Intervals between visual field tests when monitoring the glaucomatous patient: wait-and-see approach

Purpose.: Published recommendations suggest three visual field (VF) tests per year are required to identify rapid progression in a newly diagnosed glaucomatous patient over 2 years. This report aims to determine if identification of progression would be improved by clustering tests at the beginning and end of the 2-year period. Methods.: Computer-simulated “patients” were given a rapid VF (mean deviation [MD]) loss of −2 dB/year with added MD measurement variability. Linear regression of MD against time was used to estimate progression. One group of “patients” was measured every 6 months, another every 4 months, whereas the wait-and-see group were measured either 2 or 3 times at both baseline and at the end of a 2-year period. Stable “patients” (0 dB/year) were generated to examine the effect of the follow-up patterns on false-positive (FP) progression identification. Results.: By 2 years, 58% and 82% of rapidly progressing patients were correctly detected using evenly spaced 6- and 4-month VFs, respectively. This power of detection significantly improved to 62% and 95% with the wait-and-see approach (P < 0.001). When compared with evenly spaced VFs, the rate of MD loss was better estimated by the wait-and-see approach, but average detection time was slightly slower. Evenly spaced testing incurred a significantly higher FP rate: up to 5.9% compared with only 0.4% in wait-and-see (P < 0.001). Conclusions.: Compared with an evenly spaced follow-up, wait-and-see identifies more “patients” with rapid VF progression with fewer FPs, making it particularly applicable to clinical trials. Modeling experiments, as reported here, are useful for investigating and optimizing follow-up schemes

How does glaucoma look?: Patient perception of visual field loss

Objective: To explore patient perception of vision loss in glaucoma and, specifically, to test the hypothesis that patients do not recognize their impairment as a black tunnel effect or as black patches in their field of view. Design: Clinic-based cross-sectional study. Participants: Fifty patients (age range, 52-82 years) with visual acuity better than 20/30 and with a range of glaucomatous visual field (VF) defects in both eyes, excluding those with very advanced disease (perimetrically blind). Methods: Participants underwent monocular VF testing in both eyes using a Humphrey Field Analyzer (HFA; Carl Zeiss Meditec, Dublin, CA; 24-2 Swedish interactive threshold algorithm standard tests) and other tests of visual function. Participants took part in a recorded interview during which they were asked if they were aware of their VF loss; if so, there were encouraged to describe it in their own words. Participants were shown 6 images modified in a variety of ways on a computer monitor and were asked to select the image that most closely represented their perception of their VF loss. Main Outcome Measures: Forced choice of an image best representing glaucomatous vision impairment. Results: Participants had a range of VF defect severity: average HFA mean deviation was -8.7 dB (standard deviation [SD], 5.8 dB) and -10.5 dB (SD, 7.1 dB) in the right and left eyes, respectively. Thirteen patients (26%; 95% confidence interval [CI], 15%-40%) reported being completely unaware of their vision loss. None of the patients chose the images with a distinct black tunnel effect or black patches. Only 2 patients (4%; 95% CI, 0%-14%) chose the image with a tunnel effect with blurred edges. An image depicting blurred patches and another with missing patches was chosen by 54% (95% CI, 39%-68%) and 16% (95% CI, 7%-29%) of the patients, respectively. Content analysis of the transcripts from the recorded interviews indicated a frequent use of descriptors of visual symptoms associated with reported blur and missing features. Conclusions: Patients with glaucoma do not perceive their vision loss as a black tunnel effect or as black patches masking their field of view. These findings are important in the context of depicting the effects of glaucomatous vision loss and raising awareness for glaucoma detection. Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article

Quantifying discordance between structure and function measurements in the clinical assessment of glaucoma

Objective: The visual field (VF) may be predicted from retinal nerve fibre layer thickness (RNFLT) using a Bayesian Radial Basis Function (BRBF). This study aimed to evaluate a new methodology to quantify and visualise discordance between structural and functional measurements in glaucomatous eyes. Methods: Five GDxVCC RNFLT scans and 5 Humphrey SITA VF tests were obtained from 50 glaucomatous eyes from 50 patients. A best available estimate of the ‘true’ VF was calculated as the point-wise median of these 5 replications. This ‘true’ VF was compared with every single RNFLT-predicted VF from BRBF and every single measured VF. Predictability of VFs from RNFLT was established from previous data. A structure-function pattern discordance map (PDM) and structure-function discordance index (SFDI; values 0 to 1) were established from the predictability limits for each structure-function measurement pair to quantify and visualise the discordance between the structure-predicted and measured VFs. Results: Mean absolute difference (MAD) between the structure-predicted and ‘true’ VFs was 3.9dB. MAD between single and ‘true’ VFs was 2.6dB. Mean of SFDI was 0.34 (SD 0.11). 39% of the structure-predicted VFs showed significant discordance (SFDI>0.3) from measured VFs. Conclusions: BRBF, on average, predicts the ‘true’ VF from RNFLT slightly less well than a measured VF from the 5 VFs compromising the ‘true’ VF. The PDM highlights locations with structure-function discordance, with the SFDI providing a summary index. These tools may help clinicians trust the mutually confirmatory structure-function measurements with good concordance, or identify unreliable ones with poor concordance

Evaluation of Visual Field and Imaging Outcomes for Glaucoma Clinical Trials (An American Ophthalomological Society Thesis)

PURPOSE: To evaluate the ability of various visual field (VF) analysis methods to discriminate treatment groups in glaucoma clinical trials and establish the value of time-domain optical coherence tomography (TD OCT) imaging as an additional outcome. METHODS: VFs and retinal nerve fibre layer thickness (RNFLT) measurements (acquired by TD OCT) from 373 glaucoma patients in the UK Glaucoma Treatment Study (UKGTS) at up to 11 scheduled visits over a 2 year interval formed the cohort to assess the sensitivity of progression analysis methods. Specificity was assessed in 78 glaucoma patients with up to 11 repeated VF and OCT RNFLT measurements over a 3 month interval. Growth curve models assessed the difference in VF and RNFLT rate of change between treatment groups. Incident progression was identified by 3 VF-based methods: Guided Progression Analysis (GPA), 'ANSWERS' and 'PoPLR', and one based on VFs and RNFLT: 'sANSWERS'. Sensitivity, specificity and discrimination between treatment groups were evaluated. RESULTS: The rate of VF change was significantly faster in the placebo, compared to active treatment, group (-0.29 vs +0.03 dB/year, P<.001); the rate of RNFLT change was not different (-1.7 vs -1.1 dB/year, P=.14). After 18 months and at 95% specificity, the sensitivity of ANSWERS and PoPLR was similar (35%); sANSWERS achieved a sensitivity of 70%. GPA, ANSWERS and PoPLR discriminated treatment groups with similar statistical significance; sANSWERS did not discriminate treatment groups. CONCLUSIONS: Although the VF progression-detection method including VF and RNFLT measurements is more sensitive, it does not improve discrimination between treatment arms

Diagnostic accuracy of technologies for glaucoma case-finding in a community setting

DESIGN: Cross-sectional, observational, community-based study. PARTICIPANTS: A total of 505 subjects aged ≥60 years recruited from a community setting using no predefined exclusion criteria. METHODS: Subjects underwent 4 index tests conducted by a technician unaware of subjects' ocular status. FDT and MMDT were used in suprathreshold mode. iVue OCT measured ganglion cell complex and retinal nerve fiber layer (RNFL) thickness. Reference standard was full ophthalmic examination by an experienced clinician who was masked to index test results. Subjects were classified as POAG (open drainage angle, glaucomatous optic neuropathy, and glaucomatous field defect), glaucoma suspect, ocular hypertension, or non-POAG/nonocular hypertension. MAIN OUTCOME MEASURES: Test performance evaluated the individual as the unit of analysis. Diagnostic accuracy was assessed using predefined cutoffs for abnormality, generating sensitivity, specificity, and likelihood ratios. Continuous data were used to derive estimates of sensitivity at 90% specificity and partial area under the receiver operating characteristic curve (AUROC) plots from 90% to 100% specificity. RESULTS: From the reference standard examination, 26 subjects (5.1%) had POAG and 32 subjects (6.4%) were glaucoma suspects. Sensitivity (95% confidence interval) at 90% specificity for detection of glaucoma suspect/POAG combined was 41% (28-55) for FDT, 35% (21-48) for MMDT, and 57% (44-70) for best-performing OCT parameter (inferior quadrant RNFL thickness); for POAG, sensitivity was 62% (39-84) for FDT, 58% (37-78) for MMDT, and 83% (68-98) for inferior quadrant RNFL thickness. Partial AUROC was significantly greater for inferior RNFL thickness than visual-function tests (P < 0.001). Post-test probability of glaucoma suspect/POAG combined and definite POAG increased substantially when best-performing criteria were combined for FDT or MMDT, iVue OCT, and ORA. CONCLUSIONS: Diagnostic performance of individual tests gave acceptable accuracy for POAG detection. Low specificity of visual-function tests precludes their use in isolation, but case detection improves by combining RNFL thickness analysis with visual function tests

Aligning scan acquisition circles in optical coherence tomography images of the retinal nerve fibre layer

Optical coherence tomography (OCT) is widely used in the assessment of retinal nerve fibre layer thickness (RNFLT) in glaucoma. Images are typically acquired with a circular scan around the optic nerve head. Accurate registration of OCT scans is essential for measurement reproducibility and longitudinal examination. This study developed and evaluated a special image registration algorithm to align the location of the OCT scan circles to the vessel features in the retina using probabilistic modelling that was optimised by an expectation-maximization algorithm. Evaluation of the method on 18 patients undergoing large numbers of scans indicated improved data acquisition and better reproducibility of measured RNFLT when scanning circles were closely matched. The proposed method enables clinicians to consider the RNFLT measurement and its scan circle location on the retina in tandem, reducing RNFLT measurement variability and assisting detection of real change of RNFLT in the longitudinal assessment of glaucoma

Exploring Eye Movements in Patients with Glaucoma When Viewing a Driving Scene

Background: Glaucoma is a progressive eye disease and a leading cause of visual disability. Automated assessment of the visual field determines the different stages in the disease process: it would be desirable to link these measurements taken in the clinic with patient's actual function, or establish if patients compensate for their restricted field of view when performing everyday tasks. Hence, this study investigated eye movements in glaucomatous patients when viewing driving scenes in a hazard perception test (HPT). Methodology/Principal Findings: The HPT is a component of the UK driving licence test consisting of a series of short film clips of various traffic scenes viewed from the driver's perspective each containing hazardous situations that require the camera car to change direction or slow down. Data from nine glaucomatous patients with binocular visual field defects and ten age-matched control subjects were considered (all experienced drivers). Each subject viewed 26 different films with eye movements simultaneously monitored by an eye tracker. Computer software was purpose written to pre-process the data, co-register it to the film clips and to quantify eye movements and point-of-regard (using a dynamic bivariate contour ellipse analysis). On average, and across all HPT films, patients exhibited different eye movement characteristics to controls making, for example, significantly more saccades (P<0.001; 95% confidence interval for mean increase: 9.2 to 22.4%). Whilst the average region of ‘point-of-regard’ of the patients did not differ significantly from the controls, there were revealing cases where patients failed to see a hazard in relation to their binocular visual field defect. Conclusions/Significance: Characteristics of eye movement patterns in patients with bilateral glaucoma can differ significantly from age-matched controls when viewing a traffic scene. Further studies of eye movements made by glaucomatous patients could provide useful information about the definition of the visual field component required for fitness to drive

Detecting Changes in Retinal Function: Analysis with Non-Stationary Weibull Error Regression and Spatial Enhancement (ANSWERS)

Visual fields measured with standard automated perimetry are a benchmark test for determining retinal function in ocular pathologies such as glaucoma. Their monitoring over time is crucial in detecting change in disease course and, therefore, in prompting clinical intervention and defining endpoints in clinical trials of new therapies. However, conventional change detection methods do not take into account non-stationary measurement variability or spatial correlation present in these measures. An inferential statistical model, denoted ‘Analysis with Non-Stationary Weibull Error Regression and Spatial enhancement’ (ANSWERS), was proposed. In contrast to commonly used ordinary linear regression models, which assume normally distributed errors, ANSWERS incorporates non-stationary variability modelled as a mixture of Weibull distributions. Spatial correlation of measurements was also included into the model using a Bayesian framework. It was evaluated using a large dataset of visual field measurements acquired from electronic health records, and was compared with other widely used methods for detecting deterioration in retinal function. ANSWERS was able to detect deterioration significantly earlier than conventional methods, at matched false positive rates. Statistical sensitivity in detecting deterioration was also significantly better, especially in short time series. Furthermore, the spatial correlation utilised in ANSWERS was shown to improve the ability to detect deterioration, compared to equivalent models without spatial correlation, especially in short follow-up series. ANSWERS is a new efficient method for detecting changes in retinal function. It allows for better detection of change, more efficient endpoints and can potentially shorten the time in clinical trials for new therapies

HRT-3 Moorfields reference plane: effect on rim area repeatability and identification of progression

Aims: To assess the effect of the Moorfields Reference Plane on Heidelberg Retina Tomograph (HRT) rim area repeatability and its effect on progression rates using an event analysis. Methods: The HRT reference plane (RP) defines structures above as “rim” and below as “cup.” The Moorfields RP applies the Standard RP (located 50 μm posterior to the temporal disc margin) at baseline and maintains the distance between the Standard RP and the reference ring (located in the image periphery) for follow-up images. The Moorfields RP was applied to an HRT test-retest dataset, and rim area repeatability coefficients were calculated. Repeatability coefficients were compared between the Moorfields, Standard and 320 (located 320 μm posterior to the reference ring) RPs. The Moorfields RP was applied to HRT images from 198 ocular hypertensives, acquired over 6 years. HRT progression required rim area baseline/follow-up differences exceeding the repeatability coefficient in two or more sectors, with confirmation in at least one of two consecutive images. Field progression was assessed using Advanced Glaucoma Intervention Study criteria. Results: The Moorfields RP improved rim area repeatability compared with the Standard RP; repeatability was similar between the Moorfields and the 320 RP. The frequency of identified progression using Moorfields RP was 40% compared with 28% for the 320 RP. There was a greater percentage with concurrent field progression -15.1% (Moorfields RP) compared with 12.1% (320 RP). Conclusions: Although rim area repeatability was similar using the 320 RP and the Moorfields RP, the latter resulted in greater rates of detection of change

Combining optical coherence tomography with visual field data to rapidly detect disease progression in glaucoma: A diagnostic accuracy study

Background: Progressive optic nerve damage in glaucoma results in vision loss, quantifiable with visual field (VF) testing. VF measurements are, however, highly variable, making identification of worsening vision (‘progression’) challenging. Glaucomatous optic nerve damage can also be measured with imaging techniques such as optical coherence tomography (OCT). Objective: To compare statistical methods that combine VF and OCT data with VF-only methods to establish whether or not these allow (1) more rapid identification of glaucoma progression and (2) shorter or smaller clinical trials. Design: Method ‘hit rate’ (related to sensitivity) was evaluated in subsets of the United Kingdom Glaucoma Treatment Study (UKGTS) and specificity was evaluated in 72 stable glaucoma patients who had 11 VF and OCT tests within 3 months (the RAPID data set). The reference progression detection method was based on Guided Progression Analysis™ (GPA) Software (Carl Zeiss Meditec Inc., Dublin, CA, USA). Index methods were based on previously described approaches [Analysis with Non-Stationary Weibull Error Regression and Spatial enhancement (ANSWERS), Permutation analyses Of Pointwise Linear Regression (PoPLR) and structure-guided ANSWERS (sANSWERS)] or newly developed methods based on Permutation Test (PERM), multivariate hierarchical models with multiple imputation for censored values (MaHMIC) and multivariate generalised estimating equations with multiple imputation for censored values (MaGIC). Setting: Ten university and general ophthalmology units (UKGTS) and a single university ophthalmology unit (RAPID). Participants: UKGTS participants were newly diagnosed glaucoma patients randomised to intraocular pressure-lowering drops or placebo. RAPID participants had glaucomatous VF loss, were on treatment and were clinically stable. Interventions: 24-2 VF tests with the Humphrey Field Analyzer and optic nerve imaging with time-domain (TD) Stratus OCT™ (Carl Zeiss Meditec Inc., Dublin, CA, USA). Main outcome measures: Criterion hit rate and specificity, time to progression, future VF prediction error, proportion progressing in UKGTS treatment groups, hazard ratios (HRs) and study sample size. Results: Criterion specificity was 95% for all tests; the hit rate was 22.2% for GPA, 41.6% for PoPLR, 53.8% for ANSWERS and 61.3% for sANSWERS (all comparisons p ≤ 0.042). Mean survival time (weeks) was 93.6 for GPA, 82.5 for PoPLR, 72.0 for ANSWERS and 69.1 for sANSWERS. The median prediction errors (decibels) when the initial trend was used to predict the final VF were 3.8 (5th to 95th percentile 1.7 to 7.6) for PoPLR, 3.0 (5th to 95th percentile 1.5 to 5.7) for ANSWERS and 2.3 (5th to 95th percentile 1.3 to 4.5) for sANSWERS. HRs were 0.57 [95% confidence interval (CI) 0.34 to 0.90; p = 0.016] for GPA, 0.59 (95% CI 0.42 to 0.83; p = 0.002) for PoPLR, 0.76 (95% CI 0.56 to 1.02; p = 0.065) for ANSWERS and 0.70 (95% CI 0.53 to 0.93; p = 0.012) for sANSWERS. Sample size estimates were not reduced using methods including OCT data. PERM hit rates were between 8.3% and 17.4%. Treatment effects were non-significant in MaHMIC and MaGIC analyses; statistical significance was altered little by incorporating imaging. Limitations: TD OCT is less precise than current imaging technology; current OCT technology would likely perform better. The size of the RAPID data set limited the precision of criterion specificity estimates. Conclusions: The sANSWERS method combining VF and OCT data had a higher hit rate and identified progression more quickly than the reference and other VF-only methods, and produced more accurate estimates of the progression rate, but did not increase treatment effect statistical significance. Similar studies with current OCT technology need to be undertaken and the statistical methods need refinement