K
Karg MM, Lu YR, Refaian N, Cameron J, Hoffmann E, Hoppe C, Shirahama S, Shah M, Krasniqi D, Krishnan A, Shrestha M, Guo Y, Cermak JM, Walthier M, Broniowska K, Rosenzweig-Lipson S, Gregory-Ksander M, Sinclair DA, Ksander BR.
Sustained Vision Recovery by OSK Gene Therapy in a Mouse Model of Glaucoma. Cell Reprogram 2023;25(6):288-299.
AbstractGlaucoma, a chronic neurodegenerative disease, is a leading cause of age-related blindness worldwide and characterized by the progressive loss of retinal ganglion cells (RGCs) and their axons. Previously, we developed a novel epigenetic rejuvenation therapy, based on the expression of the three transcription factors Oct4, Sox2, and Klf4 (OSK), which safely rejuvenates RGCs without altering cell identity in glaucomatous and old mice after 1 month of treatment. In the current year-long study, mice with continuous or cyclic OSK expression induced after glaucoma-induced vision damage had occurred were tracked for efficacy, duration, and safety. Surprisingly, only 2 months of OSK fully restored impaired vision, with a restoration of vision for 11 months with prolonged expression. In RGCs, transcription from the doxycycline (DOX)-inducible Tet-On AAV system, returned to baseline 4 weeks after DOX withdrawal. Significant vision improvements remained for 1 month post switching off OSK, after which the vision benefit gradually diminished but remained better than baseline. Notably, no adverse effects on retinal structure or body weight were observed in glaucomatous mice with OSK continuously expressed for 21 months providing compelling evidence of efficacy and safety. This work highlights the tremendous therapeutic potential of rejuvenating gene therapies using OSK, not only for glaucoma but also for other ocular and systemic injuries and age-related diseases.
Kastner A, Stuart KV, Montesano G, De Moraes GC, Kang JH, Wiggs JL, Pasquale LR, Hysi P, Chua SYL, Patel PJ, Foster PJ, Khaw PT, Khawaja AP, and Consortium UKBEV.
Calcium Channel Blocker Use and Associated Glaucoma and Related Traits Among UK Biobank Participants. JAMA Ophthalmol 2023;141(10):956-964.
AbstractIMPORTANCE: Calcium channel blocker (CCB) use has been associated with an increased risk of glaucoma in exploratory studies. OBJECTIVE: To examine the association of systemic CCB use with glaucoma and related traits among UK Biobank participants. DESIGN, SETTING, AND PARTICIPANTS: This population-based cross-sectional study included UK Biobank participants with complete data (2006-2010) for analysis of glaucoma status, intraocular pressure (IOP), and optical coherence tomography (OCT)-derived inner retinal layer thicknesses. Data analysis was conducted in January 2023. EXPOSURE: Calcium channel blocker use was assessed in a baseline touchscreen questionnaire and confirmed during an interview led by a trained nurse. MAIN OUTCOMES AND MEASURES: The primary outcome measures included glaucoma status, corneal-compensated IOP, and 2 OCT-derived inner retinal thickness parameters (macular retinal nerve fiber layer [mRNFL] and macular ganglion cell-inner plexiform layer [mGCIPL] thicknesses). We performed logistic regression and linear regression analyses to test for associations with glaucoma status and IOP and OCT-derived inner retinal thickness parameters, respectively. RESULTS: This study included 427 480 adults. Their median age was 58 (IQR, 50-63) years, and more than half (54.1%) were women. There were 33 175 CCB users (7.8%). Participants who had complete data for glaucoma status (n = 427 480), IOP (n = 97 100), and OCT-derived inner retinal layer thicknesses (n = 41 023) were eligible for respective analyses. After adjustment for key sociodemographic, medical, anthropometric, and lifestyle factors, use of CCBs (but not other antihypertensive agents) was associated with greater odds of glaucoma (odds ratio [OR], 1.39 [95% CI, 1.14 to 1.69]; P = .001). Calcium channel blocker use was also associated with thinner mGCIPL (-0.34 μm [95% CI, -0.54 to -0.15 μm]; P = .001) and mRNFL (-0.16 μm [95% CI, -0.30 to -0.02 μm]; P = .03) thicknesses but not IOP (-0.01 mm Hg [95% CI, -0.09 to 0.07 mm Hg]; P = .84). CONCLUSIONS AND RELEVANCE: In this study, an adverse association between CCB use and glaucoma was observed, with CCB users having, on average, 39% higher odds of glaucoma. Calcium channel blocker use was also associated with thinner mGCIPL and mRNFL thicknesses, providing a structural basis that supports the association with glaucoma. The lack of association of CCB use with IOP suggests that an IOP-independent mechanism of glaucomatous neurodegeneration may be involved. Although a causal relationship has not been established, CCB replacement or withdrawal may be considered should glaucoma progress despite optimal care.
Kavitha S, Tejaswini US, Venkatesh R, Zebardast N.
Wound modulation in glaucoma surgery: The role of anti-scarring agents. Indian J Ophthalmol 2024;72(3):320-327.
AbstractFiltration surgery is one of the most frequently performed surgeries in the management of glaucoma, and trabeculectomy is considered the gold standard surgical technique for the same. Though trabeculectomy has been reported to have an excellent initial success rate, about 30% of them fail in 3 years, and nearly 50% of them fail in 5 years. The most significant risk of failure still seems to be wound scarring, especially episcleral fibrosis, leading to bleb failure. As a result, it is essential to explore the role of anti-scarring agents, including mitomycin C, and 5-fluorouracil in wound modulation and improving the bleb survival rate. Since these agents are widely used in trabeculectomy, it is crucial to understand the various modes of application, advantages, and adverse effects of these agents. On an evidence-based approach, all these points have been highlighted in this review article. In addition, the newer agents available for wound modulation and their scope for practical application are discussed.
Kempen JH, Van Natta ML, Friedman DS, Altaweel MM, Ansari H, Dunn JP, Elner SG, Holbrook JT, Lim LL, Sugar EA, Jabs DA, and Group MUST (MUST) TF-up SR.
Incidence and Outcome of Uveitic Glaucoma in Eyes With Intermediate, Posterior, or Panuveitis Followed up to 10 Years After Randomization to Fluocinolone Acetonide Implant or Systemic Therapy. Am J Ophthalmol 2020;219:303-316.
AbstractPURPOSE: To evaluate long-term risk and outcomes of glaucoma in eyes with intermediate, posterior, and panuveitis managed with systemic or fluocinolone acetonide (0.59 mg, "implant") therapy. DESIGN: Prospective Follow-up of the Multicenter Uveitis Steroid Treatment (MUST) Clinical Trial Cohort. METHODS: Patients with intermediate, posterior, or panuveitis randomized to implant or systemic therapy (corticosteroid plus immunosuppression in >90%) were followed prospectively for glaucoma incidence and outcome. RESULTS: Among 405 uveitic at-risk eyes of 232 patients (median follow-up = 6.9 years), 40% (79/196) of eyes assigned and treated with implant and 8% (17/209) of eyes assigned and treated with systemic therapy (censoring eyes receiving an implant on implantation) developed glaucoma (hazard ratio [HR] = 5.9, 95% confidence interval [CI] 3.2, 10.8; P < .001). Adjustment for intraocular pressure (IOP) elevation during follow-up only partially mitigated the association of implant treatment with glaucoma incidence: HR = 3.1 (95% CI 1.6, 6.0); P = .001. Among 112 eyes of 83 patients developing glaucoma, the 5-year cumulative incidence following diagnosis of sustained (2 or more consecutive visits) worsening of mean deviation by ≥6 dB was 20% (95% CI 12%, 33%); 5-year cumulative incidence of sustained worsening of cup-to-disc ratio by ≥0.2 was 26% (95% CI 17%, 39%). CONCLUSIONS: The implant has substantially higher risk of glaucoma than systemic therapy, a difference not entirely explained by posttreatment IOP elevation. Management of IOP elevation was effective in preventing worsening of glaucoma for the large majority of cases, but even under expert clinical management, some glaucoma worsened. Uveitis cases should be monitored carefully for IOP elevation and glaucoma indefinitely.
Khawaja AP, Cooke Bailey JN, Wareham NJ, Scott RA, Simcoe M, Igo RP, Song YE, Wojciechowski R, Cheng C-Y, Khaw PT, Pasquale LR, Haines JL, Foster PJ, Wiggs JL, Hammond CJ, Hysi PG, and Consortium UKBEV, and Consortium UKBEV.
Genome-wide analyses identify 68 new loci associated with intraocular pressure and improve risk prediction for primary open-angle glaucoma. Nat Genet 2018;50(6):778-782.
AbstractGlaucoma is the leading cause of irreversible blindness globally . Despite its gravity, the disease is frequently undiagnosed in the community . Raised intraocular pressure (IOP) is the most important risk factor for primary open-angle glaucoma (POAG). Here we present a meta-analysis of 139,555 European participants, which identified 112 genomic loci associated with IOP, 68 of which are novel. These loci suggest a strong role for angiopoietin-receptor tyrosine kinase signaling, lipid metabolism, mitochondrial function and developmental processes underlying risk for elevated IOP. In addition, 48 of these loci were nominally associated with glaucoma in an independent cohort, 14 of which were significant at a Bonferroni-corrected threshold. Regression-based glaucoma-prediction models had an area under the receiver operating characteristic curve (AUROC) of 0.76 in US NEIGHBORHOOD study participants and 0.74 in independent glaucoma cases from the UK Biobank. Genetic-prediction models for POAG offer an opportunity to target screening and timely therapy to individuals most at risk.
Khawaja AP, Cooke Bailey JN, Kang JH, Allingham RR, Hauser MA, Brilliant M, Budenz DL, Christen WG, Fingert J, Gaasterland D, Gaasterland T, Kraft P, Lee RK, Lichter PR, Liu Y, Medeiros F, Moroi SE, Richards JE, Realini T, Ritch R, Schuman JS, Scott WK, Singh K, Sit AJ, Vollrath D, Wollstein G, Zack DJ, Zhang K, Pericak-Vance M, Weinreb RN, Haines JL, Pasquale LR, Wiggs JL.
Assessing the Association of Mitochondrial Genetic Variation With Primary Open-Angle Glaucoma Using Gene-Set Analyses. Invest Ophthalmol Vis Sci 2016;57(11):5046-5052.
AbstractPurpose: Recent studies indicate that mitochondrial proteins may contribute to the pathogenesis of primary open-angle glaucoma (POAG). In this study, we examined the association between POAG and common variations in gene-encoding mitochondrial proteins. Methods: We examined genetic data from 3430 POAG cases and 3108 controls derived from the combination of the GLAUGEN and NEIGHBOR studies. We constructed biological-system coherent mitochondrial nuclear-encoded protein gene-sets by intersecting the MitoCarta database with the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. We examined the mitochondrial gene-sets for association with POAG and with normal-tension glaucoma (NTG) and high-tension glaucoma (HTG) subsets using Pathway Analysis by Randomization Incorporating Structure. Results: We identified 22 KEGG pathways with significant mitochondrial protein-encoding gene enrichment, belonging to six general biological classes. Among the pathway classes, mitochondrial lipid metabolism was associated with POAG overall (P = 0.013) and with NTG (P = 0.0006), and mitochondrial carbohydrate metabolism was associated with NTG (P = 0.030). Examining the individual KEGG pathway mitochondrial gene-sets, fatty acid elongation and synthesis and degradation of ketone bodies, both lipid metabolism pathways, were significantly associated with POAG (P = 0.005 and P = 0.002, respectively) and NTG (P = 0.0004 and P < 0.0001, respectively). Butanoate metabolism, a carbohydrate metabolism pathway, was significantly associated with POAG (P = 0.004), NTG (P = 0.001), and HTG (P = 0.010). Conclusions: We present an effective approach for assessing the contributions of mitochondrial genetic variation to open-angle glaucoma. Our findings support a role for mitochondria in POAG pathogenesis and specifically point to lipid and carbohydrate metabolism pathways as being important.
Khoueir Z, Jassim F, Braaf B, Poon LY-C, Tsikata E, Chodosh J, Dohlman CH, Vakoc BJ, Bouma BE, de Boer JF, Chen TC.
Three-Dimensional Optical Coherence Tomography Imaging For Glaucoma Associated With Boston Keratoprosthesis Type I and II. J Glaucoma 2019;28(8):718-726.
AbstractPRECIS: Three-dimensional (3D) spectral domain optical coherence tomography (OCT) volume scans of the optic nerve head (ONH) and the peripapillary area are useful in the management of glaucoma in patients with a type I or II Boston Keratoprosthesis (KPro). PURPOSE: The purpose of this study was to report the use of spectral domain OCT in the management of glaucoma in patients with a type I or II Boston KPro. MATERIALS AND METHODS: This study is an observational case series. Four consecutive patients with KPro implants were referred for glaucoma evaluation. A comprehensive eye examination was performed which included disc photography, visual field testing, and high-density spectral domain OCT volume scans of the ONH and the peripapillary area. 2D and 3D parameters were calculated using custom-designed segmentation algorithms developed for glaucoma management. RESULTS: Spectral domain OCT parameters provided useful information in the diagnosis and management of 4 KPro patients. OCT parameters which can be used in KPro patients included 2D retinal nerve fiber layer (RNFL) thickness, 3D peripapillary RNFL volume, 3D peripapillary retinal thickness and volume, 3D cup volume, and 3D neuroretinal rim thickness and volume. In 3 of 4 cases where the traditional 2D RNFL thickness scan was limited by artifacts, 3D spectral domain OCT volume scans provided useful quantitative objective measurements of the ONH and peripapillary region. Therefore, 3D parameters derived from high-density volume scans as well as radial scans of the ONH can be used to overcome the limitations and artifacts associated with 2D RNFL thickness scans. CONCLUSIONS: Spectral domain OCT volume scans offer the possibility to enhance the evaluation of KPro patients with glaucoma by using both 2D and 3D diagnostic parameters that are easily obtained in a clinic setting.
Khoueir Z, Jassim F, Poon LY-C, Tsikata E, Ben-David GS, Liu Y, Shieh E, Lee R, Guo R, Papadogeorgou G, Braaf B, Simavli H, Que C, Vakoc BJ, Bouma BE, de Boer JF, Chen TC.
Diagnostic Capability of Peripapillary Three-dimensional Retinal Nerve Fiber Layer Volume for Glaucoma Using Optical Coherence Tomography Volume Scans. Am J Ophthalmol 2017;182:180-193.
AbstractPURPOSE: To determine the diagnostic capability of peripapillary 3-dimensional (3D) retinal nerve fiber layer (RNFL) volume measurements from spectral-domain optical coherence tomography (OCT) volume scans for open-angle glaucoma (OAG). DESIGN: Assessment of diagnostic accuracy. METHODS: Setting: Academic clinical setting. STUDY POPULATION: Total of 180 patients (113 OAG and 67 normal subjects). OBSERVATION PROCEDURES: One eye per subject was included. Peripapillary 3D RNFL volumes were calculated for global, quadrant, and sector regions, using 4 different-size annuli. Peripapillary 2D RNFL thickness circle scans were also obtained. MAIN OUTCOME MEASURES: Area under the receiver operating characteristic curve (AUROC) values, sensitivity, specificity, positive and negative predictive values, positive and negative likelihood ratios. RESULTS: Among all 2D and 3D RNFL parameters, best diagnostic capability was associated with inferior quadrant 3D RNFL volume of the smallest annulus (AUROC value 0.977). Otherwise, global 3D RNFL volume AUROC values were comparable to global 2D RNFL thickness AUROC values for all 4 annulus sizes (P values: .0593 to .6866). When comparing the 4 annulus sizes for global RNFL volume, the smallest annulus had the best AUROC values (P values: .0317 to .0380). The smallest-size annulus may have the best diagnostic potential, partly owing to having no areas excluded for being larger than the 6 × 6 mm(2) scanned region. CONCLUSION: Peripapillary 3D RNFL volume showed excellent diagnostic performance for detecting glaucoma. Peripapillary 3D RNFL volume parameters have the same or better diagnostic capability compared to peripapillary 2D RNFL thickness measurements, although differences were not statistically significant.
Kim J, Aschard H, Kang JH, Lentjes MA, Do R, Wiggs JL, Khawaja AP, Pasquale LR, for Collaboration MRFG.
Intraocular Pressure, Glaucoma, and Dietary Caffeine Consumption: A Gene-Diet Interaction Study from the UK Biobank. Ophthalmology 2021;128(6):866-876.
AbstractPURPOSE: We examined the association of habitual caffeine intake with intraocular pressure (IOP) and glaucoma and whether genetic predisposition to higher IOP modified these associations. We also assessed whether genetic predisposition to higher coffee consumption was related to IOP. DESIGN: Cross-sectional study in the UK Biobank. PARTICIPANTS: We included 121 374 participants (baseline ages, 39-73 years) with data on coffee and tea intake (collected 2006-2010) and corneal-compensated IOP measurements in 2009. In a subset of 77 906 participants with up to 5 web-based 24-hour-recall food frequency questionnaires (2009-2012), we evaluated total caffeine intake. We also assessed the same relationships with glaucoma (9286 cases and 189 763 controls). METHODS: We evaluated multivariable-adjusted associations with IOP using linear regression and with glaucoma using logistic regression. For both outcomes, we examined gene-diet interactions using a polygenic risk score (PRS) that combined the effects of 111 genetic variants associated with IOP. We also performed Mendelian randomization using 8 genetic variants associated with coffee intake to assess potential causal effects of coffee consumption on IOP. MAIN OUTCOME MEASURES: Intraocular pressure and glaucoma. RESULTS: Mendelian randomization analysis did not support a causal effect of coffee drinking on IOP (P > 0.1). Greater caffeine intake was associated weakly with lower IOP: the highest (≥232 mg/day) versus lowest (<87 mg/day) caffeine consumption was associated with a 0.10-mmHg lower IOP (Ptrend = 0.01). However, the IOP PRS modified this association: among those in the highest IOP PRS quartile, consuming > 480 mg/day versus < 80 mg/day was associated with a 0.35-mmHg higher IOP (Pinteraction = 0.01). The relationship between caffeine intake and glaucoma was null (P ≥ 0.1). However, the IOP PRS also modified this relationship: compared with those in the lowest IOP PRS quartile consuming no caffeine, those in the highest IOP PRS quartile consuming ≥ 321 mg/day showed a 3.90-fold higher glaucoma prevalence (Pinteraction = 0.0003). CONCLUSIONS: Habitual caffeine consumption was associated weakly with lower IOP, and the association between caffeine consumption and glaucoma was null. However, among participants with the strongest genetic predisposition to elevated IOP, greater caffeine consumption was associated with higher IOP and higher glaucoma prevalence.
King R, Struebing FL, Li Y, Wang J, Koch AA, Cooke Bailey JN, Gharahkhani P, Gharahkhani P, Gharahkhani P, Macgregor S, Allingham RR, Hauser MA, Wiggs JL, Geisert EE.
Genomic locus modulating corneal thickness in the mouse identifies POU6F2 as a potential risk of developing glaucoma. PLoS Genet 2018;14(1):e1007145.
AbstractCentral corneal thickness (CCT) is one of the most heritable ocular traits and it is also a phenotypic risk factor for primary open angle glaucoma (POAG). The present study uses the BXD Recombinant Inbred (RI) strains to identify novel quantitative trait loci (QTLs) modulating CCT in the mouse with the potential of identifying a molecular link between CCT and risk of developing POAG. The BXD RI strain set was used to define mammalian genomic loci modulating CCT, with a total of 818 corneas measured from 61 BXD RI strains (between 60-100 days of age). The mice were anesthetized and the eyes were positioned in front of the lens of the Phoenix Micron IV Image-Guided OCT system or the Bioptigen OCT system. CCT data for each strain was averaged and used to QTLs modulating this phenotype using the bioinformatics tools on GeneNetwork (
www.genenetwork.org). The candidate genes and genomic loci identified in the mouse were then directly compared with the summary data from a human POAG genome wide association study (NEIGHBORHOOD) to determine if any genomic elements modulating mouse CCT are also risk factors for POAG.This analysis revealed one significant QTL on Chr 13 and a suggestive QTL on Chr 7. The significant locus on Chr 13 (13 to 19 Mb) was examined further to define candidate genes modulating this eye phenotype. For the Chr 13 QTL in the mouse, only one gene in the region (Pou6f2) contained nonsynonymous SNPs. Of these five nonsynonymous SNPs in Pou6f2, two resulted in changes in the amino acid proline which could result in altered secondary structure affecting protein function. The 7 Mb region under the mouse Chr 13 peak distributes over 2 chromosomes in the human: Chr 1 and Chr 7. These genomic loci were examined in the NEIGHBORHOOD database to determine if they are potential risk factors for human glaucoma identified using meta-data from human GWAS. The top 50 hits all resided within one gene (POU6F2), with the highest significance level of p = 10-6 for SNP rs76319873. POU6F2 is found in retinal ganglion cells and in corneal limbal stem cells. To test the effect of POU6F2 on CCT we examined the corneas of a Pou6f2-null mice and the corneas were thinner than those of wild-type littermates. In addition, these POU6F2 RGCs die early in the DBA/2J model of glaucoma than most RGCs. Using a mouse genetic reference panel, we identified a transcription factor, Pou6f2, that modulates CCT in the mouse. POU6F2 is also found in a subset of retinal ganglion cells and these RGCs are sensitive to injury.
Kolli A, Sekimitsu S, Wang J, Segre A, Friedman D, Elze T, Pasquale LR, Wiggs J, Zebardast N.
Background polygenic risk modulates the association between glaucoma and cardiopulmonary diseases and measures: an analysis from the UK Biobank. Br J Ophthalmol 2023;107(8):1112-1118.
AbstractAIMS: To assess whether associations of cardiopulmonary conditions and markers with glaucoma differ by background genetic risk for primary open angle glaucoma (POAG). METHODS: We constructed a POAG polygenic risk score (PRS) using genome-wide association study summary statistics from a large cross-ancestry meta-analysis. History of glaucoma (including self-report and codes for POAG, 'other glaucoma' or unspecified glaucoma), history of common cardiopulmonary conditions and cardiopulmonary measures were assessed in the UK Biobank. Stratifying by PRS decile 1 (lowest risk) versus decile 10 (highest risk), separate multivariable models were estimated to assess the associations of cardiopulmonary diseases or factors with glaucoma, adjusting for age, sex, smoking and medication use. A Bonferroni correction was used to adjust p values for multiple comparisons. RESULTS: Individuals in POAG PRS decile 1 (417 cases, 44 458 controls; mean age 56.8 years) and decile 10 (2135 cases, 42 413 controls; mean age 56.7 years) were included. Within decile 1, glaucoma cases had significantly higher glycated haemoglobin (38.5 vs 35.9 mmol/mol) and higher prevalence of diabetes (17.5% vs 6.5%), dyslipidaemia (31.2% vs 18.3%) and chronic kidney disease (CKD) (6.7% vs 2.0%) than controls (adjusted p<0.0013 for each). Within decile 10, glaucoma was associated with higher prevalence of dyslipidaemia (27.7% vs 17.3%, p=6.9E-05). The magnitude of association between glaucoma and diabetes, CKD and glycated haemoglobin differed between deciles 1 and 10 (contrast test p value for difference <0.05). CONCLUSION: The relations between systemic conditions and glaucoma vary by underlying genetic predisposition to POAG, with larger associations among those who developed glaucoma despite low genetic risk.
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.
AbstractCommunity-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.
Krawitz BD, Sirinek P, Doobin D, Nanda T, Ghiassi M, Horowitz JD, Liebmann JM, De Moraes CG.
The Challenge of Managing Bilateral Acute Angle-closure Glaucoma in the Presence of Active SARS-CoV-2 Infection. J Glaucoma 2021;30(3):e50-e53.
AbstractPURPOSE: To report a case of bilateral acute angle-closure glaucoma associated with hyponatremia in the setting of chlorthalidone use and SARS-CoV-2 infection, and to demonstrate the challenges of managing this patient given her infectious status. METHODS: This was a case report. CASE: A 65-year-old woman taking chlorthalidone for hypertension presented to the emergency room with headache, pain, and blurry vision in both eyes and was found to be in bilateral acute angle closure. On laboratory investigation, she was severely hyponatremic and also tested positive for SARS-CoV-2. B-scan ultrasound demonstrated an apparent supraciliary effusion in the right eye. Following stabilization of her intraocular pressures with medical management, she ultimately underwent cataract extraction with iridectomies and goniosynechiolysis in both eyes. CONCLUSIONS: We report a rare case of bilateral acute angle-closure glaucoma associated with hyponatremia. Chlorthalidone use and perhaps SARS-CoV-2 infection may have contributed to this electrolyte abnormality and unique clinical presentation. In addition, we discuss the challenges of managing this complex patient with active SARS-CoV-2 infection during the pandemic.
Krishnan A, Fei F, Jones A, Busto P, Marshak-Rothstein A, Ksander BR, Gregory-Ksander M.
Overexpression of Soluble Fas Ligand following Adeno-Associated Virus Gene Therapy Prevents Retinal Ganglion Cell Death in Chronic and Acute Murine Models of Glaucoma. J Immunol 2016;197(12):4626-4638.
AbstractGlaucoma is a multifactorial disease resulting in the death of retinal ganglion cells (RGCs) and irreversible blindness. Glaucoma-associated RGC death depends on the proapoptotic and proinflammatory activity of membrane-bound Fas ligand (mFasL). In contrast to mFasL, the natural cleavage product, soluble Fas ligand (sFasL) inhibits mFasL-mediated apoptosis and inflammation and, therefore, is an mFasL antagonist. DBA/2J mice spontaneously develop glaucoma and, predictably, RGC destruction is exacerbated by expression of a mutated membrane-only FasL gene that lacks the extracellular cleavage site. Remarkably, one-time intraocular adeno-associated virus-mediated gene delivery of sFasL provides complete and sustained neuroprotection in the chronic DBA/2J and acute microbead-induced models of glaucoma, even in the presence of elevated intraocular pressure. This protection correlated with inhibition of glial activation, reduced production of TNF-α, and decreased apoptosis of RGCs and loss of axons. These data indicate that cleavage of FasL under homeostatic conditions, and the ensuing release of sFasL, normally limits the neurodestructive activity of FasL. The data further support the notion that sFasL, and not mFasL, contributes to the immune-privileged status of the eye.
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.
AbstractGlaucoma 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.
Kumar S, Ichhpujani P, Thakur S, Singh RB.
Traumatic corneal perforation with exteriorisation of Ahmed glaucoma valve tube. BMJ Case Rep 2018;2018
AbstractWe report a rare case of traumatic corneal perforation with Ahmed glaucoma valve (AGV) tube. A 5-year-old female child, diagnosed with refractory glaucoma, had undergone AGV implantation, presented with the posterior migration of AGV tube after trauma to the eye. The detailed ocular history, ophthalmic findings, clinical course and surgical management are discussed.
KV S, K M, RN L, SYL C, AN W, M C, LR P, JL W, JH K, PJ F, AP K, for Collaboration MRFG.
Alcohol, intraocular pressure and open-angle glaucoma: A systematic review and meta-analysis. Ophthalmology 2022;
L
Lahola-Chomiak AA, Footz T, Nguyen-Phuoc K, Neil GJ, Fan BJ, Allen KF, Greenfield DS, Parrish RK, Linkroum K, Pasquale LR, Leonhardt RM, Ritch R, Javadiyan S, Craig JE, Allison WT, Lehmann OJ, Walter MA, Wiggs JL.
Non-Synonymous variants in premelanosome protein (PMEL) cause ocular pigment dispersion and pigmentary glaucoma. Hum Mol Genet 2019;28(8):1298-1311.
AbstractPigmentary glaucoma (PG) is a common glaucoma subtype that results from release of pigment from the iris, called pigment dispersion syndrome (PDS), and its deposition throughout the anterior chamber of the eye. Although PG has a substantial heritable component, no causative genes have yet been identified. We used whole exome sequencing of two independent pedigrees to identify two premelanosome protein (PMEL) variants associated with heritable PDS/PG. PMEL encodes a key component of the melanosome, the organelle essential for melanin synthesis, storage and transport. Targeted screening of PMEL in three independent cohorts (n = 394) identified seven additional PDS/PG-associated non-synonymous variants. Five of the nine variants exhibited defective processing of the PMEL protein. In addition, analysis of PDS/PG-associated PMEL variants expressed in HeLa cells revealed structural changes to pseudomelanosomes indicating altered amyloid fibril formation in five of the nine variants. Introduction of 11-base pair deletions to the homologous pmela in zebrafish by the clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 method caused profound pigmentation defects and enlarged anterior segments in the eye, further supporting PMEL's role in ocular pigmentation and function. Taken together, these data support a model in which missense PMEL variants represent dominant negative mutations that impair the ability of PMEL to form functional amyloid fibrils. While PMEL mutations have previously been shown to cause pigmentation and ocular defects in animals, this research is the first report of mutations in PMEL causing human disease.
Lains I, Ung C, Gong D, Parikh D, Eliott D.
Polychromatic Aqueous and Vitreous Crystals Due to Phacolytic Glaucoma in a Patient With Marfan Syndrome and Lens Dislocation. J Vitreoretin Dis 2023;7(5):435-439.
AbstractPurpose: To describe a patient with Marfan syndrome and crystalline lens luxation who developed phacolytic glaucoma with polychromatic crystals in the anterior chamber and vitreous. Methods: We present a retrospective case report. Results: A 58-year-old man with Marfan syndrome and crystalline lens luxation since childhood presented with 2 days of pain in the left eye. The visual acuity was 20/30 OS with an aphakic contact lens, and the intraocular pressure (IOP) was 31 mm Hg. Polychromatic crystals were evident in the anterior chamber and vitreous. The retina was attached. Despite medical treatment, the IOP remained elevated; therefore, a pars plana vitrectomy and lensectomy were performed. At the last follow-up, the IOP was normal and the retina remained attached. Conclusions: Phacolytic glaucoma can be seen in eyes with a subluxated or luxated mature or hypermature lens. In these rare cases, iridescent crystals can be observed in the aqueous and vitreous. Vitrectomy with lensectomy is the definitive treatment.
Laville V, Kang JH, Cousins CC, Iglesias AI, Nagy R, Cooke Bailey JN, Igo RP, Song YE, Chasman DI, Christen WG, Kraft P, Rosner BA, Hu F, Wilson JF, Gharahkhani P, Hewitt AW, Mackey DA, Hysi PG, Hammond CJ, van Duijn CM, Haines JL, Vitart V, Fingert JH, Hauser MA, Aschard H, Wiggs JL, Khawaja AP, Macgregor S, Pasquale LR, UK Biobank, International Glaucoma Genetics Consortium NEIGHBORHOODC.
Genetic correlations between diabetes and glaucoma: an analysis of continuous and dichotomous phenotypes. Am J Ophthalmol 2019;
AbstractPURPOSE: A genetic correlation is the proportion of phenotypic variance between traits that is shared on a genetic basis. Here we explore genetic correlations between diabetes- and glaucoma-related traits. DESIGN: Cross-sectional study. METHODS: We assembled genome-wide association study summary statistics from European-derived participants regarding diabetes-related traits like fasting blood sugar (FBS) and type 2 diabetes (T2D) and glaucoma-related traits (intraocular pressure (IOP), central corneal thickness (CCT), corneal hysteresis (CH), corneal resistance factor (CRF), cup-disc ratio (CDR), and primary open-angle glaucoma (POAG)). We included data from the National Eye Institute Glaucoma Human Genetics Collaboration Heritable Overall Operational Database, the UK Biobank and the International Glaucoma Genetics Consortium. We calculated genetic correlation (r) between traits using linkage disequilibrium score regression. We also calculated genetic correlations between IOP, CCT and selected diabetes-related traits based on individual level phenotype data in two Northern European population-based samples using pedigree information and Sequential Oligogenic Linkage Analysis Routines (SOLAR). RESULTS: Overall, there was little r between diabetes- and glaucoma-related traits. Specifically, we found a non-significant negative correlation between T2D and POAG (r=-0.14; p=0.16). Using SOLAR, the genetic correlations between measured IOP, CCT, FBS, fasting insulin and hemoglobin A1c, were null. In contrast, genetic correlations between IOP and POAG (r ≥0.45; p≤3.0E-04) and between CDR and POAG were high (r =0.57; p=2.8E-10). However, genetic correlations between corneal properties (CCT, CRF and CH) and POAG were low (r range: -0.18 - 0.11) and non-significant (p≥0.07). CONCLUSION: These analyses suggest there is limited genetic correlation between diabetes- and glaucoma-related traits.
