Glaucoma Progression Research Articles

Prediction of perimetric progression in ocular hypertension and open angle glaucoma based on corneal biomechanics.

PurposeTo identify parameters that are significant risk predictors of visual field (VF) progression in patients with ocular hypertension (OHT) or early primary open-angle glaucoma (POAG), using Goldmann applanation tonometry intraocular pressure (IOP-GAT), ultrasound pachymetry and biomechanical indices measured with the Corvis ST and the Ocular Response Analyser (ORA) and create a prediction model.MethodsA dataset of 65 eyes was analyzed. VF progression was determined using event analysis, the AGIS progression criteria, and experts' opinion. Progression was defined when 2 of the 3 criteria agreed on VF progression. The artificial intelligence training pipeline to predict the consolidated target consisted of an initial outlier removal process, feature selection, and training using the leave-one-out (LOO) cross-validation. Techniques based on decision trees with the XGBoost (Xtreme Gradient Boosting) algorithm were employed.ResultsThe results reveal that the most accurate predictors were those registered at 1-month follow-up, predicting glaucomatous VF progression with an accuracy of 86.2%. The main variables involved in the prediction were HC dArc length, HC Deflection Time, and the HC Deflection Length 1 month after PG therapy.ConclusionUsing AI models, glaucomatous VF progression can be predicted with relatively high accuracy using Corvis ST parameters registered one month after initiating PG treatment. Highest concavity parameters after 1 month of treatment are associated with an increased risk of perimetric progression.

Transpalpebral measurement of intraocular pressure with the Tono-Pen XL, in a young, healthy, adult population.

Identification of increased intraocular pressure has been conventionally limited by direct, corneal applanation, and indentation measurement procedures, conducted by highly trained eye-care specialists e.g. optometrists and ophthalmologists. This practice greatly limits the numbers of individuals which can and need to be screened, for increased intraocular pressures. Increased intraocular pressure is the second leading cause of preventable, irreversible blindness throughout the world and a major modifiable risk factor for the development and progression of glaucoma. Current screening practices are inadequate, leaving many undetected, resulting in high base-rates of unnecessary and preventable blindness worldwide. Three primary research questions are investigated: Can intraocular pressures be measured through the eyelid, using the Tono-Pen XL tonometer? If yes, can the transpalpebral values be transformed to approximate corneal values? If yes, are the transformed values sufficiently precise, accurate, and reliable to substitute for intraocular pressure values measured directly from the cornea, for screening purposes?. Ninety (n = 90), healthy, young, adults completed measurement of intraocular pressures, from each eye (n = 180 eyes), using the Tono-Pen XL tonometer. Intraocular pressures were measured directly from the cornea and then directly from the closed eyelid. Transpalpebral measurements were transformed by simple linear regression to estimate direct corneal measurements. Transformed values were assessed for accuracy, precision, reliability, and agreement with direct corneal measurements. Findings revealed high accuracy, precision, reliability, and agreement between direct corneal and transpalpebral measurements. Transformed transpalpebral measurements correctly classified 95% and 93% of subjects, within 4 mm Hg or less of direct corneal measurements, when intraocular pressures were measured from the right and left eyes, respectively. Intraocular pressures measured directly from the closed eyelid, using the Tono-Pen XL, can be linearly transformed, using simple linear regression, to estimate intraocular pressure values measured directly from the cornea with high agreement, precision, and reliability, in a healthy, young, adult population. Findings have implications for non-eye-care specialists e.g. primary care physicians, choosing to quickly, accurately, and reliably screen individuals for normal intraocular pressures, without the need to anesthetize the eyes or use expensive, office-bound. equipment.

Three-years follow-up of combined phacoemulsification, iStent and endocyclophotocoagulation.

ObjectivesTo assess the efficacy and safety of phacoemulsification combined with endocyclophotocoagulation (ECP) and iStent implantation in surgically naïve patients.MethodsRetrospective observational cross-sectional series of 82 surgically naïve eyes treated with combined phacoemulsification, ECP and iStent between January 2018 and July 2019 at a single centre facility.ResultsA total of 82 eyes underwent the procedure. Average age was 80.9 (±6.4) years and 61% were female. Fifteen (18.29%) eyes had preperimetric glaucoma, the remaining were primary open angle glaucoma as follows: mild 32.92% (N = 27), moderate 35.37% (N = 29) and advanced 13.41% (N = 11). Baseline mean IOP was 19.5 (±4.5) mmHg, falling to 14.4 (±3.2) mmHg at 36-months (p ≤ 0.001). 82% of eyes were a qualified success at 3-year post-op with IOP ≤ 18 mmHg. 26% of eyes were a complete success at 3-years with IOP ≤ 18 mmHg and no medications. At baseline, mean number of medications was 2 reducing to 1.3 ± 1.1 at 3-years; Nineteen (23.2%) were patients medication-free. Best corrected visual acuity improved, increasing from 0.28 ± 0.2 LogMAR preoperatively to 0.10 ± 0.1 LogMAR at 36-months follow-up (p ≤ 0.001). Two patients developed cystoid macular oedema that resolved with topical treatment. Average MD remained stable over 3-years (p = 0.94). Due to suboptimal IOP, 3 patients underwent selective laser trabeculoplasty (SLT). No patients required further glaucoma surgical intervention.ConclusionsCombination of cataract surgery with iStent and ECP is a safe and effective procedure to lower IOP and medication burden. The procedure halted glaucoma progression and prevented further surgery over a 3-years follow up.

The impact of intraocular pressure fluctuations on the progression of glaucoma and associated factors.

The impact of intraocular pressure fluctuations on the progression of glaucoma and associated factors.

Loss of monocyte chemoattractant protein-1 reduced monocyte recruitment and preserved retinal ganglion cells in a mouse model of hypertensive glaucoma.

Loss of monocyte chemoattractant protein-1 reduced monocyte recruitment and preserved retinal ganglion cells in a mouse model of hypertensive glaucoma.

Novel classification for microspherophakia and its related surgical implications: a retrospective cohort study.

A novel classification for microspherophakia (MSP) was developed using a nomogram model to stratify patients and evaluate surgical outcomes. The study involved 99 eyes from 64 MSP patients, divided into training (64 eyes) and validation (35 eyes) cohorts. Primary outcome included the best corrected distance visual acuity (BCVA) at the 1-year follow-up, and the secondary outcome was intraocular pressure (IOP) control. MSP patients achieving a BCVA of ≤0.2 logarithm of the minimal angle of resolution with successful IOP control were categorised into the favourable outcomes group, while those not meeting these criteria were placed in the unfavourable outcomes group. A nomogram model was constructed to predict unfavourable outcomes by identifying associated risk factors. In the training cohort, 39.06% (25/64) achieved favourable outcomes, while 60.94% (39/64) had unfavourable outcomes. Decreased anterior chamber depth (ACD) and the presence of glaucoma were identified as risk factors for predicting unfavourable outcomes. The concordance index for the training and validation cohorts was 0.828 and 0.768, respectively. A nomogram-derived cut-off value of 56 points stratified patients into low-risk (≤56 points) and high-risk (>56 points) groups. Postoperative BCVA was significantly better in the low-risk group at 6-month and 1-year follow-ups. MSP patients in the low-risk group achieved satisfactory outcomes. For high-risk patients with shallowing ACD, early surgical intervention is recommended to prevent secondary glaucoma. Close monitoring of IOP and glaucoma progression is crucial for patients with secondary glaucoma. This classification offers valuable insights for outcome stratification and guidance in clinical decision-making for MSP management. However, the limitations of this study include its small sample size, which may impact generalisability, and future studies with larger cohorts are needed to validate and refine the nomogram.

Optic Disc Microvasculature Reduction and Visual Field Progression in Primary Open-Angle Glaucoma.

Optic Disc Microvasculature Reduction and Visual Field Progression in Primary Open-Angle Glaucoma.

Dysfunctional one-carbon metabolism identifies vitamins B6, B9, B12, and choline as neuroprotective in glaucoma.

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.

Intranasal delivery of epigallocatechin gallate-laden platelet extracellular vesicles for mitigating retinal glaucoma.

Intranasal delivery of epigallocatechin gallate-laden platelet extracellular vesicles for mitigating retinal glaucoma.

Caspase-mediated pathways in retinal ganglion cell injury: a novel therapeutic target for glaucoma

Glaucoma is a complex disease of the optic nerve leading to vision loss and blindness, with high worldwide incidence and disproportionate prevalence in older populations. Primary open-angle glaucoma, caused by a reduction in outflow of aqueous humor through the trabecular meshwork, is the most common subset of the disease, though its underlying molecular mechanisms are not well understood. While increased intraocular pressure is the most common risk factor in glaucoma progression, the disease is ultimately characterized by the loss of retinal ganglion cells (RGCs) and destruction of the optic nerve. Given the irreversibility of RGC death, neuroprotection of RGCs is a promising avenue of glaucoma prevention and treatment. The caspase family of proteins are integral members of the apoptotic death cascade. They have been shown to play a significant role in RGC death in numerous models of retinal injury. Direct inhibition of several caspase family members, through targeted siRNAs and peptidomimetics, demonstrate promising capacity to reduce caspase expression and preserve RGCs following intraocular pressure increase or optic injury. A wide variety of alternative therapeutics targeted for RGC survival, including neurotrophins, immunomodulators, cytoprotectants, and endogenous hormones, also display indirect caspase-inhibiting capabilities. Following intraocular pressure increase or external retinal injury, both direct and indirect caspase inhibitors elicit higher RGC counts, increased RGC layer thickness, and attenuation of RGC damage, clearly demonstrating the neuroprotective abilities of caspase inhibitors. Caspase inhibition, particularly by direct approaches of siRNA or peptidomimetic-based therapeutics, has the potential to achieve substantial neuroprotection in the glaucomatous eye.

A Morphological Model of Glaucomatous Damage to the Macular Ganglion Cell Layer in Myopic Eyes.

A model of glaucomatous progression based upon patterns of macular ganglion cell layer (GCL) damage can help clinicians distinguish between glaucomatous damage and other causes of GCL abnormalities in eyes with high myopia. To evaluate a model-based approach for identifying glaucomatous macular ganglion cell layer (GCL) damage in highly myopic eyes by analyzing characteristic loss patterns. This retrospective observational study involved optical coherence tomography scans of 72 myopic eyes (axial length>25mm), including 15 normal control eyes and 57 eyes with glaucoma or glaucoma suspects. The mean axial length was 27.09±1.61mm (range 25.13-35.77mm). The mean refractive error was -7.81±2.70 diopters in 46 eyes without prior refractive or cataract surgery. The loss pattern in the thick donut-shaped region of the macular GCL thickness map was compared to a model predicting glaucomatous damage patterns, suggesting damage originates temporally and progresses nasally. As predicted, the temporal sectors of the 57 patients' GCL donuts showed the highest number of abnormalities significant at 5% (temporal superior: 28, temporal inferior: 37), followed by the middle sectors (superior: 26, inferior: 30), and then nasal sectors (nasal superior: 24, nasal inferior: 27). Among three eyes deviating from the model, two showed nasal defects without temporal involvement, while one showed an epiretinal membrane (ERM)-induced artifact. Of the 24 eyes with macular lesions (most commonly ERM in 19), 21 were diagnosed with glaucoma or glaucoma suspects. Of these, 20 conformed to the model, except one. The proposed model of glaucomatous damage patterns in macula GCL is applicable to myopic eyes, even with coexisting macular pathology. In cases deviating from the model, clinicians are advised to seek causes besides glaucoma.

High Glucose-induced transcriptomic changes in human trabecular meshwork cells

Glaucoma is a leading cause of irreversible blindness, often associated with elevated intraocular pressure (IOP) due to trabecular meshwork (TM) dysfunction. Diabetes mellitus (DM) is recognized as a significant risk factor for glaucoma; however, the molecular mechanisms through which hyperglycemia affects TM function remain unclear. This study investigated the impact of high glucose on gene expression in human TM (HTM) cells to uncover pathways that contribute to TM dysfunction and glaucoma pathogenesis under diabetic conditions. Primary HTM cells were cultured under normoglycemic (5.5 mM) and hyperglycemic (30 mM) conditions for seven days, followed by mRNA sequencing (mRNA-seq) to identify differentially expressed genes, with quantitative PCR (qPCR) used for confirmatory analysis. STRING network analysis was performed to predict potential interactions among upregulated and downregulated genes. mRNA-seq analysis revealed 25 significantly differentially expressed genes in high glucose conditions, including upregulated genes associated with oxidative stress, apoptosis, autophagy, immune response, and fibrosis. Notably, TXNIP gene was significantly upregulated, indicating increased oxidative stress and apoptosis in TM cells, while downregulation of autophagy-related genes, such as HSPA6 and LAMP3, suggests compromised protein quality control. Immune response genes, including CCL7 and CHI3L1, were upregulated, suggesting an inflammatory response to oxidative stress. Increased expression of fibrosis-related genes, such as SNAI1, FGF7, and KRT19, and an increase in ECM proteins like Collagen 1 and FN accumulation and fibril formation suggest increased fibrosis of TM in diabetic conditions, potentially elevating IOP. Metabolic changes in diabetic patients could therefore lead to TM dysfunction, impair aqueous humor outflow, and elevate IOP, thereby increasing glaucoma risk. Targeting oxidative stress and fibrosis pathways offers therapeutic strategies to mitigate glaucoma progression in diabetic populations.

Impact of Physical Activity Levels on Visual Field Progression in Individuals with Glaucoma.

Higher self-reported physical activity level was associated with a slower rate of visual field mean deviation loss in patients with primary open-angle glaucoma. To determine the impact of physical activity (PA) on visual field (VF) progression rates in patients with primary open-angle glaucoma (POAG). In this longitudinal study, POAG patients were included who had ≥5 visits, ≥2 years of follow-up VFs and underwent PA questionnaire at the baseline. PA levels were assessed using the physical activity index (PAI), metabolic equivalents of task (MET)-minutes, and walking pace. Univariable and multivariable linear mixed-effects models were used to determine the impact of PA levels on the rates of VF mean deviation (MD) loss. 131 eyes from 80 POAG patients were included over a median follow-up of 4.9 (IQR, 4.0 to 6.7) years. The median age of patients was 68.6 (IQR, 59.3 to 77.8) years and median baseline VF MD was -3.5 (IQR, -8.3 to -1.3). In the univariable analysis, slower VF MD loss was associated with active PAI category (0.30 [95%CI, 0.01 to 0.58] dB/year vs. inactive PAI category; P=0.041) and higher PA amount (0.14 [95%CI, 0.01 to 0.27] dB/year per 1000 MET-minutes; P=0.036). Significant association with the rate of VF MD loss was not found for baseline VF MD (P=0.263) and walking pace (Ps>0.05). In the multivariable analysis including glaucoma severity and other covariates, slower VF MD loss was associated with higher PA amounts (0.15 [95%CI, 0.02 to 0.28] dB/year per 1000 MET-minutes; P=0.024). Higher PA amounts is an independent predictor of slower rate of VF MD loss. Further research is needed to explore whether increased PA protects against glaucoma progression.

SMOTE-Enhanced Explainable AI Model for Predicting Visual Field Progression in Myopic Normal-Tension Glaucoma.

The AI model, enhanced by SMOTE to balance data classes, accurately predicted visual field deterioration in patients with myopic normal-tension glaucoma. Using SHAP analysis, the key variables driving disease progression were identified. To develop and validate a Synthetic Minority Over-sampling Technique (SMOTE)-enhanced artificial intelligence (AI) model for predicting visual field progression in myopic normal-tension glaucoma (NTG) patients. This retrospective cohort study included 100 eyes from myopic NTG patients with a mean follow-up of 10.3±3.2 years. Baseline parameters included intraocular pressure (IOP), central corneal thickness, axial length, and visual field metrics. A SMOTE-enhanced AI model was created to address class imbalance in progression events. Model performance was evaluated using receiver operating characteristic (ROC) analysis, cross-validation, and calibration plots. Predictive factor importance was evaluated through SHapley Additive exPlanations (SHAP) analysis. Visual field progression was observed in 28% of patients, with a median progression time of 3.2 years. The AI model achieved an area under the ROC curve (AUC) of 0.83 (95% CI, 0.75-0.91), with promising sensitivity (0.81) and specificity (0.77). SHAP analysis identified baseline mean deviation (MD), age, axial length, baseline IOP, and visual field index (VFI) as key predictors. When patients were stratified based on model-predicted risk scores, those with scores above 0.8 had significantly higher observed progression rates (82.6%) compared to those with lower risk scores. Subgroup analysis revealed strong correlations between progression risks and older age, greater axial length, and worse baseline MD. The SMOTE-enhanced AI model shows reasonable predictive performance and potential clinical utility for identifying visual field progression in myopic NTG patients, though further validation in larger cohorts is needed. By addressing class imbalance and myopia-specific challenges, this approach enables personalized risk stratification and early intervention.

Rate of progression among different age groups in glaucoma with high myopia: A 10-year follow-up cohort study.

Rate of progression among different age groups in glaucoma with high myopia: A 10-year follow-up cohort study.

Predictive modeling of rapid glaucoma progression based on systemic data from electronic medical records

This study investigated the baseline systemic features that predict rapid thinning of the retinal nerve fiber layer (RNFL) in patients with primary open-angle glaucoma (POAG). A database drawn from electronic medical records (EMRs) was searched for patients diagnosed with POAG between 2009 and 2016 who had been followed up for > 5 years with the annual evaluation of global RNFL thickness using spectral-domain optical coherence tomography. The rate of change in global RNFL thickness for each eye was determined by linear regression analysis over time. Systemic data obtained within 6 months from the time of glaucoma diagnosis were extracted from the EMRs and incorporated into a model to predict the rate of progressive RNFL thinning. The predictive model was trained and tested using a random forest (RF) method and interpreted using Shapley additive explanation plots (SHAP). The features able to explain the rate of progressive RNFL thinning were identified and interpreted. Data from 1256 eyes of 696 patients and 1107 eyes of 607 patients were included in the training and test sets, respectively. The R2 value for the RF model was 0.88 and mean absolute error of the model was 0.205 μm/year. The prediction model identified higher serum levels of aspartate aminotransferase, lower blood glucose, lower systolic blood pressure, and higher high-density lipoprotein as the four most important systemic features predicting rapid RNFL thinning over 5 years. Among the ophthalmic features, a higher global RNFL thickness and a higher intraocular pressure were the most important factors predicting rapid RNFL thinning. The study revealed baseline systemic features from the EMRs that were of predictive value for progression rate of POAG patients.

Genetic Association of Primary Angle-Closure Glaucoma and Disease Progression.

To investigate single-nucleotide polymorphisms (SNPs) reported in the largest up-to-date systematic review and meta-analysis on primary angle-closure disease (PACD), on their associations with primary angle-closure glaucoma (PACG) and disease progression. This study involved a case-control design for PACG risk and a case-only design for PACG progression risk, including 628 PACG patients and 564 controls for disease association and 386 PACG patients with up to 10-year follow-up for PACG progression analysis. Associations of 17 SNPs in 15 genes with PACG were analysed using logistic regression. Sex-stratified association analysis was performed, followed by the Breslow-Day test. Genetic risk for PACG progression was evaluated using logistic regression. Bonferroni correction of p values was adopted for multiple comparisons. LOXL1 rs3825942 (G153D; p = 0.0026; OR = 0.65) was significantly associated with PACG, while ABCC5 rs1401999 showed a nominal association (p = 0.023; OR = 1.32). ABCA1 rs2422493 was significantly associated with PACG in females (p = 0.0016; OR = 0.70) but not in males (p = 0.95; OR = 0.99); and the Breslow-Day Test (p = 0.046) suggested a sex-specific association in females. VAV3 rs6689476 showed nominal associations with PACG progression at 3-year (p = 0.045; OR = 2.86), 5-year (p = 0.037; OR = 2.84) and 10-year follow-ups (p = 0.03; OR = 2.74), but the p values could not withstand Bonferroni correction. This study demonstrated a role of LOXL1 in PACG and a sex-specific effect of ABCA1 in the Hong Kong Chinese population while suggesting a potential role of VAV3 in PACG progression, which has yet to be further confirmed.

Choroidal microvascular dropout and its relationship to progression in primary open-angle and pseudoexfoliation glaucoma

BackgroundTo compare the longitudinal change of choroidal microvascular dropout (CMvD) and its relationship with glaucoma progression between primary open angle glaucoma (POAG) and pseudoexfoliation glaucoma (PXG).MethodsThe analysis included 114 eyes of 114 patients, with 57 POAG and 57 PXG eyes matched by age and visual field (VF) mean deviation (MD). The angular circumference (AC) of CMvD was measured using the en-face choroidal layer images of optical coherence tomography angiography at baseline and the final follow-up. Progression of CMvD was defined as an increase in AC beyond measurement variability (-3.85° to + 3.28°) or the appearance of new CMvD during follow-up. Glaucoma progression was determined by MD change rate.ResultsThe prevalence of CMvD was significantly higher in POAG than in PXG eyes (68.4% vs. 43.9%, p = 0.008) at baseline. However, by the final visit, the difference in prevalence between the groups was not significant (68.4% vs. 56.1%, p = 0.178). During the study period, seven PXG eyes developed new CMvD. There was no significant difference in MD progression rate between the stable and progressed CMvD subgroups in POAG (–0.7 ± 0.8 dB/year vs. − 0.8 ± 0.5 dB/year, p = 0.715). In contrast, PXG eyes showed a significantly faster MD progression rate in the progressed CMvD subgroup than in those with stable CMvD subgroup (–0.4 ± 0.7 dB/year vs. − 1.2 ± 0.8 dB/year, p = 0.010).ConclusionsThe progression of CMvD was more frequently observed in PXG eyes than POAG eyes and showed association with faster VF progression in PXG eyes.

Comparison of Event-Based Analysis Versus Trend-Based Analysis in the Detection of Glaucoma Progression by Optical Coherence Tomography 3-Dimensional Rim Measurements.

Compared to trend-based analysis, event-based analysis detects OCT structural progression in more patients and at an earlier timepoint. Using event-based analysis, MDB rim thickness detects progression more often than RNFL thickness. To determine if event-based or trend-based analysis best detects glaucoma progression using spectral domain optical coherence tomography (OCT) retinal nerve fiber layer (RNFL) thickness and minimum distance band (MDB) neuroretinal rim measurements. Over 5 years, 124 open-angle glaucoma patients had yearly dilated eye exams, disc photography, Humphrey visual field (HVF 24-2) testing, 2-dimensional (2D) OCT RNFL thickness measurements, and 3-dimensional (3D) OCT MDB rim measurements, all on the same day. One eye of each patient was analyzed, which was randomly selected if both eyes from a patient were eligible. Using global RNFL thickness and global MDB rim thickness, event-based progression was defined as change greater than normal aging change and expected inter-test variability. Trend-based analysis used linear regression with progression defined as rate of decline greater than age-related decline. Average follow-up for the 124 open-angle glaucoma patients was 66.9±16.4 months. Event-based analysis was better than trend-based analysis, because it detected progression in more patients (15.3% by RNFL event-based analysis versus 8.1% by RNFL trend-based analysis, P=0.025; 52.4% by MDB event-based analysis versus 9.7% by MDB trend-based analysis, P<0.001) and earlier (RNFL: mean 28.8 months vs. 63.2 months; P<0.001; MDB: mean 30.7 months vs. 56.2 months; P<0.003) whether using MDB rim thickness or RNFL thickness. Using event-based analysis, MDB rim thickness detected progression more often than RNFL thickness (52.4% vs. 15.3%; P<0.001). Compared to trend-based analysis, event-based analysis detected OCT structural progression in more glaucoma patients and at an earlier timepoint.

Cellular senescence and glaucoma.

Cellular senescence and glaucoma.