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Marcus DM, Silva PS, Liu D, Aiello LP, Antoszyk A, Elman M, Friedman S, Glassman AR, Googe JM, Jampol LM, Martin DF, Melia M, Preston CM, Wykoff CC, Sun JK, Sun JK. Association of Predominantly Peripheral Lesions on Ultra-Widefield Imaging and the Risk of Diabetic Retinopathy Worsening Over Time. JAMA Ophthalmol 2022;140(10):946-954.Abstract
Importance: Ultra-widefield (UWF) imaging improves the ability to identify peripheral diabetic retinopathy (DR) lesions compared with standard imaging. Whether detection of predominantly peripheral lesions (PPLs) better predicts rates of disease worsening over time is unknown. Objective: To determine whether PPLs identified on UWF imaging are associated with increased disease worsening beyond the risk associated with baseline Early Treatment Diabetic Retinopathy Study (ETDRS) Diabetic Retinopathy Severity Scale (DRSS) score. Design, Setting, and Participants: This cohort study was a prospective, multicenter, longitudinal observational study conducted at 37 US and Canadian sites with 388 participants enrolled between February and December 2015. At baseline and annually through 4 years, 200° UWF-color images were obtained and graded for DRSS at a reading center. Baseline UWF-color and UWF-fluorescein angiography (FA) images were evaluated for the presence of PPL. Data were analyzed from May 2020 to June 2022. Interventions: Treatment of DR or diabetic macular edema was at investigator discretion. Main Outcomes and Measures: Predominantly peripheral lesions were defined as DR lesions with a greater extent outside vs inside the 7 standard ETDRS fields. Primary outcome was disease worsening defined as worsening 2 steps or more on the DRSS or receipt of DR treatment. Analyses were adjusted for baseline DRSS score and correlation between 2 study eyes of the same participant. Results: Data for 544 study eyes with nonproliferative DR (NPDR) were analyzed (182 [50%] female participants; median age, 62 years; 68% White). The 4-year disease worsening rates were 45% for eyes with baseline mild NPDR, 40% for moderate NPDR, 26% for moderately severe NPDR, and 43% for severe NPDR. Disease worsening was not associated with color PPL at baseline (present vs absent: 38% vs 43%; HR, 0.78; 95% CI, 0.57-1.08; P = .13) but was associated with FA PPL at baseline (present vs absent: 50% vs 31%; HR, 1.72; 95% CI, 1.25-2.36; P < .001). Conclusions and Relevance: Although no association was identified with color PPL, presence of FA PPL was associated with greater risk of disease worsening over 4 years, independent of baseline DRSS score. These results suggest that use of UWF-FA to evaluate retinas peripheral to standard ETDRS fields may improve the ability to predict disease worsening in NPDR eyes. These findings support use of UWF-FA for future DR staging systems and clinical care to more accurately determine prognosis in NPDR eyes.
Farhat W, Yeung V, Ross A, Kahale F, Boychev N, Kuang L, Chen L, Ciolino JB. Advances in biomaterials for the treatment of retinoblastoma. Biomater Sci 2022;10(19):5391-5429.Abstract
Retinoblastoma is the most common primary intraocular malignancy in children. Although traditional chemotherapy has shown some success in retinoblastoma management, there are several shortcomings to this approach, including inadequate pharmacokinetic parameters, multidrug resistance, low therapeutic efficiency, nonspecific targeting, and the need for adjuvant therapy, among others. The revolutionary developments in biomaterials for drug delivery have enabled breakthroughs in cancer management. Today, biomaterials are playing a crucial role in developing more efficacious retinoblastoma treatments. The key goal in the evolution of drug delivery biomaterials for retinoblastoma therapy is to resolve delivery-associated obstacles and lower nonlocal exposure while ameliorating certain adverse effects. In this review, we will first delve into the historical perspective of retinoblastoma with a focus on the classical treatments currently used in clinics to enhance patients' quality of life and survival rate. As we move along, we will discuss biomaterials for drug delivery applications. Various aspects of biomaterials for drug delivery will be dissected, including their features and recent advances. In accordance with the current advances in biomaterials, we will deliver a synopsis on the novel chemotherapeutic drug delivery strategies and evaluate these approaches to gain new insights into retinoblastoma treatment.
Shi H, Yin Z, Koronyo Y, Fuchs D-T, Sheyn J, Davis MR, Wilson JW, Margeta MA, Pitts KM, Herron S, Ikezu S, Ikezu T, Graham SL, Gupta VK, Black KL, Mirzaei M, Butovsky O, Koronyo-Hamaoui M. Regulating microglial miR-155 transcriptional phenotype alleviates Alzheimer's-induced retinal vasculopathy by limiting Clec7a/Galectin-3+ neurodegenerative microglia. Acta Neuropathol Commun 2022;10(1):136.Abstract
Single cell RNA sequencing studies identified novel neurodegeneration-associated microglial (MGnD/DAM) subtypes activated around cerebral amyloid plaques. Micro-RNA (miR)-155 of the TREM2-APOE pathway was shown to be a key transcriptional regulator of MGnD microglial phenotype. Despite growing interest in studying manifestations of Alzheimer's disease (AD) in the retina, a CNS organ accessible to noninvasive high-resolution imaging, to date MGnD microglia have not been studied in the AD retina. Here, we discovered the presence and increased populations of Clec7a+ and Galectin-3+ MGnD microglia in retinas of transgenic APPSWE/PS1L166P AD-model mice. Conditionally targeting MGnD microglia by miR-155 ablation via the tamoxifen-inducible CreERT2 system in APPSWE/PS1L166P mice diminished retinal Clec7a+ and Galectin-3+ microglial populations while increasing homeostatic P2ry12+ microglia. Retinal MGnD microglia were often adhering to microvessels; their depletion protected the inner blood-retina barrier and reduced vascular amyloidosis. Microglial miR-155 depletion further limits retinal inflammation. Mass spectrometry analysis revealed enhanced retinal PI3K-Akt signaling and predicted IL-8 and Spp1 decreases in mice with microglia-specific miR-155 knockout. Overall, this study identified MGnD microglia in APPSWE/PS1L166P mouse retina. Transcriptional regulation of these dysfunctional microglia mitigated retinal inflammation and vasculopathy. The protective effects of microglial miR-155 ablation should shed light on potential treatments for retinal inflammation and vascular damage during AD and other ocular diseases.
Oke I, Heidary G, Mantagos IS, Shah AS, Hunter DG. A decline in the strabismus surgical experience of ophthalmology residents in the United States from 2010 to 2019. J AAPOS 2022;Abstract
Subspecialty exposure during residency can influence the future pursuit of fellowship training. In this study, we compared the trends in strabismus surgical experience reported by graduating ophthalmology residents in the United States with other categories of ophthalmic surgery. Over the 10-year period (2010-2019), there was a decline in the total number of strabismus procedures performed during residency by ophthalmology residents graduating in a given year (1.4 fewer cases per year; 95% CI, 1.1-1.6 [P < 0.001]). Although several surgical categories experienced a decrease in cases performed in the assistant role, strabismus surgery was the only category with a decrease in cases performed in the surgeon role (0.4 fewer cases per year; 95% CI, 0.3-0.5 [P < 0.001]).
Xu C, Prager AJ, Alonso CD, Pawar AS. Insights From the Eye for Patients With Kidney Transplant. Transplant Proc 2022;Abstract
The eye and the kidney share structural and developmental similarities on a cellular and clinical level, and they are often affected by the same disease processes. Performing an eye exam to look for signs of conditions such as hypertension and diabetes can provide a helpful window into the health of the kidney. Patients with kidney transplants (KT) are a unique population that require close monitoring. These patients are maintained on a number of immunosuppressive medications and may face complications such as medication side effects, infections, and graft rejection. Patients with KT are at higher risk of both infectious and noninfectious eye conditions related to underlying systemic disease or use of immunosuppressive medications. Screening for eye conditions is important because preserving visual function is integral to quality of life, and also because the eye exam can help with early detection and treatment of systemic conditions. Here we describe some of the common eye findings and conditions in patients with KT. We recommend that patients with KT receive annual eye exams, and we hope that the information provided here can help nephrologists become more familiar with eye findings and identify situations where a referral to ophthalmology is warranted.
Valdes L, Cox JT, Yang J, Susarla G, Han S, Papaliodis GN, Sobrin L. Anti-infliximab antibodies and clinical response in noninfectious uveitis and scleritis patients treated with infliximab: A retrospective review. Am J Ophthalmol Case Rep 2022;27:101634.Abstract
Purpose: To investigate the clinical response to infliximab in ocular inflammation patients who develop anti-infliximab antibodies (AIA) vs. those patients who do not develop AIA. Observations: A retrospective review was performed of patients treated with infliximab for noninfectious uveitis (NIU) or scleritis. Clinical response was determined as a composite clinical endpoint and classified as complete, partial, or absent. Nine of 32 infliximab-treated patients (28%) were found to develop AIA. Among the AIA-positive patients, clinical response was complete in 7 patients (78%) and partial in 2 patients (22%). Among the AIA-negative patients, clinical response was complete in 15 patients (65%), partial in 6 patients (26%) and absent in 2 patients (9%). Serum infliximab levels tended to decrease with appearance of AIA but rarely became undetectable. Conclusions and Importance: In this pilot study, AIA-positive patients did not have diminished clinical response to infliximab when compared with AIA-negative patients. There was a high rate of complete clinical response to infliximab in this group of NIU and scleritis patients. Approximately a quarter of patients developed AIA. AIA-positive patients did not have diminished rates of clinical response when compared with AIA-negative patients. This suggests that routine AIA monitoring may not be clinically useful, although validation of this finding in larger cohorts is necessary.
Botten N, Hodges RR, Bair J, Utheim TP, Serhan CN, Yang M, Dartt DA. Resolvin D2 uses multiple Ca2+ -dependent signaling pathways to stimulate mucin secretion in rat and human conjunctival goblet cells. J Cell Physiol 2022;237(10):3816-3833.Abstract
The mucin layer of the tear film is produced by goblet cells in the conjunctiva to protect the ocular surface and maintain homeostasis. The pro-resolving lipid mediator resolvin D2 (RvD2) biosynthesized from an omega 3 fatty acid actively terminates inflammation and regulates mucin secretion from conjunctival goblet cells. Our objective was to determine which Ca2+ -dependent signaling pathways RvD2 uses to stimulate conjunctival goblet cell function (CGC). We hypothesize that RvD2 activates multiple intracellular Ca2+ signaling pathways to stimulate CGC secretion. Rat and human CGCs were cultured from conjunctival explants. The amount of RvD2 receptor GPR18/DRV2 message and protein were determined. The intracellular concentration of Ca2+ ([Ca2+ ]i ) was measured in CGCs using a fluorescent Ca2+ dye and mucin secretion was determined by measuring protein secretion enzymatically with a lectin. Goblet cells were incubated with signaling pathway inhibitors before stimulation with RvD2 and [Ca2+ ]i or secretion was measured. In rat and human CGCs RvD2 receptor and in rat CGCs IP3 (a molecule that releases Ca2+ from intracellular organelles) receptors 1-3 were detected. In both species of CGC RvD2 increased [Ca2+ ]i similarly to RvD1. In rat CGCs, the increase in [Ca2+ ]i and secretion stimulated by RvD2 was significantly blocked by inhibitors to phospholipase (PL-) C and IP3 -receptor, but not protein kinase C. Increase in [Ca2+ ]i was blocked by the PLD inhibitor, but not the PLA2 inhibitor. Secretion was blocked by PLA2 inhibitor, but not the PLD inhibitor. An inhibitor of the epidermal growth factor receptor blocked the increase in [Ca2+ ]i by RvD2 in both species of CGCs. In CGCs RvD2 activates multiple intracellular signaling pathways that are Ca2+ -dependent, along with one Ca2+ -independent and one cAMP/protein kinase A-dependent pathway. Activation of these pathways stimulate mucin secretion from rat and human CGCs into the tear film contributing to ocular surface homeostasis and health.
Wong KA, Benowitz LI. Retinal Ganglion Cell Survival and Axon Regeneration after Optic Nerve Injury: Role of Inflammation and Other Factors. Int J Mol Sci 2022;23(17)Abstract
The optic nerve, like most pathways in the mature central nervous system, cannot regenerate if injured, and within days, retinal ganglion cells (RGCs), the neurons that extend axons through the optic nerve, begin to die. Thus, there are few clinical options to improve vision after traumatic or ischemic optic nerve injury or in neurodegenerative diseases such as glaucoma, dominant optic neuropathy, or optic pathway gliomas. Research over the past two decades has identified several strategies to enable RGCs to regenerate axons the entire length of the optic nerve, in some cases leading to modest reinnervation of di- and mesencephalic visual relay centers. This review primarily focuses on the role of the innate immune system in improving RGC survival and axon regeneration, and its synergy with manipulations of signal transduction pathways, transcription factors, and cell-extrinsic suppressors of axon growth. Research in this field provides hope that clinically effective strategies to improve vision in patients with currently untreatable losses could become a reality in 5-10 years.
Chapman JJ, Heidary G, Gise R. An overview of peripapillary hyperreflective ovoid mass-like structures. Curr Opin Ophthalmol 2022;33(6):494-500.Abstract
PURPOSE OF REVIEW: The purpose of this review is to provide an overview of the ophthalmic findings associated with peripapillary hyperreflective ovoid mass-like structures (PHOMS) in both adult and pediatric patients. RECENT FINDINGS: PHOMS have recently been identified in a number of different ophthalmic disease entities ranging from nonpathologic to pathologic, including but not limited to anatomic abnormalities (tilting in myopia), optic nerve head drusen, optic disc edema from inflammation (optic neuritis, white dot syndromes), vascular insults (ischemic optic neuropathy, retinal vascular occlusion), and papilledema. The mechanism underlying the formation of PHOMS has not been fully elucidated although it has been hypothesized that PHOMS occur secondary to axoplasmic stasis from crowding at the optic nerve head. SUMMARY: Although the clinical significance of the presence of PHOMS remains unclear, PHOMS are associated with several disease processes. Understanding the mechanism behind their formation and their impact on optic nerve head structure and visual function may be relevant in patients with optic nerve head pathology. The presence of PHOMS may also correlate with disease severity and duration. Future studies to evaluate whether the formation of PHOMS may be useful as an early indicator of disease or a prognostic tool are warranted.
Chwalisz BK, Levy M. The Treatment of Myelin Oligodendrocyte Glycoprotein Antibody Disease: A State-of-the-Art Review. J Neuroophthalmol 2022;42(3):292-296.Abstract
BACKGROUND: Myelin oligodendrocyte glycoprotein antibody disease (MOGAD) is an important etiology of neurologic morbidity and specifically, atypical, and relapsing optic neuritis. This review summarizes acute treatment and long-term prevention approaches in MOGAD. EVIDENCE ACQUISITION: PubMed and Google Scholar databases were manually searched and reviewed. RESULTS: We review the evidence base for acute treatment of MOGAD with corticosteroids and adjunct therapies, such as intravenous immunoglobulin (IVIg) and plasma exchange. We discuss the utility of prolonged corticosteroid tapering after the acute attack. We then summarize the commonly used disease-modifying treatments for relapsing MOGAD, including chronic low-dose corticosteroids, classic antirheumatic immune suppressants, biologic agents, and IVIg. CONCLUSIONS: While acute MOGAD attacks are usually treated with high-dose IV corticosteroids, longer oral corticosteroid tapers may prevent rapid relapse. Multiple long-term treatment strategies are being employed in recurrent MOGAD, with IVIg is emerging as probably the most effective therapy.
West CE, Hunter DG. Carbon footprint of the 2021 and 2022 AAPOS annual meetings. J AAPOS 2022;Abstract
The COVID-19 pandemic necessitated a virtual annual meeting of the American Association for Pediatric Ophthalmology and Strabismus (AAPOS) in 2021, thus eliminating carbon emissions from travel to and from the planned meeting venue in Boston, Massachusetts. We found that the reduced carbon footprint of the virtual meeting saved 1,282 metric tonnes of CO2 emissions compared with estimated CO2 emissions for travel if the meeting had taken place in person, or 880 metric tonnes relative to the projected emissions associated with the in-person 2022 annual meeting in Scottsdale, Arizona. An entirely virtual or hybrid AAPOS meeting would reduce its environmental footprint and increase the opportunity for national and international participation and education.
Oke I, Hall N, Elze T, Miller JW, Lorch AC, Hunter DG, Hunter DG. Adjustable Suture Technique Is Associated with Fewer Strabismus Reoperations in the Intelligent Research in Sight Registry. Ophthalmology 2022;129(9):1028-1033.Abstract
PURPOSE: To compare the reoperation rates after strabismus surgery with and without the adjustable suture technique. DESIGN: Retrospective cohort study. PARTICIPANTS: Patients 18 years of age or older in the Intelligent Research in Sight (IRIS®) Registry who underwent strabismus surgery between January 1, 2013, and December 31, 2018. METHODS: Data were collected from the electronic health records of practices participating in the IRIS Registry. The primary exposure of interest was use of the adjustable suture technique, identified by Current Procedural Terminology coding. MAIN OUTCOME MEASURES: The primary outcome was repeat strabismus surgery within 1 year of initial strabismus surgery. Odds ratios (ORs) were derived from a multivariable logistic regression model evaluating the association between the use of adjustable sutures and reoperation rate, adjusting for patient demographics and surgical factors. RESULTS: A total of 34 872 patients who underwent strabismus surgery during the study interval were identified: 72% underwent horizontal muscle surgery, 17% underwent vertical muscle surgery, and 11% underwent combined horizontal and vertical muscle surgery. Adjustable sutures were used in 18% of patients. The overall reoperation rate within 1 year of strabismus surgery was 7.7%. The 1-year reoperation rate was 6.0% for patients treated with adjustable sutures and 8.1% for patients treated without adjustable sutures (P < 0.001). The multivariable regression model revealed a statistically significant 30% decrease in the odds of reoperation within 1 year of surgery when adjustable sutures were used (OR, 0.70; 95% confidence interval [CI], 0.62-0.78), a 40% increase in those with a history of prior strabismus surgery (OR, 1.40; 95% CI, 1.28-1.53), and a 9% increase per decade of age at surgery (OR, 1.09; 95% CI, 1.06-1.11). CONCLUSIONS: In adults cared for in practices participating in the IRIS Registry, the adjustable suture technique was associated with a significantly lower reoperation rate within 1 year of undergoing horizontal or combined horizontal and vertical strabismus surgery. Adjustable suture use in vertical strabismus surgery alone did not reduce the 1-year reoperation rate significantly. A history of prior strabismus surgery was associated with increased odds of reoperation.
Adomfeh J, Jastrzembski BG, Oke I. Association of Race, Ethnicity, and Socioeconomic Status With Visual Impairment in Adolescent Children in the US. JAMA Ophthalmol 2022;140(10):1006-1010.Abstract
Importance: Although racial, ethnic, and socioeconomic disparities in visual impairment have been described in adults, few studies have focused on the adolescent population, which may provide insight into the emergence of vision health inequities. Objective: To describe visual health disparities among adolescent children in the US. Design, Setting, and Participants: This was a cross-sectional study of adolescents from the 2005 to 2008 National Health and Nutrition Examination Survey. Participants were aged 12 to 18 years with a completed visual function questionnaire and eye examination. Data analyses were conducted from January 19 to July 20, 2022. Main Outcomes and Measures: Outcomes included subjective (self-reported poor vision) and objective (visual acuity worse than 20/40 in the better-seeing eye) measures of visual function. Multivariable logistic and linear regression analyses were conducted to examine the association between the sociodemographic risk factors and each outcome, adjusting for age, sex, and other covariates. Results: The 2833 included participants (mean [SD] age, 15.5 [2.0] years; 1407 female participants [49%]) represent a survey-weighted 57 million US adolescent children, of whom 14% were non-Hispanic Black participants (876), 11% were Mexican American participants (828), 63% were non-Hispanic White participants (816), and 11% were other race and ethnicity (313). A total of 5% of participants (266) were not US citizens, and 19% (773) had a family income below the poverty threshold. There were increased odds of self-reported poor vision among Black (odds ratio [OR], 2.85; 95% CI, 2.00-4.05; P < .001), Mexican American (OR, 2.83; 95% CI, 1.70-4.73; P < .001), and low-income (OR, 2.44; 95% CI, 1.63-3.65; P < .001) adolescent children. Similarly, there were increased odds of visual acuity worse than 20/40 in the better-seeing eye among Black (OR, 2.13; 95% CI, 1.41-3.24; P = .001), Mexican American (OR, 2.13; 95% CI, 1.39-3.26; P = .001), and non-US citizen (OR, 1.96; 95% CI, 1.10-3.49; P = .02) participants. Conclusions and Relevance: In this nationally representative sample from 2005 to 2008, adolescent children identifying as Black, Mexican American, low-income, or non-US citizen were more likely to report poor subjective visual function and perform worse on objective visual acuity testing. A greater understanding of the underlying etiology of these disparities may yield opportunities for improving vision at the population level.
Woreta FA, Gordon LK, Knight O'RJ, Randolph JD, Zebardast N, Pérez-González CE. Enhancing Diversity in the Ophthalmology Workforce. Ophthalmology 2022;129(10):e127-e136.Abstract
Health care teams are most effective at addressing complex problems and improving health outcomes for underserved populations when team members bring diverse life experiences and perspectives to the effort. With rates of visual impairment expected to increase in the United States by 2050, especially among minority populations, diversification of the ophthalmology workforce will be critical in reducing disparities in access to and quality of vision health care. Currently, ophthalmology is less diverse with respect to race, ethnicity, and gender than graduating medical classes and other medical specialties, as well as the general US population. In addition, data on diversity in sexual orientation and gender identity, socioeconomic status, and disability are lacking in ophthalmology. The Minority Ophthalmology Mentoring and Rabb-Venable Excellence in Ophthalmology Programs are examples of initiatives to increase racial and ethnic diversity in the workforce and can serve as models for increasing other aspects of inclusiveness. Other strategies for improving vision health care for all Americans include continuing to support existing diversity programs and creating new ones; addressing unconscious and implicit bias in medical school, residency, and faculty selections; conducting holistic reviews of medical school and residency applications; diversifying selection committees and leadership; and encouraging faculty development of underrepresented groups.

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