Lorenzo MM, Devlin J, Saini C, Cho K-S, Paschalis EI, Chen DF, Silva RNE, Chen SH, Margeta MA, Ondeck C, Solá-Del Valle D, Chodosh J, Ciolino JB, Pineda R, Pasquale LR, Shen LQ. The Prevalence of Autoimmune Diseases in Patients with Primary Open-Angle Glaucoma Undergoing Ophthalmic Surgeries. Ophthalmol Glaucoma 2022;5(2):128-136.Abstract
PURPOSE: To assess the prevalence of autoimmune disease (AiD) in patients with primary open-angle glaucoma (POAG) undergoing ophthalmic surgery. DESIGN: Retrospective, cross-sectional study. PARTICIPANTS: Patients with POAG undergoing any ophthalmic surgery and control subjects undergoing cataract surgery at the Massachusetts Eye and Ear from March 2019 to April 2020. METHODS: All available medical records with patient demographics, ocular, and medical conditions were reviewed. Differences in AiD prevalence were assessed and adjusted for covariates using multiple logistic regression. Additionally, a subgroup analysis comparing the POAG patients with and without AiD was performed. MAIN OUTCOME MEASURES: To assess the prevalence of AiD based on the American Autoimmune Related Diseases Association list. RESULTS: A total of 172 patients with POAG and 179 controls were included. The overall prevalence of AiD was 17.4% in the POAG group and 10.1% in the controls (P = 0.044); 6.4% of POAG patients and 3.4% of controls had more than 1 AiD (P = 0.18). The most prevalent AiDs in POAG group were rheumatoid arthritis (4.6%) and psoriasis (4.1%), which were also the most common in controls (2.8% each). In a fully adjusted multiple logistic regression analysis accounting for steroid use, having an AiD was associated with 2.62-fold increased odds of POAG relative to controls (95% confidence interval, 1.27-5.36, P = 0.009); other risk factors for POAG derived from the analysis included age (odds ratio [OR], 1.04, P = 0.006), diabetes mellitus (OR, 2.31, P = 0.008), and non-White ethnicity (OR, 4.75, P < 0.001). In a case-only analysis involving the eye with worse glaucoma, there was no statistical difference in visual field mean deviation or retinal nerve fiber layer (RNFL) thickness in POAG patients with AiD (n = 30) and without AiD (n = 142, P > 0.13, for both). CONCLUSIONS: A higher prevalence of AiD was found in POAG patients compared with control patients undergoing ophthalmic surgery. The presence of AiD was associated with increased risk for POAG after adjusting for covariates. Additional factors may have prevented a difference in RNFL thickness in POAG patients with and without AiD. Autoimmunity should be explored further in the pathogenesis of POAG.
Hanyuda A, Rosner BA, Wiggs JL, Willett WC, Tsubota K, Pasquale LR, Kang JH. Prospective study of dietary intake of branched-chain amino acids and the risk of primary open-angle glaucoma. Acta Ophthalmol 2022;100(3):e760-e769.Abstract
PURPOSE: Metabolomic and preclinical studies suggest that branched-chain amino acids (BCAA) may be inversely associated with neurodegenerative diseases including glaucoma. We therefore assessed the long-term association between dietary intake of BCAA and incident primary open-angle glaucoma (POAG) and POAG subtypes. METHODS: We followed biennially participants of the Nurses' Health Study (NHS; 65 531 women: 1984-2016), Health Professionals Follow-up Study (42 254 men: 1986-2016) and NHSII (66 904 women; 1991-2017). Eligible participants were 40+ years old and reported eye examinations. Repeated validated food frequency questionnaires were used to assess dietary intake of BCAA. Incident cases of POAG and POAG subtypes defined by visual field (VF) loss and untreated intraocular pressure (IOP) were confirmed by medical record review. Multivariable-adjusted relative risks (MVRRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models. RESULTS: We identified 1946 incident POAG cases. The pooled MVRRs of POAG for the highest quintile (Q5 = 17.1 g/day) versus lowest quintile (Q1 = 11.2 g/day) of total BCAA intake was 0.93 (95% CI, 0.73-1.19; ptrend  = 0.45; pheterogeneity by sex  = 0.24). For subtypes of POAG defined by IOP level or POAG with only peripheral VF loss, no associations were observed for men or women (ptrend  ≥ 0.20); however, for the POAG subtype with early paracentral VF loss, there was a suggestion of an inverse association in women (MVRRQ5versusQ1  = 0.80 [95% CI, 0.57-1.12; ptrend  = 0.12]) but not in men (MVRRQ5versusQ1  = 1.38 [95% CI, 0.81-2.34; ptrend  = 0.28; pheterogeneity by sex  = 0.06]). CONCLUSION: Higher dietary intake of BCAA was not associated with POAG risk.
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.
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.
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.
Yang S-A, Mitchell WG, Hall N, Elze T, Miller JW, Lorch AC, Zebardast N. Usage Patterns of Minimally Invasive Glaucoma Surgery (MIGS) Differ by Glaucoma Type: IRIS Registry Analysis 2013-2018. Ophthalmic Epidemiol 2021;:1-9.Abstract
Purpose: To examine patterns of standard (trabeculectomy or glaucoma drainage devices, GDDs) vs novel (minimally invasive glaucoma surgery, MIGS) surgical techniques in the US.Methods: We used the American Academy of Ophthalmology (AAO) IRIS® Registry (Intelligent Research in Sight) queried between 2013 and 2018 (inclusive) to calculate the cumulative proportion of stand-alone, concurrent (same day) or sequential (subsequent day) glaucoma surgical techniques performed in each glaucoma diagnosis type. Secondary analyses of adjusted proportions of concurrent and sequential surgeries stratified by glaucoma diagnosis were also performed.Results: Of 203,146 eyes receiving glaucoma surgeries, open angle glaucoma (OAG) was most likely to undergo all types of intervention. The iStent was the most commonly performed MIGS, primarily for those with normal tension glaucoma (NTG) or OAG (p < .001). Conversely, GDD was the most commonly performed procedure in secondary glaucoma or other (specified) glaucoma (p < .001). ECP and iStent were the most common concurrent procedures performed; most often for OAG and NTG (p < .001). After an initial standard surgery, most eyes underwent recurrent standard interventions (90.3%). ECP was the most common MIGS performed after an initial standard surgery; particularly in primary angle-closure (PACG) and secondary glaucoma eyes (p < .001).Conclusion: Glaucoma type may influence the choice of glaucoma procedures and the decision to perform concurrent as well sequential surgical procedures. Given the poorly understood long term safety and effectiveness of MIGS, and with substantially increasing use of MIGS procedures in recent years, future studies comparing their safety and effectiveness vs standard interventions, for a variety of glaucoma types, is needed.
Birnbaum FA, Neeson C, Solá-Del Valle D. Microinvasive Glaucoma Surgery: An Evidence-Based Review. Semin Ophthalmol 2021;36(8):772-786.Abstract
PURPOSE: Interest in micro-invasive glaucoma surgery (MIGS) has exploded over the last 8 years with an increase in MIGS procedures of at least 400% in the United States, according to Medicare data. MIGS is an umbrella term that can cover many different types of surgeries. This review focuses on peer-reviewed evidence for Trabectome®, iStent inject®, Kahook Dual Blade®, XEN® Gel Stent, and Hydrus®. METHODS: We present key recent studies evaluating the efficacy and safety of MIGS in various types of glaucoma patients with different stages of disease. CONCLUSION: We conclude that MIGS is generally safe and efficacious, although only some MIGS have been studied through randomized clinical trials. When comparing and contrasting the different MIGS procedures, large prospective studies are not yet the norm. High-quality large prospective studies involving MIGS will be an important next step as ophthalmologists decide how to incorporate MIGS into their surgical armamentarium.