Comparison Between 24-2 ZEST and 24-2 ZEST FAST Strategies in Glaucoma and Ocular Hypertension Using a Fundus Perimeter.

PRCIS: Using a Compass (CMP) (CMP, Centervue, Padova, Italy) fundus perimeter, Zippy Estimation by Sequential Testing (ZEST) FAST strategy showed a significant reduction in examination time compared with ZEST, with good agreement in the quantification of perimetric damage. PURPOSE: The aim of this study was to compare the test duration of ZEST strategy with ZEST FAST and to evaluate the test-retest variability of ZEST FAST strategy on patients with glaucoma and ocular hypertension. PATIENTS AND METHODS: This was a multicenter retrospective study. We analyzed 1 eye of 60 subjects: 30 glaucoma patients and 30 patients with ocular hypertension. For each eye we analyzed, 3 visual field examinations were performed with Compass 24-2 grid: 1 test performed with ZEST strategy and 2 tests performed with ZEST FAST. Mean examination time and mean sensitivity between the 2 strategies were computed. ZEST FAST test-retest variability was examined. RESULTS: In the ocular hypertension cohort, test time was 223±29 seconds with ZEST FAST and 362±48 seconds with ZEST (38% reduction, P <0.001). In glaucoma patients, it was respectively 265±62 and 386±78 seconds (31% reduction using ZEST FAST, P <0.001). The difference in mean sensitivity between the 2 strategies was -0.24±1.30 dB for ocular hypertension and -0.14±1.08 dB for glaucoma. The mean difference in mean sensitivity between the first and the second test with ZEST FAST strategy was 0.2±0.8 dB for patients with ocular hypertension and 0.24±0.96 dB for glaucoma patients. CONCLUSIONS: ZEST FAST thresholding provides similar results to ZEST with a significantly reduced examination time.

Spatial Summation in the Glaucomatous Macula: A Link With Retinal Ganglion Cell Damage.

Purpose: The purpose of this study was to test whether functional loss in the glaucomatous macula is characterized by an enlargement of Ricco's area (RA) through the application of a computational model linking retinal ganglion cell (RGC) damage to perimetric sensitivity. Methods: One eye from each of 29 visually healthy subjects <40 years old, 30 patients with glaucoma, and 20 age-similar controls was tested with a 10-2 grid with stimuli of 5 different area sizes. Structural estimates of point-wise RGC density were obtained from optical coherence tomography (OCT) scans. Structural and functional data from the young healthy cohort were used to estimate the parameters of a computational spatial summation model to generate a template. The template was fitted with a Bayesian hierarchical model to estimate the latent RGC density in patients with glaucoma and age-matched controls. We tested two alternative hypotheses: fitting the data by translating the template horizontally (H1: change in RA) or vertically (H2: loss of sensitivity without a change in RA). Root mean squared error (RMSE) of the model fits to perimetric sensitivity were compared. Ninety-five percent confidence intervals were bootstrapped. The dynamic range of the functional and structural RGC density estimates was denoted by their 1st and 99th percentiles. Results: The RMSE was 2.09 (95% CI = 1.92-2.26) under H1 and 2.49 (95% CI = 2.24-2.72) under H2 (P < 0.001). The average dynamic range for the structural RGC density estimates was only 11% that of the functional estimates. Conclusions: Macular sensitivity loss in glaucoma is better described by a model in which RA changes with RGC loss. Structural measurements have limited dynamic range.

BRUCH MEMBRANE RUPTURE AND CHOROIDAL NEOVASCULARIZATION COMPLICATING EXTENSIVE MACULAR ATROPHY WITH PSEUDODRUSEN-LIKE APPEARANCE: A CASE REPORT.

PURPOSE: To describe a case of extensive macular atrophy with pseudodrusen-like appearance complicated by Bruch membrane rupture and choroidal neovascularization, treated with intravitreal injection of an antivascular endothelial growth factor drug. METHODS: A 54-year-old woman, affected by extensive macular atrophy with pseudodrusen-like appearance, has developed Bruch membrane rupture and choroidal neovascularization. This report discusses the development of the disease and the improvement after a single intravitreal injection of Avastin. RESULTS: After treatment, the visual acuity increased from 20/400 to 20/200; clinical and anatomical improvement remained stable with a 2-month follow-up. CONCLUSION: Extensive macular atrophy with pseudodrusen-like appearance could be complicated by Bruch membrane rupture and subsequent choroidal neovascularization. Antivascular endothelial growth factor intravitreal injection could have beneficial effects on this entity, but concern could raise in respect of possible increase of chorioretinal atrophy.

Improving event-based progression analysis in glaucomatous visual fields.

Glaucoma is a progressive optic neuropathy with characteristic changes to the optic nerve head and the visual field (VF). Detecting progression of VF damage with Standard Automated Perimetry (SAP) is of paramount importance for clinical care. One common approach to detecting progression is to compare each new VF test to a baseline SAP test (event analysis). This comparison is made difficult by the test-retest variability of SAP, which increases with the level of VF damage, and the limited range of measurement, meaning that damage cannot be assessed below a certain level. We performed a prospective international multi-centre data collection of SAP data on 90 eyes from 90 people with glaucoma and different levels of VF damage over a short period of time (6 tests in 60 days). Data were collected using a fundus tracked perimeter (Compass, CenterVue). We used these data (minus the first test) to develop an improved event analysis that accounts for both the change in variability with damage and the lower bound on the measurement imposed by SAP. Using simulations, we show that our approach is more sensitive compared to previously developed methods, especially in the case of advanced glaucoma, while retaining similar specificity.

Do Additional Testing Locations Improve the Detection of Macular Perimetric Defects in Glaucoma?

PURPOSE: To evaluate the ability of additional central testing locations to improve detection of macular visual field (VF) defects in glaucoma. DESIGN: Prospective cross-sectional study. PARTICIPANTS: Four hundred forty healthy people and 499 patients with glaucomatous optic neuropathy (GON) were tested with a fundus tracked perimeter (CMP; CenterVue) using a 24-2 grid with 12 additional macular locations (24-2+). METHODS: Glaucomatous optic neuropathy was identified based on expert evaluation of optic nerve head photographs and OCT scans, independently of the VF. We defined macular defects as locations with measurements outside the 5% and 2% normative limits on total deviation (TD) and pattern deviation (PD) maps within the VF central 10°. Classification was based on the total number of affected macular locations (overall detection) or the largest number of affected macular locations connected in a contiguous cluster (cluster detection). Criteria based on the number of locations and cluster size were used to obtain equivalent specificity between the 24-2 grid and the 24-2+ grids, calculated using false detections in the healthy cohort. Partial areas under the receiver operating characteristic curve (pAUCs) were also compared at specificities of 95% or more. MAIN OUTCOME MEASURES: Matched specificity comparison of the ability to detect glaucomatous macular defects between the 24-2 and 24-2+ grids. RESULTS: At matched specificity, cluster detection identified more macular defects with the 24-2+ grid compared with the 24-2 grid. For example, the mean increase in percentage of detection was 8% (95% confidence interval [CI], 5%-11%) and 10% (95% CI, 7%-13%) for 5% TD and PD maps, respectively, and 5% (95% CI, 2%-7%) and 6% (95% CI, 4%-8%) for the 2% TD and PD maps, respectively. Good agreement was found between the 2 grids. The improvement measured by pAUCs was also significant but generally small. The percentage of eyes with macular defects ranged from about 30% to 50%. Test time for the 24-2+ grid was longer (21% increase) for both cohorts. Between 74% and 98% of defects missed by the 24-2 grid had at least 1 location with sensitivity of < 20 dB. CONCLUSIONS: Visual field examinations with additional macular locations can improve the detection of macular defects in GON modestly without loss of specificity when appropriate criteria are selected.

Systematic and Random Mapping Errors in Structure - Function Analysis of the Macula.

Purpose: Quantify the spatial error in mapping perimetric stimuli for structure-function analysis resulting from the choice of mapping scheme and eye movements. Methods: We analyzed data from 17 healthy and 30 glaucomatous participants. Structural data of the macula were collected with a spectral-domain optical coherence tomography. We extracted eye movement data and projection locations from a fundus tracking perimeter and quantified the retinal location mapping error (distance between the actual and the intended stimulus location in degrees from the fovea) for non-tracked perimetry in a 10-2 grid. First, we evaluated whether rotating the 10-2 grid to match the fovea-disc axis improved mapping accuracy. Second, we analyzed the effect of eccentric fixation, random eye movements, and gaze attraction from seen stimuli on projection accuracy and spread of fixation, measured with the 95% bivariate contour ellipse area (95% BCEA). We used generalized linear mixed models for our statistical analyses. Results: Rotating the 10-2 grid to match the fovea-disc axis significantly increased the mapping error (P < 0.001). Eye movements evoked by seen stimuli significantly increased the projection error during the test (P < 0.001). Removing such eye movements significantly reduced the 95% BCEA (P < 0.001). Eccentric fixation also significantly contributed to the projection error (P < 0.001), and its effect was larger in glaucoma patients (P < 0.001). Conclusions: Rotating the perimetric grid to match the fovea-disc axis is not recommended. Fixation eccentricity and instability should be taken into account for structure-function analyses. Translational Relevance: Accounting for fixation can improve structure-function mapping in glaucoma.

Visual Field Endpoints Based on Subgroups of Points May Be Useful in Glaucoma Clinical Trials: A Study With the Humphrey Field Analyzer and Compass Perimeter.

PRECIS: Visual field (VF) endpoints based on average deviation of specific subsets of points rather than all points may offer a more homogeneous data set without necessarily worsening test-retest variability and so may be useful in clinical trials. PURPOSE: The purpose of this study was to characterize the outcome measures encompassing particular subsets of VF points and compare them as obtained with Humphrey [Humphrey visual field analyser (HVF)] and Compass perimeters. METHODS: Thirty patients with imaging-based glaucomatous neuropathy performed a pair of 24-2 tests with each of 2 perimeters. Nonweighted mean deviation (MD) was calculated for the whole field and separate vertical hemifields, and again after censoring of points with low sensitivity (MDc) and subsequently including only "abnormal" points with a total deviation probability of <5% (MDc5%) or <2% (MDc2%). Test-retest variability was assessed using Bland-Altman 95% limits of agreement (95%LoA). RESULTS: For the whole field, using HVF, MD was -7.5±6.9 dB, MDc -3.6±2.8 dB, MDc5% -6.4±1.7 dB, and MDc2% -7.3±1.5 dB. With Compass the MD was -7.5±6.6, MDc -2.9±1.7 dB, MDc5% -6.3±1.5, and MDC2% -7.9±1.6. The respective 95%LoA were 5.5, 5.3, 4.6, and 5.6 with HVF, and 4.8, 3.7, 7.1, and 7.1 with Compass. The respective number of eligible points were 52, 42±12, 20±11, and 15±9 with HVF, and 52, 41.2±12.6, 10±7, and 7±5 with Compass. With both machines, SD and 95%LoA increased in hemifields compared with the total field, but this increase was mitigated after censoring. CONCLUSION: Restricting analysis to particular subsets of points of interest in the VF after censoring points with low sensitivity, as compared with using the familiar total field MD, can provide outcome measures with a broader range of MD, a markedly reduced SD and therefore more homogeneous data set, without necessarily worsening test-retest variability.

Revisiting the Drasdo Model: Implications for Structure-Function Analysis of the Macular Region.

Purpose: To provide a consistent implementation of a retinal ganglion cell (RGC) displacement model proposed by Drasdo et al. for macular structure-function analysis, customizable by axial length (AL). Methods: The effect of axial length on the shape of the inner retina was measured on 235 optical coherence tomography (OCT) scans from healthy eyes, to provide evidence for geometric scaling of structures with eye size. Following this assumption, we applied the Drasdo model to map perimetric stimuli on the radially displaced RGCs using two different methods: Method 1 only displaced the center of the stimuli; Method 2 applied the displacement to every point on the edge of the stimuli. We compared the accuracy of the two methods by calculating, for each stimulus, the number of expected RGC receptive fields and the number RGCs calculated from the histology map, expected to be equivalent. The same calculation was repeated on RGC density maps derived from 28 OCT scans from 28 young healthy subjects (age < 40 years) to confirm our results on clinically available measurements. Results: The size of the retinal structures significantly increased with AL (P < 0.001) and was well predicted by geometric scaling. Method 1 systematically underestimated the RGC counts by as much as 60%. No bias was observed with Method 2. Conclusions: The Drasdo model can effectively account for AL assuming geometric scaling. Method 2 should be used for structure-function analyses. Translational Relevance: We developed a free web App in Shiny R to make our results available for researchers.

Effect of fundus tracking on structure-function relationship in glaucoma.

AIMS: To investigate the effect of fundus tracking perimetry on structure-function relationship in glaucoma. METHODS: Perimetric data were acquired with the Humphrey Field Analyzer (HFA) and the Compass fundus perimeter (CMP, equipped with fundus tracking). We included data from 696 eyes from 360 healthy people and 711 eyes from 434 patients with glaucoma from the original study, for which the circumpapillary retinal nerve fibre layer optical coherence tomography scan (Cp-RNFL) was available. We explored the structure-function relationship using both global indices (mean deviation and average Cp-RNFL thickness loss) and anatomically defined visual field clusters comparing the R2 values from mixed-effect models. We then measured the diagnostic ability of a combined Structure Function Index (SFI) using perimetric data from either perimeter. The comparisons were based on partial receiver operating characteristic curves with a minimum specificity of 75% and their areas under the curve. RESULTS: The R2 for the global structure-function relationship was 0.50 for the CMP and 0.48 for the HFA. When visual field clusters were included in the model, the R2 was 0.29 for CMP and 0.30 for HFA. Overall, the discrimination ability of the SFI was not significantly higher than the Cp-RNFL for either the CMP (p=0.07) or the HFA (p=0.14). However, it was significantly better in eyes with perimetric damage (p<0.001), in which the CMP-SFI performed significantly better than the HFA-SFI (p=0.03). CONCLUSIONS: Structure-function relationship is similar between the two perimeters. Fundus tracking might improve discrimination ability with a combined SFI. TRIAL REGISTRATION NUMBER: ISRCTN13800424.

A Comparison between the Compass Fundus Perimeter and the Humphrey Field Analyzer.

PURPOSE: To evaluate relative diagnostic precision and test-retest variability of 2 devices, the Compass (CMP, CenterVue, Padova, Italy) fundus perimeter and the Humphrey Field Analyzer (HFA, Zeiss, Dublin, CA), in detecting glaucomatous optic neuropathy (GON). DESIGN: Multicenter, cross-sectional, case-control study. PARTICIPANTS: We sequentially enrolled 499 patients with glaucoma and 444 normal subjects to analyze relative precision. A separate group of 44 patients with glaucoma and 54 normal subjects was analyzed to assess test-retest variability. METHODS: One eye of recruited subjects was tested with the index tests: HFA (Swedish interactive thresholding algorithm [SITA] standard strategy) and CMP (Zippy Estimation by Sequential Testing [ZEST] strategy), 24-2 grid. The reference test for GON was specialist evaluation of fundus photographs or OCT, independent of the visual field (VF). For both devices, linear regression was used to calculate the sensitivity decrease with age in the normal group to compute pointwise total deviation (TD) values and mean deviation (MD). We derived 5% and 1% pointwise normative limits. The MD and the total number of TD values below 5% (TD 5%) or 1% (TD 1%) limits per field were used as classifiers. MAIN OUTCOME MEASURES: We used partial receiver operating characteristic (pROC) curves and partial area under the curve (pAUC) to compare the diagnostic precision of the devices. Pointwise mean absolute deviation and Bland-Altman plots for the mean sensitivity (MS) were computed to assess test-retest variability. RESULTS: Retinal sensitivity was generally lower with CMP, with an average mean difference of 1.85±0.06 decibels (dB) (mean ± standard error, P < 0.001) in healthy subjects and 1.46±0.05 dB (mean ± standard error, P < 0.001) in patients with glaucoma. Both devices showed similar discriminative power. The MD metric had marginally better discrimination with CMP (pAUC difference ± standard error, 0.019±0.009, P = 0.035). The 95% limits of agreement for the MS were reduced by 13% in CMP compared with HFA in participants with glaucoma and by 49% in normal participants. Mean absolute deviation was similar, with no significant differences. CONCLUSIONS: Relative diagnostic precision of the 2 devices is equivalent. Test-retest variability of MS for CMP was better than for HFA.

Evidence for alterations in fixational eye movements in glaucoma.

BACKGROUND: Fixation changes in glaucoma are generally overlooked, as they are not strikingly evident as in macular diseases. Fundus perimetry might give additional insights into this aspect, along with traditional perimetric measures. In this work we propose a novel method to quantify glaucomatous changes in fixation features as detected by fundus perimetry and relate them to the extent of glaucomatous damage. METHODS: We retrospectively analysed fixation data from 320 people (200 normal subjects and 120 with glaucoma) from the Preferred Retinal Locus (PRL) detection of a Compass perimeter. Fixation stability was measured as Bivariate Contour Ellipse Area (BCEA), and using two novel metrics: (1) Mean Euclidean Distance (MED) from the Preferred Retinal Locus, and (2) Sequential Euclidean Distance (SED) of sequential fixation locations. These measures were designed to capture the spread of fixation points, and the frequency of position changes during fixation, respectively. RESULTS: In the age corrected analysis, SED was significantly greater in glaucomatous subjects than controls (P = 0.002), but there was no difference in BCEA (P = 0.15) or MED (P = 0.054). Similarly, SED showed a significant association with Mean Deviation (P <  0.001), but neither BCEA nor MED were significantly correlated (P > 0.14 for both). CONCLUSION: Changes in the scanning pattern detected by SED are better than traditional measures of fixation spread (BCEA) for describing the changes in fixation stability observed in glaucoma.

Improving Visual Field Examination of the Macula Using Structural Information.

PURPOSE: To investigate a novel approach for structure-function modeling in glaucoma to improve visual field testing in the macula. METHODS: We acquired data from the macular region in 20 healthy eyes and 31 with central glaucomatous damage. Optical coherence tomography (OCT) scans were used to estimate the local macular ganglion cell density. Perimetry was performed with a fundus-tracking device using a 10-2 grid. OCT scans were matched to the retinal image from the fundus perimeter to accurately map the tested locations onto the structural damage. Binary responses from the subjects to all presented stimuli were used to calculate the structure-function model used to generate prior distributions for a ZEST (Zippy Estimation by Sequential Testing) Bayesian strategy. We used simulations based on structural and functional data acquired from an independent dataset of 20 glaucoma patients to compare the performance of this new strategy, structural macular ZEST (MacS-ZEST), with a standard ZEST. RESULTS: Compared to the standard ZEST, MacS-ZEST reduced the number of presentations by 13% in reliable simulated subjects and 14% with higher rates (≥20%) of false positive or false negative errors. Reduction in mean absolute error was not present for reliable subjects but was gradually more important with unreliable responses (≥10% at 30% error rate). CONCLUSIONS: Binary responses can be modeled to incorporate detailed structural information from macular OCT into visual field testing, improving overall speed and accuracy in poor responders. TRANSLATIONAL RELEVANCE: Structural information can improve speed and reliability for macular testing in glaucoma practice.

Features of the normal choriocapillaris with OCT-angiography: Density estimation and textural properties.

The main objective of our work is to perform an in depth analysis of the structural features of normal choriocapillaris imaged with OCT Angiography. Specifically, we provide an optimal radius for a circular Region of Interest (ROI) to obtain a stable estimate of the subfoveal choriocapillaris density and characterize its textural properties using Markov Random Fields. On each binarized image of the choriocapillaris OCT Angiography we performed simulated measurements of the subfoveal choriocapillaris densities with circular Regions of Interest (ROIs) of different radii and with small random displacements from the center of the Foveal Avascular Zone (FAZ). We then calculated the variability of the density measure with different ROI radii. We then characterized the textural features of choriocapillaris binary images by estimating the parameters of an Ising model. For each image we calculated the Optimal Radius (OR) as the minimum ROI radius required to obtain a standard deviation in the simulation below 0.01. The density measured with the individual OR was 0.52 ± 0.07 (mean ± STD). Similar density values (0.51 ± 0.07) were obtained using a fixed ROI radius of 450 µm. The Ising model yielded two parameter estimates (ß = 0.34 ± 0.03; γ = 0.003 ± 0.012; mean ± STD), characterizing pixel clustering and white pixel density respectively. Using the estimated parameters to synthetize new random textures via simulation we obtained a good reproduction of the original choriocapillaris structural features and density. In conclusion, we developed an extensive characterization of the normal subfoveal choriocapillaris that might be used for flow analysis and applied to the investigation pathological alterations.

Oral administration of forskolin and rutin contributes to intraocular pressure control in primary open angle glaucoma patients under maximum tolerated medical therapy.

BACKGROUND: Tight control of intraocular pressure (IOP) is still the only therapeutic approach available for the treatment of primary open angle glaucoma (POAG). However, some patients do not respond adequately to hypotonising drugs, and despite multiple drug combinations they cannot reach their target IOP. Forskolin is a natural compound that has already shown efficacy in IOP reduction following topical application. PURPOSE: The aim of this study was to evaluate the effects on the IOP of a food supplement containing forskolin and rutin when administered to POAG patients under maximum tolerated medical therapy (MTMT) and on a waiting list for filtrating surgery to further decrease their IOP. METHODS: The design of the study was open and case-controlled. Ninety-seven (52 in the treatment group, and 45 in the reference group) patients were enrolled in 8 different glaucoma centers in Italy, all under MTMT and with IOP enrollment values above their target pressure. During the 30 days before surgery, patients in the treatment group were prescribed 2 tablets per day of a food supplement containing rutin and forskolin in addition to their usual topical drug treatment. Their IOP values were measured at 3 time points during the day, at enrollment and once a week until surgery. Control patients continued only with their normal topical therapy. RESULTS: All patients in the treatment group, independently of the combination drug therapy that they were taking, showed a further 10% decrease (P<0.01) of their IOP, starting from 1 week after introduction of the oral supplement and lasting until the last evaluation before surgery. This decrease was more evident (15% of the enrollment value; P<0.01) in those subjects with high (IOP≥21 mmHg) enrollment values rather than in those with low (IOP<21) enrollment values (9%; P<0.01). On the contrary, IOP values in the control group remained stable from the beginning to the end of the observation period, independently of their enrollment values. CONCLUSIONS: Forskolin and rutin given as oral treatment appear to contribute to a better control and a further small reduction of IOP in patients who were poorly responsive to multitherapy treatment.

Corneal subbasal nerves changes in patients with diabetic retinopathy: an in vivo confocal study.

PURPOSE: To study the subbasal corneal plexus (SCP) in patients with diabetic retinopathy (DR) treated or nontreated with panretinal Argon laser photocoagulation (ALP). METHOD: Fifty consecutive patients with DR and 50 age- and sex-matched normal control subjects were examined with retinal tomography by a masked evaluator. The following subbasal plexus nerves parameters were considered: number per frame, tortuosity, and reflectivity. Diabetic patients were divided into two groups, according to the presence of proliferative versus nonproliferative retinopathy, according to the Early Treatment of Diabetic Retinopathy Study (ETDRS) classification. RESULTS: The number of fibers per frame and reflectivity were significantly lower in diabetic patients compared with control subjects (2.4 +/- 1 vs. 2.9 +/- 0.8, P = 0.01 and 2.3 +/- 0.9 vs. 2.6 +/- 0.9, P = 0.04, respectively). Tortuosity was significantly higher in diabetic patients (2.5 +/- 0.9 vs. 2.0 +/- 0.8, P = 0.002). Number per frame and reflectivity were significantly lower in diabetic patients with proliferative diabetic retinopathy (PDR; respectively, 2.0 +/- 0.9 vs. 2.9 +/- 0.9, P = 0.001, and 2.0 +/- 0.8 vs. 2.6 +/- 0.7, P = 0.003). Tortuosity was significantly higher in the PDR group (2.2 +/- 0.8 vs. 2.8 +/- 0.9, P = 0.008). The PDR group treated with ALP had significantly lower subbasal nerves number compared with the nontreated group (P = 0.01). CONCLUSIONS: DR may induce substantial changes in the SCP. There is a difference between proliferative and nonproliferative retinopathy and in the former group between ALP treated and nontreated patients.