Correlation of structural and functional measurements in primary open angle glaucoma (optic disc morphology and psychophysics)

Background: Primary open angle glaucoma (POAG) is the term given to a progressive optic neuropathy for which the major risk factors are raised intraocular pressure and older age. The presence of glaucoma is defined by functional (visual field) defects that are associated with loss of retinal ganglion cells and neuroretinal tissue at the optic nerve head (ONH). The relationship between the functional and structural changes is, therefore, of great importance to the understanding of the disease process, and to the clinician's interpretation of the state of the disease. This thesis sets out to define the relationship between retinal function, as measured by conventional white-on-white perimetry, and optic nerve head structure, as measured by scanning laser ophthalmoscopy. Plan of research: The investigations are divided into four parts. Firstly, the ONH structural measurements that best distinguish glaucomatous from normal eyes are determined. This includes an analysis of the relationship between the optical components of the eye and image magnification. Secondly, an analysis of the physiological relationship between ganglion cell numbers and retinal function. Thirdly, the establishment of the anatomical relationship between visual field locations and the ONH (a map relating the visual field to the ONH). And fourthly, the investigation of the correlation between structural and functional measurements in POAG. Results: Neuroretinal rim area in relation to optic disc size is the best parameter to distinguish glaucomatous from normal eyes. The physiological relationship of ganglion cell numbers to decibel light sensitivity (10*log[1/light intensity]) is curvilinear and to light sensitivity (1/light intensity) is linear. The visual field/ONH map allows a correlation of sectoral ONH and regional visual field sensitivity. Analyses demonstrate that the relationship of neuroretinal rim area to decibel light sensitivity is curvilinear in glaucoma. Clinical significance: The curvilinear relationship between decibel light sensitivity and neuroretinal rim area indicates that staging of glaucoma by decibel summary indices may underestimate the amount of structural damage in early disease. In addition, the analysis of disease progression by linear modelling of decibel light sensitivity over time may need re-evaluation

Spatiotemporal Summation of Perimetric Stimuli in Early Glaucoma

PURPOSE: To investigate achromatic temporal summation under the conditions of standard automated perimetry (SAP), using a Goldmann III (GIII) stimulus and a stimulus scaled to the local area of complete spatial summation (Ricco's area) in open-angle glaucoma (OAG) patients and healthy age-similar control participants. METHODS: Twenty patients with OAG (mean age, 63 years; mean MD, -3.3 dB) and 15 healthy controls (mean age, 64 years) were recruited. Contrast thresholds were measured for seven stimulus durations (1-24 frames, 1.8-191.9 ms) using a near-GIII stimulus (0.48° diameter) and stimuli scaled to the local Ricco's area, in four oblique meridians at 8.8° eccentricity in the visual field. The upper limit of complete temporal summation (critical duration) was estimated using iterative two-phase regression analysis. RESULTS: Median critical duration values were significantly longer (P < 0.05) in the OAG group for the near-GIII (107.2 ms; interquartile range [IQR], 38.0-190.5) and Ricco's area-scaled (83.2 ms, 41.7-151.4) stimuli, compared to those in healthy subjects (near-GIII, 34.7 ms; 18.2-47.9; Ricco's area-scaled, 49.0 ms; 25.1-64.6). The greatest difference in contrast thresholds between healthy and OAG subjects (i.e., disease signal) was found when stimuli were scaled to Ricco's area and shorter than or equal to the critical duration in healthy observers. CONCLUSIONS: Temporal summation is altered in glaucoma. The stimulus duration and area of conventional SAP may be suboptimal for identifying early functional damage. Simultaneously modulating stimulus duration, area, and luminance during the examination may improve the diagnostic capability of SAP and expand the dynamic range of current instruments

The Effect of Age on the Temporal Summation of Achromatic Perimetric Stimuli

Purpose: To examine the temporal summation of a Goldmann III–sized stimulus under the conditions of standard automated perimetry in healthy participants of varying age. Methods: Twenty-seven healthy individuals of varying age (24–80 years) were tested. Achromatic contrast thresholds were measured for seven 0.48° diameter (near Goldmann III) spot stimuli of varying presentation duration (1–24 frames, 1.8–191.9 ms) at 8.8° eccentricity in the visual field along the 45°, 135°, 225°, and 315° meridians. All stimuli were displayed on a CRT display with a background set to 10 cd/m2. Iterative two-phase regression analysis was used to estimate the critical duration from each localized temporal summation function. Results: A significant decrease in contrast sensitivity for all stimulus durations examined in this study was observed with increasing age in both the superior and inferior hemifield (P < 0.001). Despite this, no significant change in the critical duration was observed as a function of age in either the superior (r2 = 9.1 × 10−9, P = 0.99) or inferior hemifield (r2 = 2.4 × 10−5, P = 0.98). Conclusions: Age-related changes in the visual system, although leading to a reduction in contrast sensitivity, are not accompanied by a change in temporal summation for a detection task with an achromatic 0.48° diameter spot stimulus. This is important to know when proceeding to examine temporal summation changes in diseases like glaucoma

Two-year visual field outcomes of the treatment for advanced glaucoma study (TAGS)

PURPOSE: to compare visual field (VF) progression between the two arms of the Treatment of Advanced Glaucoma Study (TAGS) DESIGN: post-hoc analysis of VF data from a two-arm multicenter randomized controlled clinical trial METHODS: 453 patients with newly diagnosed advanced open-angle glaucoma in at least one eye from 27 centers in the United Kingdom were randomized to either trabeculectomy (N = 227) or medications in their index eye (N = 226) and followed-up for two years with two 24-2 VF tests at baseline, 4, 12 and 24 months. We analyzed data for participants with a reliable VF (False positive rate < 15%) at baseline and at least two other time-points. MAIN OUTCOME MEASURES: Average difference in rate of progression (RoP) was analyzed using a hierarchical Bayesian model. Time for each eye to progress from baseline beyond specific cut-offs (0.5, 1, 1.5 and 2 dB) was compared using survival analysis. RESULTS: 211 eyes in the trabeculectomy-first arm and 203 eyes in the medications-first arm were analyzed. The average RoPs (Estimate [95% Credible Intervals]) were -0.59 [-0.88, -0.31] dB/year in the medications-first arm and -0.40 [-0.67, -0.13] dB/year in the trabeculectomy-first arm. The difference was not significant (Bayesian p-value = 0.353). More eyes progressed in the medications-first arm: ≥0.5 dB (p = 0.001), ≥1dB (p = 0.014), ≥1.5dB (p = 0.071) and ≥2dB (p = 0.061). CONCLUSIONS: there was no significant difference in the average RoP at two years. Initial trabeculectomy significantly reduced the proportion of progressing eyes

Investigating the Linkage Between Mesopic Spatial Summation and Variations in Retinal Ganglion Cell Density Across the Central Visual Field:Mesopic Spatial Summation with Eccentricity

Purpose The relationship between perimetric stimulus area and Ricco's area (RA) determines measured thresholds and the sensitivity of perimetry to retinal disease. The nature of this relationship, in addition to effect of retinal ganglion cell (RGC) number on this, is currently unknown for the adaptation conditions of mesopic microperimetry. In this study, achromatic mesopic spatial summation was measured across the central visual field to estimate RA with the number of RGCs underlying RA also being established. Methods Achromatic luminance thresholds were measured for six incremental spot stimuli (0.009–2.07 deg2) and 190.4 ms duration, at four locations, each at 2.5°, 5° and 10° eccentricity in five healthy observers (mean age 61.4 years) under mesopic conditions (background 1.58 cd/m2). RA was estimated using two-phase regression analysis with the number of RGCs underlying RA being calculated using normative histological RGC counts. Results Ricco's area exhibited a small but statistically insignificant increase between 2.5° and 10° eccentricity. Compared with photopic conditions, RA was larger, with the difference between RA and the Goldmann III stimulus (0.43°) being minimised. RGC number underlying RA was also higher than reported for photopic conditions (median 70 cells, IQR 36–93), with no significant difference being observed across test locations. Conclusions Ricco's area and the number of RGCs underlying RA do not vary significantly across the central visual field in mesopic conditions. However, RA is larger and more similar to the standard perimetric Goldmann III stimulus under mesopic compared with photopic adaptation conditions. Further work is required to determine if compensatory enlargements in RA occur in age-related macular degeneration, to establish the optimal stimulus parameters for AMD-specific microperimetry

Spatiotemporal summation of perimetric stimuli in healthy observers

Spatial summation of perimetric stimuli has been used to derive conclusions about the spatial extent of retinal-cortical convergence, mostly from the size of the critical area of summation (Ricco's area, RA) and critical number of retinal ganglion cells (RGCs). However, spatial summation is known to change dynamically with stimulus duration. Conversely, temporal summation and critical duration also vary with stimulus size. Such an important and often neglected spatiotemporal interaction has important implications for modeling perimetric sensitivity in healthy observers and for formulating hypotheses for changes measured in disease. In this work, we performed experiments on visually heathy observers confirming the interaction of stimulus size and duration in determining summation responses in photopic conditions. We then propose a simplified computational model that captures these aspects of perimetric sensitivity by modelling the total retinal input, the combined effect of stimulus size, duration, and retinal cones-to-RGC ratio. We additionally show that, in the macula, the enlargement of RA with eccentricity might not correspond to a constant critical number of RGCs, as often reported, but to a constant critical total retinal input. We finally compare our results with previous literature and show possible implications for modeling disease, especially glaucoma

Estimating the Critical Duration for Temporal Summation of Standard Achromatic Perimetric Stimuli

Purpose: To estimate the critical duration of temporal summation for achromatic Goldmann III stimuli under the conditions of standard automated perimetry (SAP) and quantify response variability for short duration stimuli. Methods: Contrast thresholds were gathered using the method of constant stimuli for seven circular (0.48° diameter) incremental stimuli of varying duration (sum-of-frames equivalent: 8.3-198.3 msec), at an eccentricity of 8.8° along the four principal meridians of the visual field in two healthy, psychophysically experienced observers. Stimuli were presented on a high-resolution CRT display with a background luminance of 10 cd/m2. Psychometric functions were fitted using a probit model and non-parametric local linear analysis. The critical duration was estimated using iterative two-phase regression analysis, the results also being compared with values produced using previously published methods of analysis. Results: The median critical duration estimated using iterative two-phase regression analysis was 27.7 msec (IQR 22.5-29.8). A slight steepening of the psychometric function slope (lower variability) was observed for longer stimulus durations, using both probit and local-linear analysis techniques, but this was not statistically significant. Conclusions: Critical duration estimates in this study are substantially shorter than those previously reported for a Goldmann III stimulus under the conditions of SAP. Further work is required to firmly establish the relationship between measurement variability and the degree of local temporal and spatial summation

Investigating the linkage between mesopic spatial summation and variations in retinal ganglion cell density across the central visual field

PURPOSE: The relationship between perimetric stimulus area and Ricco's area (RA) determines measured thresholds and the sensitivity of perimetry to retinal disease. The nature of this relationship, in addition to effect of retinal ganglion cell (RGC) number on this, is currently unknown for the adaptation conditions of mesopic microperimetry. In this study, achromatic mesopic spatial summation was measured across the central visual field to estimate RA with the number of RGCs underlying RA also being established. METHODS: Achromatic luminance thresholds were measured for six incremental spot stimuli (0.009-2.07 deg2 ) and 190.4 ms duration, at four locations, each at 2.5°, 5° and 10° eccentricity in five healthy observers (mean age 61.4 years) under mesopic conditions (background 1.58 cd/m2 ). RA was estimated using two-phase regression analysis with the number of RGCs underlying RA being calculated using normative histological RGC counts. RESULTS: Ricco's area exhibited a small but statistically insignificant increase between 2.5° and 10° eccentricity. Compared with photopic conditions, RA was larger, with the difference between RA and the Goldmann III stimulus (0.43°) being minimised. RGC number underlying RA was also higher than reported for photopic conditions (median 70 cells, IQR 36-93), with no significant difference being observed across test locations. CONCLUSIONS: Ricco's area and the number of RGCs underlying RA do not vary significantly across the central visual field in mesopic conditions. However, RA is larger and more similar to the standard perimetric Goldmann III stimulus under mesopic compared with photopic adaptation conditions. Further work is required to determine if compensatory enlargements in RA occur in age-related macular degeneration, to establish the optimal stimulus parameters for AMD-specific microperimetry

Relating retinal nerve fiber layer thickness and functional estimates of ganglion cell sampling density in healthy eyes and in early glaucoma

Purpose. To investigate the relationship between retinal nerve fiber layer (RNFL) thickness and peripheral grating resolution acuity (PGRA) as well as differential light sensitivity (DLS) in healthy subjects and patients with early glaucoma. The agreement between estimates of retinal ganglion cell (GC) density from each functional test is explored. Methods. PGRA was measured in 24 patients with early glaucoma (mean deviation [MD] > −8 dB) and 26 healthy subjects using achromatic Gabor stimuli in 4 diagonal visual field locations at 10° eccentricity. DLS for a Goldmann size III equivalent was obtained from individual spatial summation functions and expressed in Humphrey Field Analyzer-equivalent decibel values. RNFL thickness was measured around the optic nerve head using Zeiss Stratus optical coherence tomography and related to functional measures using a retinotopic map. Functional GC density was estimated using structure/function models for both tests. Passing-Bablok regression was used to investigate the structure/function relationships. Results. A positive and statistically significant association was found between PGRA and RNFL thickness, and separately between DLS and RNFL thickness, for combined glaucoma and healthy data (both P 0.05). Agreement between estimates of GC density from psychophysical data was moderate. Conclusions. The relationship between PGRA and RNFL thickness is at least as great in magnitude as that between DLS and RNFL thickness; a significant structure/function association is also observed in healthy subjects alone