Huynh E, Elhusseiny AM, Nihalani BR. Paediatric anterior uveitis management in the USA: a single-centre, 10-year retrospective chart review exploring the efficacy and safety of systemic immunomodulatory therapy. Eye (Lond) 2022;Abstract
OBJECTIVE: To evaluate the efficacy of immunomodulatory therapy (IMT) in paediatric anterior uveitis. METHODS: Chart review of all patients ≤ 18 years treated for anterior uveitis using a stepladder approach during a 10-year period. The type and duration of IMT were noted. The data were analysed depending on chronicity, aetiology, and type of IMT using appropriate statistical tests. The outcome measures included ocular complications, the need for surgical intervention, and visual outcomes. RESULTS: One hundred and thirty-four patients (191 eyes) were analyzed. The median age at diagnosis was 7 years (interquartile range (IQR): 7.5 years). The median follow-up was 4 years (IQR: 6 years). The most common causes of anterior uveitis were Juvenile idiopathic arthritis (64 patients, 47.8%) and undifferentiated (33 patients, 24.6%). All patients were started on topical steroids and cycloplegics. 94 (70%) patients required IMT. 92 (68.6%) were started on Methotrexate as the first agent, of which 21 (22%) were switched to a different agent owing to side effects. Biologic agent was added in 55 (41%) patients. 21 (16%) required switch to a second biologic agent, 5 (3.7%) to third, and 1 (0.8%) to fourth biologic agent. At the last exam, 11 (8%) had persistent inflammation. 55 (41%) had ocular complications, and 113 (84%) had a best corrected visual acuity ≥ 20/40. CONCLUSION: Early introduction of IMT and switch to different agents may be required to control anterior uveitis and reduce the complications in children. IMT is safe and effective in treating paediatric anterior uveitis.
McCoskey M, Reshef ER, Wolkow N, Yoon MK. Bilateral enlargement of all extraocular muscles: a presenting ophthalmic sign of hematologic malignancy. Orbit 2022;:1-4.Abstract
Hematologic malignancies such as leukemia and lymphoma can frequently present in the orbit; however, involvement of the extraocular muscles is rare. The authors report two cases of systemic hematologic malignancy presenting with bilateral extraocular muscle enlargement and associated compressive optic neuropathy (CON). Both patients experienced clinical and radiographic improvement of ocular and systemic manifestations of disease with prompt initiation of targeted chemotherapy. These cases highlight the importance of including hematologic malignancy in the differential diagnosis of atypical bilateral extraocular muscle enlargement.
Sekimitsu S, Elze T, Zebardast N. Impact of the Affordable Care Act on Glaucoma Severity at First Presentation. Ophthalmic Epidemiol 2022;:1-4.Abstract
PURPOSE: To test whether the increase in insurance coverage in Massachusetts due to the Affordable Care Act (ACA) is associated with a decrease in glaucoma severity in patients presenting for the first time at a tertiary health system. METHODS: Clinical and billing data of first-time glaucoma patients from a tertiary health system in Massachusetts from 2006 to 2021 was used. Pre-ACA is defined as before 2014 and post-ACA is defined as after 2014. Visual field mean deviation was used to define glaucoma severity: greater than -6 dB, less than -6 dB and greater than -12 dB, and less than -12 dB was classified as "mild," "moderate," and "severe" respectively. Ordinal logistic regression models adjusted for age, race, gender, and insurance type were used to determine the odds of presenting with more severe glaucoma. RESULTS: 2,394 pre-ACA and 3,651 post-ACA first-time glaucoma patients were identified. There was no significant difference in the likelihood of more severe glaucoma at first presentation post-ACA compared to pre-ACA (OR=0.96; 95% CI 0.86-1.08; p=0.49) among the entire population. In stratified analyses, patients who utilized Medicaid for insurance had 52% decreased odds for presenting with more severe glaucoma at first presentation post-ACA compared to pre-ACA (OR=0.48; 95% CI 0.33-0.69; p<0.001). This remained significant after adjustment for age, race, and gender (adjusted OR=0.44; 95% CI 0.29-0.65; p<0.001). CONCLUSION: At a Massachusetts-based tertiary healthcare center, individuals on Medicaid were more likely to have more severe glaucoma at first presentation before the implementation of the ACA, compared to after.
PURPOSE: The purpose of this study was to evaluate the prognostic utility of the degree of vitreous attachment for predicting outcomes of vitrectomy for nonclearing vitreous hemorrhage associated with proliferative diabetic retinopathy. METHODS: Medical records of patients who underwent primary vitrectomy for dense nonclearing vitreous hemorrhage secondary to proliferative diabetic retinopathy were examined retrospectively. Eyes were divided into four groups based on the intraoperatively assessed stage of posterior vitreous detachment (PVD), ranging from Stage 0/1 (complete or near-complete vitreoretinal adhesion) to Stage 4 (complete PVD). RESULTS: Overall, 136 eyes (117 patients) were included. In comparison with eyes with a partial or complete PVD (Stages 2-4), eyes with no PVD (Stage 0/1) had a higher incidence of postoperative hypotony (8%, P = 0.03) and traction retinal detachment (27%, P = 0.002), an increased rate of repeat vitrectomy (49%, P = 0.04), and poorer best-corrected visual acuity at 6 months and 1 year postoperatively (P = 0.04 and P = 0.01, respectively). Presence of a complete PVD at baseline was independently associated with improved postoperative vision at 6 months (P = 0.04). CONCLUSION: More extensive vitreoretinal adhesion is associated with higher rates of reoperation and poorer visual outcomes after vitrectomy for dense nonclearing vitreous hemorrhage associated with proliferative diabetic retinopathy. Preoperative determination of PVD status using B-scan ultrasonography may be useful for predicting anatomical and functional outcomes after vitrectomy in these patients.
Lin JB, Serghiou S, Miller JW, Vavvas DG. Systemic Complement Activation Profiles in Nonexudative Age-Related Macular Degeneration: A Systematic Review. Ophthalmol Sci 2022;2(2)Abstract
Topic: To evaluate whether differences exist in systemic complement activation profiles in patients with early to intermediate nonexudative age-related macular degeneration (AMD) or geographic atrophy (GA) compared with control participants without AMD. Clinical Relevance: Complement inhibition has emerged as a therapeutic strategy for GA, although clinical trials to date have yielded mixed results. Despite these efforts, no clear consensus exists regarding what portions of the complement pathway are dysregulated in AMD or when this dysregulation occurs relative to AMD stage. Although past studies have compared systemic complement activation profiles in patients with AMD versus in control participants without AMD, differences in AMD case definition and differing analytical approaches complicate their interpretation. Methods: We performed a systematic review by identifying articles from database inception through October 11, 2020, that reported systemic complement activation profiles in patients with early or intermediate nonexudative AMD or GA versus control participants without AMD by searching PubMed, Google Scholar, and Embase. Risk of bias was assessed using a modified Newcastle-Ottawa score. Results: The 8 reviewed studies included 2131 independent participants. Most studies report significantly higher systemic levels of products associated with complement activation and significantly lower systemic levels of products associated with complement inhibition in patients with early and advanced nonexudative AMD compared with control participants without AMD. Discussion: Evidence suggests that systemic complement overactivation is a feature of early or intermediate and advanced nonexudative AMD. However, given significant heterogeneity, these findings are not conclusive and warrant further investigation.
Ismail AM, Saha A, Lee JS, Painter DF, Chen Y, Singh G, Condezo GN, Chodosh J, San Martín C, Rajaiya J. RANBP2 and USP9x regulate nuclear import of adenovirus minor coat protein IIIa. PLoS Pathog 2022;18(6):e1010588.Abstract
As intracellular parasites, viruses exploit cellular proteins at every stage of infection. Adenovirus outbreaks are associated with severe acute respiratory illnesses and conjunctivitis, with no specific antiviral therapy available. An adenoviral vaccine based on human adenovirus species D (HAdV-D) is currently in use for COVID-19. Herein, we investigate host interactions of HAdV-D type 37 (HAdV-D37) protein IIIa (pIIIa), identified by affinity purification and mass spectrometry (AP-MS) screens. We demonstrate that viral pIIIa interacts with ubiquitin-specific protease 9x (USP9x) and Ran-binding protein 2 (RANBP2). USP9x binding did not invoke its signature deubiquitination function but rather deregulated pIIIa-RANBP2 interactions. In USP9x-knockout cells, viral genome replication and viral protein expression increased compared to wild type cells, supporting a host-favored mechanism for USP9x. Conversely, RANBP2-knock down reduced pIIIa transport to the nucleus, viral genome replication, and viral protein expression. Also, RANBP2-siRNA pretreated cells appeared to contain fewer mature viral particles. Transmission electron microscopy of USP9x-siRNA pretreated, virus-infected cells revealed larger than typical paracrystalline viral arrays. RANBP2-siRNA pretreatment led to the accumulation of defective assembly products at an early maturation stage. CRM1 nuclear export blockade by leptomycin B led to the retention of pIIIa within cell nuclei and hindered pIIIa-RANBP2 interactions. In-vitro binding analyses indicated that USP9x and RANBP2 bind to C-terminus of pIIIa amino acids 386-563 and 386-510, respectively. Surface plasmon resonance testing showed direct pIIIa interaction with recombinant USP9x and RANBP2 proteins, without competition. Using an alternative and genetically disparate adenovirus type (HAdV-C5), we show that the demonstrated pIIIa interaction is also important for a severe respiratory pathogen. Together, our results suggest that pIIIa hijacks RANBP2 for nuclear import and subsequent virion assembly. USP9x counteracts this interaction and negatively regulates virion synthesis. This analysis extends the scope of known adenovirus-host interactions and has potential implications in designing new antiviral therapeutics.
Sokol JT, Castillejos A, Sobrin L. Purtscher-like retinopathy following a bowel movement. Am J Ophthalmol Case Rep 2022;26:101560.Abstract
Purpose: To describe a case of Purtscher-like retinopathy that developed after a bowel movement. Observations: A 32-year-old male presented with blurry vision and bilateral temporal paracentral scotomas that developed immediately after standing up from a bowel movement. Fundoscopic examination was notable for bilateral cotton wool spots in the nasal macula. Optical coherence tomography showed bilateral intraretinal fluid, subfoveal fluid, and scattered areas of inner retinal hyperreflectivity and thickening corresponding to the areas of cotton wool spots on examination. No treatment was administered and the patient had significant improvement in symptoms 2 days later with resolution of macular edema. Conclusions: Here we report a case of Purtscher-like retinopathy after a bowel movement. Although the exact mechanism of Purtscher-like retinopathy is unknown, there are multiple reports of Purtscher-like retinopathy after extreme events involving Valsalva, such as during weightlifting, and we postulate that this presentation is likely of similar pathophysiology.
White E, Walsh L. The Impact of Occlusion Therapy on Amblyopia Success Outcomes. J Binocul Vis Ocul Motil 2022;72(3):183-190.Abstract
PURPOSE: The recommended amount of occlusion therapy and amblyopia treatment success rates remains controversial. This study explores rates of occlusion therapy success and attempts to address limitations of previous literature. METHODS: A retrospective chart review was performed on patients with occlusion therapy outcomes from 2012 to 2019. Equal visual acuity (VA) or stable VA for three consecutive clinical visits, despite reported good compliance defined outcome VA. RESULTS: Results showed 90.3% of subjects obtained outcome distance VA of 0.3logMAR, 76% ≥0.3logMAR, 35% ≥0.2logMAR, and 6% ≥0.1logMAR in the amblyopic eye following treatment. Sixty-nine percent of the study population obtained equal vision following occlusion therapy. Only initial VA (amblyopic eye) and initial interocular visual optotype difference at distance predicted post-treatment success. CONCLUSION: These results support the conclusion that occlusion therapy, both PTO and FTO, can be effective in treating amblyopia when good compliance is maintained based on parental reports of compliance. Additionally, as VA gain was higher than in previous literature, it is important to continue treatment until VA is equal or three consecutive cycles of stable VA are obtained to ensure maximum VA improvement.
Bora K, Wang Z, Yemanyi F, Maurya M, Blomfield AK, Tomita Y, Chen J. Endothelial Cell Transcytosis Assay as an In Vitro Model to Evaluate Inner Blood-Retinal Barrier Permeability. J Vis Exp 2022;(184)Abstract
Dysfunction of the blood-retinal barrier (BRB) contributes to the pathophysiology of several vascular eye diseases, often resulting in retinal edema and subsequent vision loss. The inner blood-retinal barrier (iBRB) is mainly composed of retinal vascular endothelium with low permeability under physiological conditions. This feature of low permeability is tightly regulated and maintained by low rates of paracellular transport between adjacent retinal microvascular endothelial cells, as well as transcellular transport (transcytosis) through them. The assessment of retinal transcellular barrier permeability may provide fundamental insights into iBRB integrity in health and disease. In this study, we describe an endothelial cell (EC) transcytosis assay, as an in vitro model for evaluating iBRB permeability, using human retinal microvascular endothelial cells (HRMECs). This assay assesses the ability of HRMECs to transport transferrin and horseradish peroxidase (HRP) in receptor- and caveolae-mediated transcellular transport processes, respectively. Fully confluent HRMECs cultured on porous membrane were incubated with fluorescent-tagged transferrin (clathrin-dependent transcytosis) or HRP (caveolae-mediated transcytosis) to measure the levels of transferrin or HRP transferred to the bottom chamber, indicative of transcytosis levels across the EC monolayer. Wnt signaling, a known pathway regulating iBRB, was modulated to demonstrate the caveolae-mediated HRP-based transcytosis assay method. The EC transcytosis assay described here may provide a useful tool for investigating the molecular regulators of EC permeability and iBRB integrity in vascular pathologies and for screening drug delivery systems.
Gaier ED, Rasool N, Rizzo JF. Sectoral Sparing Associated With a Cilioretinal Artery in Arteritic Anterior Ischemic Optic Neuropathy. J Neuroophthalmol 2022;42(2):e514-e516.Abstract
ABSTRACT: Giant cell arteritis (GCA) is a life-threatening vasculitis occurring in older adults that can cause blindness by ischemia of the choroid, retina, and optic nerve. We report a case of a patient who presented with "occult" GCA with severe anterior ischemic optic neuropathy affecting both optic nerves, delayed choroidal filling, and a concomitant cilioretinal artery occlusion in the left eye. The retinal territory supplied by the affected cilioretinal artery was hypoperfused, yet this retinal territory at least partially corresponded to the only preserved visual field in that eye. The sector of the optic disc corresponding to the emergence of the cilioretinal artery was the only sector spared by pallid edema. This pattern of sectoral sparing associated with a cilioretinal artery has been observed in other patients with GCA and in animal models of posterior ciliary artery occlusion. This case serves as a clear example of an incompletely understood phenomenon in posterior pole circulation in vascular occlusive disease that deserves further study.
Qiu M, Avdagic E, Ramulu PY, Golnik K, Boland MV. Ophthalmology Surgical Assessment of Tube Shunt Glaucoma Surgery. Ophthalmol Glaucoma 2022;Abstract
PURPOSE: To develop an internationally standardized and validated tool to assess skill in performing tube shunt surgery. METHODS: A panel of 6 glaucoma surgeons developed a tool for assessing tube shunt surgery using a modified Dreyfus scale for skill acquisition. The tool was reviewed by a panel of 10 international content experts, and their comments were incorporated into the final rubric. A different panel of 8 international glaucoma specialists independently graded 6 surgical videos performed by surgeons at various levels of ophthalmic training to calculate inter-rater reliability for each step in the rubric. RESULTS: The tube shunt rubric contains 13 steps specific to tube shunt surgery and 7 global indices. The Cronbach's alpha statistic, a measure of internal reliability, ranged from 0.75 to 0.96, indicating strong internal reliability for all 13 steps. CONCLUSIONS: The tube shunt assessment tool has face validity, content validity, and inter-observer reliability, and can be used to assess tube shunt surgery skills. Further studies are required to determine predictive and construct validity.
Olsen MV, Lyngstadaas AV, Bair JA, Hodges RR, Utheim TP, Serhan CN, Dartt DA. Signaling Pathways Used by the Specialized Pro-Resolving Mediator Maresin 2 Regulate Goblet Cell Function: Comparison with Maresin 1. Int J Mol Sci 2022;23(11)Abstract
Specialized pro-resolving mediators (SPMs), including Maresins (MaR)-1 and 2, contribute to tear film homeostasis and resolve conjunctival inflammation. We investigated MaR2's signaling pathways in goblet cells (GC) from rat conjunctiva. Agonist-induced [Ca2+]i and high-molecular weight glycoconjugate secretion were measured. MaR2 increased [Ca2+]i and stimulated secretion. MaR2 and MaR1 stimulate conjunctival goblet cell function, especially secretion, by activating different but overlapping GPCR and signaling pathways, and furthermore counter-regulate histamine stimulated increase in [Ca2+]i. Thus, MaR2 and MaR1 play a role in maintaining the ocular surface and tear film homeostasis in health and disease. As MaR2 and MaR1 modulate conjunctival goblet cell function, they each may have potential as novel, but differing, options for the treatment of ocular surface inflammatory diseases including allergic conjunctivitis and dry eye disease. We conclude that in conjunctival GC MaR2 and MaR1, both increase the [Ca2+]i and stimulate secretion to maintain homeostasis by using one set of different, but overlapping, signaling pathways to increase [Ca2+]i and another set to stimulate secretion. MaR2 also resolves ocular allergy.
Huang X, Saki F, Wang M, Elze T, Boland MV, Pasquale LR, Johnson CA, Yousefi S. An Objective and Easy-to-Use Glaucoma Functional Severity Staging System Based on Artificial Intelligence. J Glaucoma 2022;Abstract
OBJECTIVE: To develop an objective and easy-to-use glaucoma staging system based on visual fields (VFs). SUBJECTS AND PARTICIPANTS: A total of 13,231 VFs from 8077 subjects were used to develop models and 8024 VFs from 4445 subjects were used to validate models. METHODS: We developed an unsupervised machine learning model to identify clusters with similar VF values. We annotated the clusters based on their respective mean deviation (MD). We computed optimal MD thresholds that discriminate clusters with highest accuracy based on Bayes minimum error principle. We evaluated the accuracy of the staging system and validated findings based on an independent validation dataset. RESULTS: The unsupervised k-means algorithm discovered four clusters with 6784, 4034, 1541, and 872 VFs and average MDs of 0.0▒dB (±1.4: Standard Deviation), -4.8▒dB (±1.9), -12.2▒dB (±2.9), and -23.0▒dB (±3.8), respectively. The supervised Bayes minimum error classifier identified optimal MD thresholds of -2.2▒dB, -8.0▒dB, and -17.3▒dB for discriminating normal eyes and eyes at the early, moderate, and advanced stages of glaucoma. The accuracy of the glaucoma staging system was 94%, based on identified MD thresholds with respect to the initial k-means clusters. CONCLUSIONS: We discovered that four severity levels based on MD thresholds of -2.2▒dB, -8.0▒dB, and -17.3▒dB, provides the optimal number of severity stages based on unsupervised and supervised machine learning. This glaucoma staging system is unbiased, objective, easy-to-use, and consistent, which makes it highly suitable for use in glaucoma research and for day-to-day clinical practice.