PURPOSE:Progressive visual field (VF) loss resulting from glaucoma affects quality of life (QoL). Although treatments aim to preserve vision, the extent to which slowing VF loss translates into QoL changes in advanced disease is not understood fully. We compare the 5-year rate of VF and QoL change and examined their correlation in the Treatment for Advanced Glaucoma Study. DESIGN:Multicenter randomized clinical trial (27 secondary care glaucoma departments in the UK). PARTICIPANTS:Adults (n = 453) with newly diagnosed advanced open-angle glaucoma in at least 1 eye were randomized to trabeculectomy (n = 227) or medical management (n = 226) as initial treatment. One eligible index eye was identified per participant. MAIN OUTCOME MEASURES:Mean difference in rate of change in monocular index eye VF (24-2 SITA Standard), binocular integrated (BI) VF, and the 25-item Visual Function Questionnaire (VFQ-25) composite score over 5 years (intention to treat) using a Bayesian longitudinal hierarchical model. RESULTS:Data from 442 patients with reliable VF (false-positive rate ≤15%) or VFQ-25 data from >2 time points were included (221 patients in the trabeculectomy-first arm). Baseline characteristics were similar between arms. The rate of index eye VF loss was faster in the medications-first arm (-0.75 [95% credible interval (CrI), -0.90 to -0.59] dB/year) compared with the trabeculectomy-first arm (-0.37 [95% CrI, -0.53 to -0.22] dB/year; P = 0.002). Differences between groups were not statistically significant for BI VF decline (P = 0.062) or VFQ-25 change (P = 0.392). Correlations between VF and QoL were stronger for BI VF for baseline (0.41 [95% CrI, 0.32-0.49]; P < 0.001) and rate of change (0.56 [95% CrI, 0.41-0.70]; P < 0.001) than for index eye VF (0.22 [95% CrI, 0.12-0.32]; P < 0.001 and 0.43 [95% CrI, 0.26-0.58]; P < 0.001, respectively). CONCLUSIONS:Trabeculectomy more effectively reduced the rate of VF loss compared with medical treatment in advanced glaucoma. Despite a moderately strong correlation with the BI VF, no difference was found in the measured QoL, suggesting that the VFQ-25 might not be reactive or sensitive enough to monocular glaucoma interventions. FINANCIAL DISCLOSURE(S):Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Mutations in optineurin (OPTN) are linked to neurodegenerative diseases such as normal tension glaucoma (NTG) and amyotrophic lateral sclerosis. The E50K-OPTN mutation is the most common genetic cause of NTG, where it disrupts mitophagy and leads to the accumulation of dysfunctional mitochondria. To understand how cellular metabolism is altered in these persistent mitochondria, and whether any pathological state can be reversed, we investigated NTG-patient-derived fibroblasts carrying the E50K-OPTN mutation. We identified a form of mitochondrial leak metabolism driven by elevated levels of the ATP synthase c-subunit leak channel (ACLC). These cells exhibit reversed F1FO ATP synthase activity, increased mitochondrial proton leak, and fragmented mitochondria, resulting in inefficient oxidative phosphorylation and a shift toward aerobic glycolysis and high protein synthesis rate. The ratio of ATP synthase c-subunit to β-subunit was markedly elevated, suggesting open ACLC pores. Treatment with dexpramipexole normalized ATP synthase function and cellular metabolism, promoted ATP synthesis rather than hydrolysis and reduced protein synthesis rates. Dexpramipexole reduced p62 levels in E50K fibroblasts, consistent with a reduced mitophagic burden from decreased accumulation of damaged mitochondrial cargo. These findings identify ACLC-mediated leak as a central driver of metabolic dysfunction in E50K-OPTN glaucoma and suggest ACLC closure as a viable therapeutic strategy.

PURPOSE:This study aimed to compare the statistical power of structural and visual field (VF) outcomes for randomized clinical trials (RCTs) in glaucoma. DESIGN:Analysis of retrospectively collected data. PARTICIPANTS:Eighty-two patients with glaucoma were recruited to a test-retest study, during which up to 10 24-2 Swedish Interactive Thresholding Algorithm (SITA) Standard VF and circumpapillary retinal nerve fiber layer (cpRNFL) Spectralis OCT scans were collected in separate sessions over 3 months. METHODS:Eyes with at least 3 sessions with a reliable VF (false-positives < 15%) and cpRNFL scan (quality index ≥ 25 dB) were selected (127 eyes, 68 patients) to model the test-retest variability and the structural floor effect. These estimates were combined with a published realistic structure-function progression model from the United Kingdom Glaucoma Treatment Study to simulate longitudinal RCTs (30% neuroprotective effect). Simulations only included data from eyes with early to moderate VF loss (mean deviation [MD], ≥-10 dB, 107 eyes, 65 patients). Simulations were repeated 5000 times to estimate sample size requirements to detect a significant difference (P < 0.05) in the rate of change of MD and average cpRNFL thickness, estimated with a linear mixed-effects model. We also tested the power of a significant outcome with either metric (P < 0.025). A supplementary analysis was performed including eyes with early VF loss only (MD ≥ -6 dB). MAIN OUTCOME MEASURES:Sample size at 80% power for the linear rate of MD, cpRNFL, and their combination. RESULTS:At 80% power, the required sample size (patients [95% confidence interval]) was 38% smaller for the MD rate (292 [300-283]) than the cpRNFL rate (470 [481-459]). The sample size for the combined outcome was only marginally smaller than the MD alone (275 [283-268]). The supplementary analysis on eyes with early VF loss showed similar results. CONCLUSIONS:Using realistic modeling of structure-function progression and test-retest data, MD progression showed higher statistical power cpRFNL as an outcome measure for clinical trials. FINANCIAL DISCLOSURE(S):Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Glaucoma, characterized by the loss of retinal ganglion cells (RGCs), is a leading cause of blindness for which there are no neuroprotective therapies. To explore observations of elevated homocysteine in glaucoma, we elevate vitreous homocysteine, which increases RGC death by 6% following ocular hypertension. Genetic association with higher homocysteine does not affect glaucoma-associated outcomes from the UK Biobank and serum homocysteine levels have no effect on glaucomatous visual field progression. This supports a hypothesis in which elevated homocysteine is a pathogenic, rather than causative, feature of glaucoma. Further exploration of homocysteine metabolism in glaucoma animal models demonstrates early and sustained dysregulation of genes involved in one-carbon metabolism and the interaction of essential cofactors and precursors (B6, B9, B12, and choline) in whole retina and optic nerve head and RGCs. Supplementing these provides neuroprotection in an acute model and prevents neurodegeneration and protects visual function in a chronic model of glaucoma.

PURPOSE: Evidence to support the hypothesis that visual field (VF) status can improve after initiation of intraocular pressure (IOP) reducing treatment is controversial. We take advantage of participant eligibility data from the United Kingdom Glaucoma Treatment Study (UKGTS) to test this hypothesis in newly diagnosed glaucomatous patients randomized to IOP-lowering therapy or placebo. center dot DESIGN: Multicentre, randomized, triple-masked, placebo-controlled trial. center dot METHODS: Participants were newly diagnosed open- angle glaucoma patients in the UKGTS with eligibility and baseline data (n = 202 and n = 205 participants from the treatment and placebo groups, respectively). UKGTS eligibility data, including two reliable VFs (Humphrey 24-2 SITA Standard) and IOP measurements were compared to UKGTS trial baseline data acquired after allocation to treatment (topical prostaglandin analog) or placebo eye drops. Mean change in VF mean deviation (MD) and proportion of eyes that improved MD by more than different thresholds were compared across this interval in the treatment and placebo groups. Secondary analyses included stratifying the groups by level of IOP, level of VF loss, and age, along with pointwise analyses including change in subsets of VF locations. The main outcome measure was the mean change in VF MD. center dot RESULTS: Mean (standard deviation [SD]) time between eligibility/baseline visits and reduction in IOP was 12 (3) weeks and 4.8 (4.2) and 1.0 (3.6) mmHg for the treated and placebo eyes, respectively. Mean (SD) change in MD was almost the same for the treated (-0.03 [1.45] dB) and placebo groups ( + 0.08 [1.72] dB; P = .47). The proportions of participants with an MD improvement of 1 dB or more were similar for both groups ( P = .25). No association was found between MD improvement and magnitude of IOP lowering. Stratifying data by IOP, level of VF loss and age did not reveal any differences between the treated and placebo groups, nor did any of the point- wise VF analyses. center dot CONCLUSIONS: Initial short-term VF changes in the treatment and placebo arms of UKGTS were the same. In these newly diagnosed patients with non-advanced glaucoma, we found no evidence to support the hypothesis that VF status improves after initial lowering of IOP by medical therapy. (Am J Ophthalmol 2025;269: 346354. (c) 2024 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license ( http://creativecommons.org/licenses/by/4.0/ ))

Purpose:To investigate the effect of average intraocular pressure (IOP) on the true rate of glaucoma progression (RoP) in the United Kingdom Glaucoma Treatment Study (UKGTS). Methods:UKGTS participants were randomized to placebo or Latanoprost drops and monitored for up to two years with visual field tests (VF, 24-2 SITA standard), IOP measurements, and optic nerve imaging. We included eyes with at least three structural or functional assessments (VF with <15% false-positive errors). Structural tests measured rim area (RA) with Heidelberg retina tomography (HRT) and average peripapillary retinal nerve fiber layer (pRNFL) thickness with optical coherence tomography (OCT). One eye of 436 patients (222 on Latanoprost) was analyzed. A Bayesian hierarchical model estimated the true RoP of VF and structural metrics, and their correlations, using sign-reversed multivariable exponential distribution. RA and pRNFL measurements were converted to a dB scale, matching the VF metric (mean deviation [MD]). The effect of average IOP on the true RoPs was estimated. Results:True RoP at the mean average IOP (17 mm Hg) was faster (P < 0.001) for VF-MD (-0.59 [-0.73, -0.48] dB/year) than HRT-RA (-0.05 [-0.07, -0.03] dB/year) and OCT-pRNFL (-0.08 [-0.11, -0.06] dB/year). The proportional acceleration of RoP per mm Hg increase was, however, not significantly different (smallest P = 0.15). Accounting for the structural floor-effect largely eliminated the differences in RoPs (smallest P = 0.25). Conclusions:VF appeared to deteriorate at a faster rate than structural measurements. However, this could be explained by the floor-effect from nonfunctional tissue. IOP induced a similar acceleration in RoP per mm Hg increase.

PURPOSE:To compare the 6-year rate of visual field (VF) progression in the 2 arms of the Laser in Ocular Hypertension and Glaucoma Trial (LiGHT), comparing selective laser trabeculoplasty (SLT) and drops as first treatment in ocular hypertension (OHT) and open-angle glaucoma (OAG). DESIGN:Post hoc analysis of data from randomized clinical trial. PARTICIPANTS:Patients with newly diagnosed OHT/OAG recruited in the LiGHT trial. METHODS:In each patient, we selected the better (baseline mean deviation [MD]) eligible eye with at least 3 reliable VFs (false-positive errors < 15%) over at least 6 months. We estimated the rate of MD progression using a published hierarchical linear mixed effect model (LMM), designed to increase precision by minimizing the effect of perimetric learning and test-retest noise. Secondary analyses were performed to assess the differences in rate across baseline severity groups (OHT, mild OAG, and moderate/severe OAG); the effect of glaucoma surgery and switch to SLT in the drops-first arm, by truncating the VF series; and the effect of cataract and cataract surgery, by using the mean pattern deviation (MPD) instead of the MD. MAIN OUTCOME MEASURE:Mean difference in the rate of VF MD progression between patients in the SLT-first arm and drops-first arm. RESULTS:Data from 710 eyes (482 with OAG and 354 in the SLT-first arm) were analyzed. The 2 arms had similar baseline MD (P = 0.7). The average intraocular pressure (IOP) during follow-up was 16.1 [14.2-18.2] for the drops-first arm and 16.8 [14.6-18.6] in the SLT-first arm (median [interquartile range], P = 0.057). The mean [95% credible interval] MD rate was -0.37 [-0.43 to -0.31] decibels (dB)/year in the drops-first arm and -0.26 [-0.31 to -0.21] dB/year in the SLT-first arm (P = 0.007). When stratified by severity, this difference was significant only in mild OAG (P = 0.035, the largest sub-group). The secondary analyses largely confirmed the main results. The difference in MPD rate was also significantly slower in the SLT-first arm (P < 0.001). CONCLUSIONS:First-line SLT was more effective than drops at preserving VF. Selective laser trabeculoplasty should be preferred as the first line of treatment in newly diagnosed OHT and OAG eyes. FINANCIAL DISCLOSURE(S):Proprietary or commercial disclosure may be found after the references.

Importance Primary selective laser trabeculoplasty (SLT) is a safe primary treatment for open-angle glaucoma (OAG) and ocular hypertension (OHT). However, there is limited evidence on its use as a secondary treatment, ie, after prior use of ocular hypotensive eye drops. Objective To evaluate outcomes following SLT after using hypotensive eye drops for at least 3 years. Design, Setting, and Participants This is a post hoc exploratory analysis of data from a multicenter randomized clinical trial conducted within the UK National Health Service. Participants were patients with OAG or OHT who participated in the LiGHT trial. Data were analyzed from February 2021 to December 2024. Intervention Participants were initially randomized to either primary SLT or primary hypotensive eye drops and remained on the allocated treatment pathway for 3 years. Participants using eye drops were then allowed to have secondary SLT as a treatment switch (to reduce their medication load) or as a treatment escalation (if more intense treatment was needed). Participants were treated and monitored according to a predefined protocol. Main Outcomes and Measures The outcomes of interest were rates of incisional glaucoma surgery, medication use, and intraocular pressure. Results In total, 633 participants entered the extension of the LiGHT trial, and 524 participants (82.8%) completed the extension (72 months). Of 320 participants receiving primary hypotensive eye drops, 112 (35.0%) received SLT: 70 participants switched to SLT, 29 participants had SLT as a treatment escalation, and 13 participants had SLT as a treatment escalation in 1 eye and as a treatment switch in the other eye. Switching to SLT was associated with a reduction in the number of medications (mean [SD], 1.38 [0.62] to 0.59 [0.92] active ingredients; mean difference, 0.79 [95% CI 0.66 to 0.93] active ingredients; P < .001). At 72 months, 69 eyes that switched to SLT (60.5%) needed no medical or surgical treatment, and 62 eyes receiving 1 drug before switching (83.8%) needed no medical treatment. Escalating to SLT was associated with a mean intraocular pressure reduction of 4.6 mm Hg (21.8%), and 30 eyes (62.5%) reached target intraocular pressure at 72 months without the need for surgery; 9 eyes (18.7%) needed a trabeculectomy. Conclusions and Relevance This secondary analysis of a randomized clinical trial found that secondary SLT was associated with a reduction in the medication load for stable, medically treated eyes. For medically uncontrolled eyes, there is evidence that SLT could provide additional intraocular pressure control, but the need for trabeculectomy was not eliminated.

PURPOSE:To test the association between use of calcium channel blocker (CCB) medications and the rate of visual field (VF) progression in a large cohort of patients from 5 glaucoma clinics. DESIGN:Retrospective longitudinal case-control study. SUBJECTS:Patients attending 5 glaucoma clinics in the United Kingdom using the same electronic medical record (EMR) system. METHODS:For the main analysis, we selected 1 eye from patients with at least 5 reliable (false positive errors < 15%) VFs over a period of at least 4 years. The use of systemic medications was derived from the EMR system. Calcium channel blocker users were identified as cases. Propensity score matching (PSM) and multivariable analyses (MVAs) were used to adjust for confounders. A directed acyclic graph of the relevant variables guided the selection of covariates. Linear mixed-effect models (LMMs) were used to test the effect on the rate of VF mean deviation (MD) associated with CCB use and other covariates (for the MV analysis). Sensitivity analyses were conducted with different inclusion criteria and cutoffs on the estimated duration of CCB use. MAIN OUTCOME MEASURES:The mean difference in the rate of VF MD progression between CCB users and controls. RESULTS:The main analysis included 14 475 eyes (1942 from CCB users) that met the selection criteria (1 eye per patient). The median (interquartile range) VF series length was 8 (6, 11) tests, with a follow-up of 8.6 (6, 11.5) and 8.2 (5.9, 11.2) years in CCB users and controls, respectively. One-to-one PSM pairing with controls was achieved for all CCB users. The estimated rate of MD progression was -0.31 (-0.33 to -0.28) dB/year (mean [95% confidence intervals]) in the CCB users and -0.35 (-0.37 to -0.33) dB/year in the matched controls (P = 0.016). This significant difference was confirmed with the MV analysis including all controls (P = 0.020). All sensitivity analyses confirmed the main results. CONCLUSIONS:Calcium channel blocker use was statistically significantly associated with a slower rate of VF deterioration after multivariable adjustment. The estimated difference was small and likely not clinically significant but may be influenced by the limited information on the duration of CCB exposure in this cohort. FINANCIAL DISCLOSURE(S):Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Purpose:To compare the ability of conventional luminance-modulating perimetric stimuli and an area-modulation stimulus (AMS) designed to measure changes in complete spatial summation to identify physiological retinal ganglion cell density (RGCD) gradients in healthy observers. Methods:Contrast thresholds were measured for Goldmann III (GIII; 0.43°, 200 ms) and V (GV; 1.72°, 200 ms) stimuli at 3° and 10° eccentricity in 100 healthy observers (median age, 43 years, range, 18-85 years), with mean spherical equivalent refractive errors ranging from -10.38 to +4.63 DS. Area thresholds were measured at the same locations using a fixed luminance stimulus (ΔL: 4.4 cd/m2, 200 ms). Colocalized RGCD estimates were determined using (i) optical coherence tomography (OCT) RGC layer thickness measures, and (ii) achromatic peripheral grating resolution acuity (PGRA) thresholds. Ratios of the difference in log energy threshold (ΔE) and log RGCD (ΔRGCD) between eccentricities were calculated (ΔE/|ΔRGCD|), with a value of 1 assumed to be the optimal relationship between functional thresholds and RGCD. Results:ΔE/|ΔRGCD|) values (median and interquartile range [IQR]) were largest for AMS (OCT, 0.54 [IQR, 0.37-0.78]; PGRA, 0.71 [IQR, 0.46-1.19]), followed by GIII (OCT, 0.29 [IQR, 0.08-0.44]; PGRA, 0.33 [IQR, 0.07-0.54]; and GV (OCT, 0.16 [IQR, 0.02-0.29]; and PGRA, 0.19 [IQR, 0.02-0.44]). Interstimulus differences between all stimulus pairs were statistically significant (AMS vs GIII, both P < 0.001; AMS vs GV, both P < 0.001; GIII vs GV, both P < 0.05). Conclusions:ΔE/|ΔRGCD| values were closest to 1 for AMS, suggesting this stimulus relates best to underlying physiological variations in RGCD. Translational Relevance:Thresholds measured with area modulation stimuli vary more proportionally with physiological changes in retinal ganglion cell density relative to conventional perimetric stimuli.

BACKGROUND/AIMS:The goal of health research is to improve patients care and outcomes. Thus, it is essential that research addresses questions that are important to patients and clinicians. The aim of this study was to develop a list of priorities for glaucoma research involving stakeholders from different countries in Europe. METHODS:We used a three-phase method, including a two-round electronic Delphi survey and a workshop. The clinician and patient electronic surveys were conducted in parallel and independently. For phase I, the survey was distributed to patients from 27 European countries in 6 different languages, and to European Glaucoma Society members, ophthalmologists with expertise in glaucoma care, asking to name up to five research priorities. During phase II, participants were asked to rank the questions identified in phase I using a Likert scale. Phase III was a 1 day workshop with patients and clinicians. The purpose was to make decisions about the 10 most important research priorities using the top 20 priorities identified by patients and clinicians. RESULTS:In phase I, 308 patients and 150 clinicians were involved. In phase II, the highest-ranking priority for both patients and clinicians was 'treatments to restore vision'. In phase III, eight patients and four clinicians were involved. The top three priorities were 'treatments to stop sight loss', 'treatments to restore vision' and 'improved detection of worsening glaucoma'. CONCLUSION:We have developed a list of priorities for glaucoma research involving clinicians and patients from different European countries that will help guide research efforts and investment.

PurposeTo investigate whether intraocular pressure (IOP) fluctuation is independently associated with the rate of visual field (VF) progression in the United Kingdom Glaucoma Treatment Study.DesignRandomized, double-masked, placebo-controlled multicenter trial.ParticipantsParticipants with ≥5 VFs (213 placebo, 217 treatment).MethodsAssociations between IOP metrics and the VF progression rates (mean deviation (MD) and five fastest locations) were assessed with linear mixed models. Fluctuation variables were mean ocular pulse amplitude (OPA), standard deviation (SD) of diurnal IOP (diurnal fluctuation), and SD of IOP at all visits (long-term fluctuation). Fluctuation values were normalized for mean IOP to make them independent from mean IOP. Correlated non-fluctuation IOP metrics (baseline, peak, mean, supine and peak phasing IOP) were combined with principal component analysis (PCA), and principal component 1 (PC1) was included as a covariate. Interactions between covariates and time from baseline modelled the effect of the variables on VF rates. IOP was measured with Goldmann applanation tonometry and OPA with Pascal tonometry. Analyses were conducted separately in the two treatment arms.Main Outcome MeasuresAssociations between IOP fluctuation metrics and rates of MD and five fastest test locations.ResultsIn the placebo arm, only PC1 was significantly associated with the MD rate (estimate [standard error (SE)]: -0.19 [0.04] dB/year, p<0.001), while normalized IOP fluctuation metrics were not. No variable was significantly associated with MD rates in the treatment arm. For the fastest five locations in the placebo group, PC1 (estimate [SE]: -0.58 [0.16] dB/year, p<0.001), CCT (estimate [standard error (SE)]: 0.26 [0.10] dB/year for 10 μm thicker, p=0.01) and normalized OPA (estimate [SE]: -3.50 [1.04] dB/year, p=0.001) were associated with rates of progression; normalized diurnal and long-term IOP fluctuations were not. In the treatment group, only PC1 (estimate [SE]: -0.27 [0.12] dB/year, p=0.028) was associated with the rates of progression.ConclusionsThere is no evidence to support that either diurnal or long-term IOP fluctuation, as measured in clinical practice, are independent factors for glaucoma progression; other aspects of IOP, including mean IOP and peak IOP, may be more informative. OPA may be an independent factor for faster glaucoma progression.