Gene therapy for age-related macular degeneration: potential, feasibility, and pitfalls.

PURPOSE OF REVIEW: The landscape for age-related macular degeneration (AMD) is rapidly changing with addition of biosimilars and now United States Food and Drug Administration (FDA) approved nonneovascular AMD (nnAMD) treatment options. These developments have inspired a burgeoning pipeline of gene therapy approaches focused on similar antivascular endothelial growth factors (VEGF) and complement related pathways. Historic and more recent setbacks in the gene therapy pipeline, including intraocular inflammatory reactions, have raised important concerns for adverse events related to AMD therapeutics both for gene and nongene approaches. The specific clinical profile of these therapeutics approaching later stage clinical trials are complex and under active investigation; however, these options hold promise to disrupt the current landscape and change management paradigms for one of the leading causes of vision loss worldwide. RECENT FINDINGS: This review covers current gene therapy approaches for neovascular AMD (nAMD) and nnAMD. Intravitreal, suprachoroidal, and subretinal delivery routes are discussed with attention to technical procedure, capabilities for transgene delivery to target tissue, immunogenicity, and collateral effects. Suprachoroidal delivery is an emerging approach which may bridge some of the practical drawbacks for intravitreal and subretinal methods, though with less elaborated immunologic profile. In parallel to delivery modification, viral vectors have been cultivated to target specific cells, with promising enhancements in adeno-associated viral (AAV) vectors and persistent interest in alternate viral and nonviral delivery vectors. Ongoing questions such as steroid or immunosuppressive regimen and economic considerations from a payer and societal perspective are discussed. SUMMARY: The present review discusses emerging gene therapy options which could foster new, more durable nAMD and nnAMD therapeutics. These options will need refinement with regards to route, vector, and dosage, and specialists must decipher the specific clinical risk benefit profile for individual patients. Ongoing concerns for immunogenicity or dosage related adverse events could stifle progress, while further vector development and refined delivery techniques have the potential to change the safety and efficacy of currently options in the pipeline.

Q Fever-Associated Chorioretinitis.

Coxiella burnetii is the causative agent in Q fever, a zoonotic disease. Ocular manifestations of this disease are extremely rare and have been infrequently reported. In this report, we describe a rare case of chorioretinitis in a patient incompletely treated for Q fever. We highlight the unique ocular manifestation with multimodal imaging, and the importance of a thorough history and prompt and correct treatment of the disease with systemic therapy. [Ophthalmic Surg Lasers Imaging Retina 2024;55:xx-xx.].

Ophthalmology Workforce Projections in the United States, 2020 to 2035.

PURPOSE: To analyze ophthalmology workforce supply and demand projections from 2020 to 2035. DESIGN: Observational cohort study using data from the National Center for Health Workforce Analysis (NCHWA). METHODS: Data accessed from the Department of Health and Human Services, Health Resources and Services Administration (HRSA) website were compiled to analyze the workforce supply and demand projections for ophthalmologists from 2020 to 2035. MAIN OUTCOME MEASURES: Projected workforce adequacy over time. RESULTS: From 2020 to 2035, the total ophthalmology supply is projected to decrease by 2650 full-time equivalent (FTE) ophthalmologists (12% decline) and total demand is projected to increase by 5150 FTE ophthalmologists (24% increase), representing a supply and demand mismatch of 30% workforce inadequacy. The level of projected adequacy was markedly different based on rurality by year 2035 with 77% workforce adequacy versus 29% workforce adequacy in metro and nonmetro geographies, respectively. By year 2035, ophthalmology is projected to have the second worst rate of workforce adequacy (70%) of 38 medical and surgical specialties studied. CONCLUSIONS: The HRSA's Health Workforce Simulation Model forecasts a sizeable shortage of ophthalmology supply relative to demand by the year 2035, with substantial geographic disparities. Ophthalmology is one of the medical specialties with the lowest rate of projected workforce adequacy by 2035. Further dedicated workforce supply and demand research for ophthalmology and allied professionals is needed to validate these projections, which may have significant future implications for patients and providers. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Serous Retinopathy Associated With Combination MEK and Fibroblast Growth Factor Receptor Inhibitor.

Purpose: To present a case of a chemotherapy regimen combining a fibroblast growth factor receptor (FGFR) and mitogen-activated protein kinase kinase (MEK) inhibitor leading to serous retinopathy. Methods: A retrospective chart review of a single case was performed. Results: A 67-year-old man with pancreatic and prostate cancer developed bilateral multifocal pockets of subretinal fluid while on an experimental chemotherapy regimen combining an MEK inhibitor (trametinib) and an FGFR inhibitor (erdafitinib). Conclusions: Given that FGFR lies upstream to the mitogen-activated protein kinase signaling pathway, retinal toxicity may be more severe and more common with FGFR-MEK combination therapy. Future studies are necessary to guide ophthalmic surveillance.

Trends in Imaging Utilization Among United States Medicare Beneficiaries and the Impact of the COVID-19 Pandemic.

This study characterizes trends in ophthalmic imaging volume and utilization in the United States among and assesses the potential impact of the COVID-19 pandemic using data from the Centers for Medicare and Medicaid Services. Utilization of macular optical coherence tomography (OCT), optic nerve OCT, and fundus photography steadily increased from 2013 to 2020 and was not impacted by the COVID-19 pandemic. At the same time, there was minimal adoption of anterior segment OCT and a decline in the utilization of dye-based angiography. Utilization patterns may be impacted by the advent of new technologies, role of the clinician, and alignment with treatment paradigms. [Ophthalmic Surg Lasers Imaging Retina 2023;54:661-665.].

Accuracy and Reliability of Chatbot Responses to Physician Questions.

Importance: Natural language processing tools, such as ChatGPT (generative pretrained transformer, hereafter referred to as chatbot), have the potential to radically enhance the accessibility of medical information for health professionals and patients. Assessing the safety and efficacy of these tools in answering physician-generated questions is critical to determining their suitability in clinical settings, facilitating complex decision-making, and optimizing health care efficiency. Objective: To assess the accuracy and comprehensiveness of chatbot-generated responses to physician-developed medical queries, highlighting the reliability and limitations of artificial intelligence-generated medical information. Design, Setting, and Participants: Thirty-three physicians across 17 specialties generated 284 medical questions that they subjectively classified as easy, medium, or hard with either binary (yes or no) or descriptive answers. The physicians then graded the chatbot-generated answers to these questions for accuracy (6-point Likert scale with 1 being completely incorrect and 6 being completely correct) and completeness (3-point Likert scale, with 1 being incomplete and 3 being complete plus additional context). Scores were summarized with descriptive statistics and compared using the Mann-Whitney U test or the Kruskal-Wallis test. The study (including data analysis) was conducted from January to May 2023. Main Outcomes and Measures: Accuracy, completeness, and consistency over time and between 2 different versions (GPT-3.5 and GPT-4) of chatbot-generated medical responses. Results: Across all questions (n = 284) generated by 33 physicians (31 faculty members and 2 recent graduates from residency or fellowship programs) across 17 specialties, the median accuracy score was 5.5 (IQR, 4.0-6.0) (between almost completely and complete correct) with a mean (SD) score of 4.8 (1.6) (between mostly and almost completely correct). The median completeness score was 3.0 (IQR, 2.0-3.0) (complete and comprehensive) with a mean (SD) score of 2.5 (0.7). For questions rated easy, medium, and hard, the median accuracy scores were 6.0 (IQR, 5.0-6.0), 5.5 (IQR, 5.0-6.0), and 5.0 (IQR, 4.0-6.0), respectively (mean [SD] scores were 5.0 [1.5], 4.7 [1.7], and 4.6 [1.6], respectively; P = .05). Accuracy scores for binary and descriptive questions were similar (median score, 6.0 [IQR, 4.0-6.0] vs 5.0 [IQR, 3.4-6.0]; mean [SD] score, 4.9 [1.6] vs 4.7 [1.6]; P = .07). Of 36 questions with scores of 1.0 to 2.0, 34 were requeried or regraded 8 to 17 days later with substantial improvement (median score 2.0 [IQR, 1.0-3.0] vs 4.0 [IQR, 2.0-5.3]; P < .01). A subset of questions, regardless of initial scores (version 3.5), were regenerated and rescored using version 4 with improvement (mean accuracy [SD] score, 5.2 [1.5] vs 5.7 [0.8]; median score, 6.0 [IQR, 5.0-6.0] for original and 6.0 [IQR, 6.0-6.0] for rescored; P = .002). Conclusions and Relevance: In this cross-sectional study, chatbot generated largely accurate information to diverse medical queries as judged by academic physician specialists with improvement over time, although it had important limitations. Further research and model development are needed to correct inaccuracies and for validation.

Safety of recent ophthalmic drugs and devices for wet macular degeneration.

PURPOSE OF REVIEW: With frequent antivascular endothelial growth factors (VEGF) injections well established as the standard of care in neovascular age-related macular degeneration (nAMD), focus has now shifted towards decreasing treatment burden without compromising safety and efficacy. This review summarizes clinical stage and recently approved drugs and devices for nAMD, with an emphasis paid to safety concerns and their implications for product adoption. RECENT FINDINGS: Three strategies have emerged to decrease the treatment burden associated with the current standard of care: more durable intravitreal agents, sustained-release modalities and gene therapy. The appearance of biosimilars will further impact drug availability and cost. As patterns of adverse events emerge from clinical trial or postmarketing surveillance data, manufacturers have proactively responded by appointing independent review committees or issuing voluntary recalls. However, the example of one biosimilar approved outside of the USA and European Union demonstrates how early safety concerns, even when addressed by substantive data, can generate lingering uncertainty. SUMMARY: As the number of promising new treatments in nAMD continues to grow, so too does the amount of data that providers must sift through. The perception of safety surrounding first movers in each new therapeutic area is sure to affect adoption of that modality more broadly.

Time-driven Activity-based Costing Analysis of Fluorescein Angiography.

PURPOSE: To use electronic health record (EHR) time logs and time-driven activity-based costing (TDABC) to calculate the complete cost profile of office-based fluorescein angiography (FA). DESIGN: Economic analysis. SUBJECTS: Patients undergoing routine FA (Current Procedural Terminology [CPT] 92235) at Vanderbilt Eye Institute in fiscal year 2022. METHODS: Process flow mapping for routine FA was used to define the care episode after manual observation. Deidentified time logs were sourced from the EHR and all manually validated to calculate durations for each stage. The cost of materials was calculated from internal financial figures. Cost per minute for space, equipment, and personnel were based on internal figures. Published fluorescein costs were used for base-case analysis with scenario analysis based on a range of internal figures from pharmacy quotes. These inputs were used for a TDABC analysis. MAIN OUTCOME MEASURES: Time-driven activity-based costing of FA episode of care. Secondary scenario analyses focus on breakeven scenarios for key inputs, including medication costs RESULTS: Cost analysis of office-based FA resulted in an average total cost of $152.95 (nominal) per interpreted study per patient, which was $36.52 more than the maximum Medicare reimbursement for CPT 92235 in Mac Locality for Tennessee 10312 for fiscal year 2022 ($116.43; $76.11 [technical component] and $40.33 [physician component]). The negative contribution margin is strongly influenced by the cost of fluorescein, which comprises 39.8% of the episode costs, excluding overhead. CONCLUSIONS: The current analysis here shows that the recently increased cost of fluorescein has driven up the cost of office-based FA relative to the current maximum allowable Medicare reimbursement, leading to a negative contribution margin and financial loss. Given conservative cost estimates here, it is unlikely for profitability to be achieved without changes in the cost of fluorescein or increased reimbursement. These results may be informative for policy discussion regarding appropriate reimbursement for codes using injectable fluorescein. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Variation in Perioperative Care Practices Among Vitreoretinal Surgeons in the United States.

OBJECTIVE: To describe perioperative practice patterns among retinal surgeons managing retinal detachment (RD) repair. METHODS: This was a cross-sectional pilot survey of vitreoretinal surgeons in the United States (US), identified by a previously published web-based search and cross-referencing names from the American Society of Retina Specialists. Self-reported peri-operative practices and subgroups were analyzed. RESULTS: Of the 298 surgical retina specialists who completed the survey, 115 (39%) were in practice for ≤ 5 years, 102 (34%) were in practice for 6 to 20 years, and 81 (27%) were in practice for > 20 years; 60%, 23%, and 16% were in private, academic, and hybrid practice, respectively. Fifty-nine percent reported operating with trainees. For ocular blocks, 59% perform retrobulbar, 21% peribulbar, and 20% subtenon's (ST). Use of ST block varied significantly by years in practice and presence of trainees (P < 0.0001, P = 0.004, respectively). Sixty percent perform primary scleral buckles (SB), 55% combined SB/pars plana vitrectomy (PPV), and 11% primary PPVs under general anesthesia. Use of general anesthesia for primary SB varied significantly by years in practice (P = 0.007). Surgeons with fewer years in practice were more likely to recommend facedown positioning for macula-off RDs (P < 0.0001). Forty-six percent of surgeons do not advise stopping blood thinners before surgery and this varied significantly by years in practice (P = 0.006). CONCLUSIONS: Variation exists among US vitreoretinal surgeons in relation to anesthesia, postoperative positioning, and blood thinners restrictions. Preferences are influenced by years in practice and less by trainees and practice setting. These results serve as a basis for larger, targeted US-based surveys on perioperative care and correlation with surgical outcomes. [Ophthalmic Surg Lasers Imaging Retina 2022;53:681-690.].

Spotlight on Faricimab in the Treatment of Wet Age-Related Macular Degeneration: Design, Development and Place in Therapy.

The advent of anti-vascular endothelial growth factor (VEGF) agents has revolutionized the treatment of retinal neovascular diseases including neovascular age-related macular degeneration (nAMD), a leading cause of irreversible blindness. Multiple agents and methods for drug delivery are emerging to increase the duration of treatment effect and treatment interval, reducing the overall treatment burden on patients and clinicians. The newest agent on the market is faricimab. This medication targets two distinct pathways in retinal angiogenesis, VEGF-A and Ang-2, to create a more durable effect. Phase 3 trials for this drug compared treatment intervals up to 16 weeks against aflibercept dosed at 8-week intervals for both nAMD and diabetic macular edema (DME). While the drug shows similar functional and anatomic outcomes with a low adverse effect profile and trial data demonstrating increased treatment duration, its exact place in the VEGF marketplace is yet to be determined. In this article, we discuss the mechanism of action, pivotal clinical trials leading to approval, and the anticipated role for faricimab in the treatment of retinal neovascular disease.

Numerous White Retinal Lesions Following Cataract Surgery.

A 74-year-old woman was referred for evaluation of retinal lesions in her left eye. The vitreous sample obtained at the time of treatment grew Staphylococcus caprae susceptible to vancomycin, and the patient responded well to treatment with topical steroid and cycloplegic drops. What would you do next?

Economic Evaluation of the Merit-Based Incentive Payment System for Ophthalmologists: Analysis of 2019 Quality Payment Program Data.

Importance: The Merit-Based Incentive Payment System (MIPS) is intended to promote high-value health care through quality-related Medicare payment adjustments. Objective: To assess the economic evaluation of MIPS scoring and reporting on ophthalmologists. Design, Setting, and Participants: In this retrospective, cross-sectional, multicenter economic evaluation conducted from October 10 to November 30, 2021, MIPS performance and related payment adjustments were evaluated using the US Centers for Medicare & Medicaid Service (CMS) public data files for ophthalmologists. Participants were stratified by reporting affiliation. Analysis of variance and summary statistics were used to characterize and compare total and subcategory MIPS scores and adjustments received by participants. Reported CMS methodology and performance year (PY) 2019 payment percentages were used to estimate payment adjustments for the following categories: positive MIPS adjustment plus potential additional adjustment for exceptional performance, positive MIPS adjustment, neutral payment adjustment, negative MIPS payment adjustment, and maximum negative MIPS payment adjustment. Study participants included ophthalmologists registered for Medicare Part B with participation in the Quality Payment Program (QPP) in PY 2019. Main Outcomes and Measures: Proportion of ophthalmologists qualifying for payment adjustments and payment adjustments. Results: For PY 2019, 76.5% of ophthalmologists (13 621) who registered for Medicare participated in the MIPS pathway of the QPP. Ophthalmologists practiced in a predominantly large metropolitan area (12 302; 90.3%). Roughly 99% of participants (11 182) received nonnegative reimbursement adjustments, and 92.6% (10 367) received positive adjustments. Ophthalmologists filing as individuals were less likely to achieve exceptional performance scores compared with those who had a filing category of advanced alternative payment model (APM; odds ratio [OR], 0.0003; 95% CI, 0.00002-0.00481) or group (OR, 0.21013; 95% CI, 0.19020-0.23215). When analyzing participating ophthalmologists with available Medicare payment data (11 193), a total of 8777 (78.4%) achieved exceptional MIPS scores corresponding to mean (SD) adjustments per physician of $244.60 ($217.36) to $4864.78 ($4323.08), or 0.07% ($2 146 835.21 of $3 212 011 252.88) to 1.33% ($42 698 166.89 of $3 212 011 252.88), of the total nondrug Medicare payment. Conclusions and Relevance: Results of this economic evaluation showed that although 78.4% of ophthalmologists received exceptional positive payment adjustments, roughly 84% (798916 of 954615) of all health care professionals nationally achieved this benchmark. Exceptional MIPS was associated with filing as group or APM, resulting in, on average, a relatively small additional payment per participant; this suggests that ophthalmologists who file as individuals should consider an alternative filing approach. Changes in MIPS methodology may disproportionately affect certain ophthalmologists, which warrants further study.

Hemi- and Central Retinal Vein Occlusion Associated with COVID-19 Infection in Young Patients without Known Risk Factors.

PURPOSE: Venous thromboembolic complications have been reported in association with coronavirus disease 2019 (COVID-19) infection. We raised awareness regarding a potential temporal association between COVID-19 infection and retinal vein occlusion (RVO). DESIGN: Multicenter, retrospective, nonconsecutive case series. SUBJECTS: Patients presenting with hemi-RVO (HRVO) or central RVO (CRVO) between March 2020 and March 2021, with confirmed COVID-19 infection, were included. The exclusion criteria were as follows: age >50 years, hypertension, diabetes, glaucoma, obesity, underlying hypercoagulable states, and those requiring intubation during hospitalization. METHODS: This was a multicenter, retrospective, nonconsecutive case series including patients presenting with hemi-RVO (HRVO) or central RVO (CRVO) between March 2020 and March 2021, with confirmed COVID-19 infection. The exclusion criteria were as follows: age >50 years, hypertension, diabetes, glaucoma, obesity, underlying hypercoagulable states, and those requiring intubation during hospitalization. MAIN OUTCOME MEASURES: Ophthalmic findings, including presenting and final visual acuity (VA), imaging findings, and clinical course. RESULTS: Twelve eyes of 12 patients with CRVO (9 of 12) or HRVO (3 of 12) after COVID-19 infection were included. The median age was 32 years (range, 18-50 years). Three patients were hospitalized, but none were intubated. The median time from COVID-19 diagnosis to ophthalmic symptoms was 6.9 weeks. The presenting VA ranged from 20/20 to counting fingers, with over half (7 of 12) having a VA of ≥20/40. OCT revealed macular edema in 42% of the eyes; of these, 80% (4 of 5) were treated with anti-VEGF injections. Ninety-two percent (11 of 12) had partial or complete resolution of ocular findings at final follow-up. Four eyes (33%) had retinal thinning, as determined using OCT, by the end of the study interval. The final VA ranged from 20/20 to 20/60, with 11 of the 12 (92%) eyes achieving a VA of ≥20/40 at a median final follow-up period of 13 weeks (range, 4-52 weeks). CONCLUSIONS: Although we acknowledge the high seroprevalence of COVID-19 and that a causal relationship cannot be established, we reported this series to raise awareness regarding the potential risk of retinal vascular events due to a heightened thromboinflammatory state associated with COVID-19 infection.