A machine learning system to optimise triage in an adult ophthalmic emergency department: a model development and validation study.

Background: A substantial proportion of attendances to ophthalmic emergency departments are for non-urgent presentations. We developed and evaluated a machine learning system (DemDx Ophthalmology Triage System: DOTS) to optimise triage, with the aim of reducing inappropriate emergency attendances and streamlining case referral when necessary. Methods: DOTS was built using retrospective tabular data from 11,315 attendances between July 1st, 2021, to June 15th, 2022 at Moorfields Eye Hospital Emergency Department (MEH) in London, UK. Demographic and clinical features were used as inputs and a triage recommendation was given ("see immediately", "see within a week", or "see electively"). DOTS was validated temporally and compared with triage nurses' performance (1269 attendances at MEH) and validated externally (761 attendances at the Federal University of Minas Gerais - UFMG, Brazil). It was also tested for biases and robustness to variations in disease incidences. All attendances from patients aged at least 18 years with at least one confirmed diagnosis were included in the study. Findings: For identifying ophthalmic emergency attendances, on temporal validation, DOTS had a sensitivity of 94.5% [95% CI 92.3-96.1] and a specificity of 42.4% [38.8-46.1]. For comparison within the same dataset, triage nurses had a sensitivity of 96.4% [94.5-97.7] and a specificity of 25.1% [22.0-28.5]. On external validation at UFMG, DOTS had a sensitivity of 95.2% [92.5-97.0] and a specificity of 32.2% [27.4-37.0]. In simulated scenarios with varying disease incidences, the sensitivity was ≥92.2% and the specificity was ≥36.8%. No differences in sensitivity were found in subgroups of index of multiple deprivation, but the specificity was higher for Q2 when compared to Q4 (Q4 is less deprived than Q2). Interpretation: At MEH, DOTS had similar sensitivity to triage nurses in determining attendance priority; however, with a specificity of 17.3% higher, DOTS resulted in lower rates of patients triaged to be seen immediately at emergency. DOTS showed consistent performance in temporal and external validation, in social-demographic subgroups and was robust to varying relative disease incidences. Further trials are necessary to validate these findings. This system will be prospectively evaluated, considering human-computer interaction, in a clinical trial. Funding: The Artificial Intelligence in Health and Care Award (AI_AWARD01671) of the NHS AI Lab under National Institute for Health and Care Research (NIHR) and the Accelerated Access Collaborative (AAC).

Congenital toxoplasmosis: Should we still care about screening?

Prenatal systematic screening for congenital toxoplasmosis has been performed in Austria and France since 1975 and neonatal screening for congenital toxoplasmosis has been part of the New England Newborn screening program since 1986. In this narrative review we review the data leading up to the systematic screening programs in Austria and France, highlighting the main finding of the European Union funded research in the 1990s and early 2000s. Different descriptive studies of the effect of pre- or postnatal treatment are discussed. Toxoplasma gondii has different genetic lineages with different pathogenicity in humans. This means that results in areas with a low pathogenic lineage cannot be extrapolated to an area with highly pathogenic lineages. The importance of meat as a source of infection is discussed in the light of an increased prevalence of T.gondii in organic livestock production .

The International Vitreoretinal B-Cell Lymphoma Registry: a protocol paper.

INTRODUCTION: Vitreoretinal lymphoma is a rare ocular cancer with high morbidity and mortality despite treatment. Diagnosis by cytopathology is often delayed, and various molecular and image-based investigations have been developed. Diverse treatments are used, but there is a limited medical evidence to differentiate their effectiveness. We designed an international registry that would collect diagnostic, treatment and outcomes data, to establish new evidence for the management of this cancer. METHODS AND ANALYSIS: The International Vitreoretinal B-Cell Lymphoma Registry will accrue data retrospectively for individuals aged 18 years or older, diagnosed with new or recurrent vitreoretinal B-cell lymphoma on or after 1 January 2020. A steering committee of subspecialised ophthalmologists identified 20 key clinical data items that describe patient demographics, tissue involvements, diagnostic testing, ocular and systemic treatments and treatment complications, and visual acuity and survival outcomes. Customised software was designed to permit collection of these data across a single baseline and multiple follow-up forms. The platform collects data without identifiers and at 3 month reporting intervals. Outcomes of the project will include: (1) descriptions of clinical presentations, and diagnostic and therapeutic preferences; (2) associations between clinical presentations, and diagnostics and treatments, and between diagnostics and treatments (assessed by ORs with 95% CIs); and (3) estimations of rates of vision loss, and progression-free and overall survival (assessed by Kaplan-Meier estimates). ETHICS AND DISSEMINATION: The registry has received Australia-wide approval by a national human research ethics committee. Sites located outside Australia are required to seek local human research ethics review. Results generated through the registry will be disseminated primarily by peer-reviewed publications that are expected to inform clinical practice, as well as educational materials.

Birdshot retinochoroiditis in Brazil: a multicenter review of 40 patients.

BACKGROUND: Birdshot retinochoroiditis (BRC) is a rare and chronic bilateral uveitis mostly found in Caucasians. As few data are available about the clinical course of BRC in Hispanic patients, we aimed to report the clinical findings and the evolution of BRC in Brazilian patients. METHODS: This retrospective cohort multicenter nationwide study was performed by analyzing the records of patients with BRC diagnoses from Brazilian ophthalmological centers from April 1995 to May 2020. RESULTS: Forty patients (80 eyes) with a diagnosis of BRC were evaluated. The mean age was 53 years, and there was no sex predominance. All tested patients (34/40) were positive for HLA-A29. The diagnosis of BRC was made following the Levinson et al. criteria, and all ancillary tests were performed to exclude differential diagnoses. Clinical signs and symptoms, such as complications and treatment, were described. CONCLUSIONS: BRC evolution in Brazilian patients seems to have some peculiarities that diverge from the published literature available about Caucasians, as AS inflammation is higher in this population.

Toxoplasma gondii-Induced Neutrophil Extracellular Traps Amplify the Innate and Adaptive Response.

Toxoplasmosis affects one-third of the human population worldwide. Humans are accidental hosts and are infected after consumption of undercooked meat and water contaminated with Toxoplasma gondii cysts and oocysts, respectively. Neutrophils have been shown to participate in the control of T. gondii infection in mice through a variety of effector mechanisms, such as reactive oxygen species (ROS) and neutrophil extracellular trap (NET) formation. However, few studies have demonstrated the role of neutrophils in individuals naturally infected with T. gondii. In the current study, we evaluated the activation status of neutrophils in individuals with acute or chronic toxoplasmosis and determined the role of T. gondii-induced NET formation in the amplification of the innate and adaptive immune responses. We observed that neutrophils are highly activated during acute infection through increased expression of CD66b. Moreover, neutrophils from healthy donors (HDs) cocultured with tachyzoites produced ROS and formed NETs, with the latter being dependent on glycolysis, succinate dehydrogenase, gasdermin D, and neutrophil elastase. Furthermore, we observed elevated levels of the chemokines (CXC motif) CXCL8 and (CC motif) CCL4 ligands in plasma from patients with acute toxoplasmosis and production by neutrophils from HDs exposed to T. gondii. Finally, we showed that T. gondii-induced NETs activate neutrophils and promote the recruitment of autologous CD4+ T cells and the production of interferon gamma (IFN-γ), tumor necrosis factor (TNF), interleukin 6 (IL-6), IL-17, and IL-10 by peripheral blood mononuclear cells. In conclusion, we demonstrated that T. gondii activates neutrophils and promotes the release of NETs, which amplify human innate and adaptive immune responses. IMPORTANCE Approximately one-third of the human population is estimated to be chronically infected with the obligate intracellular parasite Toxoplasma gondii. Humans are accidental hosts that are infected with T. gondii after consumption of undercooked meat or contaminated water. Neutrophils have been shown to control T. gondii growth by different mechanisms, including neutrophil extracellular traps (NETs). In the current study, we observed that neutrophils are highly activated during acute toxoplasmosis. We also determined that T. gondii-induced NETs are dependent on the energetic profile of neutrophils as well as the production of ROS and gasdermin D (GSDMD) cleavage. In addition, we showed that T. gondii-induced NETs activate neutrophils, promote the recruitment of autologous CD4+ T cells, and induce the production of cytokines by peripheral blood mononuclear cells, amplifying the innate and adaptive immune responses.

Consensus Recommendations for the Diagnosis of Vitreoretinal Lymphoma.

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.

Vogt-Koyanagi-Harada-like Disease following Yellow Fever Vaccination.

Purpose: To report the manifestation of Vogt-Koyanagi-Harada-like disease (VKH) following yellow fever vaccination.Methods: Case report.Results: A 34-year-old immunocompetent male had tinnitus, headache, and decreased vision after a booster dose of yellow fever vaccine. Visual acuity was 20/100 in the right eye and 20/80 in the left, with serous retinal detachment (SRD) and choroidal thickening identified on clinical examination and multimodal imaging. Lumbar puncture revealed pleocytosis and an increased protein content, but extensive investigations ruled out infectious/neurological diseases. Pulse intravenous methylprednisolone was given, followed by a tapering regimen of high-dose oral prednisone. Azathioprine was started early, 3 weeks after initiation of oral steroids. Intraocular inflammation and SRD rapidly resolved, with visual acuity reaching 20/20 in both eyes, after 3 weeks. No recurrence of intraocular inflammation or sign of depigmentation was so far noticed, at 2 years of follow-up.Conclusion: Yellow fever vaccine may be a possible trigger for VKH.

Circulating inflammatory mediators as biomarkers of ocular toxoplasmosis in acute and in chronic infection.

Toxoplasmosis is highly endemic worldwide. In Brazil, depending on the geographical region and socioeconomic status, 40-70% of individuals become seropositive at some point in their lives. A significant proportion of Toxoplasma gondii-chronically infected individuals who are otherwise immunocompetent develop recurrent ocular lesions. The inflammatory/immune mechanisms involved in development of ocular lesion are still unknown and, despite previous investigation, there are no reliable immune biomarkers to predict/follow disease outcome. To better understand the impact of the immune response on parasite control and immunopathology of ocular toxoplasmosis, and to provide insights on putative biomarkers for disease monitoring, we assessed the production of a large panel of circulating immune mediators in a longitudinal study of patients with postnatally acquired toxoplasmosis stratified by the presence of ocular involvement, both at the early acute stage and 6 months later during chronic infection, correlating them with presence of ocular involvement. We found that T. gondii-infected patients, especially during the acute stage of the disease, display high levels of chemokines, cytokines, and growth factors involved in the activation, proliferation, and migration of inflammatory cells to injured tissues. In particular, major increases were found in the IFN-induced chemokines CXCL9 and CXCL10 in T. gondii-infected patients regardless of disease stage or clinical manifestations. Moreover, a specific subgroup of circulating cytokines and chemokines including GM-CSF, CCL25, CCL11, CXCL12, CXCL13, and CCL2 was identified as potential biomarkers that accurately distinguish different stages of infection and predict the occurrence of ocular toxoplasmosis. In addition to serving as predictors of disease development, these host inflammatory molecules may offer promise as candidate targets for therapeutic intervention.

Multimodal Imaging in Ocular Toxoplasmosis.

Multimodal imaging relies on combination of multiple imaging modalities to precisely delineate pathological changes in the posterior segment of the eye associated with a wide range of conditions. This combined application of fundus photography, optical coherence tomography, fundus reflectance/autofluorescence and fundus angiography (with fluorescein, indocyanine green and/or optical coherence tomography) is of great utility for assessment of patients with ocular toxoplasmosis. Multimodal imaging is helpful to characterize the typical pattern of toxoplasmic retinochoroiditis, with primary focal inflammatory involvement of the neurosensory retina, and secondary changes at the level of underlying choroid, retinal blood vessels, vitreous and even optic disc. It may also be valuable to document and follow local complications, including macular edema, vascular occlusions, and choroidal neovascularization, among others.

Characterization of Retinopathy Among Patients With Yellow Fever During 2 Outbreaks in Southeastern Brazil.

IMPORTANCE: Yellow fever still threatens people in endemic areas, and besides conjunctival icterus, little is known about the ocular changes that occur in these patients. OBJECTIVE: To characterize retinal changes in patients with confirmed yellow fever during 2 recent outbreaks of the disease in Minas Gerais, Southeastern Brazil. DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional, observational study conducted at a single referral center for infectious diseases in Southeastern Brazil collected data between January 2017 and February 2018 from 94 consecutive patients with suspicion of yellow fever who were eligible for the study. MAIN OUTCOMES AND MEASURES: Patients underwent ophthalmic examination. Clinical findings, laboratory results, and occurrence of retinopathy and death during hospitalization were reported, including age, sex, comorbidities, disease severity, serum aspartate aminotransferase level, total bilirubin level, serum creatinine level, arterial lactate level, international normalized ratio, and platelet count at hospital admission. RESULTS: In total, 64 patients were included who had received a confirmed diagnosis of yellow fever, with a median (interquartile range) age of 47 (38-56) years, and 12 patients (19%) were women. Twenty eyes (16%) of 13 patients (20%) had retinopathy at the same time as yellow fever. The most common fundus changes among the 20 eyes were retinal nerve fiber layer infarcts (11 [55%]), superficial hemorrhages (7 [35%]) and grayish deep lesions (6 [30%]), possibly at the level of the outer retina or choroid. Aspartate aminotransferase levels higher than 3000 U/L (odds ratio [OR], 14.2; 95% CI, 3.5-77.8; P < .001), total bilirubin levels higher than 2.3 mg/dL (OR, 20.0; 95% CI, 4.4-159.7; P < .001), serum creatinine levels higher than 2.0 mg/dL (OR, 8.2; 95% CI, 2.1-36.0; P = .003), arterial lactate levels higher than 17.1/mg/dL (OR, 4.6; 95% CI, 1.1-19.0; P = .03), platelet count lower than 94 × 103/µL (OR, 7.8; 95% CI, 1.8-59.9; P = .004), and classification of disease as severe (OR, 11.7; 95% CI, 2.0-301.0; P = .003) were associated with retinopathy. Arterial hypertension, diabetes, international normalized ratio, and death were not associated with retinopathy. CONCLUSIONS AND RELEVANCE: Retinopathy was present in 20% of patients with yellow fever and appeared to be associated with more severe systemic disease. Retinal nerve fiber layer infarcts and superficial hemorrhages, but not the grayish deep lesions, resembled those associated with other flavivirus (eg, dengue virus) infections. The clinical relevance of these findings may warrant further investigation.

Author Correction: Clinical Manifestations and Ophthalmic Outcomes of Ocular Syphilis at a Time of Re-Emergence of the Systemic Infection.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.

Clinical Manifestations and Ophthalmic Outcomes of Ocular Syphilis at a Time of Re-Emergence of the Systemic Infection.

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.

Intravenous Ceftriaxone for Syphilitic Uveitis.

PURPOSE: Report of clinical/multimodal imaging outcomes of patients with syphilitic uveitis alternatively treated with intravenous(IV) ceftriaxone, due to unavailability of penicillin G. METHODS: Chart review of all cases of syphilitic uveitis presenting to Hospital São Geraldo/HC-UFMG and treated with intravenous ceftriaxone, between January and August 2014. Clinical, serological and ophthalmological data were collected. RESULTS: Twelve consecutive patients with syphilitic uveitis receiving IV ceftriaxone were identified. All 24 eyes had active intraocular inflammation on clinical examination. All patients received IV ceftriaxone (2-4 g daily) for 14-21 days, supplemented with oral corticosteroid as needed in 9 patients (75%), after documented clinical response. Improvement in intraocular inflammation was seen in all 24 eyes, with median best-corrected visual acuity (BCVA) increasing from 20/50 to 20/20, after a mean follow-up of 5.3 months. CONCLUSION: IV ceftriaxone may be an effective alternative for treatment of syphilitic uveitis, in the setting of unavailability of penicillin G.

Diagnosis of Ocular Tuberculosis.

Ocular tuberculosis remains a presumptive clinical diagnosis, as the gold standard tests for diagnosing ocular tuberculosis are often not useful: Mycobacterium tuberculosis cultures require weeks to process on Lowenstein-Jenson media and have low yield from ocular samples; while acid-fast bacilli smears or polymerase chain reaction detection of M. tuberculosis DNA have low sensitivities. Thus, diagnosis is often based on suggestive clinical signs, which are supported by positive investigations: tuberculin skin test or interferon-gamma release assays; chest X-ray findings suggestive of pulmonary tuberculosis, and/or evidence of associated systemic tuberculosis infections in the absence of other underlying disease. The aim of this review is to provide an update on the methods of diagnosing ocular tuberculosis, and discuss the challenges of its diagnosis. We also suggest a step-ladder approach to a more accurate diagnosis of ocular tuberculosis by combining the available diagnostic tests.

Use of intravitreal rituximab for treatment of vitreoretinal lymphoma.

AIM: Vitreoretinal lymphoma is a diffuse large B cell non-Hodgkin lymphoma. Targeting malignant cells with rituximab is being used increasingly as local chemotherapy, but information on this treatment is scant. We aimed to describe current therapeutic approaches, as well as responses to and complications of, intravitreal rituximab in patients with vitreoretinal lymphoma. METHODS: Clinical data were collected in a standardised manner retrospectively on patients with vitreoretinal lymphoma treated with intravitreal rituximab. RESULTS: 48 eyes (34 patients) with vitreoretinal lymphoma were treated with a median of 3.5 intravitreal injections of rituximab (1 mg/0.1 mL) for new diagnosis (68.8%), progressive disease (29.9%) and maintenance therapy (2.1%). Intravitreal rituximab±methotrexate was the sole treatment in 19 eyes (39.6%). 31 eyes (64.6%) eyes achieved complete remission, after a median of 3 injections; 7 of these eyes developed recurrent disease. 11 eyes (22.9%) achieved partial remission. Although rituximab may have contributed to complications reported in 12 eyes (25.0%), a 2-line loss of Snellen visual acuity occurred in only 2 of those eyes (4.2%). CONCLUSIONS: Approaches in rituximab-based intravitreal chemotherapy vary widely, but our findings suggest that this treatment may be safe and effective in inducing remission in a majority of eyes with vitreoretinal lymphoma.

Ocular manifestations of systemic disease: toxoplasmosis.

PURPOSE OF REVIEW: To provide an overview of ocular toxoplasmosis, the leading cause of infectious posterior uveitis, focusing on recent trends of disease epidemiology, pathogenesis, diagnosis, therapy and prevention. RECENT FINDINGS: Novel aspects of epidemiology, including growing importance of water transmission are discussed. The historical controversy of congenital versus postnatally acquired toxoplasmosis is revisited. Recent insights into pathogenesis of ocular toxoplasmosis are also reviewed, tipping the delicate balance between parasite virulence and host immunity. Diagnosis of ocular toxoplasmosis is also discussed in the light of serological, molecular and imaging tools. Finally, a critical analysis of current and emerging therapies for ocular toxoplasmosis is made. Preventive aspects are also commented upon. SUMMARY: Waterborne toxoplasmosis is increasingly recognized in outbreaks and in endemic areas. The importance of postnatally acquired toxoplasmosis is now well established, but should not lead to underestimation of congenital disease. Genetic determination of parasite virulence/individual susceptibility might correlate with disease outcomes. Serological, molecular and imaging tools may improve the diagnosis and follow-up of individuals with ocular toxoplasmosis. Despite emergence of alternative therapeutic regimens, including intravitreal antibiotics, classical therapy with sulfadiazine/pyrimethamine is still standard for toxoplasmic retinochoroiditis. Adequate prophylaxis is expected to have an effect in ocular burden of toxoplasmosis.

Immunopathologic processes in sympathetic ophthalmia as signified by microRNA profiling.

PURPOSE: Recent discovery of microRNAs and their negative gene regulation have provided new understanding in the pathogenesis of inflammatory diseases. This study demonstrated microRNA expression profiling and their likely role in sympathetic ophthalmia, using formalin-fixed, paraffin embedded samples. METHODS: Two groups of four enucleated globes (total eight globes) from patients with clinical and histopathological diagnosis of SO (experimental samples) and one group of four age-matched, noninflamed enucleated globes (control samples) were used. Human genome-wide microRNA PCR array was performed and results were subjected to bioinformatics calculation and P values stringency tests. The targets were searched using the recently published and periodically updated miRWalk software. Quantitative real-time PCR and immunohistochemical staining were performed to confirm the validated targets in the mRNA and in the protein levels, respectively. RESULTS: No microRNA was significantly upregulated in SO, but 27 microRNAs were significantly downregulated. Among these, four microRNAs (hsa-miR-1, hsa-let-7e, hsa-miR-9, and hsa-miR-182) were known to be associated with the inflammatory signaling pathway. Only hsa-miR-9 has the validated targets, tumor necrosis factor-α, and nuclear factor kappa B1, which have been previously shown to be associated with mitochondrial oxidative stress-mediated photoreceptor apoptosis in eyes with SO. CONCLUSIONS: Identification of altered levels of microRNAs by microRNA expression profiling may yield new insights into the pathogenesis of SO by disclosing specific microRNA signatures. In the future these may be targeted by synthetic microRNA mimic-based therapeutic strategies.

Early surgical debridement in the management of infectious scleritis after pterygium excision.

PURPOSE: The purpose of this study was to report outcomes of infectious scleritis after pterygium surgery, managed with antibiotic therapies and early scleral debridement. METHODS: Retrospective chart review of 13 consecutive cases of infectious scleritis after pterygium excision between 1999 and 2009 was conducted. Collected data included prior medical and surgical history, latency period between pterygium surgery and presentation of infectious scleritis, culture and histopathologic findings, antibiotic regimen, length of hospital stay, visual acuity before and after treatment, and complications. RESULTS: Median follow-up was at 14 months. Twelve patients underwent prompt surgical debridement after infectious scleritis diagnosis (median, 2.5 days). Debridement was delayed in one patient. Median hospital stay was 3 days. Best-corrected visual acuity improved in ten patients, remained stable in one patient, and decreased in two patients following treatment. Complications included scleral thinning requiring scleral patch graft (1/13), glaucoma (3/13), and progression to phthisis bulbi (1/13). No patients required enucleation. CONCLUSIONS: In contrast to the generally poor outcomes in the literature, early surgical debridement of pterygium-associated infectious scleritis appears to offer improved prognosis.