Glaucoma

Lowry EA, Hou J, Hennein L, Chang RT, Lin S, Keenan J, Wang SK, Ianchulev S, Pasquale LR, Han Y. Comparison of Peristat Online Perimetry with the Humphrey Perimetry in a Clinic-Based Setting. Transl Vis Sci Technol 2016;5(4):4.Abstract

PURPOSE: We determined the receiver operating characteristic (ROC) curves for Peristat online perimetry at detecting varying degrees of glaucoma and the correlation between Peristat online perimetry and Humphrey visual field. METHODS: A prospective, comparative study of Peristat online perimetry (an achromatic static computer threshold testing program) and Humphrey visual field (HVF) 24-2 SITA standard testing was performed by 63 glaucoma patients and 30 healthy controls in random order. The number of total adjacent abnormal test points were identified for each test, and compared with Spearman correlation. Receive operating characteristic curves were generated for Peristat online perimetry detection of mild and moderate-severe glaucoma patients using contrast sensitivity thresholds of -16.7, -21.7, and -26.7 dB. RESULTS: The area under the ROC curve for glaucoma detection ranged from 0.77 to 0.81 for mild disease (mean deviation [MD], >-6 dB on HVF) and 0.85 to 0.87 for moderate to severe disease (MD, <-6 dB on HVF) depending on contrast threshold. Peristat online perimetry and Humphrey visual field abnormal points were highly correlated with Spearman rank correlations ranging from 0.55 to 0.77 (all P < 0.001). CONCLUSIONS: Peristat online perimetry exhibits a reasonable ROC curve without specialized equipment and exhibited significant correlation with the conventional 24° Humphrey visual field test. TRANSLATIONAL RELEVANCE: Low cost widely available internet-based visual fields may complement traditional office-based visual field testing.

Shieh E, Lee R, Que C, Srinivasan V, Guo R, DeLuna R, Pandit S, Simavli H, Seevaratnam R, Tsikata E, de Boer J, Chen TC. Diagnostic Performance of a Novel Three-Dimensional Neuroretinal Rim Parameter for Glaucoma Using High-Density Volume Scans. Am J Ophthalmol 2016;169:168-78.Abstract

PURPOSE: To evaluate the diagnostic performance of a 3-dimensional (3D) neuroretinal rim parameter, the minimum distance band (MDB), using optical coherence tomography (OCT) high-density volume scans for open-angle glaucoma. DESIGN: Reliability analysis. METHODS: setting: Institutional. STUDY POPULATION: Total of 163 patients (105 glaucoma and 58 healthy subjects). OBSERVATION PROCEDURES: One eye of each patient was included. MDB and retinal nerve fiber layer (RNFL) thickness values were determined for 4 quadrants and 4 sectors using a spectral-domain OCT device. MAIN OUTCOME MEASURES: Area under the receiver operating characteristic curve (AUROC) values, sensitivities, specificities, and positive and negative predictive values. RESULTS: The best AUROC values of 3D MDB thickness for glaucoma and early glaucoma were for the overall globe (0.969, 0.952), followed by the inferior quadrant (0.966, 0.949) and inferior-temporal sector (0.966, 0.944), and then followed by the superior-temporal sector (0.964, 0.932) and superior quadrant (0.962, 0.924). All 3D MDB thickness AUROC values were higher than those of 2D RNFL thickness. Pairwise comparisons showed that the diagnostic performance of the 3D MDB parameter was significantly better than 2D RNFL thickness only for the nasal quadrant and inferior-nasal and superior-nasal sectors (P = .023-.049). Combining 3D MDB with 2D RNFL parameters provided significantly better diagnostic performance (AUROC 0.984) than most single MDB parameters and all single RNFL parameters. CONCLUSIONS: Compared with the 2D RNFL thickness parameter, the 3D MDB neuroretinal rim thickness parameter had uniformly equal or better diagnostic performance for glaucoma in all regions and was significantly better in the nasal region.

Chen X, Chen Y, Wiggs JL, Pasquale LR, Sun X, Fan BJ. Association of Matrix Metalloproteinase-9 (MMP9) Variants with Primary Angle Closure and Primary Angle Closure Glaucoma. PLoS One 2016;11(6):e0157093.Abstract

Shorter axial length observed in patients with primary angle closure glaucoma (PACG) might be due to altered matrix metalloproteinase-9 (MMP9) activity resulting in ECM remodeling during eye growth and development. This study aimed to evaluate common variants in MMP9 for association with PACG. Six tag SNPs of MMP9 were genotyped in a Chinese sample of 1,030 cases, including 572 PACG and 458 primary angle closure (PAC), and 499 controls. None of 6 SNPs were significantly associated with overall PAC/PACG (P > 0.07) or with PAC/PACG subgroups (Pc > 0.18). Meta-analysis of two non-Chinese studies revealed significant association between rs17576 and PACG (ORs = 0.56, P < 0.0001); however, meta-analysis of our dataset with 4 Chinese datasets did not replicate this association (ORs = 1.23, P = 0.29). Prior significant association for rs3918249 in one Caucasian study (OR = 0.63, P = 0.006) was not replicated in meta-analysis of 3 Chinese studies including this study (ORs = 0.91, P = 0.13). Significant heterogeneity between non-Chinese and Chinese datasets precluded overall meta-analysis for rs17576 and rs3918249 (Q = 0.001 and 0.04 respectively). rs17577 was nominally associated with PACG in one Caucasian study (OR = 1.71, P = 0.02), but not in 3 Chinese studies including our study (ORs = 1.20, P = 0.07). Overall meta-analysis revealed nominal association for rs17577 and PAC/PACG (ORs = 1.26, Pc = 0.05). Meta-analysis did not show significant association between the other SNPs and PAC/PACG (P > 0.47). The largest association study to date did not find significant association between MMP9 and PAC/PACG in Chinese; meta-analysis with other Chinese datasets did not produce significant association. In most instances combination with non-Chinese datasets was not possible except for one variant showing nominally significant association. More work is needed to define the role of MMP9 variants in PACG.

Yang L, Li S, Miao L, Huang H, Liang F, Teng X, Xu L, Wang Q, Xiao W, Ridder WH, Ferguson TA, Chen DF, Kaufman RJ, Hu Y. Rescue of Glaucomatous Neurodegeneration by Differentially Modulating Neuronal Endoplasmic Reticulum Stress Molecules. J Neurosci 2016;36(21):5891-903.Abstract

UNLABELLED: Axon injury is an early event in neurodegenerative diseases that often leads to retrograde neuronal cell death and progressive permanent loss of vital neuronal functions. The connection of these two obviously sequential degenerative events, however, is elusive. Deciphering the upstream signals that trigger the neurodegeneration cascades in both neuronal soma and axon would be a key step toward developing the effective neuroprotectants that are greatly needed in the clinic. We showed previously that optic nerve injury-induced neuronal endoplasmic reticulum (ER) stress plays an important role in retinal ganglion cell (RGC) death. Using two in vivo mouse models of optic neuropathies (traumatic optic nerve injury and glaucoma) and adeno-associated virus-mediated RGC-specific gene targeting, we now show that differential manipulation of unfolded protein response pathways in opposite directions-inhibition of eukaryotic translation initiation factor 2α-C/EBP homologous protein and activation of X-box binding protein 1-promotes both RGC axons and somata survival and preserves visual function. Our results indicate that axon injury-induced neuronal ER stress plays an important role in both axon degeneration and neuron soma death. Neuronal ER stress is therefore a promising therapeutic target for glaucoma and potentially other types of neurodegeneration. SIGNIFICANCE STATEMENT: Neuron soma and axon degeneration have distinct molecular mechanisms although they are clearly connected after axon injury. We previously demonstrated that axon injury induces neuronal endoplasmic reticulum (ER) stress and that manipulation of ER stress molecules synergistically promotes neuron cell body survival. Here we investigated the possibility that ER stress also plays a role in axon degeneration and whether ER stress modulation preserves neuronal function in neurodegenerative diseases. Our results suggest that neuronal ER stress is a general mechanism of degeneration for both neuronal cell body and axon, and that therapeutic targeting of ER stress produces significant functional recovery.

Dordea AC, Bray M-A, Allen K, Logan DJ, Fei F, Malhotra R, Gregory MS, Carpenter AE, Buys ES. An open-source computational tool to automatically quantify immunolabeled retinal ganglion cells. Exp Eye Res 2016;147:50-6.Abstract

A fully automated and robust method was developed to quantify β-III-tubulin-stained retinal ganglion cells, combining computational recognition of individual cells by CellProfiler and a machine-learning tool to teach phenotypic classification of the retinal ganglion cells by CellProfiler Analyst. In animal models of glaucoma, quantification of immunolabeled retinal ganglion cells is currently performed manually and remains time-consuming. Using this automated method, quantifications of retinal ganglion cell images were accelerated tenfold: 1800 images were counted in 3 h using our automated method, while manual counting of the same images took 72 h. This new method was validated in an established murine model of microbead-induced optic neuropathy. The use of the publicly available software and the method's user-friendly design allows this technique to be easily implemented in any laboratory.

Hoguet A, Grajewski A, Hodapp E, Chang TCP. A retrospective survey of childhood glaucoma prevalence according to Childhood Glaucoma Research Network classification. Indian J Ophthalmol 2016;64(2):118-23.Abstract

PURPOSE: To evaluate the Childhood Glaucoma Research Network (CGRN) classification system and describe the prevalence of each subtype according to this classification. MATERIALS AND METHODS: Retrospectively, the medical records of 205 consecutive childhood glaucoma and glaucoma suspect patients at an urban tertiary care center were reviewed. The initial diagnosis and new diagnosis according to CGRN classification were recorded. RESULTS: All patients fit one of the seven categories of the new classification. Seventy-one percent of diagnoses were changed upon reclassification. Twenty-three percent of patients had primary glaucoma (juvenile open-angle glaucoma and primary congenital glaucoma [PCG]); 36% had secondary glaucoma (glaucoma associated with nonacquired ocular anomalies; glaucoma associated with nonacquired systemic disease or syndrome; glaucoma associated with acquired condition; and glaucoma following cataract surgery); and 39% were glaucoma suspect. Of the patients diagnosed with glaucoma, PCG was the most common diagnosis, seen in 32% of patients. CONCLUSION: The CGRN classification provides a useful method of classifying childhood glaucoma.

Haleem MS, Han L, van Hemert J, Fleming A, Pasquale LR, Silva PS, Song BJ, Aiello LP. Regional Image Features Model for Automatic Classification between Normal and Glaucoma in Fundus and Scanning Laser Ophthalmoscopy (SLO) Images. J Med Syst 2016;40(6):132.Abstract

Glaucoma is one of the leading causes of blindness worldwide. There is no cure for glaucoma but detection at its earliest stage and subsequent treatment can aid patients to prevent blindness. Currently, optic disc and retinal imaging facilitates glaucoma detection but this method requires manual post-imaging modifications that are time-consuming and subjective to image assessment by human observers. Therefore, it is necessary to automate this process. In this work, we have first proposed a novel computer aided approach for automatic glaucoma detection based on Regional Image Features Model (RIFM) which can automatically perform classification between normal and glaucoma images on the basis of regional information. Different from all the existing methods, our approach can extract both geometric (e.g. morphometric properties) and non-geometric based properties (e.g. pixel appearance/intensity values, texture) from images and significantly increase the classification performance. Our proposed approach consists of three new major contributions including automatic localisation of optic disc, automatic segmentation of disc, and classification between normal and glaucoma based on geometric and non-geometric properties of different regions of an image. We have compared our method with existing approaches and tested it on both fundus and Scanning laser ophthalmoscopy (SLO) images. The experimental results show that our proposed approach outperforms the state-of-the-art approaches using either geometric or non-geometric properties. The overall glaucoma classification accuracy for fundus images is 94.4 % and accuracy of detection of suspicion of glaucoma in SLO images is 93.9 %.

Saboo US, Amparo F, Shikari H, Dana R. Prevalence of ocular hypertension and glaucoma in patients with chronic ocular graft-versus-host disease. Graefes Arch Clin Exp Ophthalmol 2016;254(5):923-8.Abstract

PURPOSE: To evaluate the prevalence of ocular hypertension (OHT) and glaucoma in patients with chronic ocular graft-versus-host disease (GVHD). METHODS: We performed a retrospective chart review of 218 patients diagnosed with chronic ocular GVHD. Ocular hypertension was defined as intraocular pressure (IOP) ≥ 24 mmHg in either eye without any glaucomatous optic disc changes. Glaucoma suspect was defined as optic disc changes with a cup-to-disc ratio ≥ 0.7 in either eye or asymmetry of ≥ 0.3 between the two eyes. Glaucoma was defined by glaucomatous optic disc changes plus glaucomatous visual field defects in two consecutive reliable visual field tests. The number of cases of ocular hypertension, glaucoma, and glaucoma suspects was evaluated. RESULTS: Thirty-three patients (15 %) were diagnosed with OHT, eight patients (3.6 %) with suspicion of glaucoma, and one patient (0.4 %) with glaucoma. OHT occurred within 6 months of developing ocular GVHD in 60 % of the cases and within the first year in 76 %. High IOP normalized in 67 % of patients when the dosage of topical or systemic corticosteroids was lowered, and 27 % of patients required anti-glaucoma therapy. CONCLUSIONS: Ocular hypertension is a common complication in patients with ocular GVHD, with a prevalence of 15 %. The rise in intraocular pressure is often transient and resolves with management of corticosteroids in most cases. However, clinicians should be aware that nearly one-third of the patients with OHT might require anti-glaucoma treatment. The prevalences of glaucoma and suspicion of glaucoma were not higher than in the general population.

Gao S, Jakobs TC. Mice Homozygous for a Deletion in the Glaucoma Susceptibility Locus INK4 Show Increased Vulnerability of Retinal Ganglion Cells to Elevated Intraocular Pressure. Am J Pathol 2016;186(4):985-1005.Abstract

A genomic region located on chromosome 9p21 is associated with primary open-angle glaucoma and normal tension glaucoma in genome-wide association studies. The genomic region contains the gene for a long noncoding RNA called CDKN2B-AS, two genes that code for cyclin-dependent kinase inhibitors 2A and 2B (CDKN2A/p16(INK4A) and CDKN2B/p15(INK4B)) and an additional protein (p14(ARF)). We used a transgenic mouse model in which 70 kb of murine chromosome 4, syntenic to human chromosome 9p21, are deleted to study whether this deletion leads to a discernible phenotype in ocular structures implicated in glaucoma. Homozygous mice of this strain were previously reported to show persistent hyperplastic primary vitreous. Fundus photography and optical coherence tomography confirmed that finding but showed no abnormalities for heterozygous mice. Optokinetic response, eletroretinogram, and histology indicated that the heterozygous and mutant retinas were normal functionally and morphologically, whereas glial cells were activated in the retina and optic nerve head of mutant eyes. In quantitative PCR, CDKN2B expression was reduced by approximately 50% in the heterozygous mice and by 90% in the homozygous mice, which suggested that the CDKN2B knock down had no deleterious consequences for the retina under normal conditions. However, compared with wild-type and heterozygous animals, the homozygous mice are more vulnerable to retinal ganglion cell loss in response to elevated intraocular pressure.

Field MG, Alasil T, Baniasadi N, Que C, Simavli H, Sobeih D, Sola-Del Valle D, Best MJ, Chen TC. Facilitating Glaucoma Diagnosis With Intereye Retinal Nerve Fiber Layer Asymmetry Using Spectral-Domain Optical Coherence Tomography. J Glaucoma 2016;25(2):167-76.Abstract

PURPOSE: To test whether increased intereye retinal nerve fiber layer (RNFL) asymmetry may be indicative of glaucoma. To determine the best statistical methods and intereye RNFL cutoffs for differentiating between normal and glaucoma subjects to better alert clinicians to early glaucomatous damage. METHODS: Sixty-six primary open-angle glaucoma (OAG) and 40 age-matched normal subjects had both eyes imaged at the Massachusetts Eye and Ear Infirmary with a commercially available spectral-domain optical coherence tomography (OCT) machine. Statistical methodologies were used to find cutoffs that achieved the best sensitivities and specificities for differentiating OAG from normal subjects. RESULTS: Intereye RNFL asymmetry for global average, all quadrants, and all sectors was significantly greater in OAG than normal subjects. Intereye RNFL asymmetry for global average showed the greatest statistical difference (P<0.001) between OAG (23.64±14.90 μm) and normal eyes (3.58±3.96 μm), with 6.60 times greater asymmetry in OAG eyes. The inferior quadrant showed the second greatest difference, with 3.91 times greater asymmetry in OAG eyes. Using a statistically determined cutoff of 6.0 μm as abnormal, intereye RNFL asymmetry for global average achieved a sensitivity of 74.24% and specificity of 90% in differentiating between normal and OAG subjects, achieving a better combination of sensitivity and specificity than intereye RNFL asymmetry of any quadrant or sector. CONCLUSIONS: Intereye RNFL asymmetry may be a useful clinical OCT measurement to provide quantitative assessment of early glaucomatous damage. Newly developed algorithms for intereye RNFL asymmetry may improve the ability to detect glaucoma.

Coleman AL, Lum FC, Gliklich RE, Velentgas P, Su Z, Su Z. Quality of life and visual acuity outcomes in the Registry in Glaucoma Outcomes Research study. J Comp Eff Res 2016;5(1):99-111.Abstract

AIMS: The RiGOR study evaluated the association of treatment and patient-reported outcomes for open-angle glaucoma patients. METHODS: The Glaucoma Symptom Scale (National Eye Institute-Visual Function Questionnaire (NEI-VFQ) and visual acuity (VA) were collected as quality of life measures. RESULTS: The proportion of patients with improvement of at least two lines of vision was highest in the incisional surgery group (14.2% compared with 9.9% for laser surgery and 10.9% for additional medication). CONCLUSION: No clinically relevant differences were seen in benefit for the laser surgery or incisional surgery groups compared with additional medications for the Glaucoma Symptom Scale or NEI-VFQ measures or subscales. Differences in quality of life by race need to be explored in further studies.

Coleman AL, Lum FC, Velentgas P, Su Z, Gliklich RE, Gliklich RE. Practice patterns and treatment changes for open-angle glaucoma: the RiGOR study. J Comp Eff Res 2016;5(1):79-85.Abstract

AIMS: The RiGOR study provides a current picture of the types of glaucoma treatment over 12 months. METHODS: Patients were identified and enrolled at the time of decision to proceed with laser surgery procedure or other procedure such as incisional surgery or drainage device implantation, or initiation of a new or additional course of therapy with medication for glaucoma treatment. RESULTS: The most frequent type of treatments were prostaglandin analogues (60%) among patients with additional medication, selective laser trabeculoplasty (87%) among patients with laser surgery and trabeculectomy (57%) among patients with incisional surgery. CONCLUSION: For 36% of patients, a treatment cascade involves two or more therapies over a year. This demonstrates the complex nature of open-angle glaucoma treatment.

Bailey JCN, Loomis SJ, Kang JH, Allingham RR, Gharahkhani P, Khor CC, Burdon KP, Aschard H, Chasman DI, Igo RP, Hysi PG, Glastonbury CA, Ashley-Koch A, Brilliant M, Brown AA, Budenz DL, Buil A, Cheng C-Y, Choi H, Christen WG, Curhan G, De Vivo I, Fingert JH, Foster PJ, Fuchs C, Gaasterland D, Gaasterland T, Hewitt AW, Hu F, Hunter DJ, Khawaja AP, Lee RK, Li Z, Lichter PR, Mackey DA, McGuffin P, Mitchell P, Moroi SE, Perera SA, Pepper KW, Qi Q, Realini T, Richards JE, Ridker PM, Rimm E, Ritch R, Ritchie M, Schuman JS, Scott WK, Singh K, Sit AJ, Song YE, Tamimi RM, Topouzis F, Viswanathan AC, Verma SS, Vollrath D, Wang JJ, Weisschuh N, Wissinger B, Wollstein G, Wong TY, Yaspan BL, Zack DJ, Zhang K, Study E-NE, Study E-NE, Weinreb RN, Pericak-Vance MA, Small K, Hammond CJ, Aung T, Liu Y, Vithana EN, Macgregor S, Craig JE, Kraft P, Howell G, Hauser MA, Pasquale LR, Haines JL, Wiggs JL. Genome-wide association analysis identifies TXNRD2, ATXN2 and FOXC1 as susceptibility loci for primary open-angle glaucoma. Nat Genet 2016;48(2):189-94.Abstract

Primary open-angle glaucoma (POAG) is a leading cause of blindness worldwide. To identify new susceptibility loci, we performed meta-analysis on genome-wide association study (GWAS) results from eight independent studies from the United States (3,853 cases and 33,480 controls) and investigated the most significantly associated SNPs in two Australian studies (1,252 cases and 2,592 controls), three European studies (875 cases and 4,107 controls) and a Singaporean Chinese study (1,037 cases and 2,543 controls). A meta-analysis of the top SNPs identified three new associated loci: rs35934224[T] in TXNRD2 (odds ratio (OR) = 0.78, P = 4.05 × 10(-11)) encoding a mitochondrial protein required for redox homeostasis; rs7137828[T] in ATXN2 (OR = 1.17, P = 8.73 × 10(-10)); and rs2745572[A] upstream of FOXC1 (OR = 1.17, P = 1.76 × 10(-10)). Using RT-PCR and immunohistochemistry, we show TXNRD2 and ATXN2 expression in retinal ganglion cells and the optic nerve head. These results identify new pathways underlying POAG susceptibility and suggest new targets for preventative therapies.

Coleman AL, Lum FC, Velentgas P, Su Z, Gliklich RE, Gliklich RE. Impact of treatment strategies for open angle glaucoma on intraocular pressure: the RiGOR study. J Comp Eff Res 2016;5(1):87-98.Abstract

AIMS: The RiGOR study's primary outcome measure was a 15% reduction in intraocular pressure (IOP) for patients with open-angle glaucoma at 1 year. METHODS: Patients received treatment according to the ophthalmologist's usual practice. RESULTS: A higher proportion of patients in the incisional and other surgery group achieved a 15% reduction in IOP than in the laser surgery or additional medication groups (82, 57, and 57% respectively). In multivariate regression analyses, incisional surgery patients were 2.7-times as likely as patients treated with additional medication to achieve a 15% reduction in IOP (odds ratio: 2.67; 95% CI: 2.01-3.57). CONCLUSION: Incisional and other surgical procedures are effective treatments. There were no differences in treatment response by race or ethnicity.

Coleman AL, Lum FC, Velentgas P, Campion D, Su Z, Gliklich RE, Gliklich RE. RiGOR: a prospective observational study comparing the effectiveness of treatment strategies for open-angle glaucoma. J Comp Eff Res 2016;5(1):65-78.Abstract

AIMS: The RigOR study was designed to assess comparative effectiveness of medications, laser trabeculoplasty and incisional surgery in patients with open-angle glaucoma (OAG) in the community initiating a new or additional course of therapy as judged necessary by their ophthalmologist. This paper focuses specifically on demographic and clinical characteristics of OAG patients at enrollment. PATIENTS & METHODS: A total of 2597 with OAG already on medical therapy were enrolled from 45 community and academic practices throughout the USA. RESULTS: Overall, 784 (30%) patients were treated with laser surgery, 436 with other surgical procedures (17%), and 1377 with additional medication (53%). Patients had mild (35%) or moderate (31%) glaucoma, with 28% with severe glaucoma. CONCLUSION: The RiGOR study enrolled a diverse population and will provide valuable information regarding visual function and treatment patterns among different racial/ethnic populations. African-American and Hispanic patients entered the study with poorer visual acuity and more severe glaucoma.

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