Hypotony Failure Criteria in Glaucoma Surgical Studies and Their Influence on Surgery Success.

PURPOSE: Review hypotony failure criteria used in glaucoma surgical outcome studies and evaluate their impact on success rates. DESIGN: Systematic literature review and application of hypotony failure criteria to 2 retrospective cohorts. PARTICIPANTS: A total of 934 eyes and 1765 eyes undergoing trabeculectomy and deep sclerectomy (DS) with a median follow-up of 41.4 and 45.4 months, respectively. METHODS: Literature-based hypotony failure criteria were applied to patient cohorts. Intraocular pressure (IOP)-related success was defined as follows: (A) IOP ≤ 21 mmHg with ≥ 20% IOP reduction; (B) IOP ≤ 18 mmHg with ≥ 20% reduction; (C) IOP ≤ 15 mmHg with ≥ 25% reduction; and (D) IOP ≤ 12 mmHg with ≥ 30% reduction. Failure was defined as IOP exceeding these criteria in 2 consecutive visits > 3 months after surgery, loss of light perception, additional IOP-lowering surgery, or hypotony. Cox regression estimated failure risk for different hypotony criteria, using no hypotony as a reference. Analyses were conducted for each criterion and hypotony type (i.e., numerical [IOP threshold], clinical [clinical manifestations], and mixed [combination of numerical or clinical criteria]). MAIN OUTCOME MEASURES: Hazard ratio (HR) for failure risk. RESULTS: Of 2503 studies found, 278 were eligible, with 99 studies (35.6%) lacking hypotony failure criteria. Numerical hypotony was predominant (157 studies [56.5%]). Few studies used clinical hypotony (3 isolated [1.1%]; 19 combined with low IOP [6.8%]). Forty-nine different criteria were found, with IOP < 6 mmHg, IOP < 6 mmHg on ≥ 2 consecutive visits after 3 months, and IOP < 5 mmHg being the most common (41 [14.7%], 38 [13.7%], and 13 [4.7%] studies, respectively). In both cohorts, numerical hypotony posed the highest risk of failure (HR, 1.51-1.21 for criteria A to D; P < 0.001), followed by mixed hypotony (HR, 1.41-1.20 for criteria A to D; P < 0.001), and clinical hypotony (HR, 1.12-1.04; P < 0.001). Failure risk varied greatly with various hypotony definitions, with the HR ranging from 1.02 to 10.79 for trabeculectomy and 1.00 to 8.36 for DS. CONCLUSIONS: Hypotony failure criteria are highly heterogenous in the glaucoma literature, with few studies focusing on clinical manifestations. Numerical hypotony yields higher failure rates than clinical hypotony and can underestimate glaucoma surgery success rates. Standardizing failure criteria with an emphasis on clinically relevant hypotony manifestations is needed. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Differential Responses of Retinal Neurons and Glia Revealed via Proteomic Analysis on Primary and Secondary Retinal Ganglion Cell Degeneration.

To explore the temporal profile of retinal proteomes specific to primary and secondary retinal ganglion cell (RGC) loss. Unilateral partial optic nerve transection (pONT) was performed on the temporal side of the rat optic nerve. Temporal and nasal retinal samples were collected at 1, 4 and 8 weeks after pONT (n = 4 each) for non-biased profiling with a high-resolution hybrid quadrupole time-of-flight mass spectrometry running on label-free SWATHTM acquisition (SCIEX). An information-dependent acquisition ion library was generated using ProteinPilot 5.0 and OneOmics cloud bioinformatics. Combined proteome analysis detected 2531 proteins with a false discovery rate of <1%. Compared to the nasal retina, 10, 25 and 61 significantly regulated proteins were found in the temporal retina at 1, 4, and 8 weeks, respectively (p < 0.05, FC ≥ 1.4 or ≤0.7). Eight proteins (ALDH1A1, TRY10, GFAP, HBB-B1, ALB, CDC42, SNCG, NEFL) were differentially expressed for at least two time points. The expressions of ALDH1A1 and SNCG at nerve fibers were decreased along with axonal loss. Increased ALDH1A1 localization in the inner nuclear layer suggested stress response. Increased GFAP expression demonstrated regional reactivity of astrocytes and Muller cells. Meta-analysis of gene ontology showed a pronounced difference in endopeptidase and peptidase inhibitor activity. Temporal proteomic profiling demonstrates established and novel protein targets associated with RGC damage.

Differential Retinal Protein Expression in Primary and Secondary Retinal Ganglion Cell Degeneration Identified by Integrated SWATH and Target-Based Proteomics.

To investigate the retinal proteins associated with primary and secondary retinal ganglion cell (RGC) degeneration and explore their molecular pathways, SWATH label-free and target-based mass spectrometry was employed to identify the proteomes in various retinal locations in response to localized optic nerve injury. Unilateral partial optic nerve transection (pONT) was performed on adult Wistar rats and their retinas were harvested 2 weeks later. To confirm the separation of primary and secondary RGC degeneration, immunohistochemistry of RNA binding protein with multiple splicing (RBPMS) and glial fibrillary acidic protein (GFAP) was performed on retinal whole-mounts. Retinal proteomes in the temporal and nasal quadrants were evaluated with high resolution hybrid quadrupole time-of-flight mass spectrometry (QTOF-MS), and SWATH-based acquisition, and their expression was compared to the corresponding retinal quadrant in contralateral control eyes and further validated by multiple reaction monitoring mass spectrometry (MRM-MS). A total of 3641 proteins (FDR < 1%) were identified using QTOF-MS. The raw data are available via ProteomeXchange with the identifier PXD026783. Bioinformatics data analysis showed that there were 37 upregulated and 25 downregulated proteins in the temporal quadrant, whereas 20 and five proteins were upregulated and downregulated, respectively, in the nasal quadrant, respectively (n = 4, p < 0.05; fold change ≥ 1.4-fold or ≤0.7). Six proteins were regulated in both the temporal and the nasal quadrants, including CLU, GFAP, GNG5, IRF2BPL, L1CAM, and CPLX1. Linear regression analysis indicated a strong association between the data obtained by means of SWATH-MS and MRM-MS (temporal, R2 = 0.97; nasal, R2 = 0.96). Gene ontology analysis revealed statistically significant changes in the biological processes and cellular components of primary RGC degeneration. The majority of the significant changes in structural, signaling, and cell death proteins were associated with the loss of RGCs in the area of primary RGC degeneration. The combined use of SWATH-MS and MRM-MS methods detects and quantifies regional changes of retinal protein expressions after localized injury. Future investigation with this integrated approach will significantly increase the understanding of diverse processes of progressive RGC degeneration from a proteomic prospective.

Longitudinal Macular Structure-Function Relationships in Glaucoma.

PURPOSE: To investigate the relationship between longitudinal changes in macular thickness measurements from OCT and changes in central visual field (VF) in patients with glaucoma with central or advanced damage at baseline. DESIGN: Longitudinal cohort study. PARTICIPANTS: A total of 116 eyes with ≥3 years of follow-up and ≥5 macular OCT images and central 10° VF tests were selected. METHODS: OCT superpixels and VF locations were matched correcting for retinal ganglion cell (RGC) displacement. Superpixel thickness and VF total deviation (TD) values, in both logarithmic and linear scales, were averaged within 3 eccentricities (3.4°, 5.6°, and 6.8°) and superior and inferior hemiretinas and hemifields. We estimated pointwise TD rates of change and rates of change at superpixels for full macular thickness (FMT), ganglion cell complex (GCC), ganglion cell inner plexiform layer (GCIPL), and ganglion cell layer (GCL). Correlation of structure-function (SF) rates of change was investigated with parametric tests. We compared the proportion of worsening and positive slopes for superpixels and VF test locations (negative vs. positive rates of change with P < 0.05) throughout the follow-up period. Permutation analyses were used to control specificity. MAIN OUTCOME MEASURES: Magnitude of correlation between structural and functional rates of change and proportion of worsening and positive slopes as a function of follow-up time. RESULTS: The median (interquartile range) follow-up and number of exams were 4.2 (3.7-4.6) years and 8 (7-9), respectively. The highest correlation of change rates was observed at 3.4° and 5.6° eccentricities (r = 0.24, 0.41, 0.40, and 0.40 for FMT, GCC, GCIPL, and GCL for 3.4° eccentricity and r = 0.28, 0.32, 0.31, and 0.32 for FMT, GCC, GCIPL, and GCL for 5.6° eccentricity, respectively). Although GCC measures demonstrated the highest overall longitudinal SF correlations, the differences were not statistically significant. Significant structural worsening was more frequently detected than functional deterioration at 3- and 5-year time points (P < 0.025). Permutation analyses also confirmed this finding. CONCLUSIONS: Correlations between central structural and functional rates of change were weak to fair in this cohort. Structural changes were detected more frequently than functional changes. Measurements of both structure and function are required for optimal detection of central progression.

Predictors of Long-Term Visual Field Fluctuation in Glaucoma Patients.

PURPOSE: To identify predictive factors for visual field (VF) fluctuation in glaucoma patients. DESIGN: Retrospective cohort study. PARTICIPANTS: A total of 1392 eyes (816 patients) with 6 or more VFs and 3 years or more of follow-up. METHODS: For each eye, the VF mean deviation (MD) and the pointwise sensitivities were regressed against time to model the series trend, and the root mean square error (RMSE) was estimated as a measure of variability. Potential predictors were selected with least absolute shrinkage and selection operator regression and included eye laterality, ethnicity, glaucoma type, intraocular pressure (IOP) fluctuation, baseline best corrected-visual acuity, intervening cataract or glaucoma surgery, length of follow-up, frequency of testing, baseline MD, rates of VF progression, and median false positive (FP) and false negative (FN) responses. MAIN OUTCOME MEASURES: Predictors of global and pointwise VF long-term fluctuation. RESULTS: In the global model, left eye (0.063 dB; P = 0.022), Asian descent (0.265 dB; P = 0.006), larger IOP fluctuation (0.051 dB; P < 0.001), intervening cataract surgery (0.090 dB; P = 0.023), longer follow-up (0.130 dB; P < 0.001), worse baseline MD (-0.145 dB; P < 0.001), faster VF decay rate (-0.090 dB; P < 0.001), and higher FP rate (0.145 dB; P < 0.001) and FN rate (0.220 dB; P < 0.001) were predictors of VF fluctuation. In the pointwise model, larger IOP fluctuation (0.039 dB; P = 0.022), longer follow-up (0.340 dB; P < 0.001), higher VF frequency (0.238 dB; P = 0.002), intervening glaucoma surgery (0.190 dB; P = 0.01), worse baseline MD (-0.535 dB; P < 0.001), faster VF decay rate (-0.340 dB; P < 0.001), and higher FP rate (0.255 dB; P < 0.001) and FN rate (0.395 dB; P < 0.001) were associated with increased fluctuation. The multivariable model explained 57% and 28% of the pointwise and global variances, respectively. CONCLUSIONS: This study identified novel predictors of VF fluctuation, and explains nearly 60% of the pointwise variance. In the presence of factors predictive of high fluctuation, increased frequency of testing and better analytics will help to identify VF progression more accurately.

RNA-binding protein Rbpms is represented in human retinas by isoforms A and C and its transcriptional regulation involves Sp1-binding site.

Rbpms (RNA-binding protein with multiple splicing) is a member of the RRM (RNA Recognition Motif) family of RNA-binding proteins, which is expressed as multiple alternatively spliced transcripts encoding different protein isoforms. We have shown earlier that Rbpms expression in the retina is restricted to retinal ganglion cells (RGCs), and have characterized this gene as a marker for RGCs. The aim of this study was to identify isoforms representing Rbpms in human retinas and to analyze its transcriptional regulation. We found that Rbpms is expressed as transcription variants 1 and 3 encoding isoforms A and C, respectively. These isoforms are encoded by the same first 6 exons but have different C-terminal ends encoded by exon 8 in variant 1 and exon 7 in variant 3. Computational analysis of the Rbpms 5' untranslated and flanking regions reveals the presence of three CpG islands and four predicted promoter regions (PPRs). The effect of PPR 1 (- 1672/- 1420) and PPR2 (- 330/- 79) on transcriptional activation was minimal, whereas PPR 3 (- 73/+ 177) and PPR4 (+ 274/+ 524) induced the expression by ~ 7 and ninefold compared to control, respectively. The maximum activity, a 30-fold increase above the control level, was obtained from the construct containing both PPRs 3 and 4. Site-directed mutagenesis of several cis-elements within PPR3 and PPR4 including five for Sp1, one for AP1, and two for NF-kB showed that mutation of the first three and especially the first GC box resulted in a threefold downregulation of gene expression. AP1, NF-kB, and two downstream Sp1 sites had no significant effect on expression level. The possible involvement of the GC box 1 at position - 54 in transcriptional regulation of Rbpms was corroborated by EMSA, which showed formation of a DNA-protein complex in the presence of the oligonucleotide corresponding to this Sp1-binding site.

NEW ULTRA-WIDE-FIELD ANGIOGRAPHIC GRADING SCHEME FOR RADIATION RETINOPATHY AFTER IODINE-125 BRACHYTHERAPY FOR UVEAL MELANOMA.

PURPOSE: Radiation retinopathy remains incompletely characterized and may cause severe vision loss. Ultra-wide-field fluorescein angiography provides a pan-fundus view of vascular alterations caused by radiation treatment and may predict visual and ocular outcomes. We have developed a grading scheme to describe pan-fundus severity and to predict the progression of radiation retinopathy in patients treated for uveal melanoma with iodine-125 brachytherapy. METHODS: A retrospective review of patients treated with standard iodine-125 brachytherapy for uveal melanoma at the Ophthalmic Oncology Center at the University of California, Los Angeles, who had undergone both baseline and postbrachytherapy ultra-wide-field fluorescein angiography. A grading scheme was devised based on observations of vascular leakage, retinal perfusion status, and retinal proliferation. The correlation of grade severity with patient characteristics, tumor features, visual acuity, optical coherence tomography findings, and neovascular glaucoma was measured with chi-square and one-way analysis of variance analyses. RESULTS: Sixty-seven patients were identified for review. Consistent wide-field angiographic patterns after brachytherapy were observed and graded as follows: Grade 0: normal; Grade 1: late foveal leakage; Grade 2: late peripheral leakage; Grade 3: presence of nonperfusion; and Grade 4: retinal neovascularization. Six eyes (8.9%) were Grade 0; 16 (23.8%) were Grade 1; 25 (37.3%) were Grade 2; 16 (23.4%) were Grade 3; and 4 (6.0%) were Grade 4. Higher grade radiation severity correlated significantly with duration of follow-up (P < 0.02); younger age (P = 0.035); worse visual acuity (P = 0.001); cystoid macular edema or atrophy on optical coherence tomography (P < 0.0001); and neovascular glaucoma (P = 0.003). CONCLUSION: Wide-field fluorescein angiography revealed distinct fundus-wide patterns of vascular damage, which were progressive in nature in eyes treated with iodine-125 brachytherapy for uveal melanoma and correlated with signs of progressive vascular injury. This grading scheme may have prognostic value to predict the progression of radiation retinopathy and to prognosticate visual outcomes in patients undergoing brachytherapy.

Risk Factors and Long-Term Outcomes in Patients with Low Intraocular Pressure after Trabeculectomy.

PURPOSE: To examine risk factors for low intraocular pressure (IOP) after trabeculectomy and to describe long-term outcomes in these eyes. DESIGN: Retrospective case-control study. PARTICIPANTS: Cases with low IOP included all patients with IOP ≤5 mmHg on 3 or more consecutive visits 3 months or later after trabeculectomy. Control patients without low IOP after trabeculectomy were randomly selected at a 1:2 case-to-control ratio. METHODS: A case-control study was performed of patients undergoing trabeculectomy at the Stein Eye Institute. Covariates included demographics, history of cataract surgery, refractive error, number of glaucoma medications, family history of glaucoma, diabetes, hypertension, visual acuity (VA), IOP, number of sutures in the scleral flap, laser suture lysis, surgeon, and laterality of surgery. Logistic regression modeling was used to examine associations between each covariate and low IOP. Postoperative outcomes that were examined included reoperation, vision loss, and surgical failure. The time between trabeculectomy and each outcome was compared between cases and controls with Cox proportional hazards regression modeling. MAIN OUTCOME MEASURES: Low IOP after trabeculectomy, reoperation, vision loss, and surgical failure. RESULTS: Of 3659 total trabeculectomies performed by 5 surgeons between 1990 and 2013, 64 eyes had low IOP (1.7%), which were compared with 130 control eyes. Fifteen of the 64 eyes with low IOP had hypotony maculopathy (23.4%). After accounting for differences in baseline IOP, laser suture lysis was negatively correlated with low IOP after trabeculectomy (odds ratio [OR], 0.33; 95% confidence interval [CI], 0.13-0.87); surgeon was correlated with high vs. low IOP after trabeculectomy (OR, 5.32; 95% CI, 1.53-18.52). There were no statistically significant associations between low IOP and time to reoperation (hazard ratio [HR], 0.73; 95% CI, 0.32-1.68), vision loss (HR, 1.77; 95% CI, 0.81-3.88) or surgical failure (HR, 1.14; 95% CI, 0.62-2.11). In patients with low IOP, there was a higher unadjusted incidence of bleb revision in patients who had maculopathy (7.6 vs. 1.9 revisions/100 person-years; for maculopathy versus no maculopathy P = 0.008). CONCLUSIONS: The absence of laser suture lysis and surgeon are factors potentially associated with low IOP after trabeculectomy. Numeric hypotony does not necessarily represent clinical failure after trabeculectomy.

Aqueous shunts for glaucoma.

BACKGROUND: Aqueous shunts are employed to control intraocular pressure (IOP) for people with primary or secondary glaucomas who fail or are not candidates for standard surgery. OBJECTIVES: To assess the effectiveness and safety of aqueous shunts for reducing IOP in glaucoma compared with standard surgery, another type of aqueous shunt, or modification to the aqueous shunt procedure. SEARCH METHODS: We searched CENTRAL (which contains the Cochrane Eyes and Vision Trials Register) (2016, Issue 8), MEDLINE Ovid (1946 to August 2016), Embase.com (1947 to August 2016), PubMed (1948 to August 2016), LILACS (Latin American and Caribbean Health Sciences Literature Database) (1982 to August 2016), ClinicalTrials.gov (www.clinicaltrials.gov); searched 15 August 2016, and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en); searched 15 August 2016. We did not use any date or language restrictions in the electronic search for trials. We last searched the electronic databases on 15 August 2016. We also searched the reference lists of identified trial reports and the Science Citation Index to find additional trials. SELECTION CRITERIA: We included randomized controlled trials that compared various types of aqueous shunts with standard surgery or to each other in eyes with glaucoma. DATA COLLECTION AND ANALYSIS: Two review authors independently screened search results for eligibility, assessed the risk of bias, and extracted data from included trials. We contacted trial investigators when data were unclear or not reported. We graded the certainty of the evidence using the GRADE approach. We followed standard methods as recommended by Cochrane. MAIN RESULTS: We included 27 trials with a total of 2099 participants with mixed diagnoses and comparisons of interventions. Seventeen studies reported adequate methods of randomization, and seven reported adequate allocation concealment. Data collection and follow-up times varied.Four trials compared an aqueous shunt (Ahmed or Baerveldt) with trabeculectomy, of which three reported one-year outcomes. At one-year, the difference in IOP between aqueous shunt groups and trabeculectomy groups was uncertain (mean difference (MD) 2.55 mmHg, 95% confidence interval (CI) -0.78 to 5.87; 380 participants; very low-certainty evidence). The difference in logMAR visual acuity was also uncertain (MD 0.12 units, 95% CI -0.07 to 0.31; 380 participants; very low-certainty evidence). In two trials, the difference in visual field score was uncertain (MD -0.25, 95% CI -1.91 to 1.40; 196 participants; very low-certainty evidence). The mean number of antiglaucoma medications was higher in the aqueous shunt group than the trabeculectomy group in one trial (MD 0.80, 95% CI 0.48 to 1.12; 184 participants; low-certainty evidence). The effect on needing additional glaucoma surgery was uncertain between groups in two trials (risk ratio (RR) 0.24, 95% CI 0.04 to 1.36; 329 participants; very low-certainty evidence). In one trial, fewer total adverse events were reported in the aqueous shunt group than the trabeculectomy group (RR 0.59, 95% CI 0.43 to 0.81; 212 participants; very low-certainty evidence). No trial reported quality-of-life outcomes at one-year follow-up.Two trials that compared the Ahmed implant with the Baerveldt implant for glaucoma found higher mean IOP in the Ahmed group at one-year follow-up (MD 2.60 mmHg, 95% CI 1.58 to 3.62; 464 participants; moderate-certainty evidence). The difference in logMAR visual acuity was uncertain between groups (MD -0.07 units, 95% CI -0.27 to 0.13; 501 participants; low-certainty evidence). The MD in number of antiglaucoma medications was within one between groups (MD 0.35, 95% CI 0.11 to 0.59; 464 participants; moderate-certainty evidence). More participants in the Ahmed group required additional glaucoma surgery than the Baerveldt group (RR 2.77, 95% CI 1.02 to 7.54; 514 participants; moderate-certainty evidence). The two trials reported specific adverse events but not overall number of adverse events. Neither trial reported visual field or quality-of-life outcomes at one-year follow-up.One trial compared the Ahmed implant with the Molteno implant for glaucoma over two-year follow-up. Mean IOP was higher in the Ahmed group than the Molteno group (MD 1.64 mmHg, 95% CI 0.85 to 2.43; 57 participants; low-certainty evidence). The differences in logMAR visual acuity (MD 0.08 units, 95% CI -0.24 to 0.40; 57 participants; very low-certainty evidence) and mean deviation in visual field (MD -0.18 dB, 95% CI -3.13 to 2.77; 57 participants; very low-certainty evidence) were uncertain between groups. The mean number of antiglaucoma medications was also uncertain between groups (MD -0.38, 95% CI -1.03 to 0.27; 57 participants; low-certainty evidence). The trial did not report the proportion needing additional glaucoma surgery, total adverse events, or quality-of-life outcomes.Two trials compared the double-plate Molteno implant with the Schocket shunt for glaucoma; one trial reported outcomes only at six-month follow-up, and the other did not specify the follow-up time. At six-months, mean IOP was lower in the Molteno group than the Schocket group (MD -2.50 mmHg, 95% CI -4.60 to -0.40; 115 participants; low-certainty evidence). Neither trial reported the proportion needing additional glaucoma surgery, total adverse events, or visual acuity, visual field, or quality-of-life outcomes.The remaining 18 trials evaluated modifications to aqueous shunts, including 14 trials of Ahmed implants (early aqueous suppression versus standard medication regimen, 2 trials; anti-vascular endothelial growth factor agent versus none, 4 trials; corticosteroids versus none, 2 trials; shunt augmentation versus none, 3 trials; partial tube ligation versus none, 1 trial; pars plana implantation versus conventional implantation, 1 trial; and model M4 versus model S2,1 trial); 1 trial of 500 mm2 Baerveldt versus 350 mm2 Baerveldt; and 3 trials of Molteno implants (single-plate with oral corticosteroids versus single-plate without oral corticosteroids, 1 trial; double-plate versus single-plate, 1 trial; and pressure-ridge versus double-plate with tube ligation, 1 trial). AUTHORS' CONCLUSIONS: Information was insufficient to conclude whether there are differences between aqueous shunts and trabeculectomy for glaucoma treatment. While the Baerveldt implant may lower IOP more than the Ahmed implant, the evidence was of moderate-certainty and it is unclear whether the difference in IOP reduction is clinically significant. Overall, methodology and data quality among existing randomized controlled trials of aqueous shunts was heterogeneous across studies, and there are no well-justified or widely accepted generalizations about the superiority of one surgical procedure or device over another.

Trabeculectomy Can Improve Long-Term Visual Function in Glaucoma.

PURPOSE: To measure the magnitude and direction of visual field (VF) rates of change in glaucoma patients after intraocular pressure (IOP) reduction with trabeculectomy. DESIGN: Retrospective, comparative, longitudinal cohort study. PARTICIPANTS: Patients with open-angle glaucoma. METHODS: Patients who underwent trabeculectomy (Trab) with mitomycin-C (74 eyes of 64 patients) with ≥4 reliable VF measurements before and after trabeculectomy and at least 4 years of follow-up before and after surgery were included. Decay or improvement exponential models were used to calculate pointwise rates of perimetric change before and after surgery. A separate comparison (Comp) group with unoperated glaucoma (71 eyes of 65 patients) with similar baseline damage, number of VF tests, and follow-up was used to address possible regression to the mean. Proportions of VF locations decaying or improving before and after surgery in the Trab group, and during the first and second halves of follow-up in the Comp group, were calculated. A multivariate analysis was used to explore variables associated with VF improvement. MAIN OUTCOME MEASURES: The rate of pointwise VF change before and after surgery in the Trab group and Comp group. RESULTS: Patients in the Trab group were followed for 5.1±2.1 years (mean ± standard deviation) before and 5.4±2.3 years after surgery, with 8.9±4.7 VF tests before and 9.0±4.4 VF tests after surgery. The mean rate of change for all VF locations slowed from -2.5±9.3%/year before surgery to -0.10±13.1%/year after surgery (P < 0.001). In the Trab group, 70% of locations decayed and 30% improved preoperatively; postoperatively, 56% decayed and 44% improved. The differences between the Trab and Comp groups were significant (P < 0.0001, chi-square test). The magnitude of IOP reduction correlated with the excess number of VF locations that exhibited long-term improvement postoperatively (P = 0.009). In the Trab group, 57% of eyes had ≥10 improving VF locations postoperatively. CONCLUSIONS: The results show that trabeculectomy slows the rate of perimetric decay and provide evidence of sustained, long-term improvement of visual function in glaucoma. These findings suggest the possibility of reversal of glaucomatous dysfunction of retinal ganglion cells and their central projections.

Prostaglandin Eyedrops Are Associated With Decreased Thicknesses of Eyelid Dermis and Orbicularis Oculi Muscle: Ultrasonographic Findings.

PURPOSE: To investigate the effect of prostaglandin analog eyedrops on the periorbital soft tissue using high-resolution ultrasonography. METHODS: In this cross-sectional study, the authors included patients with bilateral glaucoma on unilateral prostaglandin therapy for the past 12 or more contiguous months. High-resolution ultrasonography was performed bilaterally on the upper and lower eyelids of each subject to measure thicknesses of dermis, orbicularis oculi muscle, and skin to arcus marginalis distance. Comparisons were made between eyes on prostaglandin eyedrops versus those not on prostaglandin analogs. RESULTS: Twenty patients (16 females, 4 males) with a mean age of 67.2 ± 6.4 years were recruited. The mean duration of prostaglandin analog therapy was 5.4 ± 3.9 years. The authors found that eyes on prostaglandin analog therapy had statistically significantly reduced thicknesses of dermis, orbicularis oculi muscle, and skin to arcus marginalis distance in the upper and lower eyelids compared with the fellow eyes (p < 0.05 for all). In univariate regression analysis, the amount of changes in thicknesses of dermis, orbicularis oculi muscle, and skin to arcus marginalis distance among eyes on prostaglandin analog therapy and the fellow eyes was not statistically significantly associated with different variables including age, gender, years of being on prostaglandin analog therapy, type of prostaglandin analog, history of glaucoma and/or cataract surgeries, intraocular pressure, and number of glaucoma medications. CONCLUSIONS: The findings indicate that eyes on prostaglandin analog therapy have reduced thicknesses of dermis, orbicularis oculi muscle, and skin to arcus marginalis distance compared with the fellow eyes.

Programmed cell death-1 is expressed in large retinal ganglion cells and is upregulated after optic nerve crush.

Programmed cell death-1 (PD-1) is a key negative receptor inducibly expressed on T cells, B cells and dendritic cells. It was discovered on T cells undergoing classical programmed cell death. Studies showed that PD-1 ligation promotes retinal ganglion cell (RGC) death during retinal development. The purpose of this present study is to characterize PD-1 regulation in the retina after optic nerve crush (ONC). C57BL/6 mice were subjected to ONC and RGC loss was monitored by immunolabelling with RNA-binding protein with multiple splicing (Rbpms). Time course of PD-1 mRNA expression was determined by real-time PCR. PD-1 expression was detected with anti-PD-1 antibody on whole mount retinas. PD-1 staining intensity was quantitated. Colocalization of PD-1 and cleaved-caspase-3 after ONC was analyzed. Real-time PCR results demonstrated that PD-1 gene expression was significantly upregulated at day 1, 3, 7, 10 and 14 after ONC. Immunofluorescent staining revealed a dramatic increase of PD-1 expression following ONC. In both control and injured retinas, PD-1 tended to be up-expressed in a subtype of RGCs, whose somata size were significantly larger than others. Compared to control, PD-1 intensity in large RGCs was increased by 82% in the injured retina. None of the large RGCs expressed cleaved-caspase-3 at day 5 after ONC. Our work presents the first evidence of PD-1 induction in RGCs after ONC. This observation supports further investigation into the role of PD-1 expression during RGC death or survival following injury.

Common variants at 9p21 and 8q22 are associated with increased susceptibility to optic nerve degeneration in glaucoma.

Optic nerve degeneration caused by glaucoma is a leading cause of blindness worldwide. Patients affected by the normal-pressure form of glaucoma are more likely to harbor risk alleles for glaucoma-related optic nerve disease. We have performed a meta-analysis of two independent genome-wide association studies for primary open angle glaucoma (POAG) followed by a normal-pressure glaucoma (NPG, defined by intraocular pressure (IOP) less than 22 mmHg) subgroup analysis. The single-nucleotide polymorphisms that showed the most significant associations were tested for association with a second form of glaucoma, exfoliation-syndrome glaucoma. The overall meta-analysis of the GLAUGEN and NEIGHBOR dataset results (3,146 cases and 3,487 controls) identified significant associations between two loci and POAG: the CDKN2BAS region on 9p21 (rs2157719 [G], OR = 0.69 [95%CI 0.63-0.75], p = 1.86×10⁻¹8), and the SIX1/SIX6 region on chromosome 14q23 (rs10483727 [A], OR = 1.32 [95%CI 1.21-1.43], p = 3.87×10⁻¹¹). In sub-group analysis two loci were significantly associated with NPG: 9p21 containing the CDKN2BAS gene (rs2157719 [G], OR = 0.58 [95% CI 0.50-0.67], p = 1.17×10⁻¹²) and a probable regulatory region on 8q22 (rs284489 [G], OR = 0.62 [95% CI 0.53-0.72], p = 8.88×10⁻¹°). Both NPG loci were also nominally associated with a second type of glaucoma, exfoliation syndrome glaucoma (rs2157719 [G], OR = 0.59 [95% CI 0.41-0.87], p = 0.004 and rs284489 [G], OR = 0.76 [95% CI 0.54-1.06], p = 0.021), suggesting that these loci might contribute more generally to optic nerve degeneration in glaucoma. Because both loci influence transforming growth factor beta (TGF-beta) signaling, we performed a genomic pathway analysis that showed an association between the TGF-beta pathway and NPG (permuted p = 0.009). These results suggest that neuro-protective therapies targeting TGF-beta signaling could be effective for multiple forms of glaucoma.

Long-term Treatment Outcomes for Malignant Glaucoma.

PURPOSE: To report the contributing factors to the successful long-term treatment outcomes of a large series of patients with malignant glaucoma (MG). DESIGN: Retrospective, interventional, consecutive case series. PARTICIPANTS: This study used data collected from 1997 to 2022 from the Glaucoma Division of the Stein Eye Institute, University of California, Los Angeles (UCLA). All patients with MG who underwent treatment at UCLA were enrolled. METHODS: The following demographic and clinical data were collected and analyzed for their relevance to successful treatment: age, gender, ethnicity, glaucoma family history, visual acuity (VA), intraocular pressure (IOP), lens status, prior glaucoma diagnosis, prior ocular surgery, prior use of antiglaucoma agents, ultrasonic axial length, qualitative anterior chamber (AC) depth, and treatment methods and outcomes. MAIN OUTCOME MEASURES: Anatomical success was defined as restoration of normal AC depth, indicating relief of the MG episode. Complete success was defined as anatomical success and the reduction of IOP to < 21 mmHg without further surgery, with or without medications. RESULTS: A total of 74 eyes of 73 patients were identified with a diagnosis of MG. The median (interquartile range) age of the patients at the time of MG presentation was 70 years (19.5) and 49 (75.4%) patients were female. The most common prior diagnosis before MG was primary angle closure glaucoma (PACG) (34 eyes, 51.5%). The initiating event for 30 eyes (45.5%) was glaucoma surgery and for 21 eyes (31.8%) was cataract surgery. Most eyes were pseudophakic (57, 86.4%). Fifty-six eyes underwent medical treatment; MG resolved in 2 eyes with medical treatment alone. Nine eyes (7 eyes = treatment naïve; 2 eyes = failed medical treatment) underwent laser treatment and MG resolved in 5 eyes. Among the 55 eyes which had surgical treatment, 52 eyes failed medical treatment and 3 eyes were treatment naïve. The anatomical success rate with surgical treatment was 96.4% and the most commonly performed surgical procedure was combined pars plana antero-central vitrectomy, hyaloido-zonulectomy, and iridectomy. CONCLUSIONS: Female gender, PACG, and glaucoma surgery were predisposing factors for the development of MG. Medical treatment alone for MG was inadequate in the vast majority of cases. A surgical technique consisting of combined pars plana antero-central vitrectomy, hyaloido-zonulectomy and iridectomy consistently produced high long-term success. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Long-Term Rate of Optic Disc Rim Loss in Glaucoma Patients Measured From Optic Disc Photographs With a Deep Neural Network.

Purpose: This study uses deep neural network-generated rim-to-disc area ratio (RADAR) measurements and the disc damage likelihood scale (DDLS) to measure the rate of optic disc rim loss in a large cohort of glaucoma patients. Methods: A deep neural network was used to calculate RADAR and DDLS for each optic disc photograph (ODP). Patient demographics, diagnosis, intraocular pressure (IOP), and mean deviation (MD) from perimetry were analyzed as risk factors for faster progression of RADAR. Receiver operating characteristic (ROC) curves were used to compare RADAR and DDLS in their utility to distinguish glaucoma from glaucoma suspect (GS) and for detecting glaucoma progression. Results: A total of 13,679 ODPs with evidence of glaucomatous optic nerve damage from 4106 eyes of 2407 patients with glaucoma or GS were included. Of these eyes, 3264 (79.5%) had a diagnosis of glaucoma, and 842 (20.5%) eyes were GS. Mean ± SD baseline RADAR of GS and glaucoma were 0.67 ± 0.13 and 0.57 ± 0.18, respectively (P < 0.001). Older age, greater IOP fluctuation, baseline MD, right eye, and diagnosis of secondary open-angle glaucoma were associated with slope of RADAR. The mean baseline DDLS of GS and glaucoma were 3.78 and 4.39, respectively. Both RADAR and DDLS showed a less steep slope in advanced glaucoma. In glaucoma, the change of RADAR and DDLS correlated with the corresponding change in MD. RADAR and DDLS had a similar ability to discriminate glaucoma from GS and detect disease progression. Area under the ROC curve of RADAR and DDLS was 0.658 and 0.648. Conclusions: Automated calculation of RADAR and DDLS with a neural network can be used to evaluate the extent and long-term rate of optic disc rim loss and is further evidence of long-term nerve fiber loss in treated patients with glaucoma. Translational Relevance: Our study provides a large clinic-based experience for RADAR and DDLS measurements in GS and glaucoma with a neural network.

Predictors of Glaucomatous Progression in Individuals with Small and Large Optic Discs.

PURPOSE: To identify factors associated with glaucomatous progression in individuals with small and large optic discs. DESIGN: Retrospective review. SUBJECTS: 4505 individuals with glaucoma at UCLA; 233 (59.7%) with small discs, 157 (40.3%) with large discs. METHODS: Small and large disc sizes were defined by OCT or Heidelberg Retinal Tomography as disc area ≤ 5% (≤ 1.3 mm2) and ≥ 95% (≥ 2.9 mm2), respectively. Medical records were reviewed for demographics, systemic comorbidities, glaucoma type, ocular comorbidities, and ocular surgery. Logistic regression was used to identify predictors of visual field (VF) progression in individuals with small and large discs and predictors of large versus small discs. MAIN OUTCOME MEASURES: The VF deterioration with mean deviation, pointwise linear regression, and glaucoma rate index (GRI); large vs. small disc. RESULTS: In individuals with small discs, Asian versus non-Hispanic White ethnicity was associated with increased progression (adjusted odds ratio [aOR] = 4.05; 95% confidence interval [CI] = 1.12-14.59 for GRI). Higher intraocular pressure (IOP) range and peak were associated with increased progression in individuals with both small discs (aOR = 1.12; 95% CI = 1.00-1.27 and aOR = 1.05; 95% CI = 1.00-1.10 per 1 mmHg for range and peak with GRI) and large discs (aOR = 1.35; 95% CI = 1.12-1.66 and aOR = 1.11; 95% CI = 1.03-1.20 per 1 mmHg for range and peak with GRI). Multivariable predictors of having large vs. small discs included vasospastic phenotype (aOR = 2.58; 95% CI = 1.35-5.19) and Black (aOR = 20.46; 95% CI = 8.33-61.84), Hispanic/Latino (aOR = 9.65; 95% CI = 4.14-25.39), Asian (aOR = 4.87; 95% CI = 2.96-8.1), and other (aOR = 2.79; 95% CI = 1.69-4.63) versus non-Hispanic White ethnicity. CONCLUSIONS: Increased odds of glaucomatous progression were associated with Asian vs. non-Hispanic White ethnicity in glaucoma patients with small optic discs, as well as with increased IOP range and peak in those with small and large discs. Individuals with a vasospastic phenotype and those from racial and ethnic minority backgrounds had increased odds of having large vs. small optic discs. Further characterization of discernible phenotypes would improve disease prognostication and help individualize glaucoma treatment. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Detecting Fast Progressors: Comparing a Bayesian Longitudinal Model to Linear Regression for Detecting Structural Changes in Glaucoma.

PURPOSE: Demonstrate that a novel Bayesian hierarchical spatial longitudinal (HSL) model identifies macular superpixels with rapidly deteriorating ganglion cell complex (GCC) thickness more efficiently than simple linear regression (SLR). DESIGN: Prospective cohort study. SETTING: Tertiary Glaucoma Center. SUBJECTS: One hundred eleven eyes (111 patients) with moderate to severe glaucoma at baseline and ≥4 macular optical coherence tomography scans and ≥2 years of follow-up. OBSERVATION PROCEDURE: Superpixel-patient-specific GCC slopes and their posterior variances in 49 superpixels were derived from our latest Bayesian HSL model and Bayesian SLR. A simulation cohort was created with known intercepts, slopes, and residual variances in individual superpixels. MAIN OUTCOME MEASURES: We compared HSL and SLR in the fastest progressing deciles on (1) proportion of superpixels identified as significantly progressing in the simulation study and compared to SLR slopes in cohort data; (2) root mean square error (RMSE), and SLR/HSL RMSE ratios. RESULTS: Cohort- In the fastest decile of slopes per SLR, 77% and 80% of superpixels progressed significantly according to SLR and HSL, respectively. The SLR/HSL posterior SD ratio had a median of 1.83, with 90% of ratios favoring HSL. Simulation- HSL identified 89% significant negative slopes in the fastest progressing decile vs 64% for SLR. SLR/HSL RMSE ratio was 1.36 for the fastest decile of slopes, with 83% of RMSE ratios favoring HSL. CONCLUSION: The Bayesian HSL model improves the estimation efficiency of local GCC rates of change regardless of underlying true rates of change, particularly in fast progressors.

Comparison of Retinal Nerve Fiber Layer and Ganglion Cell Complex Rates of Change in Patients With Moderate to Advanced Glaucoma.

PURPOSE: To compare ganglion cell complex (GCC) and retinal nerve fiber layer (RNFL) rates of change (RoC) in eyes with central or moderate to advanced glaucoma. DESIGN: Prospective cohort study. PARTICIPANTS: A total of 918 matched macular and RNFL OCT scan pairs from 109 eyes (109 patients) enrolled in the Advanced Glaucoma Progression Study with ≥2 years of follow-up and ≥4 OCT scans. METHODS: We exported GCC and RNFL thickness measurements in 49 central macular superpixels and 12 RNFL clock-hour sectors, respectively. We applied our latest Bayesian hierarchical longitudinal model to estimate population and subject-specific baseline thickness (intercepts) and rates of change (RoC) in macular superpixels and RNFL sectors. Global RNFL and GCC RoC were analyzed in a single bivariate longitudinal model to properly compare them accounting for the correlation between their RoC. MAIN OUTCOME MEASURES: Proportion of significant negative (deteriorating) and positive (improving) RoC expressed in µm/year. Standardized RoC were calculated by dividing RoC by the corresponding population SD. Analyses were repeated in eyes with visual field mean deviation (MD) ≤-6 and > -6 dB. RESULTS: Average (SD) 24-2 visual field MD and follow-up length were -8.6 (6.3) dB and 4.2 (0.5) years, respectively. Global RNFL RoC (-0.70 µm/year) were faster than GCC (-0.44 µm/year) (P < .001); corresponding normalized RoC were not significantly different (P = .052). In bivariate analysis, patients with a significant negative global RNFL RoC (n = 63, 57%) or GCC (n = 56, 51%) frequently did so for both outcomes (n = 49, 45%). The average proportion of significantly decreasing RNFL sectors within an eye was 30.7% in eyes with MD > -6 dB compared to 20.5% in those with MD ≤ -6 dB (P = .014); the proportions for GCC superpixels were 21.1% versus 18.7%, respectively (P = .63). CONCLUSIONS: Both GCC and RNFL measures can detect structural progression in glaucoma patients with central damage or moderate to advanced glaucoma. The clinical utility of RNFL imaging decreases with worsening severity of glaucoma.

A Bayesian Hierarchical Spatial Longitudinal Model Improves Estimation of Local Macular Rates of Change in Glaucomatous Eyes.

Purpose: Demonstrate that a novel Bayesian hierarchical spatial longitudinal (HSL) model improves estimation of local macular ganglion cell complex (GCC) rates of change compared to simple linear regression (SLR) and a conditional autoregressive (CAR) model. Methods: We analyzed GCC thickness measurements within 49 macular superpixels in 111 eyes (111 patients) with four or more macular optical coherence tomography scans and two or more years of follow-up. We compared superpixel-patient-specific estimates and their posterior variances derived from the latest version of a recently developed Bayesian HSL model, CAR, and SLR. We performed a simulation study to compare the accuracy of intercept and slope estimates in individual superpixels. Results: HSL identified a significantly higher proportion of significant negative slopes in 13/49 superpixels and a significantly lower proportion of significant positive slopes in 21/49 superpixels than SLR. In the simulation study, the median (tenth, ninetieth percentile) ratio of mean squared error of SLR [CAR] over HSL for intercepts and slopes were 1.91 (1.23, 2.75) [1.51 (1.05, 2.20)] and 3.25 (1.40, 10.14) [2.36 (1.17, 5.56)], respectively. Conclusions: A novel Bayesian HSL model improves estimation accuracy of patient-specific local GCC rates of change. The proposed model is more than twice as efficient as SLR for estimating superpixel-patient slopes and identifies a higher proportion of deteriorating superpixels than SLR while minimizing false-positive detection rates. Translational Relevance: The proposed HSL model can be used to model macular structural measurements to detect individual glaucoma progression earlier and more efficiently in clinical and research settings.