The effect of changes in intraocular pressure on the risk of primary open-angle glaucoma in patients with ocular hypertension: an application of latent class analysis.

BACKGROUND: Primary open-angle glaucoma (POAG) is one of the leading causes of blindness in the United States and worldwide. While lowering intraocular pressure (IOP) has been proven to be effective in delaying or preventing the onset of POAG in many large-scale prospective studies, one of the recent hot topics in glaucoma research is the effect of IOP fluctuation (IOP lability) on the risk of developing POAG in treated and untreated subjects. METHOD: In this paper, we analyzed data from the Ocular Hypertension Treatment Study (OHTS) and the European Glaucoma Prevention Study (EGPS) for subjects who had at least 2 IOP measurements after randomization prior to POAG diagnosis. We assessed the interrelationships among the baseline covariates, the changes of post-randomization IOP over time, and the risk of developing POAG, using a latent class analysis (LCA) which allows us to identify distinct patterns (latent classes) of IOP trajectories. RESULT: The IOP change in OHTS was best described by 6 latent classes differentiated primarily by the mean IOP levels during follow-up. Subjects with high post-randomization mean IOP level and/or large variability were more likely to develop POAG. Five baseline factors were found to be significantly predictive of the IOP classification in OHTS: treatment assignment, baseline IOP, gender, race, and history of hypertension. In separate analyses of EGPS, LCA identified different patterns of IOP change from those in OHTS, but confirmed that subjects with high mean level and large variability were at high risk to develop POAG. CONCLUSION: LCA provides a useful tool to assess the impact of post-randomization IOP level and fluctuation on the risk of developing POAG in patients with ocular hypertension. The incorporation of post-randomization IOP can improve the overall predictive ability of the original model that included only baseline risk factors.

Risk factors associated with progression in exfoliative glaucoma patients.

PURPOSE: To evaluate exfoliative glaucoma (XFG) patients over 5 years, determining risk factors associated with progression or non-progression of glaucoma. METHODS: A retrospective, observational study. Patients were chosen from consecutive charts and data collected from each available visit included in the follow-up period. Data were abstracted for non-progressed XFG patients for 5 years and for progressed patients until glaucoma worsened. Progression was determined from patient records and by disc photographs. RESULTS: There were 71 (53%) progressed and 63 (47%) non-progressed XFG patients.Baseline parameters demonstrated worse visual field damage (p=0.014) and more prescribed medicines (p=0.03) in progressed patients. The mean intraocular pressure (IOP) for progressed patients was 18.7±4.3 and 17.3±3.4 mm Hg for non-progressed patients (p=0.047). The mean IOP that best separated the groups was 17 mm Hg with 60% staying non-progressed at or below this level and 30% above this level. At the last visit, progressed patients had more medicines prescribed (1.7) than non-progressed patients (1.3, p=0.005). A multivariate regression analysis showed higher mean, peak and variance of IOP, number of glaucoma medications at the final visit and presence of a disc hemorrhage (n=5) as independent risk factors for progression (p≤0.05). CONCLUSION: IOP reduction in XFG may be essential in reducing disease progression. The presence of disc hemorrhage in XFG may suggest an increased probability of progression despite treatment to within the normal IOP range.

Diagnostic validity of optic disc and retinal nerve fiber layer evaluations in detecting structural changes after optic neuritis.

PURPOSE: To assess the diagnostic validity of morphometric examination of the optic disc and retinal nerve fiber layer (RNFL) thickness to detect permanent structural changes after retrobulbar optic neuritis (ON). DESIGN: Evaluation of a diagnostic test. PARTICIPANTS: Twenty-five patients with a history of retrobulbar ON and 29 disease-free controls. METHODS: The optic discs were evaluated by means of confocal scanning laser ophthalmoscopy (Heidelberg Retinal Tomograph [HRT III]), and RNFL thickness by means of scanning laser polarimetry (GDx), and optical coherence tomography (OCT). Vision function was assessed in all subjects by testing visual acuity, contrast sensitivity, color vision, visual field (VF), and visual evoked potentials (VEPs). Statistical comparisons were made between the affected (ON) and unaffected eyes (non-ON) of the patients with ON, and between these eyes and control eyes (Mann-Whitney test and Wilcoxon's test). Receiver operating characteristic (ROC) curves, and sensitivity and specificity in discriminating ON from control eyes, were calculated for the significant parameters. Correlations between the tests were calculated by means of Spearman's correlation coefficient. MAIN OUTCOME MEASURES: We compared OCT, GDx, HRT, and visual testing results in ON eyes versus control eyes. RESULTS: All of the visual function test parameters and RNFL thickness (GDx and OCT) were significantly different between the ON eyes and both the non-ON and control eyes (P<0.01), and there were significant differences in some GDx parameters between the non-ON and control eyes. There were no significant differences in the HRT parameters. The ROC curves indicated that the greatest diagnostic validity was associated with the GDx nerve fiber indicator (AUC, 0.92; sensitivity, 0.80; specificity, 0.97 using a cutoff point of 20.5 between ON and non-ON eyes), and OCT temporal thickness (AUC, 0.92; sensitivity, 0.72; specificity, 0.95 using a cutoff point of 51.5 microm). CONCLUSIONS: When investigating permanent damage after ON, RNFL thickness is a promising biomarker. The GDx and OCT are reliable, noninvasive, user-friendly devices; both show good diagnostic validity and good correlations with functional tests in discriminating affected from unaffected eyes. Retinal nerve fiber layer thinning in non-ON eyes should be further studied as a possible subclinical indicator of disease.

Evaluation of a Primary Open-Angle Glaucoma Prediction Model Using Long-term Intraocular Pressure Variability Data: A Secondary Analysis of 2 Randomized Clinical Trials.

Importance: The contribution of long-term intraocular pressure (IOP) variability to the development of primary open-angle glaucoma is still controversial. Objective: To assess whether long-term IOP variability data improve a prediction model for the development of primary open-angle glaucoma (POAG) in individuals with untreated ocular hypertension. Design, Setting, and Participants: This post hoc secondary analysis of 2 randomized clinical trials included data from 709 of 819 participants in the observation group of the Ocular Hypertension Treatment Study (OHTS) followed up from February 28, 1994, to June 1, 2002, and 397 of 500 participants in the placebo group of the European Glaucoma Prevention Study (EGPS) followed up from January 1, 1997, to September 30, 2003. Data analyses were completed between January 1, 2019, and March 15, 2020. Exposures: The original prediction model for the development of POAG included the following baseline factors: age, IOP, central corneal thickness, vertical cup-disc ratio, and pattern SD. This analysis tested whether substitution of baseline IOP with mean follow-up IOP, SD of IOP, maximum IOP, range of IOP, or coefficient of variation IOP would improve predictive accuracy. Main Outcomes and Measures: The C statistic was used to compare the predictive accuracy of multivariable landmark Cox proportional hazards regression models for the development of POAG. Results: Data from the OHTS consisted of 97 POAG end points from 709 of 819 participants (416 [58.7%] women; 177 [25.0%] African American and 490 [69.1%] white; mean [SD] age, 55.7 [9.59] years; median [range] follow-up, 6.9 [0.96-8.15] years). Data from the EGPS consisted of 44 POAG end points from 397 of 500 participants in the placebo group (201 [50.1%] women; 397 [100%] white; mean [SD] age, 57.8 [9.76] years; median [range] follow-up, 4.9 [1.45-5.76] years). The C statistic for the original prediction model was 0.741. When a measure of follow-up IOP was substituted for baseline IOP in this prediction model, the C statistics were as follows: mean follow-up IOP, 0.784; maximum IOP, 0.781; SD of IOP, 0.745; range of IOP, 0.741; and coefficient of variation IOP, 0.729. The C statistics in the EGPS were similarly ordered. No measure of IOP variability, when added to the prediction model that included mean follow-up IOP, age, central corneal thickness, vertical cup-disc ratio, and pattern SD, increased the C statistic by more than 0.007 in either cohort. Conclusions and Relevance: Evidence from the OHTS and the EGPS suggests that long-term variability does not add substantial explanatory power to the prediction model as to which individuals with untreated ocular hypertension will develop POAG.

Exploring the gap between diagnostic research outputs and clinical use of OCT for diagnosing glaucoma.

AIMS: To explore the gap between diagnostic research outputs and clinical use of optical coherence tomography (OCT) in glaucoma and assess the reliability of a specific reference database when applied to a morphological imaging parameter for diagnostic purposes. METHODS: Consecutive subjects enrolled in the Multicenter Italian Glaucoma Imaging Study (MIGIS) have been included in this cross-sectional, comparative evaluation of diagnostic tests study. Patients underwent measurement of global and sectorial peripapillary retinal nerve fibre thickness (pRNFL) and minimum rim width (MRW) by OCT. The sensitivity and specificity of reference-database categorical classifications were calculated by means of 2×2 tables and sensitivity was compared with that of the corresponding continuous parameter extracted from the receiver operating characteristic (ROC) curves by matching the specificity. RESULTS: 280 Caucasian subjects have been included. At matched specificities, the sensitivity of pRNFL categorical classifications was statistically similar to that of the corresponding continuous parameters, whereas the sensitivity of the MRW categorical classifications was significantly lower than that of the corresponding continuous parameters. CONCLUSIONS: The diagnostic accuracy of reference database classifications might be lower than that extrapolated from the ROC curves of continuous parameters used in diagnostic research. The gap between the accuracy of these two approaches may be used to estimate the reliability of a specific reference database when applied to a continuous parameter for diagnostic purposes.

Macular versus nerve fibre layer versus optic nerve head imaging for diagnosing glaucoma at different stages of the disease: Multicenter Italian Glaucoma Imaging Study.

PURPOSE: To compare the diagnostic accuracy of minimum rim width (MRW), peripapillary retinal nerve fibre layer (pRNFL) and multilayered macular analysis by Spectralis SD-OCT (Heidelberg Engineering, Germany) in discriminating perimetric glaucoma at different stages of the disease from healthy eyes. METHODS: In this multicentre, prospective, evaluation of diagnostic tests study, multilayered macular analysis and MRW and pRNFL were obtained from one eye of 197 glaucoma (76 early, 68 moderate and 53 advanced) and of 83 healthy controls from the Multicenter Italian Glaucoma Imaging Study (MIGIS). The reference standard for classifying eyes as glaucomatous and for staging the disease was the visual field. The main outcome measures were area under the ROC curve (AUC) and sensitivity at fixed specificity (95%). RESULTS: Average MRW and average pRNFL showed the highest and similar diagnostic accuracy in both the whole study population (AUC 0.968 and 0.939) and early glaucoma (AUC 0.956 and 0.929). Among the macular parameters, the three innermost retinal layers combined as the Ganglion Cell Complex provided the highest diagnostic accuracy (AUC 0.931) in the whole population, which was statistically similar to that of average pRNFL but inferior to that of average MRW. Compared to both average MRW and pRNFL, all macular parameters showed statistically significant lower accuracy in early glaucoma, but accuracy in moderate and advanced glaucoma showed no statistically significant differences among three protocols. CONCLUSION: The diagnostic accuracy of MRW, pRNFL and macular analysis by Spectralis SD-OCT is overall good. MRW and pRNFL analysis performs statistically and clinically better than macular analysis to discriminate early glaucoma from healthy eyes.

Risk factors for glaucoma onset and progression.

In this review, we distinguish among risk factors associated with the development of open-angle glaucoma in individuals with healthy eyes, predictive determinants for the development of open-angle glaucoma in subjects with ocular hypertension, and prognostic factors for the progression of open-angle glaucoma in individuals who already have the disease. We primarily reviewed recent longitudinal population-based epidemiological studies, prospectively planned clinical trials, and cohort studies. Risk factors consistently associated with the development of open-angle glaucoma in individuals with healthy eyes include older age and an approximately 1 mm Hg increase in intraocular pressure (IOP) at baseline. Family history for open-angle glaucoma may be associated with the development of open-angle glaucoma as well. Predictive factors for the development of open-angle glaucoma in individuals with ocular hypertension may be older age, thinner central corneal thickness, higher cup-to-disk ratios of the optic disc, and higher pattern standard deviation values on the Humphrey automated perimeter at baseline. Given multi-center trials that showed similar predictive factors for the development of open-angle glaucoma in individuals with ocular hypertension, a calculator is available to clinicians for assessing the 5-year likelihood of developing open-angle glaucoma in ocular hypertensive patients with certain characteristics. Prognostic factors for the progression of open-angle glaucoma in individuals who already have the condition include older age at baseline, higher IOP at baseline, and thinner central conreal thickness. Self-report of diabetes may be associated with open-angle glaucoma progression. In conclusion, the only modifiable factor associated with open-angle glaucoma that has been consistently identified is elevated baseline IOP. Future research needs to evaluate the importance of others modifiable factors such as IOP fluctuation or nutritional factors.

Predictive factors for open-angle glaucoma among patients with ocular hypertension in the European Glaucoma Prevention Study.

OBJECTIVE: To evaluate the predictive factors of open-angle glaucoma (OAG) in patients affected by ocular hypertension enrolled in the European Glaucoma Prevention Study (EGPS). DESIGN: Randomized, double-masked, controlled clinical trial. PARTICIPANTS: One thousand seventy-seven patients, > or =30 years old, were enrolled at 18 European centers. The patients met inclusion criteria: intraocular pressure, 22 to 29 mmHg; 2 normal and reliable visual fields (VFs) (on the basis of mean deviation and corrected pattern standard deviation [PSD]); and a normal optic disc, as determined by an optic disc reading center. INTERVENTION: Treatment with dorzolamide or a placebo (the vehicle of dorzolamide) in one or both eyes. MAIN OUTCOME MEASURES: Efficacy end points were VF and/or optic disc changes. Baseline demographic and clinical data were collected before randomization, except for corneal thickness measurements, which were determined during follow-up. Proportional hazards models were used to identify factors that predicted which participants in the EGPS had developed OAG. RESULTS: In multivariate analyses, factors that predicted the development of OAG included older age (hazard ratio [HR], 1.32; 95% confidence interval [CI], 1.04-1.69), larger vertical cup-to-disc (C/D) ratio (HR, 1.34; 95% CI, 1.14-1.58), larger vertical C/D ratio asymmetry (HR, 1.46; 95% CI, 1.11-1.93), higher PSD (HR, 1.66; 95% CI, 1.15-2.38), and lesser central corneal thickness (HR, 1.32; 95% CI, 1.05-1.67). CONCLUSIONS: Baseline age, vertical C/D ratio, vertical C/D ratio asymmetry, and PSD were good predictors of the onset of OAG in the EGPS. Central corneal thickness was found to be a powerful predictor of the development of OAG. The EGPS results agree with the findings of the Ocular Hypertension Treatment Study and support the need for a thorough evaluation of patients with ocular hypertension.

Central corneal thickness in the European Glaucoma Prevention Study.

PURPOSE: To measure central corneal thickness (CCT) within the participants of the European Glaucoma Prevention Study (EGPS). This study was designed to test if lowering intraocular pressure (IOP) by means of dorzolamide is able to prevent or delay conversion from ocular hypertension to glaucoma. DESIGN: Randomized, double-masked, controlled, observational clinical trial. PARTICIPANTS: Eight hundred fifty-four of 1077 ocular hypertensive participants within the EGPS were investigated. Four hundred twenty-nine patients were treated with dorzolamide and 425 patients received placebo. INTERVENTION: Treatment with dorzolamide or placebo (the vehicle of dorzolamide) in 1 or both eyes. MAIN OUTCOME MEASURES: Central corneal thickness as measured by ultrasound pachymetry (DGH-500 Pachette; DGH Technologies, Exton, PA). The CCT measurements were obtained in the morning before measuring IOP. Five measurements were taken from each eye of each patient within 5 minutes of application of anesthetic eye drops. RESULTS: Mean CCT was 572.6+/-37.4 microm (range, 458.5-695.6 microm). The CCT was higher in younger patients, male patients, and diabetic patients. Mean CCTs for the 429 patients receiving dorzolamide were 574.2+/-38.48 microm (range, 458.5-695.6 microm) and 571.0+/-36.21 microm (469.7-690.1 microm) for the 425 patients receiving placebo (P = 0.205). Central corneal thickness did not correlate with refraction, baseline IOP, or systemic hypertension. CONCLUSION: Central corneal thickness measurements within the EGPS were greater than those reported in other studies of normal eyes without ocular hypertension. Larger CCT measurements correlated with male gender, younger age, and diabetes.

Validated prediction model for the development of primary open-angle glaucoma in individuals with ocular hypertension.

OBJECTIVE: To test the validity and generalizability of the Ocular Hypertension Treatment Study (OHTS) prediction model for the development of primary open-angle glaucoma (POAG) in a large independent sample of untreated ocular hypertensive individuals and to develop a quantitative calculator to estimate the 5-year risk that an individual with ocular hypertension will develop POAG. DESIGN: A prediction model was developed from the observation group of the OHTS and then tested on the placebo group of the European Glaucoma Prevention Study (EGPS) using a z statistic to compare hazard ratios, a c statistic for discrimination, and a calibration chi2 for systematic overestimation/underestimation of predicted risk. The 2 study samples were pooled to increase precision and generalizability of a 5-year predictive model for developing POAG. PARTICIPANTS: The OHTS observation group (n = 819; 6.6 years' median follow-up) and EGPS placebo group (n = 500; 4.8 years' median follow-up). TESTING: Data were collected on demographic characteristics, medical history, ocular examination visual fields (VFs), and optic disc photographs. MAIN OUTCOME MEASURE: Development of reproducible VF abnormality or optic disc progression as determined by masked readers and attributed to POAG by a masked end point committee. RESULTS: The same predictors for the development of POAG were identified independently in both the OHTS observation group and the EGPS placebo group-baseline age, intraocular pressure, central corneal thickness, vertical cup-to-disc ratio, and Humphrey VF pattern standard deviation. The pooled multivariate model for the development of POAG had good discrimination (c statistic, 0.74) and accurate estimation of POAG risk (calibration chi2, 7.05). CONCLUSIONS: The OHTS prediction model was validated in the EGPS placebo group. A calculator to estimate the 5-year risk of developing POAG, based on the pooled OHTS-EGPS predictive model, has high precision and will be useful for clinicians and patients in deciding the frequency of tests and examinations during follow-up and advisability of initiating preventive treatment.

Intercurrent factors associated with the development of open-angle glaucoma in the European glaucoma prevention study.

PURPOSE: To evaluate the intercurrent factors for the development of open-angle glaucoma (OAG) in ocular hypertensive patients who were enrolled in the European Glaucoma Prevention Study (EGPS). DESIGN: Randomized, double masked, controlled clinical trial. METHODS: setting: Multicenter. study population: A total of 1,077 patients fulfilled a series of inclusion criteria, including intraocular pressure (IOP) 22 to 29 mm Hg, normal and reliable visual fields (VFs) and normal optic disks. intervention: Treatment with dorzolamide or placebo. main outcome measures: Glaucoma-related VF or optic disk changes. Clinical data were collected every six months during a five-year follow-up. Proportional hazards models were used to identify the factors that during follow-up (intercurrent factors) were associated with the development of OAG. RESULTS: In multivariate analyses, adjusting for treatment arms and baseline predictive factors, mean follow-up IOP reduction (hazard ratio [HR] 0.89, 95% confidence intervals [CI] 0.80 to 0.98), mean follow-up IOP (HR 1.12, 95% CI 1.03 to 1.22), area under the curve of IOP (mm Hg per year) (HR 1.09, 95% CI 1.06 to 1.12), disk hemorrhages (HR 1.97, 95% CI 1.21 to 3.22), and use of systemic diuretics (HR 2.41, 95% CI 1.12 to 5.19) were associated with the development of OAG. Baseline central corneal thickness, vertical cup/disk ratio, vertical cup/disk ratio asymmetry, and pattern standard deviation remained statistically significant. CONCLUSIONS: These results suggest the need for future investigations to better elucidate the role of systemic diuretics in the development of OAG, because IOP and disk hemorrhages have already been shown to be important intercurrent factors in the Ocular Hypertension Treatment Study (OHTS) and Early Manifest Glaucoma Trial (EMGT).

Retinal sensitivity and retinal nerve fiber layer thickness measured by optical coherence tomography in glaucoma.

PURPOSE: To define the relationship between retinal light sensitivity and peripapillary retinal nerve fiber layer (RNFL) thickness as measured using the Stratus optical coherence tomograph (OCT). DESIGN: Prospective study. SETTING: Institutional. STUDY POPULATION: A total of 126 healthy subjects, 42 patients with ocular hypertension (OHT) and 64 patients with primary open-angle glaucoma (POAG) were examined by the 24/II program of the Humphrey Field Analyzer (Carl Zeiss Meditec, Inc, Dublin, California, USA), and the Fast RNFL Thickness examination of the OCT. Individual visual field (VF) test scores and peripapillary RNFL thickness measurements were grouped into six topographically corresponding sectors whose mean values were then calculated. One eye per patient was randomly chosen. MAIN OUTCOME MEASURES: The correlations between mean retinal sensitivity (expressed both in decibel and unlogged scales) and RNFL thickness were described with linear and logarithmic regression analyses. RESULTS: With reference to all 232 individuals, the equation that best explained the model was logarithmic when using the decibel scale, and either linear or logarithmic when using the unlogged scale. A statistically significant, age-adjusted correlation between function and structure was found in most sectors both using the decibel (logarithmic regression analysis r(2) 0.24 to 0.61, P < .001), and the unlogged scale (r(2) 0.37 to 0.53, P < .001 in both linear and logarithmic regression analyses). CONCLUSIONS: When using the decibel scale, the logarithmic equation may better explain the function/structure relationship between retinal sensitivity and OCT-measured RNFL thickness along a wide spectrum of glaucoma continuum. These results support the need to combine functional and structural tests in the detection of early glaucoma.

Criteria for choosing clinically effective glaucoma treatment: A discussion panel consensus.

UNLABELLED: Abstract. BACKGROUND: In the clinical management of patients at risk for or diagnosed with primary open-angle glaucoma (POAG), the aim of medical treatment is to reduce intraocular pressure (IOP) and then maintain it over time at a level that preserves both the structure and function of the optic nerve. OBJECTIVE: The objective of this report was to establish a consensus on the criteria that should be used to determine the characteristics of IOP-lowering medication. METHODS: Discussion was held among a panel of 12 physicians considered to be experts in glaucoma to develop a consensus on the criteria used by them to determine the characteristics of the IOP-lowering medication chosen for initial monotherapy and adjunctive treatment of ocular hypertension (OHT) or POAG. Consensus development combined available evidence and the impressions of these physicians regarding the clinical effectiveness of IOP-lowering medication for OHT and POAG. Once the panel identified the criteria, the order of priority and the relative importance of these criteria were then established in the setting of 3 risk categories (low, medium, and high) for a patient to experience significant visual disability from glaucoma over their expected life span. RESULTS: The panel identified 5 criteria to determine the characteristics of IOP-lowering medication for OHT and POAG: IOP-lowering effect, systemic adverse events (AEs), ocular tolerability, compliance/administration, and cost of treatment. IOP-lowering effect was consistently ranked as the highest priority and cost as the lowest. The priority of compliance/administration did not vary by clinical situation. Systemic AEs and ocular tolerability were ranked as higher priorities in initial monotherapy than in adjunctive treatment and ranked lower as the risk for visual disability increased. The priority given to the criteria used to determine clinical effectiveness varied both with the risk for functional vision loss from glaucoma and whether initial monotherapy or adjunctive treatment was being considered. CONCLUSION: Glaucoma treatment should be assessed with regard to the need not only to lower IOP but also to minimize systemic and ocular AEs, promote patient compliance, and minimize cost. The order of priority and relative importance given to these treatment criteria will vary as part of individualizing patient care.

Clinical ability of pattern electroretinograms and visual evoked potentials in detecting visual dysfunction in ocular hypertension and glaucoma.

OBJECTIVE: To assess the presence of normal or abnormal pattern electroretinogram (PERG) and visual evoked potential (VEP) responses in patients with ocular hypertension or open-angle glaucoma (OAG). DESIGN: Retrospective, cross-sectional, case-control study. PARTICIPANTS: Eighty normal control subjects (mean age, 51.77+/-6.04 years; 80 eyes), 68 ocular hypertension patients (mean age, 51.58+/-7.12; 68 eyes; intraocular pressure [IOP] < 18 mmHg under pharmacological treatment; Humphrey field analysis [HFA] 24/2 mean deviation [MD] > -2 decibels [dB]), and 84 OAG patients (mean age, 52.77+/-5.28; 84 eyes; IOP < 18 mmHg under pharmacological treatment; HFA 24/2 mean deviation between -2 and -23 dB) were enrolled. METHODS: Simultaneous recording of PERGs and VEPs using high-contrast (80%) 15' checkerboard stimuli reversed at the rate of 2 reversals per second. MAIN OUTCOME MEASURES: Pattern electroretinogram P50 and VEP P100 implicit times were considered delayed when exceeding the limit of mean values of controls plus 2 standard deviations (SDs). Pattern electroretinogram P50 to N95 and VEP N75 to P100 amplitudes were considered reduced when exceeding the limit of mean values of controls minus 2 SDs. RESULTS: Pattern electroretinogram: P50 implicit times were delayed in 58 of 68 (85.30%) ocular hypertension eyes and 83 of 84 (98.80%) OAG eyes; P50 to N95 amplitudes were reduced in 47 (69.12%) ocular hypertension eyes and 84 (100%) OAG eyes. Visual evoked potential: P100 implicit times were delayed in 58 (85.30%) ocular hypertension eyes and 84 (100%) OAG eyes; reduced N75 to P100 amplitudes were observed in 39 (57.35%) ocular hypertension eyes and 73 (86.90%) OAG eyes. Ocular hypertension eyes showed no significant correlations (Pearson test, P>0.01) between electrophysiological parameters and age, IOP before or under medical treatment, HFA, and corneal thickness values. Significant correlations (P<0.01) were observed in OAG eyes between electrophysiological results and HFA values. Pattern electroretinogram and VEP responses were normal in all control eyes. CONCLUSIONS: Combined PERG/VEP recordings identified a large percentage of ocular hypertension eyes with impairment of the innermost retinal layers, notwithstanding normal optic disc morphology and normal HFA. In OAG eyes, PERG P50 to N95 amplitude and VEP P100 implicit time showed the highest sensitivity/specificity for the detection of a visual dysfunction. The presence of abnormal PERG and/or VEP responses did not allow a clearcut separation between ocular hypertension and OAG eyes.

Learning effect of short-wavelength automated perimetry in patients with ocular hypertension.

AIM: To evaluate the learning effect of short-wavelength automated perimetry (SWAP) on a group of patients with ocular hypertension experienced with standard automated perimetry (SAP). METHODS: Thirty patients with ocular hypertension underwent 5 full-threshold SWAP tests at intervals of 7+/-2 days. The parameters investigated to detect a learning effect were duration, the perimetric indices, and the number of points with a P of <5% and 1% in the total and pattern deviation maps. Differences in learning effect were also evaluated by comparing the sensitivities of central, paracentral, and peripheral areas, hemifields and quadrants. RESULTS: Learning effects were demonstrated for mean defect (P<0.0001, analysis of variance), duration (P=0.0001), the number of points with P<5% in the pattern deviation map (P=0.003), and short fluctuations (P=0.03). The effect was greater in the peripheral than in central areas (P=0.04). Mean defect was the most sensitive parameter, for which the learning effect was statistically significant between the first and the fifth test. CONCLUSIONS: The results of this study demonstrate a significant learning effect at full-threshold SWAP. This may limit the efficacy of this kind of perimetry in detecting early glaucoma, and should therefore be carefully considered when creating normative databases for new SWAP strategies.

Correlations Between the Individual Risk for Glaucoma and RNFL and Optic Disc Morphometrical Evaluations in Ocular Hypertensive Patients.

PURPOSE: To assess the correlation between the 5-year risk of developing primary open-angle glaucoma (POAG) [on the basis of the Ocular Hypertension Treatment Study (OHTS)-European Glaucoma Prevention Study (EGPS) model] and optic nerve head and retinal nerve fiber layer (RNFL) indices as evaluated by optical coherence tomography (Stratus OCT), scanning laser polarimetry (GDx ECC), and confocal laser ophthalmoscopy [Heidelberg Retinal Tomograph (HRT) III] in ocular hypertensive (OHT) individuals. PARTICIPANTS AND METHODS: Sixty-eight OHT individuals with the untreated intraocular pressure in both eyes between 22 and 32 mm Hg, an ophthalmoscopically normal optic disc with a cup/disc ratio asymmetry between the 2 eyes of ≤0.2, and a visual field with glaucoma hemifield test within normal limits, and pattern SD within P<0.05 were recruited. A comprehensive glaucoma workup and examination by means of OCT, GDx ECC, and HRT III were performed in all of the patients. The probability of developing POAG in 5 years was calculated by means of the OHTS-EGPS model (risk calculator score-RS), which has been developed by the OHTS-EGPS Collaborative Study Group by taking into account the age and the mean values of the central corneal thickness, the intraocular pressure, the pattern SD, and the cup/disc ratio collected in the 2 eyes. Correlations between the individual RS and OCT, GDx, and HRT parameters were then assessed by regression analysis (exponential and linear), with a statistically significant level of P<0.01. RESULTS: The RS of the 68 individuals ranged between 1.5% and 28.6%, with a mean of 10.2% (SD 6.4). Only OCT RNFL-related parameters showed a statistically significant correlation with the RS. The average RNFL thickness had an exponential regression r of 0.21 (P<0.0001) and a linear regression r of 0.14 (P=0.0012); the superior average RNFL thickness had an exponential regression r of 0.26 (P<0.0001) and a linear regression r of 0.23 (P<0.0001); the nasal average RNFL thickness had an exponential regression r of only 0.12 (P=0.0031). Neither GDx RNFL-related parameters nor HRT disc-related parameters showed statistically significant correlations with the RC score. CONCLUSIONS: This explorative study showed that the individual risk to develop POAG within 5 years in OHT individuals is significantly correlated with OCT RNFL parameters, but not with GDx RNFL parameters or HRT disc parameters. OCT parameters could explain about 20% to 25% of the variability in individual RS. The RS seems to take into account the subclinical RNFL thinning shown by the OCT.

24-h Efficacy of Glaucoma Treatment Options.

Current management of glaucoma entails the medical, laser, or surgical reduction of intraocular pressure (IOP) to a predetermined level of target IOP, which is commensurate with either stability or delayed progression of visual loss. In the published literature, the hypothesis is often made that IOP control implies a single IOP measurement over time. Although the follow-up of glaucoma patients with single IOP measurements is quick and convenient, such measurements often do not adequately reflect the untreated IOP characteristics, or indeed the quality of treated IOP control during the 24-h cycle. Since glaucoma is a 24-h disease and the damaging effect of elevated IOP is continuous, it is logical that we should aim to understand the efficacy of all treatment options throughout the 24-h period. This article first reviews the concept and value of diurnal and 24-h IOP monitoring. It then critically evaluates selected available evidence on the 24-h efficacy of medical, laser and surgical therapy options. During the past decade several controlled trials have significantly enhanced our understanding on the 24-h efficacy of all glaucoma therapy options. Nevertheless, more long-term evidence is needed to better evaluate the 24-h efficacy of glaucoma therapy and the precise impact of IOP characteristics on glaucomatous progression and visual prognosis.

Results of the European Glaucoma Prevention Study.

OBJECTIVE: The European Glaucoma Prevention Study (EGPS) seeks to evaluate the efficacy of reduction of intraocular pressure (IOP) by dorzolamide in preventing or delaying primary open-angle glaucoma (POAG) in patients affected by ocular hypertension (OHT). DESIGN: Randomized, double-masked, controlled clinical trial. PARTICIPANTS: One thousand eighty-one patients (age, > or =30 years) were enrolled by 18 European centers. The patients fulfilled a series of inclusion criteria, including: IOP 22 to 29 mmHg; 2 normal and reliable visual fields (on the basis of mean deviation and corrected pattern standard deviation or corrected loss variance of standard 30/II Humphrey or Octopus perimetry); normal optic disc as determined by the Optic Disc Reading Center. INTERVENTION: Patients were randomized to treatment with dorzolamide or placebo (the vehicle of dorzolamide). MAIN OUTCOME MEASURES: Efficacy end points were visual field, optic disc changes, or both. A visual field change during follow-up had to be confirmed by 2 further positive tests. Optic disc change was defined on the basis of the agreement of 2 of 3 independent observers evaluating optic disc stereo slides. The safety end point was an IOP of more than 35 mmHg on 2 consecutive examinations. RESULTS: During the course of the study, the mean percent reduction in IOP in the dorzolamide group was 15% after 6 months and 22% after 5 years. Mean IOP declined by 9% after 6 months and by 19% after 5 years in the placebo group. At 60 months, the cumulative probability of converting to an efficacy end point was 13.4% in the dorzolamide group and 14.1% in the placebo group (hazard ratio, 0.86; 95% confidence interval [CI], 0.58-1.26; P = 0.45). The cumulative probability of developing an efficacy or a safety end point was 13.7% in the dorzolamide group and 16.4% in the placebo group (hazard ratio, 0.73; 95% CI, 0.51-1.06; P = 0.1). CONCLUSIONS: Dorzolamide reduced IOP by 15% to 22% throughout the 5 years of the trial. However, the EGPS failed to detect a statistically significant difference between medical therapy and placebo in reducing the incidence of POAG among a large population of OHT patients at moderate risk for developing POAG, because placebo also significantly and consistently lowered IOP.

the impact of definition of primary open-angle glaucoma on the cross-sectional assessment of diagnostic validity of Heidelberg retinal tomography.

PURPOSE: To evaluate the impact of different definitions of primary open angle glaucoma (POAG) on assessment of the diagnostic validity of Heidelberg Retinal Tomography (HRT). DESIGN: Retrospective, cross-sectional study. METHODS: A search of medline (1992-2003) led to the retrieval of 181 papers containing definitions of POAG, including the eight visual field (VF)-based definitions used for this study. A sample of 193 normal subjects, 222 patients with suspected POAG, and 103 with POAG underwent HRT and the 24 II Humphrey VF examinations to assess the diagnostic validity of HRT. POAG was defined on the basis of Glaucoma Hemifield Test (GHT) "out of normal limits" associated with corrected pattern standard deviation (CPSD) > 2 dB and intraocular pressure (IOP) > or =22 mm Hg. The VFs were re-analyzed and categorized according to the other eight definitions of POAG: IOP formed part of all the definitions, whereas the appearance of the optic disk did not. The sensitivity and specificity of each scenario were calculated by standard procedures. RESULTS: The definitions of POAG found in the literature included 17 IOP criteria, more than 15 optic disk criteria, and more than 30 VF criteria. The sensitivity of HRT ranged from 0.51 to 0.80, and its specificity from 0.94 and 0.95 when the patients with suspected POAG were excluded; diagnostic validity was much lower and still variable when the POAG suspects were included with the normal or the POAG groups. CONCLUSIONS: The most commonly used VF-based definitions of POAG led to substantial differences in the sensitivity and specificity of HRT when using the same large sample of normal subjects and POAG patients. A standard definition of POAG is needed to make diagnostic investigations more accurate and comparable.

Exfoliative glaucoma: new evidence in the pathogenesis and treatment.

Exfoliation or pseudoexfoliation syndrome (PXF) is an age-related ocular and systemic disease in which abnormal extracellular material is produced and accumulates in many tissues. PXF is the most common identifiable cause of open-angle glaucoma (OAG). PXFG is a particularly aggressive type of OAG, which runs with a faster rate of progression and poorer response to medical therapy than primary OAG (POAG). The prevalence of the condition shows huge variations among different population, Scandinavian and Mediterranean race being the most affected. Many genetics and environmental factors are involved in the pathogenesis and remarkable progresses in understanding the involved factors have been achieved in the past years. Population-based studies have identified mutations on the lysil-oxidase-like 1(LOXL1) gene as a risk factor for PXFS. Environmental and behavioral factors such as latitude of residence, caffeine intake, and vitamins deficiency are under investigation for a possible involvement in determining the disease in genetically predisposed individuals. Treatment options are similar to those recommended for POAG. Exfoliation syndrome predisposes to capsular rupture, zonular dehiscence, and vitreous loss during cataract extraction. Laser trabeculoplasty has been demonstrated to show good clinical outcomes in PXF patients. A review of the current literature and scientific evidences on pathogenesis and treatment is presented.