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Xiong J, Yu C, Su T, Ge Q-M, Shi W-Q, Tang L-Y, Shu H-Y, Pan Y-C, Liang R-B, Li Q-Y, Shao Y. Altered brain network centrality in patients with mild cognitive impairment: an fMRI study using a voxel-wise degree centrality approach. Aging (Albany NY) 2021;13(11):15491-15500.Abstract
PURPOSE: Previous studies in patients with Alzheimer's disease have shown amyloid beta accumulation in the brain and abnormal brain activity, with mild cognitive impairment (MCI) in early stages of the disease. The aim of the current study was to investigate functional connectivity in patients with MCI. METHODS: We recruited 24 subjects in total, including 12 patients with MCI (6 men and 6 women) and 12 healthy controls (HCs) (6 men and 6 women), matched for age, gender, and lifestyle factors. All subjects underwent resting-state functional magnetic resonance imaging scans and voxel-wise degree centrality (DC) was used to evaluate alterations in the strength of brain network connectivity. RESULTS: The DC value of the left inferior temporal gyrus was lower in MCI but significantly higher in the right fusiform gyrus and the left supplementary motor area, compared with HCs. The DC value in left inferior temporal gyrus correlated positively with disease duration and negatively with Mini-Mental State Examination. ROC curve analysis of brain regions showed acceptable specificity and accuracy of DC values between MCIs and HCs in the area under the curve (right fusiform gyrus, 0.955; left supplementary motor area, 0.992; left inferior temporal gyrus, 1.000). CONCLUSIONS: Abnormal functional connectivity in brain regions of patients with MCI may reflect the pathological process of Alzheimer's disease development and could prove useful in clinical diagnosis and treatment.
Oswald J, Kegeles E, Minelli T, Volchkov P, Baranov P. Transplantation of miPSC/mESC-derived retinal ganglion cells into healthy and glaucomatous retinas. Mol Ther Methods Clin Dev 2021;21:180-198.Abstract
Optic neuropathies, including glaucoma, are a group of neurodegenerative diseases, characterized by the progressive loss of retinal ganglion cells (RGCs), leading to irreversible vision loss. While previous studies demonstrated the potential to replace RGCs with primary neurons from developing mouse retinas, their use is limited clinically. We demonstrate successful transplantation of mouse induced pluripotent stem cell (miPSC)/mouse embryonic stem cell (mESC)-derived RGCs into healthy and glaucomatous mouse retinas, at a success rate exceeding 65% and a donor cell survival window of up to 12 months. Transplanted Thy1-GFP+ RGCs were able to polarize within the host retina and formed axonal processes that followed host axons along the retinal surface and entered the optic nerve head. RNA sequencing of donor RGCs re-isolated from host retinas at 24 h and 1 week post-transplantation showed upregulation of cellular pathways mediating axonal outgrowth, extension, and guidance. Additionally, we provide evidence of subtype-specific diversity within miPSC-derived RGCs prior to transplantation.
Ozawa H, Usui Y, Takano Y, Horiuchi N, Kuribayashi T, Kurihara T, Smith LEH, Tsubota K, Tomita Y. Iris metastasis as the initial presentation of metastatic esophageal cancer diagnosed by fine needle aspiration biopsy: A case report. Medicine (Baltimore) 2021;100(22):e26232.Abstract
RATIONALE: Metastasis of neoplasms to the eye is quite uncommon. In this case report, we describe a patient where primary esophageal cancer was diagnosed by fine needle aspiration biopsy (FNAB) of an iris tumor. PATIENT CONCERNS: A 70-year-old male complained of redness and discomfort in the right eye. DIAGNOSIS AND INTERVENTIONS: The patient's right eye was diagnosed as idiopathic uveitis, and a topical steroid was administered. As vitreous opacities were observed even after topical therapy, oral prednisolone was administered. On slit-lamp examination of the right eye, an iris mass with neovascularization was seen in the anterior chamber. A metastatic tumor was suspected, and FNAB was performed. Histology revealed squamous cell carcinoma. Systemic workup revealed esophageal cancer with several metastases. Best-corrected visual acuity decreased to 20/400, and intraocular pressure was 40 mmHg in the right eye. Two iris tumors with neovascularization were present extending into the anterior chamber with posterior iris synechiae and 360 degree peripheral anterior synechiae. Intraocular pressure in the right eye was medically managed with hypotensive eye drops and oral acetazolamide. Iris metastases were treated with 40 Gray of radiation therapy and concurrent chemotherapy. OUTCOMES: The tumor regressed, but intraocular pressure was refractory to treatment because of 360 degree goniosynechial closure. The right eye lost light perception six months after treatment commenced, and the patient died 9 months after the onset of therapy due to multiple systemic metastases. LESSONS: This is a rare case of masquerade syndrome without systemic symptoms in which FNAB of an iris tumor led to a diagnosis of metastatic esophageal squamous cell carcinoma. Although the patient lost his sight due to uncontrollable ocular hypertension, systemic chemotherapy, and radiation therapy were initially effective in the treatment of the metastatic iris tumor. As the prognosis of patients with metastatic iris tumors is poor, it is important for ophthalmologists to consider such diagnoses and conduct systemic investigations when necessary.
Ou J, Zhou Z, Dai R, Zhang J, Zhao S, Wu X, Lan W, Ren Y, Cui L, Lan Q, Lu L, Seto D, Chodosh J, Wu J, Zhang G, Zhang Q. V367F Mutation in SARS-CoV-2 Spike RBD Emerging during the Early Transmission Phase Enhances Viral Infectivity through Increased Human ACE2 Receptor Binding Affinity. J Virol 2021;95(16):e0061721.Abstract
The current pandemic of COVID-19 is caused by a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The SARS-CoV-2 spike protein receptor-binding domain (RBD) is the critical determinant of viral tropism and infectivity. To investigate whether naturally occurring RBD mutations during the early transmission phase have altered the receptor binding affinity and infectivity, we first analyzed in silico the binding dynamics between SARS-CoV-2 RBD mutants and the human angiotensin-converting enzyme 2 (ACE2) receptor. Among 32,123 genomes of SARS-CoV-2 isolates (December 2019 through March 2020), 302 nonsynonymous RBD mutants were identified and clustered into 96 mutant types. The six dominant mutations were analyzed applying molecular dynamics simulations (MDS). The mutant type V367F continuously circulating worldwide displayed higher binding affinity to human ACE2 due to the enhanced structural stabilization of the RBD beta-sheet scaffold. The MDS also indicated that it would be difficult for bat SARS-like CoV to infect humans. However, the pangolin CoV is potentially infectious to humans. The increased infectivity of V367 mutants was further validated by performing receptor-ligand binding enzyme-linked immunosorbent assay (ELISA), surface plasmon resonance, and pseudotyped virus assays. Phylogenetic analysis of the genomes of V367F mutants showed that during the early transmission phase, most V367F mutants clustered more closely with the SARS-CoV-2 prototype strain than the dual-mutation variants (V367F+D614G), which may derivate from recombination. The analysis of critical RBD mutations provides further insights into the evolutionary trajectory of early SARS-CoV-2 variants of zoonotic origin under negative selection pressure and supports the continuing surveillance of spike mutations to aid in the development of new COVID-19 drugs and vaccines. IMPORTANCE A novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused the pandemic of COVID-19. The origin of SARS-CoV-2 was associated with zoonotic infections. The spike protein receptor-binding domain (RBD) is identified as the critical determinant of viral tropism and infectivity. Thus, whether mutations in the RBD of the circulating SARS-CoV-2 isolates have altered the receptor binding affinity and made them more infectious has been the research hot spot. Given that SARS-CoV-2 is a novel coronavirus, the significance of our research is in identifying and validating the RBD mutant types emerging during the early transmission phase and increasing human angiotensin-converting enzyme 2 (ACE2) receptor binding affinity and infectivity. Our study provides insights into the evolutionary trajectory of early SARS-CoV-2 variants of zoonotic origin. The continuing surveillance of RBD mutations with increased human ACE2 affinity in human or other animals is critical to the development of new COVID-19 drugs and vaccines against these variants during the sustained COVID-19 pandemic.
Saeedi O, Boland MV, D'Acunto L, Swamy R, Hegde V, Gupta S, Venjara A, Tsai J, Myers JS, Wellik SR, DeMoraes G, Pasquale LR, Shen LQ, Li Y, Elze T. Development and Comparison of Machine Learning Algorithms to Determine Visual Field Progression. Transl Vis Sci Technol 2021;10(7):27.Abstract
Purpose: To develop and test machine learning classifiers (MLCs) for determining visual field progression. Methods: In total, 90,713 visual fields from 13,156 eyes were included. Six different progression algorithms (linear regression of mean deviation, linear regression of the visual field index, Advanced Glaucoma Intervention Study algorithm, Collaborative Initial Glaucoma Treatment Study algorithm, pointwise linear regression [PLR], and permutation of PLR) were applied to classify each eye as progressing or stable. Six MLCs were applied (logistic regression, random forest, extreme gradient boosting, support vector classifier, convolutional neural network, fully connected neural network) using a training and testing set. For MLC input, visual fields for a given eye were divided into the first and second half and each location averaged over time within each half. Each algorithm was tested for accuracy, sensitivity, positive predictive value, and class bias with a subset of visual fields labeled by a panel of three experts from 161 eyes. Results: MLCs had similar performance metrics as some of the conventional algorithms and ranged from 87% to 91% accurate with sensitivity ranging from 0.83 to 0.88 and specificity from 0.92 to 0.96. All conventional algorithms showed significant class bias, meaning each individual algorithm was more likely to grade uncertain cases as either progressing or stable (P ≤ 0.01). Conversely, all MLCs were balanced, meaning they were equally likely to grade uncertain cases as either progressing or stable (P ≥ 0.08). Conclusions: MLCs showed a moderate to high level of accuracy, sensitivity, and specificity and were more balanced than conventional algorithms. Translational Relevance: MLCs may help to determine visual field progression.
Binenbaum G, Chang MY, Heidary G, Morrison DG, Trivedi RH, Galvin JA, Pineles SL. Botulinum Toxin Injection for the Treatment of Strabismus: A Report by the American Academy of Ophthalmology. Ophthalmology 2021;128(12):1766-1776.Abstract
PURPOSE: To review the available evidence comparing the effectiveness of extraocular muscle botulinum toxin type A (BTXA) injection with eye muscle surgery for restoring ocular alignment in children and adults with nonparalytic, nonrestrictive horizontal strabismus. METHODS: Literature searches in the PubMed Cochrane Library, and clinical trial databases with no date restrictions, but limited to articles published in English, were conducted last on January 10, 2021. The searches yielded 515 citations, 40 of which were reviewed in full text by the first author. Fourteen articles met the criteria for inclusion (randomized or nonrandomized comparative studies, or case series with a minimum 50 patients; evaluating extraocular muscle BTXA injection for initial or repeat treatment of horizontal, nonparalytic, nonrestrictive strabismus; with at least 6 months of follow-up) and were graded by a methodologist. RESULTS: The 14 included studies consisted of 2 randomized clinical trials, 3 nonrandomized comparative studies, and 9 case series. All 5 comparative studies were graded level II evidence, and the 9 case series were graded level III evidence. Successful motor outcomes after BTXA injection were relatively consistent across 4 of the 5 comparative studies at 60%, when adjustment was made for differential selection bias in 1 of the studies. In the 4 studies, successful motor outcomes after surgery ranged from 66% to 77% with a mean follow-up of 23 to 75 months, and the outcomes were not significantly different from those after BTXA injection. In the fifth level II study, success was significantly higher with BTXA injection than with surgery (94% vs. 72%). The level III BTXA case series demonstrated higher motor success rates of 87% to 89% when children were treated in 2 muscles at a time; rates were lower in adults treated with single-muscle BTXA injection. CONCLUSIONS: Extraocular muscle injection of BTXA achieves a high rate of successful motor alignment, comparable with that achieved after eye muscle surgery for nonparalytic, nonrestrictive horizontal strabismus. Good alignment may require multiple BTXA injections, and it is not yet clear whether sensory outcomes are equivalent for BTXA injections versus eye muscle surgery in young children.
Chen T, Jin L, Zhu W, Wang C, Zhang G, Wang X, Wang J, Yang K, Cochrane GM, Lamoureux EL, Friedman DS, Gilbert S, Lansingh VC, Resnikoff S, Zhao J, Xiao B, He M, Congdon N. Knowledge, attitudes and eye health-seeking behaviours in a population-based sample of people with diabetes in rural China. Br J Ophthalmol 2021;105(6):806-811.Abstract
AIMS: To assess knowledge of diabetes and acceptance of eye care among people with diabetes in rural China, to improve service uptake. METHODS: Population-based study of people in Guangdong, China, with glycosylated haemoglobin A1c≥6.5% and/or known history of diabetes. Between August and November 2014, participants answered a questionnaire (based on Delphi process/previous focus groups) on medical history, demographic characteristics, self-rated health and vision, knowledge about diabetes and diabetic retinopathy, quality of local healthcare, barriers to treatment, likely acceptance of eye exams and treatment, and interventions rated most likely to improve service uptake. Presenting visual acuity was assessed, fundus photography performed and images graded by trained graders. Potential predictors of accepting care were evaluated and confounders adjusted for using logistic regression. RESULTS: A total of 562 people (9.6% (256/5825), mean age 66.2±9.84 years, 207 (36.8%) men) had diabetes, 118 (22.3%) previously diagnosed. 'Very likely' or 'likely' acceptance of laser treatment (140/530=26.4%) was lower than for eye exams (317/530=59.8%, p<0.001). Predictors of accepting both exams and laser included younger age (p<.001) and prior awareness of diabetes diagnosis (p=0.004 and p=0.035, respectively). The leading barrier to receiving diabetes treatment was unawareness of diagnosis (409/454, 97.2%), while interventions rated most likely to improve acceptance of eye exams included reimbursement of travel costs (387/562, 73.0%), video or other health education (359/562, 67.7%) and phone call reminders (346/562, 65.3%). CONCLUSIONS: Improving diagnosis of diabetes, along with incentives, education and communication strategies, is most likely to enhance poor acceptance of diabetic eye care in this setting.
Chang MY, Morrison DG, Binenbaum G, Heidary G, Trivedi RH, Galvin JA, Pineles SL. Home- and Office-Based Vergence and Accommodative Therapies for Treatment of Convergence Insufficiency in Children and Young Adults: A Report by the American Academy of Ophthalmology. Ophthalmology 2021;128(12):1756-1765.Abstract
PURPOSE: To review home- and office-based vergence and accommodative therapies for treatment of convergence insufficiency (CI) in children and young adults up to 35 years of age. METHODS: Literature searches were conducted through October 2020 in the PubMed database for English-language studies. The combined searches yielded 359 abstracts, of which 37 were reviewed in full text. Twelve of these were considered appropriate for inclusion in this assessment and assigned a level of evidence rating by the panel methodologist. RESULTS: Of the 12 studies included in this assessment, 8 were graded as level I evidence, 2 were graded as level II evidence, and 2 were graded as level III evidence. Two of the level I studies included older teenagers and young adults; the remainder of the studies exclusively evaluated children. Two randomized controlled trials found that office-based vergence and accommodative therapies were effective in improving motor outcomes in children with symptomatic CI. However, the studies reported conflicting results on the efficacy of office-based therapy for treating symptoms of CI. Data were inconclusive regarding the effectiveness of home-based therapies (including pencil push-ups and home computer therapy) compared with home placebo. In young adults, office-based vergence and accommodative therapies were not superior to placebo in relieving symptoms of CI. CONCLUSIONS: Level I evidence suggests that office-based vergence and accommodative therapies improve motor outcomes in children with symptomatic CI, although data are inconsistent regarding symptomatic relief. Evidence is insufficient to determine whether home-based therapies are effective.
Sangermano R, Deitch I, Peter VG, Ba-Abbad R, Place EM, Zampaglione E, Wagner NE, Fulton AB, Coutinho-Santos L, Rosin B, Dunet V, AlTalbishi A'a, Banin E, Sousa AB, Neves M, Larson A, Quinodoz M, Michaelides M, Ben-Yosef T, Pierce EA, Rivolta C, Webster AR, Arno G, Sharon D, Huckfeldt RM, Bujakowska KM. Broadening INPP5E phenotypic spectrum: detection of rare variants in syndromic and non-syndromic IRD. NPJ Genom Med 2021;6(1):53.Abstract
Pathogenic variants in INPP5E cause Joubert syndrome (JBTS), a ciliopathy with retinal involvement. However, despite sporadic cases in large cohort sequencing studies, a clear association with non-syndromic inherited retinal degenerations (IRDs) has not been made. We validate this association by reporting 16 non-syndromic IRD patients from ten families with bi-allelic mutations in INPP5E. Additional two patients showed early onset IRD with limited JBTS features. Detailed phenotypic description for all probands is presented. We report 14 rare INPP5E variants, 12 of which have not been reported in previous studies. We present tertiary protein modeling and analyze all INPP5E variants for deleteriousness and phenotypic correlation. We observe that the combined impact of INPP5E variants in JBTS and non-syndromic IRD patients does not reveal a clear genotype-phenotype correlation, suggesting the involvement of genetic modifiers. Our study cements the wide phenotypic spectrum of INPP5E disease, adding proof that sequence defects in this gene can lead to early-onset non-syndromic IRD.
Singh RB, Gupta P, Kartik A, Farooqui N, Singhal S, Shergill S, Singh KP, Agarwal A. Ocular Manifestations of Neuronal Ceroid Lipofuscinoses. Semin Ophthalmol 2021;36(7):582-595.Abstract
Neuronal ceroid lipofuscinoses (NCLs) are a group of rare neurodegenerative storage disorders associated with devastating visual prognosis, with an incidence of 1/1,000,000 in the United States and comparatively higher incidence in European countries. The pathophysiological mechanisms causing NCLs occur due to enzymatic or transmembrane defects in various sub-cellular organelles including lysosomes, endoplasmic reticulum, and cytoplasmic vesicles. NCLs are categorized into different types depending upon the underlying cause i.e., soluble lysosomal enzyme deficiencies or non-enzymatic deficiencies (functions of identified proteins), which are sub-divided based on an axial classification system. In this review, we have evaluated the current evidence in the literature and reported the incidence rates, underlying mechanisms and currently available management protocols for these rare set of neuroophthalmological disorders. Additionally, we also highlighted the potential therapies under development that can expand the treatment of these rare disorders beyond symptomatic relief.
Nigalye A, Pundlik S, Kim J, Luo G, Husain D. Delayed dark adaptation in central serous chorioretinopathy. Am J Ophthalmol Case Rep 2021;22:101098.Abstract
Purpose: To evaluate the effect of central serous chorioretinopathy (CSCR) on retinal function using dark adaptation in a human subject, and to follow it through resolution of the disease. Patients: Single patient, 50 years old male patient, with acute CSCR in one eye and resolved old CSCR in the other eye. Observations: Observational study in patient with CSCR followed through resolution of the subretinal fluid (52 days). Dark adaptation was assessed using the AdaptDx® (Maculogix Inc.) measured by Rod Intercept time (RIT) in minutes. A normal retinal locus of the same eye on the opposite side of the fovea was used as control. Retinal separation (microns) was measured using Spectralis Optical Coherence Tomography (Spectralis®, HRA + OCT, Heidelberg engineering). Change in time to dark adapt, were correlated with retinal separation measured in microns, during the course of CSCR.The Rod Intercept time was delayed in the area of detached retina compared to the normal region (control) on presentation with retinal separation (RS) of 104 μm. The Rod Intercept time returned to normal as the retinal separation from retinal pigment epithelium decreased and eventually resolved. Conclusions: This case shows that delay in dark adaptation is proportional to the amount of separation of neurosensory retina from retinal pigment epithelium in CSCR, this may offer a potential of using DA to characterize visual function in CSCR. The association of dark adaptation response with the state of retinal pigment epithelial function and its ability to predict the recurrence of CSCR needs further evaluation.
Jacobs HIL, Schoemaker D, Torrico-Teave H, Zuluaga Y, Velilla-Jimenez L, Ospina-Villegas C, Lopera F, Arboleda-Velasquez JF, Quiroz YT. Specific Abnormalities in White Matter Pathways as Interface to Small Vessels Disease and Cognition in Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy Individuals. Brain Connect 2021;Abstract
Background: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is characterized by leukoencephalopathy leading to cognitive impairment. Subtle cognitive deficits can be observed early in the course of the disease, before the occurrence of the first stroke. Therefore, markers that can predict disease progression at this early stage, when interventions are likely to alter disease course, are needed. We aimed to examine the biological cascade of microstructural and macrostructural white matter (WM) abnormalities underlying cognitive deficits in CADASIL. Methods: We examined 20 nondemented CADASIL mutation carriers and 23 noncarriers who underwent neuropsychological evaluation and magnetic resonance imaging. Using probabilistic tractography of key WM tracts, we examined group differences in diffusivity measures and WM hyperintensity volume. Successive mediation models examined whether tract-specific WM abnormalities mediated subtle cognitive differences between CADASIL mutation carriers and noncarriers. Results: The largest effect size differentiating the two groups was observed for left superior longitudinal fasciculus-temporal (SLFt) diffusivity (Cohen's f = 0.49). No group differences were observed with a global diffusion measure. These specific microstructural differences in the SLFt were associated with higher WM hyperintensities burden, and subtle executive deficits in CADASIL mutation carriers. Discussion: Worse diffusivity in the left SLFt is related to greater severity of small vessel disease and worse executive functioning in the asymptomatic stage of the disease. Worse diffusivity of the left SLFt may potentially hold promise as an indicator of disease progression.
Agarwal K, Hatch K. Femtosecond Laser Assisted Cataract Surgery: A Review. Semin Ophthalmol 2021;36(8):618-627.Abstract
Femtosecond laser assisted cataract surgery (FLACS) offers a level of precision, accuracy and customization that is not possible with manual phacoemulsification (MP). With the increase of patient expectations and premium intraocular lens utilization in the era of refractive cataract surgery, predictability and accuracy has become of utmost importance. FLACS has four main functions: creation of a consistently sized round capsulotomy, treatment of keratometric astigmatism with arcuate incisions, construction of clear corneal incisions, and fragmentation and/or softening of the lens. However, FLACS may have limitations due to suction loss, incomplete capsulotomy or poor pupillary dilation. Patient selection and surgeon experience is critical. This review article will focus on the various platforms available for FLACS, the steps in cataract surgery it can perform, and overall advantages and limitations of the technology.
Ung L, Chodosh J. Foundational concepts in the biology of bacterial keratitis. Exp Eye Res 2021;:108647.Abstract
Bacterial infections of the cornea, or bacterial keratitis (BK), are notorious for causing rapidly fulminant disease and permanent vision loss, even among treated patients. In the last sixty years, dramatic upward trajectories in the frequency of BK have been observed internationally, driven in large part by the commercialization of hydrogel contact lenses in the late 1960s. Despite this worsening burden of disease, current evidence-based therapies for BK - including broad-spectrum topical antibiotics and, if indicated, topical corticosteroids - fail to salvage vision in a substantial proportion of affected patients. Amid growing concerns of rapidly diminishing antibiotic utility, there has been renewed interest in urgently needed novel treatments that may improve clinical outcomes on an individual and public health level. Bridging the translational gap in the care of BK requires the identification of new therapeutic targets and rational treatment design, but neither of these aims can be achieved without understanding the complex biological processes that determine how bacterial corneal infections arise, progress, and resolve. In this chapter, we synthesize the current wealth of human and animal experimental data that now inform our understanding of basic BK pathophysiology, in context with modern concepts in ocular immunology and microbiology. By identifying the key molecular determinants of clinical disease, we explore how novel treatments can be developed and translated into routine patient care.
Kühn T, Rohrmann S, Karavasiloglou N, Friedman DS, Cassidy A, Bärnighausen T, Schuster AK, Nickels S. Glaucoma and mortality risk: findings from a prospective population-based study. Sci Rep 2021;11(1):11771.Abstract
Glaucoma is a neurodegenerative disease with a structural change of the optic nerve head, leading to visual field defects and ultimately blindness. It has been proposed that glaucoma is associated with increased mortality, but previous studies had methodological limitations (selective study samples, lack of data on potential confounders, self-reported or secondary data on glaucoma diagnoses). We evaluated the association between diagnosed glaucoma and mortality in the population-based National Health and Nutrition Examination Survey (NHANES), a representative health survey in the United States. The survey cycles 2005-2006 and 2007-2008 included an extensive ophthalmic examination with fundus photography, which were used to derive standardized glaucoma diagnoses. Risk of all-cause mortality was assessed with multivariable Cox proportional hazards regression models accounting for the complex survey design of NHANES. Time to death was calculated from the examination date to date of death or December 31, 2015 whichever came first. 5385 participants (52.5% women) were eligible, of which 138 had glaucoma at baseline, and 833 died during follow-up. Participants with glaucoma were more likely to be older than those without glaucoma (mean age 69.9 vs. 56.0 years). Mean follow-up time was 8.4 years for participants with glaucoma, and 8.6 years for participants without glaucoma. Glaucoma was associated with increased mortality in an unadjusted Cox regression model (hazard ratio 2.06, 95% confidence interval 1.16 to 3.66), but the association was no longer statistically significant after adjusting for age and sex (hazard ratio 0.74, 95% confidence interval 0.46 to 1.17). Additional adjustment for a range of potential confounders did not significantly change the results. In this representative population-based study, we found no evidence of increased mortality risk in glaucoma patients.

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