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

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

Analysis of HRT Images: Comparison of Reference Planes

PURPOSE. The values of Heidelberg Retinal Tomograph (HRT; Heidelberg Engineering, Heidelberg, Germany) stereometric parameters depend on the reference plane (RP), the instability of which results in parameter variability. Identification of change depends on RP stability. This study was undertaken to evaluate the influence of various RPs on rim areas (RAs) in a longitudinal image series. METHODS. A longitudinal image series of 31 subjects with ocular hypertension who had reproducible visual field loss and 19 normal subjects was analyzed using five different RPs: the standard RP (HRT software version 3.1.2.0), two 320-m RPs (software ver. 3.1.2.0 and 1.7.0), a previously described experimental RP, and a new Moorfields RP. The Moorfields RP takes the standard RP at baseline and then is fixed relative to the reference ring for subsequent images. Classic methods, such as ophthalmoscopy and stereophotography, are widely used and are still important. These techniques involve the clinical examination of the ONH, to detect abnormalities associated with glaucoma, such as rim narrowing and notching, and recognition of large or asymmetric cup-to-disc ratios. However, these methods have limitations, since they rely on subjective judgment, and agreement between even expert observers on the presence of glaucoma or progressive change is not optimal. 5-10 Objective and reproducible measurements of the ONH surface topography are possible with scanning laser tomography. 11,12 Although scanning laser tomography appears to be reproducible, The HRT software applies two approaches to detection of change. The first is topographic change analysis, 14 in which the surface height in groups of pixels (super pixels) in follow-up images is compared with the surface height in the baseline image. Statistically significant change in surface height is color coded (red for relative depression, and green for relative elevation, compared to baseline). The second approach is to plot stereometric data, such as rim area (RA), over time. Currently, there is no statistical support in the software for this latter approach, but the potential value of quantifying RA over time to identify progression has been reported. Many different reference surfaces have been proposed

Sensitivity loss in early glaucoma can be mapped to an enlargement of the area of complete spatial summation

Purpose. The area of complete spatial summation (Ricco's area) is the largest stimulus size for which area × intensity is constant at threshold. The authors sought to investigate whether Ricco's area changes in early glaucoma to account for the decreased visual signal/noise ratio that may accompany retinal ganglion cell loss. Methods. Spatial summation functions were measured, and Ricco's area was determined at four 10° retinal locations in 24 patients with early glaucoma (total deviation at test locations, mean, −1.3 dB; range, +2 dB to −8 dB) and 26 age-similar healthy subjects under achromatic and S-cone isolation conditions. Achromatic grating resolution acuity was measured at the same locations to estimate functional ganglion cell density. Results. Ricco's area was enlarged in patients compared with controls for both achromatic (enlarged by: superior field, 0.57 log units, P < 0.01; inferior field, 0.72 log units, P < 0.01) and chromatic (enlarged by: superior field, 0.26 log units, P < 0.01; inferior field, 0.25 log units, P = 0.065) stimuli, with negligible vertical summation curve shifts along the intensity axis. Resolution acuity was significantly reduced in glaucoma patients in both hemifields (P < 0.001). There was a weak, but significant, relationship between Ricco's area and resolution acuity. Conclusions. Enlargement of Ricco's area completely compensates for reduced perimetric sensitivity in early glaucoma to maintain constant threshold at Ricco's area, suggesting an increase in signal pooling in response to ganglion cell loss. The rightward displacement of the spatial summation curve indicates that perimetric stimuli should be capable of modulating in size as well as/instead of contrast, which may boost the glaucoma signal within measurement noise

The effect of age on the area of complete spatial summation for chromatic and achromatic stimuli

Purpose. Previously, an association between the area of complete spatial summation (Ricco's area) and age under scotopic conditions had been found. The authors sought to determine whether Ricco's area is similarly associated with age under photopic achromatic and selective S-cone conditions in peripheral vision and whether any association relates to a loss of ganglion cell density as determined by measurements of peripheral grating resolution acuity. Methods. Achromatic spatial summation functions were plotted for 68 healthy subjects (aged 20–77 years) in four oblique meridians on a gray background field of 10 cd/m2. Similar functions were generated for the S-cone pathway (isolated using Stiles' two-color threshold method) for the same locations. Ricco's area was determined using two-phase regression analysis. Achromatic peripheral grating resolution acuity was measured at the same locations using high-contrast Gabor stimuli, as an estimate of localized functional ganglion cell density. Results. There was a notable decrease in overall contrast sensitivity with age for all stimulus sizes. However, there was no evidence of age-related change in Ricco's area for either achromatic (superior field, r2 = 0.05; inferior field, r2 = 0.0007; all P > 0.05) or chromatic (superior field, r2 = 0.01; inferior field, r2 = 0.006; all P > 0.05) stimuli, despite a significant decrease in peripheral grating resolution acuity with age (superior field, r2 = 0.15; inferior field, r2 = 0.17; both P < 0.05). Conclusions. An age-related decline in functional ganglion cell density is not accompanied by a significant change in Ricco's area for achromatic or chromatic stimuli