of syphilitic uveitis in the validation set was 100% (99% CI 99.5, 100) – i.e. the validation sets misclassification rates were 0% for each uveitic class. CONCLUSIONS: The criteria for syphilitic uveitis had a low misclassification rate and appeared to perform sufficiently well for use in clinical and translational research.

Purpose To provide recommendations for diagnosis of vitreoretinal lymphoma (VRL). Methods Literature was reviewed for reports supporting the diagnosis of VRL. A questionnaire (Delphi 1 round) was distributed to 28 participants. In the second round (Delphi 2), items of the questionnaire not reaching consensus (75% agreement) were discussed to finalize the recommendations. Results Presenting symptoms include floaters and painless loss of vision, vitreous cells organized into sheets or clumps. Retinal lesions are usually multifocal creamy/white in the outer retina. Other findings include retinal lesions with "leopard-skin" appearance and retinal pigment epithelium atrophy. Severe vitreous infiltration without macular edema is the most likely presentation. Diagnostic vitrectomy should be performed. Systemic corticosteroid should be discontinued at least 2 weeks before surgery. An interleukin (IL)-10:IL-6 ratio > 1, positive mutation for the myeloid differentiation primary response 88 gene and monoclonality are indicators of VRL. Multi-modal imaging (optical coherence tomography, fundus autofluorescence) are recommended. Conclusions A consensus meeting allowed the establishment of recommendations important for the diagnosis of VRL.

Topic An international, expert-led consensus initiative organized by the Collaborative Ocular Tuberculosis Study (COTS), along with the International Ocular Inflammation Society and the International Uveitis Study Group, systematically developed evidence- and experience-based recommendations for the treatment of tubercular choroiditis. Clinical relevance The diagnosis and management of tubercular uveitis (TBU) pose a significant challenge. Current guidelines and literature are insufficient to guide physicians regarding the initiation of antitubercular therapy (ATT) in patients with TBU. Methods An international expert steering subcommittee of the COTS group identified clinical questions and conducted a systematic review of the published literature on the use of ATT for tubercular choroiditis. Using an interactive online questionnaire, guided by background knowledge from published literature, 81 global experts (including ophthalmologists, pulmonologists, and infectious disease physicians) generated preliminary consensus statements for initiating ATT in tubercular choroiditis, using Oxford levels of medical evidence. In total, 162 statements were identified regarding when to initiate ATT in patients with tubercular serpiginous-like choroiditis, tuberculoma, and tubercular focal or multifocal choroiditis. The COTS group members met in November 2018 to refine these statements by a 2-step modified Delphi process. Results Seventy consensus statements addressed the initiation of ATT in the 3 subtypes of tubercular choroiditis, and in addition, 10 consensus statements were developed regarding the use of adjunctive therapy in tubercular choroiditis. Experts agreed on initiating ATT in tubercular choroiditis in the presence of positive results for any 1 of the positive immunologic tests along with radiologic features suggestive of tuberculosis. For tubercular serpiginous-like choroiditis and tuberculoma, positive results from even 1 positive immunologic test were considered sufficient to recommend ATT, even if there were no radiologic features suggestive of tuberculosis. Discussion Consensus guidelines were developed to guide the initiation of ATT in patients with tubercular choroiditis, based on the published literature, expert opinion, and practical experience, to bridge the gap between clinical need and available medical evidence.

Topic The Collaborative Ocular Tuberculosis Study (COTS), supported by the International Ocular Inflammation Society, International Uveitis Study Group, and Foster Ocular Immunological Society, set up an international, expert-led consensus project to develop evidence- and experience-based guidelines for the management of tubercular uveitis (TBU). Clinical Relevance The absence of international agreement on the use of antitubercular therapy (ATT) in patients with TBU contributes to a significant heterogeneity in the approach to the management of this condition. Methods Consensus statements for the initiation of ATT in TBU were generated using a 2-step modified Delphi technique. In Delphi step 1, a smart web-based survey based on background evidence from published literature was prepared to collect the opinion of 81 international experts on the use of ATT in different clinical scenarios. The survey included 324 questions related to tubercular anterior uveitis (TAU), tubercular intermediate uveitis (TIU), tubercular panuveitis (TPU), and tubercular retinal vasculitis (TRV) administered by the experts, after which the COTS group met in November 2019 for a systematic and critical discussion of the statements in accordance with the second round of the modified Delphi process. Results Forty-four consensus statements on the initiation of ATT in TAU, TIU, TPU, and TRV were obtained, based on ocular phenotypes suggestive of TBU and corroborative evidence of tuberculosis, provided by several combinations of immunologic and radiologic test results. Experts agreed on initiating ATT in recurrent TAU, TIU, TPU, and active TRV depending on the TB endemicity. In the presence of positive results for any 1 of the immunologic tests along with radiologic features suggestive of past evidence of tuberculosis infection. In patients with a first episode of TAU, consensus to initiate ATT was reached only if both immunologic and radiologic test results were positive. Discussion The COTS consensus guidelines were generated based on the evidence from published literature, specialists’ opinions, and logic construction to address the initiation of ATT in TBU. The guidelines also should inform public policy by adding specific types of TBU to the list of conditions that should be treated as tuberculosis.

The management of noninfectious uveitis is constantly evolving. A new "biologic era" in treatment began after the effectiveness of tumor necrosis factor-alpha blocking drugs was demonstrated in rheumatologic inflammatory diseases. The goal of specific immunomodulation with a biologic drug is to target inflammation at the molecular level with a low rate of serious adverse events. The purpose of this review is to summarize current knowledge of biologic drugs in the treatment of noninfectious uveitis by describing clinical studies and recent pharmacological developments.

Importance Australian- and New Zealand-based, uveitis-specialized ophthalmologists have produced recommendations for the management of juvenile idiopathic arthritis (JIA)-type chronic anterior uveitis. Background Historically, the visual prognosis of JIA-type chronic anterior uveitis has been poor. New medical advances are likely to improve outcomes, but recently published guidelines are tailored for ophthalmic care in Europe and the United States. Design This work involved a consensus survey and a panel meeting. Participants The Australian and New Zealand JIA-Uveitis Working Group (29 ophthalmologists) participated in the work. Methods The Delphi technique was used to achieve consensus. Main outcome measures This work yielded consensus statements. Results The Working Group achieved consensus around 18 statements related to clinical evaluation, use of topical and regional corticosteroids, use of systemic corticosteroid and non-corticosteroid immunomodulatory drugs, and management of secondary cataract and glaucoma in childhood JIA-type uveitis. Conclusions and relevance Recommendations of the Australian and New Zealand JIA-Uveitis Working Group provide current and regionally applicable advice for managing chronic anterior uveitis in children with JIA.

AimsTo establish expert recommendations for the management of ocular sarcoidosis (OS).MethodsA question-based survey on the management of OS was circulated to international uveitis experts (members of the International Uveitis Study Group and the International Ocular Inflammation Society) electronically. Subsequently, a consensus workshop was conducted at the 7th International Workshop on Ocular Sarcoidosis (IWOS) in June 2019 in Sapporo, Japan as part of the Global Ocular Inflammation Workshops. Statements on the management of OS that were supported by a two-thirds majority of 10 international panel members of the workshop, after discussion and voting, were taken as consensus agreement.ResultsA total of 98 participants from 29 countries responded to the questionnaire survey. The subsequent consensus workshop established recommendations for the management of OS in five sections. The first section concerned evaluation and monitoring of inflammation. The second, third and fourth sections described ocular manifestations that were indications for treatment, and the management of anterior uveitis, intermediate uveitis and posterior uveitis. In the fifth section, the use of systemic corticosteroids and systemic immunosuppressive drugs were detailed.ConclusionsRecommendations for management of OS were formulated through an IWOS consensus workshop.

Primary central nervous system lymphoma (PCNSL) may manifest initially in the eye (termed vitreoretinal lymphoma or VRL) or in non-ocular CNS compartments, or in both. The nature of the onset of PCNSL implies two clinical specialists - ophthalmologists and neuro-oncologists - independently may assess the primary presentation of this rare malignancy. Clinically relevant perspectives on expectations of PCNSL manifestation in both ocular and non-ocular CNS compartments would help inform management practices in each specialty, which should impact clinical outcomes. A recent increase in the number of published PCNSL cohort studies provides new opportunity to review the current prevalence rates of ocular involvement, and the timing of this involvement over the course of disease. In PCNSL cohorts defined by non-ocular CNS compartment involvement, with or without ocular involvement (termed "PCNSL ± ocular involvement" cohorts), mean rates of concomitant VRL at diagnosis, or at any time during the course, are 10% and 16%, respectively. Only a few individuals within this cohort group present with exclusive eye disease (

Purpose: To describe the epidemiology, clinical characteristics, diagnosis and treatment of human immunodeficiency virus (HIV)-related primary vitreoretinal lymphoma (PVRL).Methods: Narrative literature review.Results: HIV-related PVRL occurs in persons who are relatively young and generally have very low CD4+ T-cell counts. Vitritis with subretinal or sub-retinal pigment epithelial infiltrates is typical. Vitreous cytology remains the gold standard for diagnosis, supplemented by flow cytometry and genetic analyses of tumor cells, and measurement of aqueous or vitreous interleukin-10 levels. Concurrent brain involvement also may establish the diagnosis. Treatment includes antiretroviral therapy (ART), systemic chemotherapy (usually methotrexate-based) and local ocular treatment (intravitreal methotrexate, intravitreal rituximab, external beam radiotherapy). Systemic chemotherapy is of uncertain value for PVRL without other central nervous system involvement. Prognosis is poor, but has improved significantly compared to the pre-ART era.Conclusions: Ophthalmologists should consider the diagnosis of PVRL in HIV-positive individuals who present with intermediate or posterior uveitis.

Uveitis is a broad term that refers to a large group of eye disorders categorized by intraocular inflammation, a leading cause of visual impairment. Historically, treatment of noninfectious uveitis has depended on corticosteroid drugs. Owing to the myriad of side effects caused by corticosteroids, immunomodulatory therapy has become the preferred treatment for chronic noninfectious intraocular inflammation. Recently, biological response modifiers have established a new era in uveitis therapy, with the range of targets continuing to expand. In this review, we aimed to convey up-to-date information on the treatment of noninfectious uveitis to the general ophthalmologist.

Purpose: To investigate prevalence and trends in women's authorship of articles in ophthalmic review journals over 2 decades. Design: Literature survey. Methods: Total number of authors, and number and gender of first and senior (last-named) authors, were identified in all full reviews published in Prog Retin Eye Res, Surv Ophthalmol, and Curr Opin Ophthalmol for the calendar years 1999, 2009, and 2019. The gender of authors was assigned manually by multiple methods. The subspecialty area of each review was captured by keyword and text search. Country of origin was determined from attributions of first and senior authors. Results: The gender of 841 first and senior authors was assigned unequivocally for 471 articles (96%). The frequency of women's authorship rose significantly over time (1999, 2009, 2019) for both first authors (19%, 32%, 44%; P

Ocular involvement is a rare manifestation of tuberculosis. Four key issues historically faced by clinicians when diagnosing and treating ocular tuberculosis - diagnostic uncertainty, naturally heterogeneous presentations, limitations of existing laboratory diagnostic tools, and non-uniform treatment guidelines - continue to test today's physicians. Unparalleled scientific and clinical developments over the past century have greatly expanded the knowledge surrounding this challenging ophthalmic condition. Experience with large volumes of cases at tuberculosis-endemic centres has led to recent growth in knowledge and physician experience, perhaps more so in developing countries. Looking forward, the role of diverse new technologies, including artificial intelligence and proteomics, will advance ocular tuberculosis research. Efforts have been made to address the lack of standardized nomenclature, diagnostic uncertainty, and unvalidated, geographically variable treatment guidelines.

The pursuit of simple, yet fair, unbiased, and objective measures of researcher performance has occupied bibliometricians and the research community as a whole for decades. However, despite the diversity of available metrics, most are either complex to calculate or not readily applied in the most common assessment exercises (e.g., grant assessment, job applications). The ubiquity of metrics like the h-index (h papers with at least h citations) and its time-corrected variant, the m-quotient (h-index ÷ number of years publishing) therefore reflect the ease of use rather than their capacity to differentiate researchers fairly among disciplines, career stage, or gender. We address this problem here by defining an easily calculated index based on publicly available citation data (Google Scholar) that corrects for most biases and allows assessors to compare researchers at any stage of their career and from any discipline on the same scale. Our ε′-index violates fewer statistical assumptions relative to other metrics when comparing groups of researchers, and can be easily modified to remove inherent gender biases in citation data. We demonstrate the utility of the ε′-index using a sample of 480 researchers with Google Scholar profiles, stratified evenly into eight disciplines (archaeology, chemistry, ecology, evolution and development, geology, microbiology, ophthalmology, palaeontology), three career stages (early, mid-, late-career), and two genders. We advocate the use of the ε′-index whenever assessors must compare research performance among researchers of different backgrounds, but emphasize that no single index should be used exclusively to rank researcher capability.

AimsInternational criteria for the diagnosis of ocular sarcoidosis (OS) was established by the first International Workshop on Ocular Sarcoidosis (IWOS) and validations studies revealed certain limitations of the criteria. To overcome the limitations, revised IWOS criteria was established in an international meeting. This manuscript was aimed at reporting the revised IWOS criteria.MethodsA consensus workshop was carried out to discuss and revise the IWOS criteria. The workshop was held on 27 April 2017, in Nusa Dua, Bali, Indonesia. Prior to the workshop, a questionnaire proposing revised criteria and consisting of one item for differential diagnosis, seven items for ocular clinical signs, 10 items for systemic investigations and three categories of diagnostic criteria was circulated to 30 uveitis specialists. Questionnaire items with over 75% support were taken as consensus agreement; items with below 50% support were taken as consensus disagreement and items with 50%–75% support were discussed at the workshop. Of the latter items, those supported by two-thirds majority in the workshop were taken as consensus agreement.ResultsThe survey and subsequent workshop reached consensus agreements of the revised criteria for the diagnosis of OS as follows: (1) other causes of granulomatous uveitis must be ruled out; (2) seven intraocular clinical signs suggestive of OS; (3) eight results of systemic investigations in suspected OS and (4) three categories of diagnostic criteria depending on biopsy results and combination of intraocular signs and results of systemic investigations.ConclusionsRevised IWOS criteria were proposed by a consensus workshop.

To describe the epidemiology of macular edema (ME) in patients with uveitis.Review of articles listed on PubMed pertaining to uveitic ME.Reported rates of uveitic ME ranging from 20% to 70%, depending on the ancillary tests used (fundus examination, fluorescein angiography, optical coherence tomography). Macular edema might develop due to uveitis itself, or occur as an adverse effect of drugs taken for different diseases. It is more frequently observed in adults than in children, in chronic uveitis, and in intermediate uveitis. Males with ankylosing spondylitis are more prone to develop ME than females. Three patterns of uveitic ME are observed, either isolated or in combination: cystoid ME, the most frequently encountered pattern seen in up to 80% of cases, diffuse ME and serous retinal detachment.Older age, chronicity of uveitis and intermediate uveitis are risk factors for the development of ME in patients with uveitis.

BackgroundSyphilitic uveitis is re-emerging alongside the systemic infection. In July 2017, an international group of uveitis-specialised ophthalmologists formed the International Ocular Syphilis Study Group to define current practice patterns.Methods103 Study Group members based in 35 countries completed a 25-item questionnaire focused on case load, clinical presentations, use and interpretation of investigations, treatment and clinical indicators of poor prognosis.ResultsMembers managed a mean of 6.1 patients with syphilitic uveitis in clinics that averaged 707 annual cases of uveitis (0.9%); 53.2% reported increasing numbers over the past decade. Patients presented to more members (40.2%) during secondary syphilis. Uveitis was usually posterior (60.8%) or pan (22.5%); complications included optic neuropathy, macular oedema and posterior synechiae. All members diagnosed syphilitic uveitis using serological tests (simultaneous or sequential testing algorithms), and 97.0% routinely checked for HIV co-infection. Cerebrospinal fluid (CSF) analysis was ordered by 90.2% of members, and 92.7% took uveitis plus Venereal Disease Research Laboratory test (VDRL) or fluorescent treponemal antibody absorption test (FTA-ABS) to indicate neurosyphilis. Patients were commonly co-managed with infectious disease physicians, and treated with penicillin for at least 10–14 days, plus corticosteroid. Features predicting poor outcome included optic neuropathy (86.3%) and initial misdiagnosis (63.7%). Reasons for delayed diagnosis were often practitioner-related. 82.5% of members tested every patient they managed with uveitis for syphilis.ConclusionThis comprehensive report by an international group of uveitis-specialised ophthalmologists provides a current approach for the management of syphilitic uveitis.

PURPOSE: To determine classification criteria for toxoplasmic retinitis. DESIGN: Machine learning of cases with toxoplasmic retinitis and 4 other infectious posterior/panuveitides. METHODS: Cases of infectious posterior/panuveitides were collected in an informatics-designed preliminary database, and a final database was constructed of cases achieving supermajority agreement on diagnosis, using formal consensus techniques. Cases were split into a training set and a validation set. Machine learning using multinomial logistic regression was used on the training set to determine a parsimonious set of criteria that minimized the misclassification rate among the infectious posterior/panuveitides. The resulting criteria were evaluated on the validation set. RESULTS: Eight hundred three cases of infectious posterior/panuveitides, including 174 cases of toxoplasmic retinitis, were evaluated by machine learning. Key criteria for toxoplasmic retinitis included: 1) focal or paucifocal necrotizing retinitis and either; 2) positive polymerase chain reaction assay for Toxoplasma gondii from an intraocular specimen or 3) the characteristic clinical picture of a round or oval retinitis lesion proximal to a hyperpigmented and/or atrophic chorioretinal scar. Overall accuracy for infectious posterior/panuveitides was 92.1% in the training set and 93.3% (95% confidence interval 88.2, 96.3) in the validation set. The misclassification rates for toxoplasmic retinitis were 8.2% in the training set and 10% in the validation set. CONCLUSIONS: The criteria for toxoplasmic retinitis had a low misclassification rate and appeared to perform sufficiently well for use in clinical and translational research.

"The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in December 2019 in Wuhan city, Hubei province, China. This is the third and largest coronavirus outbreak since the new millennium after SARS in 2002 and Middle East respiratory syndrome (MERS) in 2012. Over 3?million people have been infected and the COVID-19 has caused more than 217 000 deaths. A concern exists regarding the vulnerability of patients who have been treated with immunosuppressive drugs prior or during this pandemic. Would they be more susceptible to infection by the SARS-CoV-2 and how would their clinical course be altered by their immunosuppressed state? This is a question the wider medical fraternity—including ophthalmologists, rheumatologists, gastroenterologist and transplant physicians among others—must answer. The evidence from the SARS and MERS outbreak offer some degree of confidence that immunosuppression is largely safe in the current COVID-19 pandemic. Preliminary clinical experiences based on case reports, small series and observational studies show the morbidity and mortality rates in immunosuppressed patients may not differ largely from the general population. Overwhelmingly, current best practice guidelines worldwide recommended the continuation of immunosuppression treatment in patients who require them except for perhaps high-dose corticosteroid therapy and in patients with associated risk factors for severe COVID-19 disease. This article is made freely available for use in accordance with BMJ's website terms and conditions for the duration of the COVID-19 pandemic or until otherwise determined by BMJ. You may use, download and print the article for any lawful, non-commercial purpose (including text and data mining) provided that all copyright notices and trade marks are retained."

Ocular toxoplasmosis is the leading cause of posterior uveitis worldwide. We conducted an observational study of 262 consecutive individuals (n = 344 eyes) with ocular toxoplasmosis who were followed over a 34-month period. Most subjects were T. gondii IgG + /IgM- (n = 242; 92.4%; 317 eyes), and 140 eyes (40.7%) had active lesions. For eyes in which retinal lesions were active at recruitment and best-corrected visual acuity (BCVA) could be measured (n = 133), 21.0% (n = 28) remained blind (BCVA below 20/400) after inflammation resolved. In these eyes, atypical ocular toxoplasmosis (OR 4.99; 95% CI 1.14–22.85; p = 0.0330), macular lesion (OR 9.95; 95% CI 2.45–47.15; p = 0.0019) and any complication (OR 10.26; 95% CI 3.82–30.67; p p = 0.0013) and macular lesion (OR 5.69; 95% CI 2.53–13.54; p p = 0.0493) and active disease at presentation (OR 4.74; 95% CI 1.95–12.91; p = 0.0011) were associated with recurrences. Additional clinical attention should be directed towards patients with risk factors for poor visual outcome.

Purpose To develop an agreed upon set of outcomes known as a “core outcome set” (COS) for noninfectious uveitis of the posterior segment (NIU-PS) clinical trials. Design Mixed-methods study design comprising a systematic review and qualitative study followed by a 2-round Delphi exercise and face-to-face consensus meeting. Participants Key stakeholders including patients diagnosed with NIU-PS, their caregivers, and healthcare professionals involved in decision-making for patients with NIU-PS, including ophthalmologists, nurse practitioners, and policymakers/commissioners. Methods A long list of outcomes was developed based on the results of (1) a systematic review of clinical trials of NIU-PS and (2) a qualitative study of key stakeholders including focus groups and interviews. The long list was used to generate a 2-round Delphi exercise of stakeholders rating the importance of outcomes on a 9-point Likert scale. The proportion of respondents rating each item was calculated, leading to recommendations of “include,” “exclude,” or “for discussion” that were taken to a face-to-face consensus meeting of key stakeholders at which they agreed on the final COS. Main Outcome Measure Items recommended for inclusion in the COS for NIU-PS. Results A total of 57 outcomes grouped in 11 outcome domains were presented for evaluation in the Delphi exercise, resulting in 9 outcomes directly qualifying for inclusion and 15 outcomes being carried forward to the consensus meeting, of which 7 of 15 were agreed on for inclusion. The final COS contained 16 outcomes organized into 4 outcome domains comprising visual function, health-related quality of life, treatment side effects, and disease control. Conclusions This study builds on international work across the clinical trials community and our qualitative research to construct the world’s first COS for NIU-PS. The COS provides a list of outcomes that represent the priorities of key stakeholders and provides a minimum set of outcomes for use in all future NIU-PS clinical trials. Adoption of this COS can improve the value of future uveitis clinical trials and reduce noninformative research. Some of the outcomes identified do not yet have internationally agreed upon methods for measurement and should be the subject of future international consensus development.

After the outbreak of the disease COVID-19, it has reached pandemic proportions within a very short time. It is mainly transmitted human-to-human through direct contact with secretions from an infected person or through inhalation of droplets containing SARS-CoV-2. It is controversial whether the virus may be transmitted via tears. Exposed ocular surface can serve as a gateway in transmission and acquiring respiratory diseases. Considering the reported cases on healthcare workers indicating nosocomial transmission and the anatomical and physiological aspects it is perceived that ophthalmic healthcare professionals are at higher risk of contracting the virus by virtue of their job. In this narrative review we discuss current evidence around detection of SARS-CoV-2 in human tears and forms of transmissions reported to date. We also provide a comprehensive approach that may be implemented in an ophthalmic care facility to protect healthcare personnel, as well as patients, from contracting the virus.

Introduction: Uveitic macular edema (UME) is a significant cause of visual impairment in all uveitis types. Methods: Reports that were cited in the MEDLINE database, that analyzed the effectiveness of biologics for UME in at least five patients, with a minimum follow-up of 3 months, published prior to April 1, 2019 were included. Reports that did not compare UME findings before and after the therapy, using either OCT or fluorescein angiography, were excluded. Results: Case series that analyzed the efficacy of intravitreal anti-VEGF agents showed modest, short-term benefit. Studies that investigated systemic anti-TNF agents in patients with noninfectious uveitis reported a therapeutic effect on UME. Anti-IL-6 antibodies have shown promising results for most severe cases of noninfectious UME. Interferon represents an option for patients with persistent UME in infectious and noninfectious uveitis. Conclusion: Multicenter, randomized controlled trials are needed to assess the effectiveness of each group of biologic agents in sufficient number of patients.

An international, expert led consensus initiative was set up by the Collaborative Ocular Tuberculosis Study (COTS) group to develop systematic, evidence, and experience-based recommendations for the treatment of ocular TB using a modified Delphi technique process. In the first round of Delphi, the group identified clinical scenarios pertinent to ocular TB based on five clinical phenotypes (anterior uveitis, intermediate uveitis, choroiditis, retinal vasculitis, and panuveitis). Using an interactive online questionnaires, guided by background knowledge from published literature, 486 consensus statements for initiating ATT were generated and deliberated amongst 81 global uveitis experts. The median score of five was considered reaching consensus for initiating ATT. The median score of four was tabled for deliberation through Delphi round 2 in a face-to-face meeting. This report describes the methodology adopted and followed through the consensus process, which help elucidate the guidelines for initiating ATT in patients with choroidal TB.

Recent reports from different world regions suggest ocular syphilis is re-emerging, in parallel with an increasing incidence of the systemic infection globally. We conducted a large observational study of 127 persons consecutively treated for ocular syphilis at public medical centers in Brazil over a 2.5-year period ending July 2015. Of 104 individuals serologically tested for human immunodeficiency virus (HIV), 34.6% were positive. Ophthalmological evaluations included measurement of Snellen visual acuity and intraocular pressure, and assessment of inflammation by slit lamp examination and dilated posterior eye examination. Involvements in 214 eyes were anterior (6.1%), intermediate (8.4%), posterior (76.2%) and pan- (8.4%) uveitis, and scleritis (0.9%). Multiple anterior and posterior eye complications were observed, including cataract in the anterior eye (incidence rate, 0.18/eye-year) and epiretinal membrane in the posterior eye (incidence rate, 0.09/eye-year); incidence rates of reduction in best-corrected visual acuity to ≤20/50 and ≤20/200 were 0.10 and 0.06/eye-year, respectively. Rates of complications and visual acuity loss did not differ significantly between HIV- positive and negative individuals. In an era of re-emergence, syphilis has ocular complications that may compromise vision, despite treatment with appropriate anti-microbial drugs.

In the wake of the international Ebola virus disease (EVD) outbreak from 2014 to 2016, thousands of EVD survivors are at-risk of ophthalmic manifestations, as well as systemic sequelae including arthralgias, abdominal pain, psychosocial stressors, and risk of viral persistence in immune-privileged organs. Ophthalmic manifestations in EVD survivors include a spectrum of disease ranging from anterior uveitis to panuveitis, which confers a high risk of vision impairment and blindness, particularly given the access and resource limitations for ophthalmic subspecialty care in West Africa. Clinical studies in EVD survivors, animal models of EVD and translational investigation, have provided early insight into eye disease pathogenesis. Specifically, ocular inflammation recently observed in EVD survivors is thought to involve direct viral infection, inflammation, and tissue edema. Future research is needed to understand the timing of uveitis onset and management strategies, including the role of antiviral and anti-inflammatory therapies.

Vitreoretinal lymphoma, which most commonly is diffuse large B-cell non-Hodgkin in type, is a rare cancer with high morbidity and high mortality. Making a tissue diagnosis of vitreoretinal lymphoma is a major challenge for clinicians due to biological and technical factors. Yet, the delay in start of treatment may have vision- and life-threatening consequences, and there is considerable interest in the application of molecular assays to improve the accuracy of the diagnostic process: detection of a clonal immunoglobulin heavy-chain rearrangements in lymphoma cells by polymerase chain reaction; measurement of vitreous or aqueous interleukin-10 protein levels in ocular fluids; and identification of mutations in the myeloid differentiation primary response gene 88 in tumour cells. In this article, we review the historical development and current application of each of these molecular methods. We also discuss future opportunities for the molecular diagnosis of vitreoretinal lymphoma through next-generation sequencing technologies.

Background Over-production of reactive oxygen species (ROS) and resulting oxidative stress contribute to retinal damage in vascular diseases that include diabetic retinopathy, retinopathy of prematurity and major retinal vessel occlusions. NADPH oxidase (Nox) proteins are professional ROS-generating enzymes, and therapeutic targeting in these diseases has strong appeal. Pharmacological inhibition of Nox4 reduces the severity of experimental retinal vasculopathy. We investigated the potential application of this drug approach in humans. Methods Differential Nox enzyme expression was studied by real-time-quantitative polymerase chain reaction in primary human retinal endothelial cell isolates and a characterized human retinal endothelial cell line. Oxidative stress was triggered chemically in endothelial cells, by treatment with dimethyloxalylglycine (DMOG; 100 μM); Nox4 and vascular endothelial growth factor (VEGFA) transcript were measured; and production of ROS was detected by 2',7'-dichlorofluorescein. DMOG-stimulated endothelial cells were treated with two Nox1/Nox4 inhibitors, GKT136901 and GKT137831; cell growth was monitored by DNA quantification, in addition to VEGFA transcript and ROS production. Results Nox4 (isoform Nox4A) was the predominant Nox enzyme expressed by human retinal endothelial cells. Treatment with DMOG significantly increased endothelial cell expression of Nox4 over 72 h, accompanied by ROS production and increased VEGFA expression. Treatment with GKT136901 or GKT137831 significantly reduced DMOG-induced ROS production and VEGFA expression by endothelial cells, and the inhibitory effect of DMOG on cell growth. Conclusions Our findings in experiments on activated human retinal endothelial cells provide translational corroboration of studies in experimental models of retinal vasculopathy and support the therapeutic application of Nox4 inhibition by GKT136901 and GKT137831 in patients with retinal vascular diseases.

Purpose: To standardize a nomenclature system for defining clinical phenotypes, and outcome measures for reporting clinical and research data in patients with ocular tuberculosis (OTB).Methods: Uveitis experts initially administered and further deliberated the survey in an open meeting to determine and propose the preferred nomenclature for terms related to the OTB, terms describing the clinical phenotypes and treatment and reporting outcomes.Results: The group of experts reached a consensus on terming uveitis attributable to tuberculosis (TB) as tubercular uveitis. The working group introduced a SUN-compatible nomenclature that also defines disease "remission" and "cure", both of which are relevant for reporting treatment outcomes.Conclusion: A consensus nomenclature system has been adopted by a large group of international uveitis experts for OTB. The working group recommends the use of standardized nomenclature to prevent ambiguity in communication and to achieve the goal of spreading awareness of this blinding uveitis entity.

The most common human disease caused by infection with Toxoplasma gondii is ocular toxoplasmosis, which typically is manifest as recurrent attacks of necrotizing retinal inflammation with subsequent scarring. The multilayered retina contains specialized cell populations, including endothelial cells, epithelial cells, neurons and supporting cells, all of which may be involved in this condition. In vitro investigations of basic mechanisms operating in human ocular toxoplasmosis use cellular and molecular methods that are common to the study of many pathological processes, and the novel aspect of this research is the use of human retinal cell subsets. Most in vivo research on ocular toxoplasmosis is conducted in the laboratory mouse. Experimental models involve local or systemic inoculation of parasites to induce acute disease, or sequential systemic and local parasite inoculations to trigger recurrent disease. We present methods for in vitro and in vivo studies of ocular toxoplasmosis, including dissection of the human eye, and culture and infection of differentiated cell populations from the retina, as well as induction of mouse ocular toxoplasmosis by intraocular, or sequential systemic and intraocular, inoculations, and imaging of toxoplasmic retinal lesions.

Background: Retinopathy is a common adverse event with mitogen-activated extracellular signal-regulated kinase (MEK) inhibitors. Little is known about the pathophysiology of MEK inhibitor-associated retinopathy (MEKAR). Since MEKAR has many similarities to central serous chorioretinopathy (CSCR), they may share common risk factors. The aim of this study was to evaluate the association between baseline characteristics and MEKAR in melanoma patients initiating MEK inhibitor treatment. Methods: Data from patients treated with cobimetinib and vemurafenib for advanced melanoma in the coBRIM trial were subjected to secondary analysis. Consistent with CSCR risk factors, assessed baseline characteristics included: age, gender, past ocular disease, weight, hypertension, diabetes, dyslipidemia, glomerular filtration rate (eGFR) and corticosteroid use. Associations between characteristics and retinopathy events (any grade and symptomatic) were evaluated using univariate logistic regression and represented as odds ratios (OR). Results: A total of 247 patients were treated with cobimetinib and vemurafenib, of whom 72 (29%) had retinopathy of any grade and 33 (13%) had symptomatic retinopathy. Patients with a history of ocular disease were at significantly higher risk of retinopathy (any grade, 44%; symptomatic, 22%) than those with no ocular disease history (any grade, 22%; symptomatic, 10%). Individuals with a history of ocular inflammation or infection were at highest risk: 4 of 5 developed symptomatic retinopathy during MEK inhibitor therapy. Increased age was associated with a higher risk of any grade retinopathy {decade increase OR [95% confidence interval (CI)] = 1.03 (1.01–1.05); p = 0.009}, while increasing eGFR was significantly associated with a decreased risk of any grade retinopathy [0.98 (0.96–0.99); p = 0.004]; the associations were not statistically significant with symptomatic retinopathy. Other assessed CSCR risk factors were not significantly associated with MEKAR. Conclusion: Age, glomerular filtration rate and history of ocular disease (particularly inflammatory eye disease) were associated with a risk of MEK inhibitor induced retinopathy. Patients who are at increased risk of MEKAR may benefit from more regular ophthalmologic assessment during treatment.

Vitreoretinal lymphomas are rare ocular cancers, and the subset of primary central nervous system lymphomas that are based in the posterior eye. These tumours are challenging to treat, and today management generally involves a multispecialty team coordinating a treatment protocol that may include intraocular chemotherapy, ocular irradiation, systemic chemotherapy and/or autologous stem cell transplantation. The ophthalmologist has specific responsibility for the intraocular chemotherapy, which is delivered to the eye by intravitreal injection. The most commonly injected drugs are methotrexate-an anti-metabolite-and rituximab-an anti-human B cell monoclonal antibody. A range of intraocular chemotherapy treatment schedules have been described in the medical literature, although to date there have been no randomized clinical trials of these schedules. In this article, we review the development and current status of intraocular chemotherapy for vitreoretinal lymphoma.

When a person becomes infected with Toxoplasma gondii, ocular toxoplasmosis is the most common clinical presentation. The medical literature describes retinitis with surrounding hyperpigmentation secondary to proliferative changes in the retinal pigment epithelium, which is sufficiently characteristic that investigation often is not needed to make the diagnosis. We aimed to establish the frequency of &ldquo, typical&rdquo, ocular toxoplasmosis and delineate its molecular basis. Among 263 patients presenting consecutively with ocular toxoplasmosis to Ribeir&atilde, o Preto General Hospital in Brazil, where T. gondii infection is endemic, 94.2% of 345 eyes had retinal hyperpigmentation. In ARPE-19 and primary human retinal pigment epithelial cell monolayers exposed to minimal numbers of T. gondii tachyzoites, the proliferation marker&ndash, KI-67&ndash, was increased in uninfected cells, which also were rendered more susceptible to infection. RT-qPCR and ELISA detected increased expression of vascular endothelial growth factor A (VEGF) and insulin-like growth factor (IGF)1, and decreased expression of thrombospondin (TSP)1 by infected cells. Blockade of VEGF and IGF1&mdash, or supplementation of TSP1&mdash, reversed the proliferation phenotype in uninfected cells. Our findings confirm that hyperpigmentation is a characteristic feature of retinitis in ocular toxoplasmosis, and demonstrate that T. gondii-infected human retinal pigment epithelial cells secrete VEGF and IGF1, and reduce production of TSP1, to promote proliferation of adjacent uninfected cells and create this disease-specific appearance.

Conventional immunosuppressive drugs are effective treatment for some, but not all, patients with noninfectious uveitis. An additional consideration in the use of these drugs is the potential for serious systemic complications. Multiple alternative therapeutic approaches are under development, targeted to the cells and molecular pathways that mediate noninfectious uveitis. Leukocyte drug targets include CD4+ T cells, mononuclear phagocytes, and B cells. Migration of leukocytes into the eye may be inhibited with agents designed to block adhesion molecules expressed on the endothelium. Inflammatory cytokines that direct leukocyte activities within the eye are also logical pharmaceutical targets. Other therapeutic options include drugs directed against components of the complement system and the antioxidants. This chapter presents a summary of current experimental work and clinical developments on novel approaches to the treatment of noninfectious uveitis.

Primary central nervous system lymphoma (PCNSL) is a rare brain cancer that remains challenging to study. Epidemiology of PCNSL in the Australian population, which is racially and ethnically diverse, has not been examined previously. Using ICD-O-3.1 Morphology and Topography Codes to identify cases, we analyzed complete datasets from the comprehensive Australian Cancer Database (1982&ndash, 2014, adults aged &ge, 20 years) to establish incidence rates and trends of PCNSL, and to define survival outcomes of individuals diagnosed with PCNSL, including the predominant diffuse large B-cell lymphoma (DLBCL) type. Age-standardized incidence of PCNSL increased by an average annual 6.8% percent over the study period, with current incidence of 0.43 (95% confidence interval, 0.41&ndash, 0.46) per 100,000 person-years, in comparison to 21.89 (21.41&ndash, 22.38) per 100,000 person-years for non-CNS lymphoma. Increase in incidence was characterized by an acute rise between 1996 and 1999, was more pronounced with increasing age, and was driven by increasing incidence of DLBCL. Overall survival for persons diagnosed with PCNSL improved significantly across the study period, with 5-year survival probability increasing from 0.21 (95% confidence interval, 0.16&ndash, 0.26) to 0.33 (0.30&ndash, 0.36), and median survival increasing from 318 to 600 days, between 1982&ndash, 1999 and 2000&ndash, 2014. Increase in survival was significantly higher for persons with DLBCL versus non-DLBCL PCNSL, but substantially lower than that for persons with non-CNS lymphoma, who had a 5-year survival probability of 0.62 (0.62&ndash, 0.62) and a median survival of 3388 days in 2000&ndash, 2014. This study links increasing incidence of PCNSL in Australia to increasing incidence of DLCBL, including in younger adults, and highlights the improving, but low, survival outcome of this cancer.

A number of authors have reviewed the epidemiology, diagnosis, and treatment of uveitis in children and adolescents.1–16 Data from both clinic- and population-based surveys have shown that children...

The 2018 Ocular Oncogenesis and Oncology Conference was held through a partnership of the Association for Research in Vision and Ophthalmology (ARVO) and the Champalimaud Foundation. Twenty-one experts from international ocular oncology centers, from the Champalimaud Clinical Centre and the Champalimaud Foundation Cancer Research Program, and from patient advocacy organizations, delivered lectures on subjects that ranged from global ocular oncology, to basic research in mechanisms of ocular malignancy, to clinical research in ocular cancers, and to anticipated future developments in the area. The scientific program of the conference covered a broad range of ocular tumors-including uveal melanoma, retinoblastoma, ocular surface tumors, and adnexal and intraocular lymphomas-and pathogenesis and management were deliberated in the context of the broader systemic cancer discipline. In considering the latest basic and clinical research developments in ocular oncogenesis and oncology, and providing the opportunity for cross-talk between ocular cancer biologists, systemic cancer biologists, ocular oncologists, systemic oncologists, patients, and patient advocates, the forum generated new knowledge and novel insights for the field. This report summarizes the content of the invited talks at the 2018 ARVO-Champalimaud Foundation Ocular Oncogenesis and Oncology Conference.

Recently recognized forms of uveitis include intraocular inflammations that occur during or following one of several emerging infectious diseases: chikungunya fever, dengue, Zika virus disease and Ebola virus disease. Anterior, intermediate, posterior and pan-uveitis have been described in individuals infected with chikungunya virus. Persons who contract dengue or Zika viruses also may develop different types of uveitis in the course of the infection: maculopathy is a common manifestation of dengue eye disease, and Zika eye disease may cause hypertensive anterior uveitis or mimic a white dot syndrome. Up to one-third of Ebola survivors develop aggressive uveitis, which is frequently associated with vision loss and complicated by cataract. There are no specific anti-viral drugs for these forms of uveitis, and thus treatment is largely supportive. In this article, we summarize the systemic infectious diseases and virology, and describe the clinical presentations, outcomes and management of emerging viral forms of uveitis.

Recent reports from different world regions suggest ocular syphilis is re-emerging, in parallel with an increasing incidence of the systemic infection globally. We conducted a large observational study of 127 persons consecutively treated for ocular syphilis at public medical centers in Brazil over a 2.5-year period ending July 2015. Of 104 individuals serologically tested for human immunodeficiency virus (HIV), 34.6% were positive. Ophthalmological evaluations included measurement of Snellen visual acuity and intraocular pressure, and assessment of inflammation by slit lamp examination and dilated posterior eye examination. Involvements in 214 eyes were anterior (6.1%), intermediate (8.4%), posterior (76.2%) and pan- (8.4%) uveitis, and scleritis (0.9%). Multiple anterior and posterior eye complications were observed, including cataract in the anterior eye (incidence rate, 0.18/eye-year) and epiretinal membrane in the posterior eye (incidence rate, 0.09/eye-year); incidence rates of reduction in best-corrected visual acuity to ≤20/50 and ≤20/200 were 0.10 and 0.06/eye-year, respectively. Rates of complications and visual acuity loss did not differ significantly between HIV- positive and negative individuals. In an era of re-emergence, syphilis has ocular complications that may compromise vision, despite treatment with appropriate anti-microbial drugs.