Glaucoma

Glaucoma Publications

Collantes ERA, Delfin MS, Fan BJ, Torregosa JMR, Siguan-Bell C, de Florcruz NVG, Martinez JMD, Masna-Hidalgo BJ, Guzman VPT, Anotado-Flores JF, Levina FD, Hernandez SRC, Collantes AA, Sibulo MC, Rong SS, Wiggs JL. EFEMP1 rare variants cause familial juvenile-onset open-angle glaucoma. Hum Mutat 2021;Abstract
Juvenile open-angle glaucoma (JOAG) is a severe type of glaucoma with onset before age 40 and dominant inheritance. Using exome sequencing we identified 3 independent families from the Philippines with novel EFEMP1 variants (c.238A>T, p.Asn80Tyr; c.1480T>C, p.Ter494Glnext*29; and c.1429C>T, p.Arg477Cys) co-segregating with disease. Affected variant carriers (N = 34) exhibited severe disease with average age of onset of 16 years and with 76% developing blindness. To investigate functional effects, we transfected COS7 cells with vectors expressing the three novel EFEMP1 variants and showed that all three variants found in JOAG patients caused significant intracellular protein aggregation and retention compared to wild type and also compared to EFEMP1 variants associated with other ocular phenotypes including an early-onset form of macular degeneration, Malattia Leventinese/Doyne's Honeycomb retinal dystrophy. These results suggest that rare EFEMP1 coding variants can cause JOAG through a mechanism involving protein aggregation and retention, and that the extent of intracellular retention correlates with disease phenotype. This is the first report of EFEMP1 variants causing JOAG, expanding the EFEMP1 disease spectrum. Our results suggest that EFEMP1 mutations appear to be a relatively common cause of JOAG in Filipino families, an ethnically diverse population.
Guzman Aparicio MA, Chen TC. New views on three-dimensional imaging technologies for glaucoma: an overview. Curr Opin Ophthalmol 2021;Abstract
PURPOSE OF REVIEW: To summarize the literature on three-dimensional (3D) technological advances in ophthalmology, the quantitative methods associated with this, and their improved ability to help detect glaucoma disease progression. RECENT FINDINGS: Improvements in measuring glaucomatous structural changes are the result of dual innovations in optical coherence tomography (OCT) imaging technology and in associated quantitative software. SUMMARY: Compared with two-dimensional (2D) OCT parameters, newer 3D parameters provide more data and fewer artifacts.
Yu C, Li C-Q, Ge Q-M, Shu H-Y, Liao X-L, Pan Y-C, Wu J-L, Su T, Zhang L-J, Liang R-B, Shao Y, Zeng E-M. Altered Resting State Functional Activity of Brain Regions in Neovascular Glaucoma: A Resting-State Functional Magnetic Resonance Imaging Study. Front Neurosci 2021;15:800466.Abstract
Background: Neovascular glaucoma (NVG) is a serious eye disease that causes irreversible damage to the eye. It can significantly increase intraocular pressure and cause severe pain, as well as abnormal activity in the cortical and pre-cortical visual systems. However, there are few studies in this area. This trial assessed the altered regional brain activity in patients with NVG using the percentage of fluctuation amplitude (PerAF) method. Methods: Resting-state functional MRI (rs-fMRI) scans were conducted in 18 individuals with NVG and 18 healthy controls (HCs), matched for education level, gender, and age. The PerAF method was applied to assess brain activity. Mean PerAF values of brain regions in NVG and HCs were compared using receiver operating characteristic (ROC) curves. Results: Lower PerAF values were found in the NVG group than in controls in the right anterior cingulate and paracingulate gyri (ACG.R), right superior occipital gyrus (SOG.R) and left superior frontal gyrus (orbital part) (ORBsup.L) (p < 0.001). In contrast, PerAF value was higher in NVG patients than in controls in the left inferior temporal gyrus (ITG.L) (p < 0.001). The hospital anxiety and depression scale (HADS) and visual analog score (VAS) were significantly and positively correlated with PerAF in ITG.L (r = 0.9331, p < 0.0001; and r = 0.7816, p = 0.0001, respectively). Conclusion: Abnormal activity in the patient's brain regions further confirms that the NVG affects the entire brain, not just the visual pathways and posterior retinal mechanisms (including the hypothalamic lateral geniculate nucleus and the primary visual cortex). This strengthens our understanding of the NVG and provides potential diagnostic and therapeutic support for patients who are difficult to diagnose and treat early.
Xu BY, Friedman DS, Foster PJ, Jiang Y, Porporato N, Pardeshi AA, Jiang Y, Munoz B, Aung T, He M. Ocular Biometric Risk Factors for Progression of Primary Angle Closure Disease: The Zhongshan Angle Closure Prevention Trial. Ophthalmology 2021;Abstract
PURPOSE: To assess baseline ocular biometric risk factors for progression from primary angle closure suspect (PACS) to primary angle closure (PAC) or acute angle closure (AAC). DESIGN: Prospective observational study. PARTICIPANTS: 643 mainland Chinese aged 50 to 70 years with untreated PACS. METHODS: Participants received baseline clinical examinations including gonioscopy, anterior segment OCT (AS-OCT) imaging (Visante OCT, Carl Zeiss Meditec, Dublin, CA), and A-scan ultrasound biometry as part of the Zhongshan Angle Closure Prevention (ZAP) Trial. PACS was defined as inability to visualize pigmented trabecular meshwork in two or more quadrants based on static gonioscopy. PAC was defined as development of elevated intraocular pressure (IOP) > 24 mmHg or peripheral anterior synechiae (PAS). Progression was defined as development of PAC or an acute angle closure (AAC) attack. Multivariable logistic regression models were developed to assess biometric risk factors for progression. MAIN OUTCOME MEASURES: Progression from PACS to PAC or AAC over 6 years. RESULTS: 643 untreated eyes (609 non-progressors, 34 progressors) of 643 ZAP participants were included in the primary analysis. In a multivariable model with continuous parameters, narrower horizontal angle opening distance 500 μm from the scleral spur (AOD500; OR=1.10 per 0.01 mm decrease, p=0.03), flatter horizontal iris curvature (IC; OR=1.96 per 0.1 mm decrease, p=0.01), and older age (OR=1.11 per year increase, p=0.01) at baseline were significantly associated with progression (AUC=0.73). Smaller cumulative gonioscopy score was not associated with progression (OR=1.03 per 1 modified Shaffer grade decrease; p=0.85) when replacing horizontal AOD500 in the multivariable model. In a separate multivariable model with categorical parameters, participants in the lowest quartile of horizontal AOD500 (OR=3.10, p=0.002) and IC (OR=2.48, p=0.014) measurements and aged 59 years and older (OR=2.68, p=0.01) at baseline had higher odds of progression (AUC=0.72). CONCLUSIONS: Ocular biometric measurements can help risk stratify patients with early angle closure for more severe disease. AS-OCT measurements of biometric parameters describing the angle and iris are predictive of progression from PACS to PAC or AAC, whereas gonioscopy grades are not.
E J-Y, Mihailovic A, Schrack JA, Garzon C, Li T, Friedman DS, West SK, Gitlin LN, Ramulu PY. Longitudinal changes in daily patterns of objectively measured physical activity after falls in older adults with varying degrees of glaucoma. EClinicalMedicine 2021;40:101097.Abstract
Background: Visually impaired older adults have a greater risk of falling, making them particularly susceptible to fall-related health consequences and restricted physical activity. Unclear however, is the relationship between having falls and longitudinal changes in daily patterns of objectively measured physical activity in older adults with visual impairments. Methods: We created a three-year prospective cohort study (Falls in Glaucoma Study) of older adults with primary or suspected glaucoma at the Johns Hopkins Wilmer Eye Institute from 2013 to 2015. Cumulative incidence of falls was determined through self-reported fall calendars over 12 months. Participants were then classified into one of three groups: multiple fallers (≥2 falls), single fallers (1 fall), and non-fallers (0). Daily physical activity was measured over 1 week using a waist-bound accelerometer during baseline and three-year follow-ups. Activity fragmentation was defined as the reciprocal of the mean activity bout length, with higher fragmentation reflecting shorter, more fractured bouts of continuous activity. Multivariate linear mixed-effects models were used to assess three-year longitudinal changes in: 1) activity fragmentation, and 2) accumulation of activity across six three-hour intervals from 5 AM to 11 PM. Findings: In adjusted models accounting for visual field damage and other factors, multiple fallers demonstrated greater annual declines (per year) in daily active bouts (-1.79 bouts/day, 95% confidence interval [CI]: -3.35, -0.22), daily active minutes (-17.15 min/day, 95% CI: -26.35, -7.94), and increased fragmentation (1%, 95% CI: 0, 2%) over the three-year follow-up period as compared to non-fallers; no such changes were seen when comparing single fallers and non-fallers. In time-of-day analyses, multiple fallers experienced greater annual declines in average hourly steps over all periods of the day, though the rate of decline was only significant between 5 PM and 8 PM (-27.07 steps/hour, 95% CI: -51.15, -2.99) compared to non-fallers. Interpretation: In an older population with visual impairment, multiple falls over 12 months were associated with more transient and fragmented activity over a subsequent three-year period, and activity declines during evening hours, compared to non-fallers. These findings suggest that multiple fallers with visual impairment may be at high risk for a decline in physical capacity and endurance, warranting clinical interventions. Funding: The research was supported in part by National Institutes of Health Grant EY022976.
Halawa OA, Kolli A, Oh G, Mitchell WG, Glynn RJ, Kim DH, Friedman DS, Zebardast N. Racial and socioeconomic differences in eye care utilization among Medicare beneficiaries with glaucoma. Ophthalmology 2021;Abstract
PURPOSE: Evaluate differences in eyecare utilization among glaucoma patients by race and socioeconomic status (SES). DESIGN: Retrospective cohort study. SUBJECTS: Representative 5% sample of Medicare beneficiaries >65 years with continuous part A/B enrollment between 1/1/2014 and 7/1/2014, at least one diagnosis code for glaucoma within that period, and a glaucoma diagnosis in the Chronic Conditions Warehouse before 1/1/2014. METHODS: The following race/ethnicity categories were defined in our cohort: Non-Hispanic White, Black/African American, Hispanic and Asian/Pacific Islander. Low SES was defined as having two or more enrollment-based low-income indicators (dual eligibility for Medicare/Medicaid, Part D limited income subsidies, and eligibility for Part A and B State buy-in). Negative binomial regression analyses were carried out to compare relative rate ratios (RR) of eye care utilization among racial groups, stratified by low- and non-low-SES. MAIN OUTCOME MEASURES: Measured from 7/1/2014-12/31/2016: eye examinations and eye care-related office visits; eye care-related inpatient and ED encounters; eye care-related nursing home and home-visit encounters; visual field and retinal nerve fiber optical coherence tomography tests; glaucoma lasers and surgeries. RESULTS: Among 78,526 participants with glaucoma, mean age was 79.1 years (SD 7.9 years), 60.9% were female, 78.4% were non-Hispanic White and 13.8% met enrollment-based criteria for low-SES. Compared to White beneficiaries, Blacks had lower counts of outpatient visits (rate ratio [RR] 0.92, 95% CI 0.90-0.93), VF tests (RR 0.92, 95% CI 0.90-0.94), but more inpatient/ED encounters (RR 2.42, 95% CI 1.55-3.78), and surgeries (RR 1.14, 95% CI 1.03-1.7). Hispanics had fewer outpatient visits (RR 0.97, 95% CI 0.95-0.98) and RNFL OCT tests (RR 0.89, 95% CI 0.86-0.93), but more inpatient/ED encounters (RR 2.32, 95% CI 1.18-4.57) and SLT (RR 1.25, 95% CI 1.11-1.42) vs. non-Hispanic Whites. In the non-low-SES group, Black vs. White disparities persisted in outpatient visits (RR 0.93 95% CI 0.92-0.95), VF (RR 0.96 95% CI 0.94-0.98), RNFL OCT (RR 0.81, 95% CI 0.78-0.83) and inpatient/ED encounters (RR 2.57, 95% CI 1.55-4.26). CONCLUSIONS: Disparities were found in eye care utilization among Black and Hispanic glaucoma patients. These differences persisted among Blacks after stratification by SES, suggesting systemic racism may be an independent driver in this population.
Kolomeyer NN, Katz LJ, Hark LA, Wahl M, Gajwani P, Aziz K, Myers JS, Friedman DS. Lessons Learned From 2 Large Community-based Glaucoma Screening Studies. J Glaucoma 2021;30(10):875-877.Abstract
Community-based screening programs have had limited success in preventing vision loss from glaucoma due to overall low prevalence of glaucoma, screening limitations, and barriers to follow-up appointments. This editorial highlights lessons learned from 2 large prospective trials: the Philadelphia Telemedicine Glaucoma Detection and Follow-up Study and the Screening To Prevent Glaucoma Study. While some lessons are specific to ophthalmology, many lessons are applicable to screening for asymptomatic diseases in underserved, vulnerable communities.
Boland MV, Corcoran KJ, Lee AY. Changes in Performance of Glaucoma Surgeries 1994 through 2017 Based on Claims and Payment Data for United States Medicare Beneficiaries. Ophthalmol Glaucoma 2021;4(5):463-471.Abstract
PURPOSE: To evaluate trends in glaucoma procedures in the United States Medicare population and to evaluate which physicians are performing newer procedures. DESIGN: Analysis of publicly available claims and payment data. PARTICIPANTS: Surgeons and beneficiaries enrolled in United States Medicare between 1994 and 2017. METHODS: Data regarding payments to physicians by the Centers for Medicare and Medicaid Services (CMS) were downloaded for the years 2012 through 2017. Data regarding claims to CMS by physicians were requested and processed between 1994 and 2017. Procedure counts from both data sets then were normalized for changes in the Medicare population, with 1995 as the baseline. The normalized volumes of procedures over time were visualized, as were geographic distributions of surgeons and their volume of procedures. MAIN OUTCOME MEASURES: Trends in procedure counts over time, geographic distribution of surgeons, and their volume of procedures. RESULTS: The number of trabeculectomies continues to decline and now is similar to the number of tubes. Use of the relatively new trabecular bypass shunts has increased rapidly. Surgeons performing these procedures are less likely to be performing traditional glaucoma surgeries as well. The number of laser-based cyclodestruction procedures increased after introduction of the endoscopic technique and again with the introduction of so-called micropulse procedures. The procedure counts obtained with physician payment data consistently are lower than those from claims data given the limitations of the payment data. CONCLUSIONS: Glaucoma practice patterns change each time a new device or procedure is introduced. Collectively, the use of new microinvasive glaucoma surgery procedures has increased rapidly such that they now account for a significant majority of glaucoma surgeries. Given the almost complete lack of comparative data to inform surgeon choices regarding these procedures, it will be important that randomized studies are carried out to fill this gap.
Li Y, Mitchell W, Elze T, Zebardast N. Association Between Diabetes, Diabetic Retinopathy, and Glaucoma. Curr Diab Rep 2021;21(10):38.Abstract
PURPOSE OF REVIEW: The strength of the relationship between diabetes, diabetic retinopathy (DR), and glaucoma remains controversial. We review evidence supporting and refuting this association and explore mechanistic pathological and treatment relationships linking these diseases. RECENT FINDINGS: While studies have shown diabetes/DR may increase the risk for glaucoma, this remains inconsistently demonstrated. Diabetes/DR may contribute toward glaucomatous optic neuropathy indirectly (either by increasing intraocular pressure or vasculopathy) or through direct damage to the optic nerve. However, certain elements of diabetes may slow glaucoma progression, and diabetic treatment may concurrently be beneficial in glaucoma management. Diabetes plays a significant role in poor outcomes after glaucoma surgery. While the relationship between diabetes/DR and glaucoma remains controversial, multiple mechanistic links connecting pathophysiology and management of diabetes, DR, and glaucoma have been made. However, a deeper understanding of the causes of disease association is needed.
Walton DS, Yeung HH. Glaucoma following Infant Lensectomy: 2021 Update. Klin Monbl Augenheilkd 2021;238(10):1065-1068.Abstract
PURPOSE: To review information pertaining to glaucoma following infant lensectomy surgery and to provide evidence to support the responsible mechanism of this condition. METHODS AND RESULTS: Described risk factors and proposed mechanisms for infantile aphakic glaucoma were assessed. The clinical evidence observed in affected glaucoma patients was analyzed, and evidence of postoperative anterior chamber fibrosis was reviewed and interpreted. CONCLUSION: The review and assessment of laboratory and clinical evidence support the proposal that infantile aphakic glaucoma is caused, in part, by postoperative anterior chamber fibroization related to lens cell dispersion and active epithelial-mesenchymal transition with resultant filtration angle tissue injury and loss of function.
Doshi H, Solli E, Elze T, Pasquale LR, Wall M, Kupersmith MJ. Unsupervised Machine Learning Identifies Quantifiable Patterns of Visual Field Loss in Idiopathic Intracranial Hypertension. Transl Vis Sci Technol 2021;10(9):37.Abstract
Purpose: Archetypal analysis, a form of unsupervised machine learning, identifies archetypal patterns within a visual field (VF) dataset such that any VF is described as a weighted sum of its archetypes (ATs) and has been used to quantify VF defects in glaucoma. We applied archetypal analysis to VFs affected by nonglaucomatous optic neuropathy caused by idiopathic intracranial hypertension (IIH). Methods: We created an AT model from 2862 VFs prospectively collected from 330 eyes in the IIH Treatment Trial (IIHTT). We compared baseline IIH AT patterns with their descriptive VF classifications from the IIHTT. Results: The optimum IIH AT model yielded 14 ATs resembling VF patterns reported in the IIHTT. Baseline VFs contained four or fewer meaningful ATs in 147 (89%) of study eyes. AT2 (mild general VF depression pattern) demonstrated the greatest number of study eyes with meaningful AT weight at baseline (n = 114), followed by AT1 (n = 91). Other ATs captured patterns of blind spot enlargement, hemianopia, arcuate, nasal defects, and more nonspecific patterns of general VF depression. Of all ATs, AT1 (normal pattern) had the strongest correlation with mean deviation (r = 0.69, P < 0.001). For 65 of the 93 VFs with a dominant AT, this AT matched the expert classification. Conclusions: Archetypal analysis identifies quantifiable, archetypal VF defects that resemble those commonly seen in IIH. Translational Relevance: Archetypal analysis provides a quantitative, objective method of measuring and monitoring disease-specific regional VF defects in IIH.
Coyle S, Khan MN, Chemaly M, Callaghan B, Doyle C, Willoughby CE, Atkinson SD, Gregory-Ksander M, McGilligan V. Targeting the NLRP3 Inflammasome in Glaucoma. Biomolecules 2021;11(8)Abstract
Glaucoma is a group of optic neuropathies characterised by the degeneration of retinal ganglion cells, resulting in damage to the optic nerve head (ONH) and loss of vision in one or both eyes. Increased intraocular pressure (IOP) is one of the major aetiological risk factors in glaucoma, and is currently the only modifiable risk factor. However, 30-40% of glaucoma patients do not present with elevated IOP and still proceed to lose vision. The pathophysiology of glaucoma is therefore not completely understood, and there is a need for the development of IOP-independent neuroprotective therapies to preserve vision. Neuroinflammation has been shown to play a key role in glaucoma and, specifically, the NLRP3 inflammasome, a key driver of inflammation, has recently been implicated. The NLRP3 inflammasome is expressed in the eye and its activation is reported in pre-clinical studies of glaucoma. Activation of the NLRP3 inflammasome results in IL-1β processing. This pro inflammatory cytokine is elevated in the blood of glaucoma patients and is believed to drive neurotoxic inflammation, resulting in axon degeneration and the death of retinal ganglion cells (RGCs). This review discusses glaucoma as an inflammatory disease and evaluates targeting the NLRP3 inflammasome as a therapeutic strategy. A hypothetical mechanism for the action of the NLRP3 inflammasome in glaucoma is presented.
Pasquale LR, Gong L, Wiggs JL, Pan L, Yang Z, Wu M, Yang Z, Chen DF, Zeng W. Development of Primary Open Angle Glaucoma-Like Features in a Rhesus Macaque Colony From Southern China. Transl Vis Sci Technol 2021;10(9):20.Abstract
Purpose: To describe the ocular phenotype of spontaneous glaucoma in a non-human primate colony. Methods: In total, 722 Rhesus macaque monkeys aged 10 to 25 years underwent optical coherence tomography (OCT), fundus photography (FP), and intraocular pressure (IOP) measurements. Monkeys with baseline cup-to-disc ratio (CDR) <0.5 were used to establish baseline ocular features. A subset was followed longitudinally for three years and compared to glaucoma suspects on the basis of OCT/FP criteria. Results: The average IOP under ketamine sedation and average CDR for the entire colony was 13.0 ± 4.3 mm Hg and 0.38 ± 0.07, respectively. The mean baseline conscious IOP of glaucoma suspects (N = 18) versus controls (N = 108) was 16.2 ± 3.5 mm Hg and 13.9 ± 2.3 mm Hg, respectively (P = 0.001). All glaucoma suspects had unremarkable slit lamp examinations and open angles based on anterior segment OCT. Baseline global circumpapillary retinal nerve fiber layer (RNFL) thickness was 91.5 ± 11.0 µM versus 102.7 ± 8.5 µM in suspects and controls, respectively (P < 0.0001). All sectors on the baseline circumpapillary OCT showed a significant reduction in RNFL thickness versus controls (P ≤ 0.0022) except for the temporal sector (P ≥ 0.07). In three-year longitudinal analysis, neither CDR nor OCT parameters changed in controls (N = 40; P ≥ 0.16), whereas significant increase in CDR (P = 0.018) and nominally significant decreases in two OCT sectors (nasal, P = 0.023 and nasal inferior, P = 0.046) were noted in suspects. Conclusions: Members of a nonhuman primate colony exhibit important ophthalmic features of human primary open-angle glaucoma. Translational Relevance: Identification of a spontaneous model of glaucoma in nonhuman primates represents an unprecedented opportunity to elucidate the natural history, pathogenesis and effective therapeutic strategies for the disease.

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