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Truong TN, Li H, Hong Y-K, Chen L.
Novel characterization and live imaging of Schlemm's canal expressing Prox-1. PLoS One 2014;9(5):e98245.
AbstractSchlemm's canal is an important structure of the conventional aqueous humor outflow pathway and is critically involved in regulating the intraocular pressure. In this study, we report a novel finding that prospero homeobox protein 1 (Prox-1), the master control gene for lymphatic development, is expressed in Schlemm's canal. Moreover, we provide a novel in vivo method of visualizing Schlemm's canal using a transgenic mouse model of Prox-1-green fluorescent protein (GFP). The anatomical location of Prox-1⁺ Schlemm's canal was further confirmed by in vivo gonioscopic examination and ex vivo immunohistochemical analysis. Additionally, we show that the Schlemm's canal is distinguishable from typical lymphatic vessels by lack of lymphatic vessel endothelial hyaluronan receptor (LYVE-1) expression and absence of apparent sprouting reaction when inflammatory lymphangiogenesis occurred in the cornea. Taken together, our findings offer new insights into Schlemm's canal and provide a new experimental model for live imaging of this critical structure to help further our understanding of the aqueous humor outflow. This may lead to new avenues toward the development of novel therapeutic intervention for relevant diseases, most notably glaucoma.
Tsikata E, Lee R, Shieh E, Simavli H, Que CJ, Guo R, Khoueir Z, de Boer J, Chen TC.
Comprehensive Three-Dimensional Analysis of the Neuroretinal Rim in Glaucoma Using High-Density Spectral-Domain Optical Coherence Tomography Volume Scans. Invest Ophthalmol Vis Sci 2016;57(13):5498-5508.
AbstractPurpose: To describe spectral-domain optical coherence tomography (OCT) methods for quantifying neuroretinal rim tissue in glaucoma and to compare these methods to the traditional retinal nerve fiber layer thickness diagnostic parameter. Methods: Neuroretinal rim parameters derived from three-dimensional (3D) volume scans were compared with the two-dimensional (2D) Spectralis retinal nerve fiber layer (RNFL) thickness scans for diagnostic capability. This study analyzed one eye per patient of 104 glaucoma patients and 58 healthy subjects. The shortest distances between the cup surface and the OCT-based disc margin were automatically calculated to determine the thickness and area of the minimum distance band (MDB) neuroretinal rim parameter. Traditional 150-μm reference surface-based rim parameters (volume, area, and thickness) were also calculated. The diagnostic capabilities of these five parameters were compared with RNFL thickness using the area under the receiver operating characteristic (AUROC) curves. Results: The MDB thickness had significantly higher diagnostic capability than the RNFL thickness in the nasal (0.913 vs. 0.818, P = 0.004) and temporal (0.922 vs. 0.858, P = 0.026) quadrants and the inferonasal (0.950 vs. 0.897, P = 0.011) and superonasal (0.933 vs. 0.868, P = 0.012) sectors. The MDB area and the three neuroretinal rim parameters based on the 150-μm reference surface had diagnostic capabilities similar to RNFL thickness. Conclusions: The 3D MDB thickness had a high diagnostic capability for glaucoma and may be of significant clinical utility. It had higher diagnostic capability than the RNFL thickness in the nasal and temporal quadrants and the inferonasal and superonasal sectors.
Turalba A, Payal AR, Gonzalez-Gonzalez LA, Cakiner-Egilmez T, Chomsky AS, Vollman DE, Baze EF, Lawrence M, Daly MK.
Cataract Surgery Outcomes in Glaucomatous Eyes: Results From the Veterans Affairs Ophthalmic Surgery Outcomes Data Project. Am J Ophthalmol 2015;160(4):693-701.e1.
AbstractPURPOSE: To compare visual acuity outcomes, vision-related quality of life, and complications related to cataract surgery in eyes with and without glaucoma. DESIGN: Retrospective cohort study. METHODS: Cataract surgery outcomes in cases with and without glaucoma from the Veterans Affairs Ophthalmic Surgical Outcomes Data Project were compared. RESULTS: We identified 608 glaucoma cases and 4306 controls undergoing planned cataract surgery alone. After adjusting for age, pseudoexfoliation, small pupil, prior ocular surgery, and anterior chamber depth, we found that glaucoma cases were more likely to have posterior capsular tear with vitrectomy (odds ratio [OR] 1.8, P = .03) and sulcus intraocular lens placement (OR 1.65, P = .03) during cataract surgery. Glaucoma cases were more likely to have postoperative inflammation (OR 1.73, P < .0001), prolonged elevated intraocular pressure (OR 2.96, P = .0003), and additional surgery within 30 days (OR 1.92, P = .03). Mean best-corrected visual acuity (BCVA) and Visual Function Questionnaire (VFQ) scores significantly improved after cataract surgery in both groups (P < .0001), but there were larger improvements in BCVA (P = .01) and VFQ composite scores (P < .0001) in the nonglaucoma vs the glaucoma group. A total of 3621 nonglaucoma cases (94.1%) had postoperative BCVA 20/40 or better, compared to 466 glaucoma cases (89.6%) (P = .0003). CONCLUSIONS: Eyes with glaucoma are at increased risk for complications and have more modest visual outcomes after cataract surgery compared to eyes without glaucoma. Despite this, glaucoma patients still experience significant improvement in vision-related outcomes after cataract extraction. Further study is needed to explore potential factors that influence cataract surgery outcomes in glaucomatous eyes.
Turalba AV, Shah AS, Andreoli MT, Andreoli CM, Rhee DJ.
Predictors and outcomes of ocular hypertension after open-globe injury. J Glaucoma 2014;23(1):5-10.
AbstractPURPOSE: Evaluate predictors and outcomes of ocular hypertension after open-globe injury. PATIENTS AND METHODS: This is a retrospective, case-control study reviewing records of consecutive patients with open-globe injuries treated at Massachusetts Eye and Ear Infirmary between February 1999 and January 2007. Of 658 patients treated, 382 had at least 2 months of follow-up and sufficient data to be included. Main outcome measures are visual acuity, intraocular pressure (IOP), and type of glaucoma intervention employed. RESULTS: Sixty-five (17%) patients developed ocular hypertension defined as IOP≥22 mm Hg at >1 visit or requiring treatment. Increased age (P<0.001), hyphema (0.025), lens injury (P<0.0001), and zone II injury (P=0.0254) are risk factors for developing ocular hypertension after open-globe injury. Forty-eight (74%) patients with ocular hypertension were treated medically, 8 (12%) underwent filtering or glaucoma drainage device surgery, 5 (8%) had IOP normalization with observation, while 4 (6%) required anterior chamber washout with no other glaucoma surgery. Patients with ocular hypertension had an average maximum IOP=33.4 mm Hg at a median follow-up of 21 days, with most patients maintaining normal IOP at all follow-up time points. Visual acuity improved over time with median acuity of hand motions preoperatively, and 20/60 at 12 and 36 months. CONCLUSIONS: Ocular hypertension is a significant complication after open-globe injury that sometimes requires surgical intervention. Predictive factors can alert physicians to monitor for elevated IOP in the first month after trauma. Most patients with traumatic ocular hypertension had improved visual acuity and IOP normalization over time.
Turalba AV, Pasquale LR.
Hypertensive phase and early complications after Ahmed glaucoma valve implantation with intraoperative subtenon triamcinolone acetonide. Clin Ophthalmol 2014;8:1311-6.
AbstractOBJECTIVE: To evaluate intraoperative subtenon triamcinolone acetonide (TA) as an adjunct to Ahmed glaucoma valve (AGV) implantation. DESIGN: Retrospective comparative case series. PARTICIPANTS: Forty-two consecutive cases of uncontrolled glaucoma undergoing AGV implantation: 19 eyes receiving intraoperative subtenon TA and 23 eyes that did not receive TA. METHODS: A retrospective chart review was performed on consecutive pseudophakic adult patients with uncontrolled glaucoma undergoing AGV with and without intraoperative subtenon TA injection by a single surgeon. Clinical data were collected from 42 eyes and analyzed for the first 6 months after surgery. MAIN OUTCOME MEASURES: Primary outcomes included intraocular pressure (IOP) and number of glaucoma medications prior to and after AGV implantation. The hypertensive phase (HP) was defined as an IOP measurement of greater than 21 mmHg (with or without medications) during the 6-month postoperative period that was not a result of tube obstruction, retraction, or malfunction. Postoperative complications and visual acuity were analyzed as secondary outcome measures. RESULTS: Five out of 19 (26%) TA cases and 12 out of 23 (52%) non-TA cases developed the HP (P=0.027). Mean IOP (14.2±4.6 in TA cases versus [vs] 14.7±5.0 mmHg in non-TA cases; P=0.78), and number of glaucoma medications needed (1.8±1.3 in TA cases vs 1.6±1.1 in the comparison group; P=0.65) were similar between both groups at 6 months. Although rates of serious complications did not differ between the groups (13% in the TA group vs 16% in the non-TA group), early tube erosion (n=1) and bacterial endophthalmitis (n=1) were noted with TA but not in the non-TA group. CONCLUSIONS: Subtenon TA injection during AGV implantation may decrease the occurrence of the HP but does not alter the ultimate IOP outcome and may pose increased risk of serious complications within the first 6 months of surgery.
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Vajaranant TS, Ray RM, Pasquale LR, Mares JA, Ritch R, Gower EW, Haan MN, Jackson RD, Maki PM.
Racial Differences in the Effects of Hormone Therapy on Incident Open-Angle Glaucoma in a Randomized Trial. Am J Ophthalmol 2018;195:110-120.
AbstractPURPOSE: We conducted a secondary analysis of a randomized, placebo-controlled trial to test if hormone therapy (HT) altered the risk of open-angle glaucoma (OAG), and if the risk reduction varied by race. DESIGN: Secondary analysis of randomized controlled trial data. METHODS: We linked Medicare claims data to 25 535 women in the Women's Health Initiative. Women without a uterus were randomized to receive either oral conjugated equine estrogens (CEE 0.625 mg/day) or placebo, and women with a uterus received oral CEE and medroxyprogesterone acetate (CEE 0.625 mg/day + MPA 2.5 mg/day) or placebo. We used Cox proportional hazards models to calculate hazard ratios (HR) and 95% confidence interval. RESULTS: After exclusion of women with prevalent glaucoma or without claims for eye care provider visits, the final analysis included 8102 women (mean age = 68.5 ± 4.8 years). The OAG incidence was 7.6% (mean follow-up = 11.5 ± 5.2 years; mean HT duration = 4.4 ± 2.3 years). Increased age (P trend = .01) and African-American race (HR = 2.69, 95% CI = 2.13-3.42; white as a reference) were significant risk factors for incident OAG. We found no overall benefit of HT in reducing incident OAG (HR = 1.01, 95% CI = 0.79-1.29 in the CEE trial, and HR = 1.05, 95% CI = 0.85-1.29 in the CEE + MPA trial). However, race modified the relationship between CEE use and OAG risk (P interaction = .01), and risk was reduced in African-American women treated with CEE (HR = 0.49, 95% CI = 0.27-0.88), compared to placebo. Race did not modify the relation between CEE + MPA use and OAG risk (P interaction = .68). CONCLUSIONS: Analysis suggests that HT containing estrogen, but not a combination of estrogen and progesterone, reduces the risk of incident OAG among African-American women. Further investigation is needed.
Vajaranant TS, Grossardt BR, Maki PM, Pasquale LR, Sit AJ, Shuster LT, Rocca WA.
Risk of glaucoma after early bilateral oophorectomy. Menopause 2014;21(4):391-8.
AbstractOBJECTIVE: Because early estrogen deficiency may increase the susceptibility of the optic nerve to glaucoma, we studied the association of early bilateral oophorectomy with glaucoma. METHODS: In the Mayo Clinic Cohort Study of Oophorectomy and Aging, we studied the risk of glaucoma by comparing women who underwent bilateral oophorectomy from 1950 to 1987 with age-matched referent women who did not undergo unilateral or bilateral oophorectomy. Glaucoma diagnostic codes were identified in the records linkage system of the Rochester Epidemiology Project. Hazard ratios (HRs) were calculated during a median follow-up of 25.5 years. Analyses were stratified by age at the time of bilateral oophorectomy (in tertiles). RESULTS: Of 1,044 women who underwent bilateral oophorectomy before menopause, 147 developed glaucoma. Of 1,070 referent women, 133 developed glaucoma. Women who underwent bilateral oophorectomy showed no increased risk of glaucoma in the overall group (HR, 1.12; 95% CI, 0.89-1.42). However, women who underwent oophorectomy before the age of 43 years (n = 344; first tertile) had a significantly increased risk of glaucoma (HR, 1.60; 95% CI, 1.15-2.23). The results did not change after adjustment for hypertension, obesity, diabetes, or disorders of lipid metabolism at baseline. Approximately 11% of women who had undergone bilateral oophorectomy before the age of 43 years were treated with estrogen up to the age of 50 years; however, treatment did not reduce the association (HR, 1.59; 95% CI, 0.81-3.13). CONCLUSIONS: Bilateral oophorectomy before the age of 43 years may increase the risk of glaucoma, and estrogen treatment does not seem to attenuate the risk.
Verma SS, Cooke Bailey JN, Lucas A, Bradford Y, Linneman JG, Hauser MA, Pasquale LR, Peissig PL, Brilliant MH, McCarty CA, Haines JL, Wiggs JL, Vrabec TR, Tromp G, Ritchie MD, Ritchie MD, Ritchie MD.
Epistatic Gene-Based Interaction Analyses for Glaucoma in eMERGE and NEIGHBOR Consortium. PLoS Genet 2016;12(9):e1006186.
AbstractPrimary open angle glaucoma (POAG) is a complex disease and is one of the major leading causes of blindness worldwide. Genome-wide association studies have successfully identified several common variants associated with glaucoma; however, most of these variants only explain a small proportion of the genetic risk. Apart from the standard approach to identify main effects of variants across the genome, it is believed that gene-gene interactions can help elucidate part of the missing heritability by allowing for the test of interactions between genetic variants to mimic the complex nature of biology. To explain the etiology of glaucoma, we first performed a genome-wide association study (GWAS) on glaucoma case-control samples obtained from electronic medical records (EMR) to establish the utility of EMR data in detecting non-spurious and relevant associations; this analysis was aimed at confirming already known associations with glaucoma and validating the EMR derived glaucoma phenotype. Our findings from GWAS suggest consistent evidence of several known associations in POAG. We then performed an interaction analysis for variants found to be marginally associated with glaucoma (SNPs with main effect p-value <0.01) and observed interesting findings in the electronic MEdical Records and GEnomics Network (eMERGE) network dataset. Genes from the top epistatic interactions from eMERGE data (Likelihood Ratio Test i.e. LRT p-value <1e-05) were then tested for replication in the NEIGHBOR consortium dataset. To replicate our findings, we performed a gene-based SNP-SNP interaction analysis in NEIGHBOR and observed significant gene-gene interactions (p-value <0.001) among the top 17 gene-gene models identified in the discovery phase. Variants from gene-gene interaction analysis that we found to be associated with POAG explain 3.5% of additional genetic variance in eMERGE dataset above what is explained by the SNPs in genes that are replicated from previous GWAS studies (which was only 2.1% variance explained in eMERGE dataset); in the NEIGHBOR dataset, adding replicated SNPs from gene-gene interaction analysis explain 3.4% of total variance whereas GWAS SNPs alone explain only 2.8% of variance. Exploring gene-gene interactions may provide additional insights into many complex traits when explored in properly designed and powered association studies.
Verticchio Vercellin AC, Jassim F, Poon LY-C, Tsikata E, Braaf B, Shah S, Ben-David G, Shieh E, Lee R, Simavli H, Que CJ, Papadogeorgou G, Guo R, Vakoc BJ, Bouma BE, de Boer JF, Chen TC.
Diagnostic Capability of Three-Dimensional Macular Parameters for Glaucoma Using Optical Coherence Tomography Volume Scans. Invest Ophthalmol Vis Sci 2018;59(12):4998-5010.
AbstractPurpose: To compare the diagnostic capability of three-dimensional (3D) macular parameters against traditional two-dimensional (2D) retinal nerve fiber layer (RNFL) thickness using spectral domain optical coherence tomography. To determine if manual correction and interpolation of B-scans improve the ability of 3D macular parameters to diagnose glaucoma. Methods: A total of 101 open angle glaucoma patients (29 with early glaucoma) and 57 healthy subjects had peripapillary 2D RNFL thickness and 3D macular volume scans. Four parameters were calculated for six different-sized annuli: total macular thickness (M-thickness), total macular volume (M-volume), ganglion cell complex (GCC) thickness, and GCC volume of the innermost 3 macular layers (retinal nerve fiber layer + ganglion cell layer + inner plexiform layer). All macular parameters were calculated with and without correction and interpolation of frames with artifacts. The areas under the receiver operating characteristic curves (AUROC) were calculated for all the parameters. Results: The 3D macular parameter with the best diagnostic performance was GCC-volume-34, with an inner diameter of 3 mm and an outer of 4 mm. The AUROC for RNFL thickness and GCC-volume-34 were statistically similar for all regions (global: RNFL thickness 0.956, GCC-volume-34 0.939, P value = 0.3827), except for the temporal GCC-volume-34, which was significantly better than temporal RNFL thickness (P value = 0.0067). Correction of artifacts did not significantly change the AUROC of macular parameters (P values between 0.8452 and 1.0000). Conclusions: The diagnostic performance of best macular parameters (GCC-volume-34 and GCC-thickness-34) were similar to or better than 2D RNFL thickness. Manual correction of artifacts with data interpolation is unnecessary in the clinical setting.
Villarreal G, Chatterjee A, Oh SS, Oh D-J, Rhee DJ.
Pharmacological regulation of SPARC by lovastatin in human trabecular meshwork cells. Invest Ophthalmol Vis Sci 2014;55(3):1657-65.
AbstractPURPOSE: Statins have been shown to increase aqueous outflow facility. The matricellular protein SPARC (secreted protein acidic and rich in cysteine) is a critical mediator of aqueous outflow and intraocular pressure (IOP). Here, we examine the effects of lovastatin on SPARC expression in trabecular meshwork (TM) cells, exploring the molecular mechanisms involved. METHODS: Primary cultured human TM cells were incubated for 24, 48, and 72 hours with 10 μM lovastatin. In separate cultures, media was supplemented with either farnesyl pyrophosphate (FPP) or geranylgeranyl pyrophosphate (GGPP) for the duration of the 72-hour time point experiment. Trabecular meshwork cells were also pretreated for 24 hours with lovastatin followed by 24-hour stimulation with 3 ng/mL TGF-β2. Cell lysates and media were harvested and relative mRNA and protein level changes were determined. Krüppel-like factor 4 (KLF4) localization in normal human anterior segments was examined by immunofluorescence. Adenovirus expressing human KLF4 was used and relative changes in SPARC mRNA and protein levels were assessed. RESULTS: Incubating TM cells with lovastatin suppressed SPARC mRNA and protein levels. This effect was reversed upon media supplementation with GGPP but not FPP. Pretreating cells with lovastatin inhibited TGF-β2 induction of SPARC. The KLF4 transcription factor was expressed throughout the TM and the inner and outer walls of Schlemm's canal. Lovastatin treatment upregulated KLF4 mRNA and protein levels. Overexpression of KLF4 downregulated SPARC expression. CONCLUSIONS: Collectively, our data identify lovastatin as an important pharmacological suppressor of SPARC expression in TM cells, and provide further insight into the molecular mechanisms mediating statin enhancement of aqueous outflow facility.
Vu KTH, Jager MJ, Chen DF.
The Immunology of Glaucoma. Asia Pac J Ophthalmol (Phila) 2012;1(5):303-11.
AbstractThe presence of specific antibodies and T cells that are specific in patients with glaucoma supports the idea that the immune system may play an important role in the initiation and/or sustainment of glaucomatous optic neuropathy, at least in some patients. At present, our understanding regarding immunological mechanisms associated with glaucomatous optic neuropathy is far from satisfactory. In this review, we examined evidence suggesting involvement of autoimmune responses in the pathogenesis of glaucoma. These include detection of autoantibodies and T cells and expression of cytokines and stress proteins in patients with glaucoma. Although immune responses are thought to be detrimental, some responses may exert a protective effect against neurodegenerative damage. Likely, the balance between positive and negative regulators determines the survival or demise of cells. It is vital that research continues to elucidate the roles of the immune system in glaucomatous neurodegeneration and the possibility of alternative modalities of treatment. These studies may also provide valuable molecular biomarkers for the diagnosis and identification of a specific cohort of patients with glaucoma, that is, those with normal-tension glaucoma.
Vu DM, Elze T, Miller JW, Lorch AC, VanderVeen DK, Oke I, Oke I.
Risk Factors for Glaucoma Diagnosis and Surgical Intervention following Pediatric Cataract Surgery in the IRIS® Registry. Ophthalmol Glaucoma 2024;7(2):131-138.
AbstractPURPOSE: To compare demographic and clinical factors associated with glaucoma following cataract surgery (GFCS) and glaucoma surgery rates between infants, toddlers, and older children using a large, ophthalmic registry. DESIGN: Retrospective cohort study. PARTICIPANTS: Patients in the IRIS® Registry (Intelligent Research in Sight) who underwent cataract surgery at ≤ 17 years old and between January 1, 2013 and December 31, 2020. METHODS: Glaucoma diagnosis and procedural codes were extracted from the electronic health records of practices participating in the IRIS Registry. Children with glaucoma diagnosis or surgery before cataract removal were excluded. The Kaplan-Meier estimator was used to determine the cumulative probability of GFCS diagnosis and glaucoma surgery after cataract surgery. Multivariable Cox regression was used to identify factors associated with GFCS and glaucoma surgery. MAIN OUTCOME MEASURES: Cumulative probability of glaucoma diagnosis and surgical intervention within 5 years after cataract surgery. RESULTS: The study included 6658 children (median age, 10.0 years; 46.2% female). The 5-year cumulative probability of GFCS was 7.1% (95% confidence interval [CI], 6.1%-8.1%) and glaucoma surgery was 2.6% (95% CI, 1.9%-3.2%). The 5-year cumulative probability of GFCS for children aged < 1 year was 22.3% (95% CI, 15.7%-28.4%). Risk factors for GFCS included aphakia (hazard ratio [HR], 2.63; 95% CI, 1.96-3.57), unilateral cataract (HR, 1.48; 95% CI, 1.12-1.96), and Black race (HR, 1.61; 95% CI, 1.12-2.32). The most common surgery was glaucoma drainage device insertion (32.6%), followed by angle surgery (23.3%), cyclophotocoagulation (15.1%), and trabeculectomy (5.8%). CONCLUSIONS: Glaucoma following cataract surgery diagnosis in children in the IRIS Registry was associated with young age, aphakia, unilateral cataract, and Black race. Glaucoma drainage device surgery was the preferred surgical treatment, consistent with the World Glaucoma Association 2013 consensus recommendations for GFCS management. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
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Waksmunski AR, Song YE, Kinzy TG, Laux RA, Sewell J, Fuzzell D, Fuzzell S, Miller S, Wiggs JL, Pasquale LR, Skarie JM, Haines JL, Cooke Bailey JN.
The GGLEAM Study: Understanding Glaucoma in the Ohio Amish. Int J Environ Res Public Health 2021;18(4)
AbstractGlaucoma leads to millions of cases of visual impairment and blindness around the world. Its susceptibility is shaped by both environmental and genetic risk factors. Although over 120 risk loci have been identified for glaucoma, a large portion of its heritability is still unexplained. Here we describe the foundation of the Genetics of GLaucoma Evaluation in the AMish (GGLEAM) study to investigate the genetic architecture of glaucoma in the Ohio Amish, which exhibits lower genetic and environmental heterogeneity compared to the general population. To date, we have enrolled 81 Amish individuals in our study from Holmes County, Ohio. As a part of our enrollment process, 62 GGLEAM study participants (42 glaucoma-affected and 20 unaffected individuals) received comprehensive eye examinations and glaucoma evaluations. Using the data from the Anabaptist Genealogy Database, we found that 80 of the GGLEAM study participants were related to one another through a large, multigenerational pedigree containing 1586 people. We plan to integrate the health and kinship data obtained for the GGLEAM study to interrogate glaucoma genetics and pathophysiology in this unique population.
Walton DS, Yeung HH.
Glaucoma following Infant Lensectomy: 2021 Update. Klin Monbl Augenheilkd 2021;238(10):1065-1068.
AbstractPURPOSE: 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.
Walton DS, Nagao K, Yeung HH, Kane SA.
Late-recognized primary congenital glaucoma. J Pediatr Ophthalmol Strabismus 2013;50(4):234-8.
AbstractPURPOSE: To describe a cohort of children with late-recognized primary congenital glaucoma (LRPCG), including age of presentation, age-related diagnostic signs, clinical abnormalities, and results of glaucoma surgery. METHODS: The medical records of 31 patients (49 eyes) with PCG recognized after 1 year of age were reviewed retrospectively. Patients were confirmed to have PCG based on their increased intraocular pressure (IOP), anterior segment abnormalities including findings on gonioscopy, and the absence of other causes of childhood glaucoma. The outcome of glaucoma surgery was reviewed and success measured by assessment of the relative control of IOP, occurrence of significant complications, and need for additional glaucoma surgery. RESULTS: Average age at diagnosis of glaucoma was 4.7 years (36% diagnosed at > 4 years of age). The most common initial diagnostic signs were corneal enlargement (46%, average age of 2.0 years), photophobia (20%, average age of 3.3 years), and suspected poor visual acuity (32%, average age of 9.9 years). Corneal cloudiness was not an initial sign for any patient. Haab's striae were present in 60% of the affected 49 eyes. Gonioscopy findings were abnormal in 82%, but the ciliary body band was seen in 81% and the scleral spur was visible in 47%. Sixty-one goniotomy procedures were performed for 39 eyes with overall success in 95% (37 eyes) and complete success in 65% (27 eyes). The final visual acuity was 20/200 or worse in 31% (15 eyes) and 20/40 or better in 60% (29 eyes). CONCLUSIONS: An awareness of and familiarity with the subtle diagnostic signs of LRPCG can enable its differentiation from primary juvenile glaucoma and contribute to earlier recognition and treatment. Glaucoma surgery is often required for LRPCG and goniosurgery is the recommended initial procedure.
Wang M, Shen LQ, Pasquale LR, Petrakos P, Formica S, Boland MV, Wellik SR, De Moraes CG, Myers JS, Saeedi O, Wang H, Baniasadi N, Li D, Tichelaar J, Bex PJ, Elze T.
An Artificial Intelligence Approach to Detect Visual Field Progression in Glaucoma Based on Spatial Pattern Analysis. Invest Ophthalmol Vis Sci 2019;60(1):365-375.
AbstractPurpose: To detect visual field (VF) progression by analyzing spatial pattern changes. Methods: We selected 12,217 eyes from 7360 patients with at least five reliable 24-2 VFs and 5 years of follow-up with an interval of at least 6 months. VFs were decomposed into 16 archetype patterns previously derived by artificial intelligence techniques. Linear regressions were applied to the 16 archetype weights of VF series over time. We defined progression as the decrease rate of the normal archetype or any increase rate of the 15 VF defect archetypes to be outside normal limits. The archetype method was compared with mean deviation (MD) slope, Advanced Glaucoma Intervention Study (AGIS) scoring, Collaborative Initial Glaucoma Treatment Study (CIGTS) scoring, and the permutation of pointwise linear regression (PoPLR), and was validated by a subset of VFs assessed by three glaucoma specialists. Results: In the method development cohort of 11,817 eyes, the archetype method agreed more with MD slope (kappa: 0.37) and PoPLR (0.33) than AGIS (0.12) and CIGTS (0.22). The most frequently progressed patterns included decreased normal pattern (63.7%), and increased nasal steps (16.4%), altitudinal loss (15.9%), superior-peripheral defect (12.1%), paracentral/central defects (10.5%), and near total loss (10.4%). In the clinical validation cohort of 397 eyes with 27.5% of confirmed progression, the agreement (kappa) and accuracy (mean of hit rate and correct rejection rate) of the archetype method (0.51 and 0.77) significantly (P < 0.001 for all) outperformed AGIS (0.06 and 0.52), CIGTS (0.24 and 0.59), MD slope (0.21 and 0.59), and PoPLR (0.26 and 0.60). Conclusions: The archetype method can inform clinicians of VF progression patterns.
Wang M, Tichelaar J, Pasquale LR, Shen LQ, Boland MV, Wellik SR, De Moraes CG, Myers JS, Ramulu P, Kwon MY, Saeedi OJ, Wang H, Baniasadi N, Li D, Bex PJ, Elze T.
Characterization of Central Visual Field Loss in End-stage Glaucoma by Unsupervised Artificial Intelligence. JAMA Ophthalmol 2020;
AbstractImportance: Although the central visual field (VF) in end-stage glaucoma may substantially vary among patients, structure-function studies and quality-of-life assessments are impeded by the lack of appropriate characterization of end-stage VF loss. Objective: To provide a quantitative characterization and classification of central VF loss in end-stage glaucoma. Design, Setting, and Participants: This retrospective cohort study collected data from 5 US glaucoma services from June 1, 1999, through October 1, 2014. A total of 2912 reliable 10-2 VFs of 1103 eyes from 1010 patients measured after end-stage 24-2 VFs with a mean deviation (MD) of -22 dB or less were included in the analysis. Data were analyzed from March 28, 2018, through May 23, 2019. Main Outcomes and Measures: Central VF patterns were determined by an artificial intelligence algorithm termed archetypal analysis. Longitudinal analyses were performed to investigate whether the development of central VF defect mostly affects specific vulnerability zones. Results: Among the 1103 patients with the most recent VFs, mean (SD) age was 70.4 (14.3) years; mean (SD) 10-2 MD, -21.5 (5.6) dB. Fourteen central VF patterns were determined, including the most common temporal sparing patterns (304 [27.5%]), followed by mostly nasal loss (280 [25.4%]), hemifield loss (169 [15.3%]), central island (120 [10.9%]), total loss (91 [8.3%]), nearly intact field (56 [5.1%]), inferonasal quadrant sparing (42 [3.8%]), and nearly total loss (41 [3.7%]). Location-specific median total deviation analyses partitioned the central VF into a more vulnerable superonasal zone and a less vulnerable inferotemporal zone. At 1-year and 2-year follow-up, new defects mostly occurred in the more vulnerable zone. Initial encroachments on an intact central VF at follow-up were more likely to be from nasal loss (11 [18.4%]; P < .001). One of the nasal loss patterns had a substantial chance at 2-year follow-up (8 [11.0%]; P = .004) to shift to total loss, whereas others did not. Conclusions and Relevance: In this study, central VF loss in end-stage glaucoma was found to exhibit characteristic patterns that might be associated with different subtypes. Initial central VF loss is likely to be nasal loss, and 1 specific type of nasal loss is likely to develop into total loss.
Wang SV, Li N, Rice DS, Grosskreutz CL, Dryja TP, Prasanna G, Lii J, Gagne JJ.
Using Healthcare Databases to Refine Understanding of Exploratory Associations Between Drugs and Progression of Open-Angle Glaucoma. Clin Pharmacol Ther 2019;106(4):874-883.
AbstractWe sought to refine understanding about associations identified in prior studies between angiotensin-II receptor blockers, metformin, selective serotonin reuptake inhibitors, fibric-acid derivatives, or calcium channel blockers and progression to glaucoma filtration surgery for open-angle glaucoma (OAG). We used new-initiator, active-comparator cohort designs to investigate these drugs in two data sources. We adjusted for confounders using stabilized inverse-probability-of-treatment weights and evaluated results using "intention-to-treat" and "as-treated" follow-up approaches. In both data sources, Kaplan-Meier curves showed trends for more rapid progression to glaucoma filtration surgery in patients taking calcium channel blockers compared with thiazides with as-treated (MarketScan P = 0.15; Medicare P = 0.03) and intention-to-treat follow-up (MarketScan P < 0.01; Medicare P = 0.10). There was suggestion of delayed progression for selective serotonin reuptake inhibitor compared with tricyclic antidepressants in Medicare, which was not observed in MarketScan. Our study provided support for a relationship between calcium channel blockers and OAG progression but not for other investigated drugs.
Wang R, Seifert P, Jakobs TC.
Astrocytes in the Optic Nerve Head of Glaucomatous Mice Display a Characteristic Reactive Phenotype. Invest Ophthalmol Vis Sci 2017;58(2):924-932.
AbstractPurpose: Optic nerve head astrocytes, a subtype of white-matter astrocytes, become reactive early in the course of glaucoma. It was shown recently that in the DBA/2J mouse model of inherited glaucoma optic nerve astrocytes extend new longitudinal processes into the axon bundles before ganglion cell loss becomes apparent. The present study aims at testing whether this behavior of astrocytes is typical of early glaucomatous damage. Methods: Mice expressing green fluorescent protein in individual astrocytes were used to evaluate the early response of astrocytes in the glial lamina of the optic nerve head after increasing the IOP using the microbead occlusion method. Tissue sections from the glial lamina were imaged consecutively by confocal and electron microscopy. Results: Confocal and electron microscope images show that astrocytes close to the myelination transition zone in the hypertensive nerve heads extend new processes that follow the longitudinal axis of the optic nerve and invade axon bundles in the nerve head. Ultrastructurally, the longitudinal processes were largely devoid of subcellular organelles except for degenerating mitochondria. Conclusions: The longitudinal processes are a common feature of glaucomatous optic nerve astrocytes, whereas they are not observed after traumatic nerve injury. Thus, astrocytes appear to fine-tune their responses to the nature and/or timing of the injury to the neurons that they surround.
Wang R, Wiggs JL.
Common and Rare Genetic Risk Factors for Glaucoma. Cold Spring Harb Perspect Med 2014;
AbstractThe characterization of genes responsible for glaucoma is the critical first step toward the development of gene-based diagnostic and screening tests, which could identify individuals at risk for disease before irreversible optic nerve damage occurs. Early-onset forms of glaucoma affecting children and young adults are typically inherited as Mendelian autosomal dominant or recessive traits whereas glaucoma affecting older adults has complex inheritance. In this report, we present a comprehensive overview of the genes and genomic regions contributing to inherited glaucoma.
