Deep sequencing as a diagnostic tool in patients with suspected primary vitreoretinal lymphoma.

PURPOSE: To compare the diagnostic utility of metagenomic deep sequencing (MDS) to cytology, flow cytometry and gene rearrangement by PCR in ocular samples of patients with suspected vitreoretinal lymphoma (VRL). METHODS: Patients with suspected VRL underwent ocular sampling of one or both eyes at the Emory Eye Center from September 2017 to June 2022. Ocular samples were evaluated with MDS and conventional diagnostics. MDS was performed at the Ralph and Sophie Heintz Laboratory at the F.I. Proctor Foundation. Relevant demographic and clinical data were retrospectively collected from medical records. Patients were diagnosed with VRL based on clinical assessment and conventional diagnostic testing. RESULTS: This study included 13 patients with suspected VRL who underwent diagnostic vitrectomy, including 1 patient who had an additional subretinal biopsy. Six patients (46.2%) were diagnosed with VRL. Among patients diagnosed with VRL, MDS detected pathogenic mutations in 5 out of 6 patients (83.3%) while cytology was positive for VRL in 4 out of 6 patients (66.7%), flow cytometry in 4 out of 4 patients (100.0%) and PCR in 4 out of 4 patients (100.0%). MDS detected mutations in MYD88 in 2 out of 6 patients diagnosed with VRL. In 7 patients (53.8%) not diagnosed with VRL, MDS detected pathogenic lymphoma mutations in 2 patients (28.6%). DISCUSSION: MDS detected pathogenic mutations in five out of six patients diagnosed with VRL, including in two patients with negative cytology, demonstrating its potential to improve diagnostic rates of VRL as an adjunctive test.

Suprachoroidal Drug Delivery for Macular Edema Associated With Noninfectious Uveitis.

Purpose: To evaluate clinical trials in the literature that focus on suprachoroidal drug delivery for the treatment of noninfectious uveitis and other posterior segment diseases. Methods: A synthesis of the literature was performed. Results: In 2021, suprachoroidal space triamcinolone acetonide, a corticosteroid delivery system used for the treatment of uveitic macular edema (ME), was approved by the US Food and Drug Administration. The drug-delivery system targets the suprachoroidal space using a microneedle-based device and has a favorable pharmacokinetic profile. Suprachoroidally administered investigational therapies have also been assessed in clinical trials for other posterior segment diseases, including diabetic ME, retinal vein occlusion, age-related macular degeneration, and choroidal melanoma. Conclusions: The safety and efficacy of suprachoroidal corticosteroid injections to treat uveitic ME have been shown in recent phase III clinical trials. Multiple programs are also investigating this modality of drug delivery for use in many other retinal and choroidal pathologies.

Common Practice Patterns in the Diagnosis and Management of Acute Retinal Necrosis: A Survey Study of Uveitis Specialists.

PURPOSE: Due to lack of large randomized clinical trials to determine best practices in treating acute retinal necrosis (ARN), there is not a clear consensus amongst ophthalmologists on how to best manage this potentially blinding condition. The aim of this study is to survey common practice patterns and analyze the factors that affect ophthalmologists' management of ARN. METHODS: An anonymous survey was distributed to uveitis and retina specialists who are members of the American Uveitis Society (AUS) via email to query practice patterns regarding ARN. The survey included 22 questions with an additional 10 questions based on response. Survey question topics included demographic information, diagnostic testing, antiviral therapy, corticosteroids, and surgical procedures. RESULTS: 67 surveys were included for analysis. Most respondents (87%) always or frequently obtain intraocular aqueous fluid for diagnostic PCR testing. The majority of respondents would administer intravitreal antiviral injections to a unilateral immunocompetent ARN patient (67%), but would be even more likely to do so for a bilateral immunosuppressed ARN patient (87%). Respondents tend to treat ARN with systemic rather than local corticosteroids, with the majority (63%) of respondents initiating corticosteroid treatment 48 hours after treatment. Most respondents (79%) never perform a vitrectomy to manage ARN unless the patient has a retinal detachment or tear. The majority (63%) rarely or never perform prophylactic laser barricade, but may consider laser treatment if there is extensive retinal involvement. CONCLUSION: Current practice patterns for diagnosis and management of ARN among AUS members generally align with the suggested practices outlined by the American Academy of Ophthalmology.

Outcomes in Patients With Vogt-Koyanagi-Harada Disease From the First-Line Antimetabolites for Steroid-Sparing Treatment Uveitis Trial.

PURPOSE: To compare the effectiveness of methotrexate (MTX) and mycophenolate mofetil (MMF) in achieving corticosteroid-sparing control of uveitis in patients with Vogt-Koyanagi-Harada (VKH) disease. METHODS: A subanalysis of patients with VKH from the First-line Antimetabolites as Steroid-sparing Treatment Uveitis Trial, a randomized, observer-masked, comparative effectiveness trial, with comparisons by treatment (MTX vs MMF) and disease stage (acute vs chronic). Individuals with noninfectious uveitis were placed on a standardized corticosteroid taper and block randomized 1:1 to either 25 mg weekly oral MTX or 1.5 g twice daily oral MMF. The primary outcome was treatment success defined by corticosteroid-sparing control of uveitis at 6 months. Additional outcomes included change in best spectacle-corrected visual acuity (BSCVA), retinal central subfield thickness (CST), and resolution of serous retinal detachment (SRD). RESULTS: Ninety-three out of 216 enrolled patients had VKH; 49 patients were randomized to MTX and 44 to MMF, of which 85 patients (46 on MTX, 39 on MMF) contributed to the primary outcome. There was no significant difference in treatment success by antimetabolite (80.4% for MTX compared to 64.1% for MMF; P = .12) or in BSCVA improvement (P = .78). MTX was superior to MMF in reducing CST (P = .003) and resolving SRD (P = .02). There was no significant difference in treatment success by disease stage (P = .25), but patients with acute VKH had greater improvement in BSCVA (P < .001) and reduction of CST (P = .02) than chronic VKH patients. CONCLUSIONS: MTX and MMF have comparable outcomes as corticosteroid-sparing immunosuppressive therapies for VKH. Visual acuity improvement was greater in acute vs chronic VKH. NOTE: Publication of this article is sponsored by the American Ophthalmological Society TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00182929.

Acute neuroretinitis as a delayed manifestation of tubulointerstitial nephritis and uveitis syndrome.

Purpose: Tubulointerstitial nephritis syndrome with uveitis (TINU) is a rare, acquired syndrome characterized by interstitial nephritis with bilateral uveitis. We report a case of TINU with typical bilateral anterior uveitis complicated by an atypical, delayed-onset neuroretinitis in a 12-year old patient. Observation: A 12-year-old female with a 21-month history of TINU featuring chronic bilateral anterior uveitis presented with one week of blurred vision in her left eye. On exam she was found to have new-onset disc edema in the right eye and neuroretinitis in the left eye. After a negative infectious disease workup, the patient was treated with a course of intravenous (IV) solumedrol with prednisone taper and advancement of her systemic immunosuppression. In follow up she demonstrated resolution of her disc edema and neuroretinitis with improved visual acuity and clinical exam. Conclusion: This case stresses the importance of monitoring for additional ocular manifestations including neuroretinitis years after the onset of anterior uveitis in TINU. In comparison to the two published cases of TINU with neuroretinitis, this case shares features of uveitis progression, and thus highlights the value of further description of TINU-associated neuroretinitis.

Variations in Electronic Health Record-Based Definitions of Diabetic Retinopathy Cohorts: A Literature Review and Quantitative Analysis.

Purpose: Use of the electronic health record (EHR) has motivated the need for data standardization. A gap in knowledge exists regarding variations in existing terminologies for defining diabetic retinopathy (DR) cohorts. This study aimed to review the literature and analyze variations regarding codified definitions of DR. Design: Literature review and quantitative analysis. Subjects: Published manuscripts. Methods: Four graders reviewed PubMed and Google Scholar for peer-reviewed studies. Studies were included if they used codified definitions of DR (e.g., billing codes). Data elements such as author names, publication year, purpose, data set type, and DR definitions were manually extracted. Each study was reviewed by ≥ 2 authors to validate inclusion eligibility. Quantitative analyses of the codified definitions were then performed to characterize the variation between DR cohort definitions. Main Outcome Measures: Number of studies included and numeric counts of billing codes used to define codified cohorts. Results: In total, 43 studies met the inclusion criteria. Half of the included studies used datasets based on structured EHR data (i.e., data registries, institutional EHR review), and half used claims data. All but 1 of the studies used billing codes such as the International Classification of Diseases 9th or 10th edition (ICD-9 or ICD-10), either alone or in addition to another terminology for defining disease. Of the 27 included studies that used ICD-9 and the 20 studies that used ICD-10 codes, the most common codes used pertained to the full spectrum of DR severity. Diabetic retinopathy complications (e.g., vitreous hemorrhage) were also used to define some DR cohorts. Conclusions: Substantial variations exist among codified definitions for DR cohorts within retrospective studies. Variable definitions may limit generalizability and reproducibility of retrospective studies. More work is needed to standardize disease cohorts. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Childhood vision impairment and blindness in West Africa: public health measures and implications for systemic health.

Childhood blindness is an issue of global health impact, affecting approximately 2 million children worldwide. Vision 2020 and the United Nations Sustainable Development Goals previously identified childhood blindness as a key issue in the twentieth century, and while public health measures are underway, the precise etiologies and management require ongoing investigation and care, particularly within resource-limited settings such as sub-Saharan Africa. We systematically reviewed the literature on childhood blindness in West Africa to identify the anatomic classification and etiologies, particularly those causes of childhood blindness with systemic health implications. Treatable causes included cataract, refractive error, and corneal disease. Systemic etiologies identified included measles, rubella, vitamin A deficiency, and Ebola virus disease. While prior public health measures including vitamin A supplementation and vaccination programs have been deployed in most countries with reported data, multiple studies reported preventable or reversible etiologies of blindness and vision impairment. Ongoing research is necessary to standardize reporting for anatomies and/or etiologies of childhood blindness to determine the necessity of further development and implementation of public health measures that would ameliorate childhood blindness and vision impairment.

TOWARD AN IMAGING-CENTRIC DEFINITION OF NONPARANEOPLASTIC AUTOIMMUNE RETINOPATHY.

PURPOSE: To explore characteristic imaging features of nonparaneoplastic autoimmune retinopathy (npAIR) to augment diagnostic criteria. METHODS: This is a retrospective cohort study of patients with npAIR evaluated at the Emory Eye Center between 2013 and 2019. Multimodal fundus images were evaluated to characterize the evolution of the disease. RESULTS: Twenty-one eyes of 12 patients were classified as having npAIR. Five patients (42%) were female, with median (range) age of 59 years (45-85 years). Median baseline visual acuity was 20/30 (20/20 to hand motions). Disease was asymmetric in 11 patients (92%). Common imaging findings included absence of bone spicules (86% of affected eyes), presence of attenuated vessels (86%), and speckled hypoautofluorescence in perimacular and perivenular regions. Three eyes were noted to present early with subtle splotchy fundus autofluorescence abnormality, ultimately developing characteristic speckled perimacular hypoautofluorescence. On optical coherence tomography, 18 eyes (86%) had loss of outer retinal bands with relative foveal sparing and a tapered transition zone. CONCLUSION: Many eyes with npAIR exhibit a subacute, asymmetric, generalized photoreceptor degeneration featuring outer retinal atrophy with relative foveal sparing, retinal vascular attenuation, absence of bone spicules, and speckled hypoautofluorescence often in a perimacular and perivenular distribution. Findings of this study augment diagnostic criteria to improve specificity and accessibility of testing for npAIR.

Anxiety and depression in patients with uveitis: a comprehensive review of observational studies.

PURPOSE OF THE REVIEW: The purpose of this review is to provide a comprehensive summary of observational studies evaluating anxiety and depression in patients with uveitis. RECENT FINDINGS: A higher prevalence of depression was reported in patients with uveitis compared to healthy controls in most observational studies. Symptoms of anxiety were often, but not always, significantly worse in patients with uveitis compared to controls. Most studies found that patients with uveitis had reduced vision-related quality of life that was associated with anxiety and depression symptoms. SUMMARY: Patients with uveitis have a higher risk of experiencing symptoms of depression and could benefit from screening and treatment. Preliminary screening for vision-related quality of life could also help determine if the patient requires assistance in mental health or other aspects of daily living.

Visual Morbidity and Outcomes of Scleritis Associated with Intraocular Inflammation Compared to Isolated Scleritis.

PURPOSE: To compare visual outcomes, ocular complications and therapies for patients with scleritis-associated intraocular inflammation (SAI) and patients with isolated scleritis (IS). RESULTS: A total of 52 patients (36 with SAI and 16 with IS) were reviewed. Mean age (standard deviation) at presentation was 48.4 years old (± 15.4) in the SAI group and 53 years old (± 17.1) in the IS group (p = .37). Visual acuity was worse at presentation and last visit for patients with SAI compared to IS (p = .04). Patients in the SAI group developed greater posterior segment complications than in the IS group (p = .002). CONCLUSIONS: Scleritis with intraocular inflammation was associated with a higher rate of visual morbidity compared to isolated scleritis. More aggressive management strategies may be needed for patients who present with scleritis associated with inflammation.

Refractive Outcomes of Combined Cataract Surgery and Vitrectomy Compared to Cataract Surgery Alone.

PURPOSE: The aim of the study was to evaluate the refractive outcomes of combined cataract surgery and vitrectomy compared to cataract surgery alone. METHODS: This retrospective chart review study included two groups: (1) combined surgery in 103 eyes (101 patients) who underwent cataract surgery with posterior chamber intraocular lens (PCIOL) placement by a single cataract surgeon and vitrectomy by a single vitreoretinal surgeon at the same surgical setting; (2) cataract surgery alone by the same surgeon in 107 eyes (84 patients). Refractive outcomes and complications between the combined and cataract surgery alone group were compared. The predicted refractive error was compared to postoperative refractive outcomes in both groups, surgically induced astigmatism (SIA), intraoperative or postoperative complications of either cataract surgery or vitrectomy, and cystoid macular edema. RESULTS: There was no statistically significant difference between predicted and actual postoperative refractive outcomes between the combined and cataract surgery alone groups (within ±0.5 diopters [D], p = 0.099; within ±1.0 D, p = 0.721). There was no difference in SIA refractive outcomes between the two groups (p = 0.509). The use of intraoperative gas for retina tamponade did not significantly affect postoperative refractive outcomes. Both cataract surgery and vitrectomy were successfully performed without unexpected complications from either procedure affecting the other. DISCUSSION/CONCLUSION: Combined cataract surgery and vitrectomy allows excellent refractive outcomes equal to cataract surgery alone, allowing each procedure to be performed independently by separate anterior and posterior segment surgeons. Combined procedures can be performed in eyes with a variety of retinal indications and can include fluid-gas exchange with minimal risk of PCIOL malposition or change in targeted refraction.

Common practice patterns in the diagnosis and management of Vogt-Koyanagi-Harada syndrome: a survey study of uveitis specialists.

Introduction: Vogt-Koyanagi-Harada (VKH) syndrome is an inflammatory condition characterized by bilateral, granulomatous panuveitis with or without systemic manifestations, and accounts for up to 18% of referrals for panuveitis at tertiary centers in the United States of America. Despite ongoing research, there is limited evidence and no clear consensus on how to diagnose and treat patients with VKH, leading to variations in practice patterns among uveitis specialists. Methods: An anonymous, online survey was distributed to uveitis specialists in the American Uveitis Society (AUS). The survey included 21 questions that asked for non-identifiable demographics and covered topics such as preferred imaging modalities, treatment for the first episode of VKH, and perceived efficacy of immunomodulatory therapy (IMT). Results: A total of 104 surveys were included for analysis, representing a 38.4% response rate from the AUS listserv. A majority of respondents were uveitis fellowship trained and practiced in North America in an academic setting. Fluorescein angiography and enhanced depth imaging with optical coherence tomography were rated as the most consistently useful methods for the diagnosis of VKH. For treatment of acute initial-onset VKH, responses were divided between a preference for high-dose systemic corticosteroids with IMT (61.5%) and without IMT (37.5%). Methotrexate and mycophenolate mofetil were the most common IMTs to be used as first-line therapies, but adalimumab and infliximab were perceived to be the most effective for the treatment for VKH. Discussion: While there are some common trends in the practice patterns for the diagnosis and treatment of patients with VKH, there was no clear consensus on the topic of IMT. There was a slight preference among uveitis specialists to use both IMT and systemic corticosteroids for the first episode of acute VKH.

Visual acuity and vision-related quality of life outcomes following cataract surgery in Ebola virus disease survivors.

Objectives: The objectives of this study were to assess relationships between vision-related quality of life (QoL) and visual acuity (VA) in Ebola virus disease (EVD) survivors after cataract surgery in the Ebola Viral Persistence in Ocular Tissues and Fluids (EVICT) Study. Materials and Methods: EVD survivors with undetectable Ebola virus (EBOV) ribonucleic acid in their aqueous humour were eligible to receive manual small-incision cataract surgery (MSICS). Among those that received surgery, assessments of VA and vision-related QoL were assessed pre-and post-cataract surgery. VA was converted from units on a tumbling 'E' chart to the logarithm of the minimal angle of resolution VA (logMAR VA). Vision-related QoL was assessed using the 25-item National Eye Institute Visual Function Questionnaire (NEI VFQ-25). Linear regression was used to evaluate the associations between VA and vision-related QoL. P = 0.05 was considered statistically significant for all analyses. Results: Thirty-four EVD survivors underwent cataract surgery in the EVICT study. Before MSICS, the mean logMAR VA was 2.24 (standard deviation [SD]: 0.98), and the mean NEI-VFQ-25 composite score was 54 (SD: 15); however, there was no significant association between the pre-surgery measurements (average difference in VA/10 unit increase in NEI-VFQ-25: -0.04, 95% confidence interval (CI): -0.33-0.26, P = 0.80). There was a significant improvement in logMAR VA after MSICS (mean: 1.6, P < 0.001), but there was no significant change in the NEI-VFQ-25 composite (-0.87, 95% (CI): -10.32-8.59, P = 0.85). None of the subscales showed significant improvements (P > 0.12 for all); however, the magnitude of the mean change for distance activities (6.65), near activities (6.76), general vision (-7.69), social functioning (-9.13) and colour vision (13.33) met the criteria for a clinically meaningful difference (4-6). In the subset with paired measurements (n = 16), there were no significant association changes in logMAR VA and NEI VFQ-25 composite scores (P > 0.12 for all). Conclusion: Following cataract surgery, VA in EVD survivors improved, but these improvements were not reflected in NEI VFQ-25 composite scores or specific subscales; however, the small sample size limits generalizability absent more research. Differences in sociocultural context and activities that affect the QoL in resource-limited areas may contribute to the limitations seen with NEI VFQ-25. In addition, better eye dominance could contribute to any lack of association as NEI VFQ-25 evaluates vision as a whole. Further, assessment of factors contributing to improved QoL may help to define the impact of vision health in varied environments.

Persistent intraocular Ebola virus RNA is associated with severe uveitis in a convalescent rhesus monkey.

Despite increasing evidence that uveitis is common and consequential in survivors of Ebola virus disease (EVD), the host-pathogen determinants of the clinical phenotype are undefined, including the pathogenetic role of persistent viral antigen, ocular tissue-specific immune responses, and histopathologic characterization. Absent sampling of human intraocular fluids and tissues, these questions might be investigated in animal models of disease; however, challenges intrinsic to the nonhuman primate model and the animal biosafety level 4 setting have historically limited inquiry. In a rhesus monkey survivor of experimental Ebola virus (EBOV) infection, we observed and documented the clinical, virologic, immunologic, and histopathologic features of severe uveitis. Here we show the clinical natural history, resultant ocular pathology, intraocular antigen-specific antibody detection, and persistent intraocular EBOV RNA detected long after clinical resolution. The association of persistent EBOV RNA as a potential driver of severe immunopathology has pathophysiologic implications for understanding, preventing, and mitigating vision-threatening uveitis in EVD survivors.

COVID-19 and the eye: Systemic and laboratory risk factors for retinopathy and detection of tear film SARS-CoV-2 RNA with a triplex RT-PCR assay.

PURPOSE: To assess hospitalized COVID-19 inpatients for the prevalence of retinopathy and tear film SARS-CoV-2 RNA, and associated risk factors for their detection. METHODS: Hospitalized COVID-19 patients underwent dilated ophthalmic examination and fundus photography. Conjunctival swabs were assessed for SARS-CoV-2 RT-PCR via a triple target assay. We assessed the relationships of retinopathy with clinical outcomes, systemic risk factors and laboratory data. RESULTS: The median age was 59.5 years and 29 (48%) were female. Retinopathy associated with COVID-19 was observed in 12 of 60 patients (20%). The median age of patients with COVID-19 retinopathy was 51.5 compared to 62.5 years in individuals without retinopathy (p = 0.01). Median BMI was 34.3 in patients with retinopathy versus 30.9 in those without retinopathy (p = 0.04). Fifteen of 60 patients (25%) tested SARS-CoV-2 RNA-positive in their tear film without a relationship with timing of illness and hospitalization. The N2 gene was particularly sensitive with 18 of 19 eyes (94.7%) showing N2-positivity, including 2 patients with alpha variant-positivity (B.1.1.7). CONCLUSION: Retinopathy was observed in 20% of patients hospitalized for COVID-19. Patients with retinopathy were more likely to be younger and have higher BMI than hospitalized patients without retinopathy. Tear film SARS-CoV-2 RNA was detected in 25% of patients. The relationship of obesity and age with retinopathy requires further investigation.

Ophthalmic sequelae and psychosocial impact in pediatric ebola survivors.

Background: Ebola virus disease (EVD) outbreaks in West Africa (2013-2016) and the Democratic Republic of Congo (2018-2020) have resulted in thousands of EVD survivors who remain at-risk for survivor sequelae. While EVD survivorship has been broadly reported in adult populations, pediatric EVD survivors are under-represented. In this cross-sectional study, we investigated the prevalence of eye disease, health-related quality-of-life, vision-related quality-of-life, and the burden of mental illness among pediatric EVD survivors in Sierra Leone. Methods: Twenty-three pediatric EVD survivors and 58 EVD close contacts were enrolled. Participants underwent a comprehensive ophthalmic examination and completed the following surveys: Pediatric Quality of Life Inventory Version 4.0, Effect of Youngsters Eyesight on Quality-of-Life, and the Revised Child Anxiety and Depression Scale. Findings: A higher prevalence of uveitis was observed in EVD survivor eyes (10·8%) cohort compared to close contacts eyes (1·7%, p=0·03). Overall, 47·8% of EVD survivor eyes and 31·9% of close contact eyes presented with an eye disease at the time of our study (p=0·25). Individuals diagnosed with an ocular complication had poorer vision-related quality-of-life (p=0·02). Interpretation: Both health related quality-of-life and vision-related quality-of-life were poor among EVD survivors and close contacts. The high prevalence of eye disease associated with reduced vision health, suggests that cross-disciplinary approaches are needed to address the unmet needs of EVD survivors. Funding: National Institutes of Health R01 EY029594, K23 EY030158; National Eye Institute; Research to Prevent Blindness (Emory Eye Center); Marcus Foundation Combating Childhood Illness; Emory Global Health Institute; Stanley M. Truhlsen Family Foundation.

Cytomegalovirus retinitis in the highly active anti-retroviral therapy era.

Cytomegalovirus (CMV) retinitis is an opportunistic infection that has traditionally affected those who have HIV/AIDS or immunosuppressed individuals. CMV retinitis previously infected one-third of AIDS patients in the pre-highly active antiretroviral therapy (HAART) era, but since HAART, Western countries have seen an 80% decrease in the incidence of the disease. More recently, CMV retinitis has been reported in patients who are immunosuppressed, often due to chemotherapy or immunomodulatory medications. The diagnosis of CMV retinitis is often suspected based on clinical findings, with polymerase chain reaction for confirmation of CMV, especially in atypical cases. Highly active antiretroviral therapy and anti-CMV medications (systemic or local) remain the mainstay of treatment. However, for those who are not responsive to HAART, CMV retinitis remains a challenge, and can still lead to significant vision loss. Moreover, a regimen of anti-CMV medications can sometimes lead to viral resistance or organ toxicity. Complications such as immune recovery retinitis and rhegmatogenous retinal detachments continue to threaten the vision of patients who develop CMV retinitis. These complications can arise following initiation of treatment or if patients show disease progression. Proper vision screening for CMV retinitis in immunosuppressed patients at-risk is necessary for early detection and treatment.