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Purpose This study evaluated the ability of topographically correspondent (TC) minimum rim width (MRW) and peripapillary retinal nerve fiber layer thickness (pRNFLT) criteria to detect optical coherence tomography (OCT) structural abnormality in glaucoma (GL) and glaucoma suspect (GLS) eyes. Design Retrospective cross-sectional study. Methods A total of 196 GL eyes, 150 GLS eyes, and 303 heathy eyes underwent pRNFL and 24 radial optic nerve head OCT imaging and manual correction of the internal limiting membrane, Bruch's membrane opening (BMO), and outer pRNFL segmentations. MRW and pRNFLT were quantified in 6 Garway-Heath or 12 30-degree (clock-hour) sectors. OCT abnormality for each parameter was defined to be less than the 5th percentile of the healthy eye distribution. OCT abnormality for individual eyes was defined using global, sectoral, and combined parameter criteria that achieved ≥95% specificity in the healthy eyes. TC combination criteria required the sectoral location of MRW and pRNFLT abnormality to be topographically aligned and included comMR (a previously reported TC combination consisting of MRW and pRNFLT parameter: [MRW + pRNFLT × (average MRW healthy eyes/average pRNFLT healthy eyes) MRW]. Results TC sectoral criteria (1 Garway-Heath MRW + corresponding Garway-Heath RNFLT), (one 30-degree MRW + any 1 corresponding or adjacent 30-degree pRNFLT), 30-degree and Garway-Heath comMR-TI and global comMR were the best performing criteria, demonstrating (96%-99% specificity), 86%-91% sensitivity for GL, 80%-84% sensitivity for early GL (MD ≥ −4.0 dB) and 93%-96% sensitivity for moderate-to-advanced GL (MD Conclusions Clinically intuitive TC MRW and pRNFLT combination criteria identified the sectoral location of OCT abnormality in GL eyes with high diagnostic precision.

PRéCIS:: There are errors in automated segmentation of the retinal nerve fiber layer (RNFL) in glaucoma suspects or patients with mild glaucoma that appear to persist over time; however, automated segmentation has greater repeatability than manual segmentation.To identify whether optical coherence tomography (OCT) segmentation errors in RNFL thickness measurements persist longitudinally.This was a cohort study. We used spectral domain OCT (Spectralis) to measure RNFL thickness in a 6-degree peripapillary circle, and exported the native "automated segmentation only" results. In addition, we exported RNFL thickness results after "manual refinement" to correct errors in the automated segmentation, and used the differences in these measurements as "error" in segmentation. We used Bland-Altman plots and linear regression to determine the magnitude, location, and repeatability of RNFL thickness error in all twelve 30-degree sectors and compared the error at baseline to follow-up time points at 6 months, 2 years, 3 years, and 4 years.We included 406 eyes from 213 participants. The 95% confidence interval for errors at baseline was -6.5 to +13.2 μm. The correlation between the baseline error and the errors in the follow-up time periods were high (r0.5, P0.001 for all). Automated segmentation had a smaller SD of residuals from the longitudinal trend line when compared to manual refinement (1.56 vs. 1.80 μm, P0.001), and a higher ability (P=0.009) to monitor progression using an analysis of a longitudinal signal-to-noise ratio.Errors in automated segmentation remain relatively stable, and baseline error is highly likely to persist in the same direction and magnitude in subsequent time periods. However, automated segmentation (without manual refinement) is more repeatable and may be more sensitive to glaucomatous progression. Future segmentation algorithms could exploit these findings to improve automated segmentation in the future.

PURPOSE: To assess glaucoma specialists’ detection of optic nerve head (ONH) rim tissue that is thin by optical coherence tomography (OCT) criteria. DESIGN: Reliability analysis METHODS: 5 clinicians marked the disc margin (DM) and rim margin (RM) on stereo-photos of 151 glaucoma or glaucoma suspect eyes obtained within 3 months of OCT imaging. The photo and OCT infrared image for each eye were colocalized and regionalized into twelve sectors relative to the axis between Bruch’s membrane opening (BMO) centroid and the fovea. For each clinician, the distance from BMO centroid to their DM (DM radius) and RM (RM radius) was used to generate sectoral rim width (RW) (DM radius – RM radius) and cup-to-disc ratio (CDR) (RM radius / DM radius) estimates. OCT minimum rim width (MRW) was determined by sector. Among all eyes, for each OCT MRW suspicious sector (< 5% of OCT normative data base), we determined each clinician’s detection (clinician CDR ≥ 0.7). RESULTS: Clinicians most commonly failed to detect OCT suspicious rim tissue in the nasal sectors. Among 502 sectors with suspicious OCT MRW all 5 clinicians rated CDR ≥ 0.7 in only 29.5% and all 5 clinicians rated CDR < 0.7 in 21%. OCT suspicious rim thickness was most common (32% of eyes) in the nasal and inferior sectors. MRW vs clinician RW discordance was greatest nasally, while BMO vs clinician DM discordance was greatest temporally. CONCLUSIONS: Clinicians most commonly failed to detect OCT suspicious rim thickness nasally where suspicious rim tissues were also most common.

PURPOSE: To compare the frequency of observing optic nerve head (ONH) prelaminar schisis by optical coherence tomography (OCT) in glaucoma and glaucoma suspect (GL/S) eyes versus healthy control (HC) eyes and to assess its association other markers of glaucoma severity. METHODS: This cross-sectional study included 298 eyes of 150 GL/S patients and 88 eyes of 44 HC. OCT scans were obtained by SPECTRALIS (Heidelberg Engineering GmbH), including 24 radial B-scans, each comprised of 768 A-lines spanning 15°, centered on the ONH. Two reviewers masked to all other clinical, demographic and ocular information, independently graded the OCT scans for the presence of ONH prelaminar schisis on a 4-point scale: 0 (none) to 3 (severe). The probability of ONH schisis was compared between groups and against demographic and ocular factors, including structural and functional measures of glaucoma severity. RESULTS: The frequency and severity of ONH prelaminar schisis were greater in GL/S than in HC (p=0.009). Among the GL/S group, 165 eyes (55.4%) had no visible schisis (Grade-0), 71 (23.8%) had Grade-1, 46 (15.4%) had Grade-2 and 16 (5.4%) had Grade-3 schisis. Among HC eyes, 59 (67.0%) had Grade-0, 24 (27.3%) had Grade-1, 5 (5.7%) had Grade-2, none had Grade-3. ONH schisis was more common in eyes with thinner MRW and a deeper cup. CONCLUSIONS: ONH prelaminar schisis may be a sign of glaucomatous deformation and reflect ongoing pathophysiological damage. ONH prelaminar schisis can impact OCT image segmentation and diagnostic parameters, resulting in substantial overestimation of the true rim tissue thickness and underestimation of cup depth.

Purpose To use optical coherence tomography (OCT) to 3-dimensionally characterize the optic nerve head (ONH) in peripapillary scleral bowing in non-highly myopic healthy eyes. Design Cross-sectional, multicenter study. Methods A total of 362 non-highly myopic (+6 diopters [D] > spherical equivalent > −6D) eyes of 362 healthy subjects from 20-90 years old underwent OCT ONH radial B-scan imaging. Bruch's membrane (BM), BM opening (BMO), anterior scleral canal opening (ASCO), and the peripapillary scleral surface were segmented. BMO and ASCO planes were fit, and their centroids, major axes, ovality, areas and offsets were determined. Peripapillary scleral bowing was characterized by 2 parameters: peripapillary scleral slope (ppSS) of 3 anterior peripapillary scleral segments (0-300, 300-700, and 700-1,000 μm from the ASCO centroid); and ASCO depth relative to a peripapillary scleral reference plane (ASCOD-ppScleral). Peripapillary choroidal thickness (ppCT) was calculated relative to the ASCO as the minimum distance between the anterior scleral surface and BM. Results Both ppSS and ASCOD-ppScleral ranged from slightly inward through profoundly outward in direction. Both parameters increased with age and were independently associated with decreased ppCT. Conclusions In non-highly myopic healthy eyes, outward peripapillary scleral bowing achieved substantial levels, was markedly increased with age, and was independently associated with decreased peripapillary choroidal thickness. These findings provide a normative foundation for characterizing this anatomy in cases of high myopia and glaucoma and in eyes with optic disc tilt, torsion, and peripapillary atrophy.

PURPOSE: To quantify the variability of 5 glaucoma specialists’ optic disc margin (DM), rim margin (RM) and rim width (RW) estimates. DESIGN: Inter-Observer Reliability analysis. METHODS: Clinicians viewed stereo-photos from 214 subjects with glaucoma or ocular hypertension and digitally marked the DM and RM. For each photo, the centroid of each clinician’s DM was calculated, and an averaged DM(centroid) was determined. The axis between the DM(centroid) and the fovea was used to establish twelve 30° sectors. Measurements from the DM centroid to each clinician’s DM (DM(radius)) and RM (RM(radius)) were used to generate a RW (DM(radius) – RM(radius)) and cup disc ratio (CDR) (RM(radius)/DM(radius)) by sector. Parameter means, standard deviations and coefficient of variations (COVs) were calculated across all clinicians for each eye. Parameter means for each clinician, and intra-class correlation coefficients (ICC), were calculated across all eyes by sector. RESULTS: Among all eyes, the median COV by sector ranged from 3–5% for DM(radius), 20–25% for RM(radius), and 26–30% for RW. Sectoral ICCs for CDR ranged from 0.566 to 0.668. Sectors suspicious for rim thinning by one clinician were frequently overlooked by others. Among 1724 sectors in which at least one clinician was suspicious for rim thinning, (CDR ≥ 0.7), all 5 clinicians’ CDRs were ≥ 0.7 in only 499 (29%) and 2 of the 5 clinicians failed to detect rim thinning (CDR < 0.7) in 442 (26%). CONCLUSION: In this study, glaucoma specialist RM, DM and RW discordance was frequent and substantial even in sectors that were suspicious for rim thinning.

PurposeTo determine the frequency with which retinal tissues other than the nerve fibre layer, hereafter referred to as protruded retinal layers (PRL), are a component of optical coherence tomography (OCT) neuroretinal rim measurements.MethodsNinety healthy (30 White, Black and Japanese, respectively) subjects were included in the study. A radial scan pattern (24 B-scans centred on Bruch's membrane opening [BMO]) was used. For each of the 48 minimum rim width (MRW) measurement points, we determined whether PRL were present, absent or indeterminate. When present, the proportion of PRL within the MRW was quantified.ResultsProtruded retinal layers were present in 503 (11.6%), absent in 3805 (88.1%) and indeterminate in 12 (0.3%) measurement points. Overall, 69 (76.6%) subjects had ≥1 points with PRL, with White subjects having the highest frequency and Japanese the lowest (29 [97%] and 18 [60%], respectively; p&nbsp

Purpose Various global indices are available to summarize results from standard automated perimetry. This study asks which index can detect significant deterioration earliest, for a fixed specificity. Design Comparison of prognostic indices. Methods Two cohorts were tested. A test-retest cohort contained 5 reliable visual fields, within a short interval, from 45 eyes of 23 participants with glaucoma and/or likelihood of developing glaucoma. A separate longitudinal cohort contained 508 eyes from 330 participants, tested on average 13 times. Three global indices were extracted: mean deviation (MD), pattern standard deviation (PSD), and visual field index (VFI). For each index we defined a critical P value Crit Index , such that 5% of test-retest series showed significant deterioration with P Index , using artificial "test dates" in random order. Therefore these criteria have 95% specificity over series of 5 tests. The times to detect significant deterioration in the longitudinal cohort were compared using a survival analysis model. Results The median time to detect significant deterioration with MD was 7.3 years (95% confidence interval [CI] 6.8–7.9 years). For VFI, the median was 8.5 years (95% CI 7.9–9.0 years); this comparison had P = .088. For PSD, the median was 10.5 years (95% CI 9.3–11.7 years), slower than MD with P P = .0013) and 107 for PSD ( P = .029). Conclusions MD detected significant deterioration sooner than VFI or PSD. In particular, MD detected more eyes in the first 5 years of their follow-up, which were presumably undergoing more rapid progression.

OBJECTIVE: We determined the differential aging effects of the inner six layers of the macula in contrast to the minimum neuroretinal rim width (MRW) and peripapillary retinal nerve fibre layer (RNFL) thickness. DESIGN: Cross-sectional, multi-centre study. PARTICIPANTS: Approximately equal number of White subjects with a normal ocular and visual field examination in each decade group from 20-90 years. METHODS: Optical coherence tomography of the macula, optic nerve head and peripapillary retina. MAIN OUTCOME MEASURES: (i) Sectoral measurements of the inner six layers of the macula; (ii) age-related decline of each of these layers; (iii) strength of the associations with age of the macular parameters, MRW and peripapillary RNFL thickness; (iv) association between ganglion cell layer (GCL) thickness and MRW and peripapillary RNFL thickness. RESULTS: The study sample comprised one eye of 246 subjects with median (range) age of 52.9 (19.8 – 87.3) years. Of the six layers, there was a statistically significant decline with age of only the GCL, inner plexiform layer and inner nuclear layer thickness with rates of −0.11 μm/y, −0.07 μm/y and −0.03 μm/y, respectively. These rates corresponded to 2.92%, 2.15% and 0.88% loss per decade, respectively, and were generally uniform across sectors. The rate of loss of MRW and peripapillary RNFL thickness was −1.22 μm/y and −0.20 μm/y, corresponding to 3.63% and 2.04% loss per decade. However, the association of GCL thickness change with age (R(2) = 0.28) was approximately twice that of MRW and RNFL thickness (R(2) = 0.14 for each). CONCLUSIONS: In concordance with histopathological studies showing age-related loss of retinal ganglion cell axons, we showed a significant decline in GCL thickness, as well as MRW and peripapillary RNFL thickness. The stronger relationship between aging and GCL thickness compared to the rim or peripapillary RNFL may indicate that GCL thickness could be better suited to measure progression of structural glaucomatous loss.

Author(s): Yang, Hongli; Luo, Haomin; Gardiner, Stuart K; Hardin, Christy; Sharpe, Glen P; Caprioli, Joseph; Demirel, Shaban; Girkin, Christopher A; Liebmann, Jeffrey M; Mardin, Christian Y; Quigley, Harry A; Scheuerle, Alexander F; Fortune, Brad; Chauhan, Balwantray C; Burgoyne, Claude F | Abstract: Purpose:To quantify peripapillary choroidal thickness (PCT) and the factors that influence it in healthy participants who represent the racial and ethnic composition of the U.S. population. Methods:A total of 362 healthy participants underwent optical coherence tomography (OCT) enhanced depth imaging of the optic nerve head with a 24 radial B-scan pattern aligned to the fovea to Bruch's membrane opening axis. Bruch's membrane, anterior scleral canal opening (ASCO), and the anterior scleral surface were manually segmented. PCT was measured at 100, 300, 500, 700, 900, and 1100 μm from the ASCO globally and within 12 clock-hour sectors. The effects of age, axial length, intraocular pressure, ethnicity, sex, sector, and ASCO area on PCT were assessed by ANOVA and univariable and multivariable regressions. Results:Globally, PCT was thicker further from the ASCO border and thinner with older age, longer axial length, larger ASCO area, European descent, and female sex. Among these effectors, age and axial length explained the greatest proportion of variance. The rate of age-related decline increased further from the ASCO border. Sectorally, the inferior-temporal sectors were thinnest (10.7%-20.0% thinner than the thickest sector) and demonstrated a higher rate of age-related loss (from 15.6% to 20.7% faster) at each ASCO distance. Conclusions:In healthy eyes, PCT was thinnest in the inferior temporal sectors and thinner PCT was associated with older age, European descent, longer axial length, larger ASCO area, and female sex. Among these associations, age had the strongest influence, and its effect was greatest within the inferior temporal sectors.

PurposeTo assess anterior scleral canal opening (ASCO) offset relative to Bruch's membrane opening (BMO) (ASCO/BMO offset) so as to determine neural canal direction, obliqueness, and minimum cross-sectional area (NCMCA) in 362 healthy eyes.DesignCross-sectional study.MethodsAfter optical coherence tomography optic nerve head and retinal nerve fiber layer thickness (RNFLT) imaging, BMO and ASCO were manually segmented. Planes, centroids, size, and shape were calculated. Neural canal direction was defined by projecting the neural canal axis vector (connecting BMO and ASCO centroids) onto the BMO plane. Neural canal obliqueness was defined by the angle between the neural canal axis and the BMO plane perpendicular vector. NCMCA was defined by projecting BMO and ASCO points onto a neural canal axis perpendicular plane and measuring the area of overlap. The angular distance between superior and inferior peak RNFLT was measured, and correlations between RFNLT, BMO, ASCO, ASCO/BMO offset, and NCMCA were assessed.ResultsMean (SD) NCMCA was significantly smaller than either the BMO or ASCO area (1.33 (0.42), 1.82 (0.38), 2.22 (0.43) mm2, respectively), and most closely correlated to RNFLT (P < .001, R2= 0.158). Neural canal direction was most commonly superior-nasal (55%). Mean neural canal obliqueness was 39.4° (17.3°). The angular distance between superior and inferior peak RNFLT correlated to neural canal direction (P ≤ .008, R2= 0.093).ConclusionsASCO/BMO offset underlies neural canal direction, obliqueness, and NCMCA. RNFLT is more strongly correlated to NCMCA than to BMO or ASCO, and its peripapillary distribution is influenced by neural canal direction.

In clinic, “deep” vs. “shallow” cupping is well established in human glaucoma. Our central hypothesis is that the “shallow” or senile sclerotic cupping of aged eyes is a manifestation of their stiffer connective tissues. We predicted that there are age-related differences in structure/function relationships. The relationship between the magnitude of laminar deformation and visual field loss will be different in young (“compliant”) eyes compared to old (“stiff”) eyes.

PURPOSE To determine the association of vision-related quality of life (QoL) to demographic factors and visual function in glaucoma suspect or early glaucoma patients. MATERIALS AND METHODS We administered the 25-item National Eye Institute Visual Function Questionnaire (VFQ-25) on the same day as a comprehensive ocular examination to participants either with glaucoma or at high risk for developing glaucoma. Regression models were used to determine the association between VFQ-25 composite and subscale scores, visual field status, logMAR equivalent visual acuity (VA), age, and sex. In all analyses we used data from the eye with the best mean deviation (MD), best pattern SD, and best VA. RESULTS Data from 198 participants were analyzed. The mean best MD (±SD) was 0.02±1.52 dB (range, -5.11 to 2.63 dB) and the mean best pattern SD was 1.75±1.03 dB (range, 0.91 to 8.36 dB). The mean VFQ-25 composite score was 91.6±6.7 (range, 54.5 to 100.0). Composite score and the Distance Activities, Color Vision subscale scores were associated with best MD (P≤0.05). The General Vision and Driving subscale scores were associated with best VA (P≤0.03). The composite score and the Distance Activities, Driving, and Color Vision subscale scores were associated with age (P≤0.05). Finally, the Distance Activities, Driving, and Peripheral Vision subscale scores were associated with sex (P≤0.04). CONCLUSIONS Vision-related QoL is associated with visual field status even in early and suspected glaucoma. It is also associated with VA, age, and sex. Particular decreases in QoL are related to distance activities, driving, and color vision.

PURPOSE We determined whether longitudinal changes in retinal nerve fiber layer (RNFL) reflectance provide useful prognostic information about longitudinal changes in function in glaucoma. METHODS The reflectance intensity of each pixel within spectral-domain optical coherence tomography (SD-OCT) circle scans was extracted by custom software. A repeatability cohort comprising 53 eyes of 27 participants (average visual field mean deviation [MD] -1.65 dB) was tested five times within a few weeks. To minimize test-retest variability in their data, a reflectance intensity ratio was defined as the mean reflectance intensity of pixels within the RNFL divided by the mean between the RNFL and RPE. This was measured in a separate longitudinal cohort comprising 310 eyes of 205 participants tested eight times at 6-month intervals (average MD, -0.99 dB; median rate of change, -0.09 dB/y). The rate of change of this ratio, together with the rate of RNFL thinning, and their interaction, were used to predict the rate of change of MD. RESULTS In univariate analyses, the rate of RNFL thinning was predictive of the rate of MD change (P < 0.0001), but the rate of change of reflectance intensity ratio was not (P = 0.116). However, in a multivariable model, the interaction between these two rates significantly improved upon predictions of the rate of functional change made using RNFL thickness alone (P = 0.038). CONCLUSIONS For a given rate of RNFL thinning, a reduction in the RNFL reflectance intensity ratio is associated with more rapid functional deterioration. Incorporating SD-OCT reflectance information may improve the structure-function relation in glaucoma.

Purpose:To quantify the influence of ocular and demographic factors on central laminar depth (LD) in healthy participants. Methods:A total of 362 normal subjects underwent optical coherence tomography (OCT) enhanced depth imaging of the optic nerve head (ONH) with a 24 radial B-scan pattern aligned to the fovea-to-Bruch's membrane opening (BMO) axis. BMO, anterior lamina, anterior scleral canal opening (ASCO), Bruch's membrane (BM), and the peripapillary scleral surface were manually segmented. The extent of laminar segmentation was quantified within 72 ASCO subsectors. Central LD was quantified relative to four reference planes: BMO, ASCO, BM, and scleral. The effects of age, sex, ethnicity, IOP, BMO area, ASCO area, and axial length on LD were assessed. Results:Laminar visibility was most consistent within the central ASCO (median 89%, range, 69%-95%). LDBMO and LDBM were significantly shallower in eyes with greater age, BMO area, and axial length and in females. LDASCO was shallower in eyes with greater ASCO area and axial length and in European and Hispanic descent compared to African descent eyes. LDSclera behaved similarly, but was not associated with axial length. BMO and ASCO area were not different between African descent and European descent eyes. Conclusions:Central LD was deeper in African descent eyes and influenced least by age, axial length, and sex, but more by ASCO area, when measured relative to the ASCO and sclera. However, the magnitude of these effects for all four reference planes was small, and their clinical importance in the detection of glaucoma and its progression remains to be determined.

Visual field testing uses high-contrast stimuli in areas of severe visual field loss. However, retinal ganglion cells saturate with high-contrast stimuli, suggesting that the probability of detecting perimetric stimuli may not increase indefinitely as contrast increases. Driven by this concept, this study examines the lower limit of perimetric sensitivity for reliable testing by standard automated perimetry.Evaluation of a diagnostic test.A total of 34 participants with moderate to severe glaucoma; mean deviation at their last clinic visit averaged -10.90 dB (range, -20.94 to -3.38 dB). A total of 75 of the 136 locations tested had a perimetric sensitivity of ≤ 19 dB.Frequency-of-seeing curves were constructed at 4 nonadjacent visual field locations by the Method of Constant Stimuli (MOCS), using 35 stimulus presentations at each of 7 contrasts. Locations were chosen a priori and included at least 2 with glaucomatous damage but a sensitivity of ≥ 6 dB. Cumulative Gaussian curves were fit to the data, first assuming a 5% false-negative rate and subsequently allowing the asymptotic maximum response probability to be a free parameter.The strength of the relation (R(2)) between perimetric sensitivity (mean of last 2 clinic visits) and MOCS sensitivity (from the experiment) for all locations with perimetric sensitivity within ± 4 dB of each selected value, at 0.5 dB intervals.Bins centered at sensitivities ≥ 19 dB always had R(2) 0.1. All bins centered at sensitivities ≤ 15 dB had R(2) 0.1, an indication that sensitivities are unreliable. No consistent conclusions could be drawn between 15 and 19 dB. At 57 of the 81 locations with perimetric sensitivity19 dB, including 49 of the 63 locations ≤ 15 dB, the fitted asymptotic maximum response probability was80%, consistent with the hypothesis of response saturation. At 29 of these locations the asymptotic maximum was50%, and so contrast sensitivity (50% response rate) is undefined.Clinical visual field testing may be unreliable when visual field locations have sensitivity below approximately 15 to 19 dB because of a reduction in the asymptotic maximum response probability. Researchers and clinicians may have difficulty detecting worsening sensitivity in these visual field locations, and this difficulty may occur commonly in patients with glaucoma with moderate to severe glaucomatous visual field loss.

There are currently several functional and structural assessments used clinically to assist with the diagnosis and management of patients with glaucoma. However, none of these tests have sufficiently good diagnostic performance (sensitivity and specificity) to be relied upon in isolation. Identifying structural features that change concurrently with functional measures could indicate a causal relationship, shedding light on the pathophysiological processes leading to vision loss. Moreover, relating structural and functional findings in eyes that are developing, or that have developed glaucoma, provides an opportunity to improve our understanding of this disease. This in turn may lead to the development of better diagnostic tools and better methods for monitoring change over time. It may also allow structural measures that have fewer drawbacks than perimetry (e.g. better repeatability1, 2, shorter test times, better patient acceptance3) to be used as surrogates for function. One additional benefit to understanding structure-function relationships is that differences in the strength of correlation between function and structural tests that all purport to measure the same anatomical feature can be used to make conclusions about the relative ‘noisiness’ of the different structural tests. An improvement in correlation strength brought about by using a different structural test or a better model of the structure-function relation (i.e. exponential vs linear) would imply that variability has been reduced. Even with these enhancements, the correlation between structure and function will almost certainly never reach 1.0 due to factors such as inter-subject variability and temporal disconnects between structural and functional change. Functional deficits are related to decreases in the density of retinal ganglion cells and a corresponding thinning of the retinal nerve fiber layer (RNFL) in experimental models of glaucoma.4 Even though both structural and functional measures describe important aspects of the glaucomatous disease process, and they should certainly be related, some patients display seemingly conflicting results: loss in one, and no loss in the other. One reason for discrepancies between structure and function is variability both between and within patients.5 A second reason is the reliance of different structural measures on distinct theoretical underpinnings. This results in different definitions of the term RNFL, each referring to the presence, or estimated integrity, of different underlying structures. A third reason is that functional testing (such as SAP) typically only assesses a small portion of the retina, in particular the central 25 to 30°. In contrast, most structural measures assess the entire optic nerve head (ONH) or the vast majority of the axons within the RNFL. As a result, there are portions of the ONH and peripapillary RNFL that are not represented within the most commonly used visual field patterns. Three techniques are commonly used in clinical practice to obtain objective measurements of the ‘thickness’ of the peripapillary RNFL. Of these, only one directly measures RNFLT: optical coherence tomography (OCT) measures the distance between the vitreoretinal boundary at the inner limiting membrane (ILM) and the anterior border of the retinal ganglion cell layer (RGCL).6 Scanning laser polarimetry (SLP) measures the relative phase retardance of a scanning laser beam as its polarization state is varied over 360 deg at each double pass traverse through the tissue.7 Normal retardance of the RNFL is known to be dependent on the integrity of the axonal cytoskeleton.8, 9 The retardance measurement is then typically converted to RNFLT by assuming a linear relation between them.7, 10 Confocal scanning laser tomography (CSLT) calculates the average height of the peripapillary retinal surface around the disc margin relative to a reference plane and uses this as its measure of RNFLT. The indirect measures of RNFLT produced by SLP and CSLT do not preclude their ability to provide an important structural measure that correlates with function. For the sake of simplicity, all three estimates (from spectral domain [SD] OCT, SLP and CSLT) will be referred to as ‘RNFLT’ for the remainder of this manuscript. The literature contains studies that employ a range of techniques to analyze structure-function relations. This has resulted in many structure-function relations that are difficult to compare due to differences in study design. In order to determine the strongest structure-function relation among several techniques, it is necessary to study the same cohort, preferably acquiring multiple structural and/or functional measures on the same day. One such study by Bowd et al (2006)11 assessed the relation between SAP and three measures of RNFLT (SLP, time domain [TD] OCT and CSLT as measured by GDxVCC, Stratus OCT, and HRT II respectively). SAP hemifield sensitivity was better correlated with the corresponding sectors of the peripapillary RNFLT measured with TDOCT than with SLP or CSLT. This was true both when assuming linear or logarithmic relations between RNFLT and visual function. A secondary analysis of global RNFLT versus mean visual field sensitivity found that TDOCT produced the strongest association and CSLT the weakest. Since the Bowd et al study was performed, newer forms of OCT and SLP have become available. SDOCT has greater axial resolution and faster scanning times (with potentially less eye movement artifact) than TDOCT. For SLP, the introduction of enhanced corneal compensation (GDx ECC) has reduced the number of patients who manifest an atypical retardation pattern, which were difficult to interpret when using variable corneal compensation (GDx VCC).12 Since these advancements have been made, no studies have compared correlations of these three structural measures to visual function. The current study was designed to determine which of three estimates of RNFLT (SDOCT, SLP and CSLT) correlated best with SAP in a cohort of participants who were either high-risk ocular hypertensives or who had non-endstage glaucoma.

PURPOSE To determine the clinical features of optic disc progression in patients with ocular hypertension and early glaucoma. PATIENTS A total of 336 eyes of 168 patients with ocular hypertension or early glaucoma. METHODS Two glaucoma specialists independently graded the baseline and most recent optic disc photographs for optic disc progression. Optic disc progression was defined as: new or increased neuroretinal rim thinning (2 or more clock hours), notching (1 clock hour or less of thinning of the neuroretinal rim), excavation (undermining of the neuroretinal rim or disc margin), and nerve fiber layer defect(s). They also determined the location of these changes. RESULTS Ninety-two of 336 eyes (27.4%) showed optic disc progression after a median of 6.1 years. Of those with progression, excavation occurred in 89% of eyes; rim thinning occurring in 54%; and notching occurring in 16%. Fifty-six percent (56%) had 2 or more features of progression. The inferotemporal quadrant was the most common location for progression, but more than 1 location of progression occurred in at least 30% of eyes with progression. CONCLUSIONS Optic disc progression occurred frequently in this cohort of ocular hypertension and early glaucoma patients. When evaluating the optic disc for glaucomatous progression, eye care providers should pay particular attention to increased excavation and neuroretinal rim thinning-especially in the inferotemporal quadrant.

To characterize the error of optical coherence tomography (OCT) measurements of retinal nerve fiber layer (RNFL) thickness when using automated retinal layer segmentation algorithms without manual refinement.Cross-sectional study.This study was set in a glaucoma clinical practice, and the dataset included 3490 scans from 412 eyes of 213 individuals with a diagnosis of glaucoma or glaucoma suspect. We used spectral domain OCT (Spectralis) to measure RNFL thickness in a 6-degree peripapillary circle, and exported the native "automated segmentation only" results. In addition, we exported the results after "manual refinement" to correct errors in the automated segmentation of the anterior (internal limiting membrane) and the posterior boundary of the RNFL. Our outcome measures included differences in RNFL thickness and glaucoma classification (i.e., normal, borderline, or outside normal limits) between scans with automated segmentation only and scans using manual refinement.Automated segmentation only resulted in a thinner global RNFL thickness (1.6 μm thinner, P.001) when compared to manual refinement. When adjusted by operator, a multivariate model showed increased differences with decreasing RNFL thickness (P.001), decreasing scan quality (P.001), and increasing age (P.03). Manual refinement changed 298 of 3486 (8.5%) of scans to a different global glaucoma classification, wherein 146 of 617 (23.7%) of borderline classifications became normal. Superior and inferior temporal clock hours had the largest differences.Automated segmentation without manual refinement resulted in reduced global RNFL thickness and overestimated the classification of glaucoma. Differences increased in eyes with a thinner RNFL thickness, older age, and decreased scan quality. Operators should inspect and manually refine OCT retinal layer segmentation when assessing RNFL thickness in the management of patients with glaucoma.

To test the hypothesis that development of glaucomatous visual fields can be predicted several years earlier from prior visual field information. One-hundred and seven eyes with glaucomatous optic neuropathy (n = 47 eyes) or which were suspicious for glaucoma (n = 60) were prospectively enrolled in a longitudinal study. Visual fields were evaluated on an annual basis using standard automated perimetry (SAP), the original version of frequency doubling technology (FDT) perimetry, and a custom version of FDT that used the 24-2 stimulus pattern. All SAP fields were within normal limits at the initial visit. When the SAP glaucoma hemifield test was ‘outside normal limits’ or the pattern standard deviation probability was worse than the lower 5th percentile or more than two clustered locations at the p

Purpose To determine how well rates of localized retinal nerve fiber layer thickness (RNFLT) change correlate with rates of sensitivity change at corresponding locations in the visual field in glaucoma. Design Retrospective cohort study. Methods Three hundred and sixty-four eyes of 191 participants with suspected or confirmed glaucoma, as judged by experienced clinicians, were tested every 6 months with perimetry and optical coherence tomography (OCT). For each 24-2 visual field location, the corresponding sectoral peripapillary RNFLT was defined using a 30-degree sector, centered on the angle of nerve fiber entry into the optic nerve head. Rates of change of pointwise sensitivity and sectoral RNFLT were calculated over the last 8 visits at which reliable data were obtained. Passing-Bablok regression was used to predict the rate of pointwise sensitivity change from the rate of sectoral RNFLT change, for each location. Results Rates of sectoral RNFLT change were significantly predictive of rates of pointwise sensitivity change at all locations in the field. Correlations were modest, averaging 0.15, ranging from 0.03 to 0.25 depending on the location. A 1 μm/y more rapid thinning in corresponding sectors was associated with 0.3 dB/y more rapid loss in the superior visual field but less than 0.1 dB/y more rapid loss at many locations in the inferior visual field. Conclusions Localized RNFL thinning is associated with sensitivity loss at corresponding locations in the visual field, and their rates of change are significantly correlated. Peripapillary RNFLT may be used to monitor localized changes caused by glaucoma that have measurable consequences for a patient's vision.

Glaucoma is the third leading cause of blindness in the USA, and the second leading cause worldwide.1 Whether a patient’s vision will deteriorate rapidly, slowly or remain relatively stable is one of the most important questions in glaucoma management.2 It has been estimated that 15% of patients with glaucoma will have visual fielddamage within their lifetime that is so severe that it falls outside the dynamic range of automated perimetry.3 However, predicting the rate of progression remains challenging. This is partly because little is known about the exact course of the disease over time, due to there being limited information from well-controlled longitudinal studies, and due to the variability of currently available testing methods. Individuals progress differently, and diagnostic test procedures are constantly being refined. While glaucoma is commonly diagnosed and followed using a combination of structural and functional tests, the most important practical issue for patients is loss of visual function and its impact on their quality of life and activities of daily living.4, 5 Therefore, predicting the rate of functional change remains a high priority. The most widely used functional test for glaucoma is Standard Automated Perimetry (SAP), in which contrast sensitivities for small white stimuli displayed on a uniform white background are measured at numerous locations throughout the visual field.6 Various factors have been reported to be associated with an increased probability of future progression, and/or the rate of future progression. These include higher Intraocular Pressure (IOP),2, 7–10 IOP fluctuation,7, 11 increased age 3, 7–10 and being of a certain race,3, 9, 12 although some of these factors have been disputed.2, 10, 12, 13 It has also been reported that structural damage is often detectable before functional loss with the tools currently available,14 so it may be predictive of future functional change (although it has also been reported that for other patients functional loss is detectable first15). Given that measurements of structure are generally better tolerated by patients than visual field testing,16 it is appealing to use such tests as part of a prognostic evaluation. However, the agreement between structural and functional measures of progression is relatively weak,15, 17, 18 and individual patients can follow very different disease courses. Neuroretinal rim area in particular has been shown to be both globally and topographically correlated with retinal nerve fiber layer thickness and with function,19–21 and has been reported to be the structural parameter from Confocal Scanning Laser Ophthalmoscopy (CSLO) that is best related to current functional status.22 However, its usefulness as a predictor of subsequent functional progression is uncertain. The CSLO Ancillary Study to the Ocular Hypertension Treatment Study (OHTS) found that a decreased rim area, among other CSLO parameters, was predictive of reaching a primary open angle glaucoma endpoint.23 However, the study incorporated not only functional but also structural endpoints (determined using the examination of stereophotographs). Perhaps more importantly, such an endpoint-based analysis is dependent not only on the stage of disease, but also on the exact endpoint used, and provides only limited information about the rate at which functional progression may occur. Therefore we aim to determine the utility of CSLO parameters to predict the rate of subsequent functional change. In this study, we examine the relations between CSLO parameters and both the current functional status and the rate of subsequent functional change. Although clinical decisions are unlikely to be made based on the value of one index at a single time point, assessing the predictive strength of a measure can remove much of the uncertainty caused by confounding factors, and would be expected to be indicative of the utility of that measure in a more complete predictive model. Such a predictive model may be helpful in the management of patients over time.

Currently, global indices that summarize the visual field combine sensitivities on a logarithmic (decibel) scale. Recent structure–function models for glaucoma suggest that contrast sensitivity should be converted to a linear scale before averaging across visual field locations, to better relate sensitivity with the number of surviving retinal ganglion cells (RGCs). New indices designed to represent the number of RGCs already lost are described. At least one was found to be a significantly better predictor of subsequent rate of change than traditional Mean Deviation (p=0.014) in participants with glaucomatous optic neuropathy. Issues concerning the creation of optimal global indices are discussed.

Purpose: To determine whether the hill of vision for Short-Wavelength Automated Perimetry (SWAP) is shallower for women who consume phyto-oestrogen-rich foods than for women who do not. Methods: Visual field data were compared for two groups of healthy amenorrhoeic women 48–69 years-old with normal vision and not using hormone replacement: (1) 24 subjects who reported consuming soy and/or flax products and (2) 20 subjects who reported not consuming these products. Two types of 24-2 visual fields were measured: (1) Full Threshold SWAP and (2) a white-on-white (W/W) field obtained using a Swedish Interactive Threshold Algorithm (SITA Standard). Results: The reduction of SWAP sensitivity from the centre of the field (4 loci, mean eccentricity = 4.2°) to the periphery (20 loci, mean eccentricity = 21.9°) was less for soy/flax consumers than for nonconsumers, both with age-referencing (mean difference = 1.7 dB, p = 0.018) and without (p = 0.012). Corresponding distinctions existed for the SWAP – W/W difference, and there was minimal effect for W/W fields alone. The peripheral age-referenced SWAP sensitivities averaged 2.5 dB higher for consumers than nonconsumers (p = 0.022). Conclusion: The between-group distinctions are consistent with the possibility (derived from the women’s health literature) that phyto-oestrogens may counteract a decline of short-wavelength-sensitive cone-mediated response among postmenopausal women. These results suggest another potential application for SWAP outside its original intended purpose as a glaucoma test. Future studies should assess whether phyto-oestrogen consumption is most beneficial for women who are sufficiently young and/or not too far beyond menopause.

Purpose To examine demographic and clinical factors associated with glaucomatous peripapillary retinoschisis (PPRS) and assess its association with glaucoma progression. Methods Using a case control study design and longitudinal data from a cohort of 166 subjects with a diagnosis of glaucoma or glaucoma suspect, we compared functional, structural, clinical, and demographic characteristics between PPRS cases and controls. Results The frequency of PPRS was 6.0% (12 eyes from 10/166 subjects) with two eyes having PPRS in different sectors for a total of 15 retinoschisis events. There were no significant differences (P > 0.05) in age, sex, visual acuity, central corneal thickness, intraocular pressure, or presence of vitreous adhesion between PPRS and controls. However, eyes with PPRS tended to have a higher cup-to-disc ratio (P = 0.06), thinner RNFL (P = 0.02), and worse visual field mean deviation (MD, P = 0.06) than controls. The rate of RNFL thinning was faster in PPRS (average: -2.8%/year; range: -7.4% to 0.0%/year) than controls (-1.3%/year; range: -4.4% to 0.6%/year; P = 0.021). The rate of visual field MD change was faster in PPRS (-0.49 dB/year; range: -2.0 to 0.9 dB/year) than controls (-0.06 dB/year; range: -0.8 to 0.3 dB/year; P = 0.030). OCT scans showed hyperreflective structures spanning the PPRS whose morphology and spacing (50 ± 7 μm) are consistent with Muller glia, causing signal attenuation casting "shadows" onto distal retina. Conclusions This is the first report showing that glaucomatous PPRS is associated with a faster overall rate of RNFL thinning and visual field deterioration and to specifically identify OCT signs of Muller cell involvement.

Purpose To evaluate the reproducibility of the Heidelberg retina tomograph (HRT) Glaucoma Probability Score (GPS) and assess its potential for monitoring progression. Design Evaluation of diagnostic tests in a randomized, controlled clinical trial. Participants For reproducibility, we included 43 ocular hypertensive (OHT) and 31 glaucoma subjects. For progression, we included 198 OHT and 21 control subjects. Methods To study reproducibility, global GPS values were generated for HRT images acquired in a test–retest study. Images were acquired at 2 visits within 6 weeks of each other, by 2 different observers. To study progression, GPS values were generated for HRT images acquired prospectively (1993–2001). Linear regression of GPS against time was performed, with progression defined as a significant negative slope ( P Main Outcome Measures Reproducibility of GPS was assessed using Bland–Altman analysis (mean difference, 95% limits of agreement). Progression was assessed by the number of OHT subjects identified as progressing, and by agreement with VF progression. Results Reproducibility of GPS was better at its extremes (−0.01±0.20 for GPS 0–0.30, and 0.02±0.09 for GPS 0.78–1.00) than in its mid range (0.07±0.54 for GPS 0.30–0.78). Estimated criterion specificity ranged from 95.2% (95% confidence interval, 76.1%–99.9%) to 96.8% (93.2%–98.5%). Twenty-five OHT subjects (12.6%) progressed by GPS, with 11 of the 25 (5.6%) also progressing by VF; 26 subjects (13.1%) progressed by VF alone. Conclusions Changes in HRT GPS values between 0.30 and 0.78 should be interpreted with caution because the index has poorer reproducibility in this range. The global GPS progression algorithm performs at least as well as previously described rim area-based HRT progression strategies. Financial Disclosure(s) Proprietary or commercial disclosure may be found after the references.

To evaluate the effect on diagnostic performance of reducing multifocal visual-evoked potential (mfVEP) recording duration from 16 to 8 minutes per eye.Both eyes of 185 individuals with high-risk ocular hypertension or early glaucoma were studied. Two 8-minute mfVEP recordings were obtained for each eye in an ABBA order using VERIS. The first recording for each eye was compared against single run (1-Run) mfVEP normative data; the average of both recordings for each eye was compared against 2-Run normative data. Visual fields (VFs) were obtained by standard automated perimetry (SAP) within 22.3+/-27.0 days of the mfVEP. Stereo disc photographs and Heidelberg Retina Tomograph images were obtained together, within 24.8+/-50.4 days of the mfVEP and 33.1+/-62.9 days of SAP. Masked experts graded disc photographs as either glaucomatous optic neuropathy or normal. The overall Moorfields Regression Analysis result from the Heidelberg Retina Tomograph was used as a separate diagnostic classification. Thus, 4 diagnostic standards were applied in total, 2 based on optic disc structure alone and 2 others based on disc structure and SAP.Agreement between the 1-Run and 2-Run mfVEP was 90%. Diagnostic performance of the 1-Run mfVEP was similar to that of the 2-Run mfVEP for all 4 diagnostic standards. Sensitivity was slightly higher for the 2-Run mfVEP, whereas specificity was slightly higher for the 1-Run mfVEP.If higher sensitivity is sought, the 2-Run mfVEP will provide better discrimination between groups of eyes with relatively high signal-to-noise ratio (eg, early glaucoma or high-risk suspects). But if higher specificity is a more important goal, the 1-Run mfVEP provides adequate sensitivity and requires only half the test time. Considered alongside prior studies, the present results suggest that the 1-Run mfVEP is an efficient way to confirm (or refute) the extent of VF loss in patients with moderate or advanced glaucoma, particularly in those with unreliable VFs, including malingering or other "functional" forms of VF loss.

Purpose Decreased reflectance within the retinal nerve fiber layer (RNFL), observable using optical coherence tomography (OCT), appears to be related to functional loss in glaucoma. In order to investigate this in a quantitative manner, reliable measurements of reflectance intensity are needed. However, reflectance may not only be affected by pathophysiological changes in tissue properties but also confounded by other effects of ocular media and image quality. This study assesses the repeatability of intensity measurements, before and after normalization aimed to reduce test-retest variability. Methods Data were taken from participants with glaucoma in a test-retest study. Each had peripapillary circle scans acquired from both eyes 5 times within 10 weeks. For each scan, the following were extracted: average RNFL thickness; RNFL intensity, defined as the mean reflectance intensity of pixels within the delineated RNFL; sub-RNFL intensity, defined as the mean intensity of pixels between the outer boundary of the RNFL and Bruch's Membrane; and intensity ratio, defined as RNFL intensity divided by sub-RNFL intensity. For each parameter, deviations from the per-eye mean were calculated. The intra-eye standard deviations (SD) were expressed as percentage of the width of the range of observed measurements. Results The intra-eye SD of RNFL intensity was 12.5% of the range. Normalization reduced the intra-eye SD of intensity ratio to 4.9% of the range, representing a significant reduction in absolute deviations with p

PURPOSE To assess the repeatability of the multifocal visual evoked potential (mfVEP) and to compare it with the repeatability of standard automated perimetry (SAP) in the same group of 50 normal controls retested after 1 year. Our second aim was to assess the repeatability of false alarm rates determined previously for the mfVEP using various cluster criteria. METHODS Fifty individuals with normal vision participated in this study (33 females and 17 males). The age range was 26.7 to 77.9 years and the group average age (+/- SD) was 51.4 (+/- 12.1) years. Pattern-reversal mfVEPs were obtained using a dartboard stimulus pattern in VERIS and two 8-minute runs per eye were averaged. The average number of days between the first and second mfVEP tests was 378 (+/- 58). SAP visual fields were obtained within 17.4 (+/- 20.3) days of the mfVEP using the SITA-standard threshold algorithm. Repeatability of mfVEPs and SAP total deviation values were evaluated by calculating point-wise limits of agreement (LOA). Specificity (1-false alarm rate) was evaluated for a range of cluster criteria, whereby the number and probability level of the points defining a cluster were varied. RESULTS Point-wise LOA for the mfVEP signal-to-noise ratio (SNR) ranged from 2.0 to 4.3 dB, with an average of 2.9 dB across all 60 locations. For SAP, LOA ranged from 2.4 to 8.9 dB, with an average of 4.0 dB (excluding the points immediately above and below the blind spot). Clusters of abnormal points were not likely to repeat on either mfVEP or SAP. When an mfVEP abnormality was defined as the repeat presence (confirmation) of a 3-point (P < 0.05) cluster anywhere within a single hemifield, only 1 (of 200) monocular hemifield was deemed abnormal. Although the LOA of the mfVEP were similar throughout the field, the limited dynamic range of SNR at superior field locations will limit the ability to follow progression in "depth" at those locations. CONCLUSIONS Repeatability of the mfVEP was slightly better than SAP visual fields in this group of controls with a 1-year retest interval. This suggests that progression in early stages should be more easily detectable by mfVEP. However, in certain field locations (eg, superior periphery), the relatively more narrow dynamic range of the SNR of the mfVEP may limit detection of progression to just 1 event. Confirmation of a 3-point cluster abnormality is highly suggestive of a true defect on the mfVEP.

This article provides a basis for understanding modern visual field analysis techniques. It describes some of these tests, including their advantages and disadvantages, and the settings in which different tests might be used most successfully. It also includes an examination of the value of visual field assessment from a public health standpoint with particular attention paid to morbidity, cost/benefit ratios, and quality of life correlations.

Purpose: To describe a normative database for the multifocal VEP (mfVEP) and to evaluate specificity for a range of cluster criteria. Methods: One hundred persons (62 females and 38 males) with normal visual fields and ranging in age from 21.6 to 92.4 years participated in this study. Self-reported race in 80 of these 100 persons was `White or Caucasian,' eight were `Black or African-American,' eight were `Asian,' and four were `Hispanic or Latino.' Pattern-reversal mfVEPs were obtained using a dartboard stimulus pattern in VERISTM and two 8-min runs per eye were averaged. A bootstrap technique was used to estimate the normal range of mfVEP response signal-to-noise ratio (SNR) and inter-ocular amplitude ratio at each location. Specificity (1 – false alarm rate) was evaluated for a range of cluster criteria, whereby the number and probability level of the points defining a cluster were varied. Results: There was no overall effect of age on SNR (r2=0.16, p=0.22) nor was the interaction between age and location significant (F=0.83, p=0.82, ANOVA). The location with the largest age effect had an r2 of only 0.13. There was a small but significant effect of sex (t=2.1, p=0.04) such that SNR was slightly (11) larger in females than males, but there was no significant interaction between sex and age (t=0.82, p=0.41). There was a slight trend toward higher SNR in the Asian group and lower SNR in the African-American group, but the overall effect of race was not significant (F=1.99, p=0.12). Specificity depended on the number and probability level of the points defining a cluster. Specificity did not vary by age group in a simple monotonic manner. False positive rates were slightly higher in females than males, and slightly higher in the African-American group as compared with the Asian group. Conclusions: Excellent specificity can be achieved for the mfVEP by using particular cluster criteria for monocular and inter-ocular tests. The effects of age, sex, and race were all very small and only the effect of sex was statistically significant. This normative database can be used for analyses of mfVEP results from individual patients with little risk that demographic factors such as age and sex will confound diagnostic accuracy.

Purpose Recent evidence suggests that increasing perimetric contrast all the way to 0 dB may not be clinically useful. This study examines whether raising the floor for point-wise sensitivities affects the ability of global indices to detect change. Methods Longitudinal data from eyes with progressive glaucoma were used. Point-wise sensitivities were censored at various cutoffs (12–19 dB). At each cutoff, mean deviations (MD) were recalculated using censored sensitivities, called censored mean deviation (CMD). Both MD and CMD were fitted using a linear model. MD and CMD rate of changes (signal) and the standard deviations (SD) of the residuals (noise) were obtained from the fitted models. The linear signal to noise ratio (LSNR) for MD (LSNRMD) and CMD (LSNRCMD) were compared. Additionally, at each cutoff, the ratios of LSNRCMD to LSNRMD were calculated and tested. Results CMD provided significantly (P

Purpose Global analyses using mean deviation (MD) assess visual field progression, but can miss localized changes. Pointwise analyses are more sensitive to localized progression, but more variable so require confirmation. This study assessed whether cluster trend analysis, averaging information across subsets of locations, could improve progression detection. Methods A total of 133 test–retest eyes were tested 7 to 10 times. Rates of change and P values were calculated for possible re-orderings of these series to generate global analysis (“MD worsening faster than x dB/y with P < y”), pointwise and cluster analyses (“n locations [or clusters] worsening faster than x dB/y with P < y”) with specificity exactly 95%. These criteria were applied to 505 eyes tested over a mean of 10.5 years, to find how soon each detected “deterioration,” and compared using survival models. This was repeated including two subsequent visual fields to determine whether “deterioration” was confirmed. Results The best global criterion detected deterioration in 25% of eyes in 5.0 years (95% confidence interval [CI], 4.7–5.3 years), compared with 4.8 years (95% CI, 4.2–5.1) for the best cluster analysis criterion, and 4.1 years (95% CI, 4.0–4.5) for the best pointwise criterion. However, for pointwise analysis, only 38% of these changes were confirmed, compared with 61% for clusters and 76% for MD. The time until 25% of eyes showed subsequently confirmed deterioration was 6.3 years (95% CI, 6.0–7.2) for global, 6.3 years (95% CI, 6.0–7.0) for pointwise, and 6.0 years (95% CI, 5.3–6.6) for cluster analyses. Conclusions Although the specificity is still suboptimal, cluster trend analysis detects subsequently confirmed deterioration sooner than either global or pointwise analyses.

Purpose To quantify the effects of using the fovea to Bruch's membrane opening (FoBMO) axis as the nasal-temporal midline for 30° sectoral (clock-hour) spectral domain optical coherence tomography (SDOCT) optic nerve head (ONH) minimum rim width (MRW) and area (MRA) calculations. Methods The internal limiting membrane and BMO were delineated within 24 radial ONH B-scans in 222 eyes of 222 participants with ocular hypertension and glaucoma. For each eye the fovea was marked within the infrared reflectance image, the FoBMO angle (θ) relative to the acquired image frame (AIF) horizontal was calculated, the ONH was divided into 30°sectors using a FoBMO or AIF nasal/temporal axis, and SDOCT MRW and MRA were quantified within each FoBMO vs. AIF sector. For each sector, focal rim loss was calculated as the MRW and MRA gradients (i.e. the difference between the value for that sector and the one clockwise to it divided by 30°). Sectoral FoBMO vs. AIF discordance was calculated as the difference between the FoBMO and AIF values for each sector. Generalized estimating equations were used to predict the eyes and sectors of maximum FoBMO vs. AIF discordance. Results The mean FoBMO angle was −6.6±4.2° (range: −17° to +7°). FoBMO vs. AIF discordance in sectoral mean MRW and MRA was significant for 7 of 12 and 6 of 12 sectors, respectively (p

PURPOSE To determine whether "isolation" of short wavelength sensitive mechanisms (i.e., exclusive detection of a threshold stimulus by a short wavelength sensitive mechanism) is maintained in areas of glaucomatous visual field damage as measured with short-wavelength automated perimetry (SWAP). METHODS Data from conventional automated perimetry and SWAP were analyzed for both eyes of 60 normal control subjects, 38 patients with ocular hypertension, and 22 patients with early to moderate glaucomatous field damage (mean defect better than -12 dB). Comparisons of results of SWAP and conventional perimetry were performed by determining the deviation from the mean normal sensitivity for the two procedures. Locations with sensitivity

To determine whether the weakness of the structure–function relationship could be produced by test variability alone, without implying underlying dissociation between the true rates of structural and functional change. Perimetric mean deviation (MD), and rim area (RA) and cup volume (CV) from confocal scanning laser ophthalmoscopy, over six visits, were taken from 166 eyes of 92 participants with high-risk ocular hypertension or suspected/early glaucoma in the Portland Progression Project. Models were created of each measure’s variability. A further model predicted the rate of functional change from the rate of structural change. These were used to generate realistic simulated sequences of both functional and structural data with different standard deviations σ between the underlying rates of change. ‘Observed’ structure–function relationships were calculated. An empirical p-value was derived, equaling the proportion of simulated series for which the ‘observed’ structure–function dissociation was greater than that seen in patient data. The correlation between the rates of structural (RA) and functional (MD) change was 0.171, consistent with σ

The aim of glaucoma management is to protect a patient’s visual function and maintain their vision-related quality of life. Consequently, predicting whether a patient’s vision will deteriorate rapidly or remain relatively stable is a critical part of this endeavor. Although glaucoma is commonly diagnosed and followed up based on a combination of tonometric, structural, and functional tests, the most important issue for patients is loss of their visual function. It has been estimated that within their lifetime, 15% of patients with glaucoma will have visual fields that are so badly damaged that they can no longer be monitored with standard automated perimetry (SAP),1 with associated consequences for their quality of life. It is desirable to identify these patients as early as possible so that appropriate management strategies can be implemented. Deriving better predictive models of glaucomatous progression is also a key aim for future clinical trials of glaucoma medications.2 However, predicting the rate of functional change for a subject remains challenging. Subjects may progress in very different manners based on their physiology and glaucomatous pathology. In addition, the currently available testing methods such as SAP suffer from high variability. Various factors have been reported to be associated with an increased probability of future progression and/or the rate of future progression. These include higher intraocular pressure (IOP),3–6 IOP fluctuation,4,7 increased age,1,3–6 and having certain racial backgrounds1,5,8 (although some of these factors have been disputed).6,8,9 It could be posited that patients who already display functional loss indicative of glaucoma are more likely to have a rapid rate of progression in the future, as there is a decreased probability that they have a “false positive” diagnosis and do not have glaucoma. It may also be expected that patients whose disease has already progressed to a stage where functional loss is clinically detectable would be more likely to progress further. However, empirical evidence for the predictability of future change based on the current visual field is weak, and estimates of the predictive value of initial perimetry vary. In the Early Manifest Glaucoma Treatment (EMGT) trial, mean deviation (MD) at baseline was found to be significantly associated with the probability of progression (hazard ratio 1.58, p = 0.01)3; the effects of other visual field indices were not reported. In the Ocular Hypertension Treatment Study (OHTS),5 baseline pattern standard deviation (PSD) was found to have significant predictive value for reaching a primary open-angle glaucoma endpoint, but baseline MD was not. In the Collaborative Normal-Tension Glaucoma Study (CNTGS),8 baseline MD was not found to be predictive of future progression. Similarly, in the Advanced Glaucoma Intervention Study (AGIS),3 baseline visual field status (field score) was not found to be predictive of future progression. Each of these studies had different inclusion and exclusion criteria, making it difficult to generalize their conclusions. In particular, the AGIS cohort had more severe glaucoma at baseline than the other studies cited above. The majority of work to date, including the clinical studies cited above, has sought to classify subjects as “glaucoma/normal” or as “stable/progressing.” However, in a clinical situation, it is also desirable to determine the likely rate of progression.10 The management strategies for subjects with ocular hypertension, stable glaucoma, or slowly progressing glaucoma could be similar, with the exception perhaps of follow-up intervals. However, a rapidly progressing subject would likely require a more aggressive management strategy, possibly including an earlier move to laser or incisional surgery, to prevent a significant reduction in vision-related quality of life and/or eventual visual disability. The current study has two aims. First, in view of the equivocal findings from different studies, we seek to determine the extent to which summary measures from one SAP test could be used to predict which subjects with early or suspected glaucoma are most likely to undergo a rapid subsequent rate of functional change. Second, we seek to determine which of the currently available global indices of the visual field provide the best means to monitor and predict future rapid progression.

Purpose—The existence of learning effects in perimetry, whereby a subject’s first test is more variable and has lower mean sensitivity (MS) than subsequent tests, is well established. However, studies have typically examined this issue by testing subjects at a frequency that would be unusual in a clinical setting. This study seeks to determine the validity of these conclusions for less frequent, yet more clinically realistic, testing rates. Methods—One hundred sixty eyes of 80 subjects with suspected or early glaucoma were included. Subjects were tested annually for 8 years using white-on-white standard automated perimetry (SAP) and short wavelength automated perimetry (SWAP). All subjects had undergone at least one test with both paradigms before entering the study. Results—For SAP, MS increased by 0.5 dB over the first year, and then showed no significant change until after year 5 (despite expected effects of aging and disease progression), after which it started to decline. For SWAP, MS of the average eye continued to improve until year 6 of the study. Conclusions—Our findings seem to indicate a prolonged learning effect for SWAP, with MS increasing for several years. A smaller prolonged learning effect may also be present for SAP, counteracting the effects of aging and disease progression. Deterioration of the subject’s visual field may be underestimated within this period.

Perimetry is a commonly used clinical test for visual function, limited by high variability. The sources of this variability need to be better understood. In this paper, we investigate whether noise intrinsic to neural firing could explain the variability in normal subjects. We present the most physiologically accurate model to date for stimulus detection in perimetry combining knowledge of the physiology of components of the visual system with signal detection theory, and show that it requires that detection be mediated by multiple cortical cells in order to give predictions consistent with psychometric functions measured in human observers.

Purpose. The “frequency-doubling” effect or illusion, in which the apparent spatial frequency of a grating appears to be doubled, is produced when a low spatial frequency sinusoidal grating is counterphase flickered at a high temporal frequency. This study examines changes in apparent spatial frequency of sinusoids of various spatiotemporal content after equating them for detectability. Methods. Detection contrast thresholds were determined for various spatiotemporal gratings. The perceived spatial frequency was then evaluated using stimuli that were four and six times detection threshold. Match ratios were determined for each spatiotemporal combination, whereby the periodicity of a stationary sinusoid was matched with that of a counterphase flickered grating. The same matching task was repeated under different matching task instructions for five randomly chosen spatiotemporal combinations. Results. Match ratios were fractional for many spatiotemporal combinations. Apparent spatial frequency ranged from less than veridical to greater than double depending on observer and spatiotemporal stimulus content. The effect of task instruction on match ratios was very small, yet significant. Conclusions. The appearance of fractional spatial frequency percepts draws into question the notion that frequencydoubling is solely generated by spatially non-linear Y-type magnocellular ganglion cells. (Optom Vis Sci 2008;85:318–329)

Purpose To compare different tests used in the clinical management of glaucoma, with respect to the testing experience for patients undergoing each test. Design Evaluation of diagnostic tests. Participants A total of 101 subjects with high-risk ocular hypertension or early glaucoma. Methods Subjects were asked to give their opinion on 7 tests used clinically in glaucoma management by assigning each a score between 0 (absolute dislike) and 10 (perfect satisfaction). Main Outcome Measure Tests were ranked for each subject from 1 (favorite test) to 7 (least favorite test) on the basis of patient-assigned scores. Results Goldmann applanation tonometry for measurement of intraocular pressure was ranked significantly better than any other test (median rank 2.5, P ≤0.01). This was followed by confocal scanning laser ophthalmoscopy using a Heidelberg Retina Tomograph (median rank 3.3); frequency doubling technology perimetry (4.0); multifocal visual evoked potential (4.0); optic nerve photography (4.3); and standard automated perimetry (4.8). Short-wavelength automated perimetry was ranked significantly worse than any other test (median rank 5.3, P ≤0.04). Conclusions In many cases, statistically significant differences were found between the patients' opinions of the tests. Information on this issue has to date largely been anecdotal or subjective. To our knowledge, this is the most comprehensive study to assess and compare the patient experience when undergoing these tests. Financial Disclosure(s) The authors have no proprietary or commercial interest in any materials discussed in this article.

PURPOSE To compare the diagnostic performance of multifocal visual evoked potential (mfVEP) and standard automated perimetry (SAP), in eyes with high-risk ocular hypertension or early glaucoma. METHODS Both eyes of 185 individuals with high-risk ocular hypertension or early glaucoma were evaluated. Subjects ranged in age from 37 to 87 (mean +/- SD: 61 +/- 11 years). Pattern-reversal mfVEPs were obtained by using VERIS (Electro-Diagnostic Imaging, San Mateo, CA) with a four-electrode array and were analyzed with custom software. SAP visual fields (SITA-standard; Carl Zeiss Meditec, Inc., Dublin, CA) were obtained within 22.3 +/- 27.0 days of the mfVEP. Stereo disc photographs and Heidelberg Retina Tomograph (HRT) images were obtained during one visit, which was within 24.8 +/- 50.4 days of the mfVEP and 33.1 +/- 62.9 days of the SAP visual field. Abnormalities on the mfVEP were defined by using a variety of cluster criteria: SAP with pattern standard deviation (PSD) P

For many years, it has been appreciated that both structural and functional changes occur in glaucomatous eyes. Cupping/rim thinning can be observed using ophthalmoscopy and is predictive of loss of visual field sensitivity.1 In recent years, quantitative structural measurements of tissues such as the neuroretinal rim area of the optic nerve head (ONH) have become possible, provided by confocal scanning laser tomography and now optical coherence tomography (OCT). In particular, the retinal nerve fiber layer thickness (RNFLT) measured by OCT has become a standard measurement, and has been shown to be closely related to the number of retinal ganglion cell axons remaining.2 Use of spectral-domain OCT (SDOCT) has for the first time permitted reliable visualization and quantification of clinically relevant subsurface structures such as Bruch's membrane opening (BMO). Using this technique, it has been noted that the structure referred to as the disc margin when the ONH is viewed with an ophthalmoscope or in stereophotographs does not correspond to a consistent anatomical structure. The edge of the rim tissue can correspond to any one of several different structures at different regions around the ONH, and/or in different eyes.3 Similarly, the inner border of the rim tissue (traditionally referred to as the border of the optic “cup”) is difficult to define without a fixed, reliable axial reference plane since it is often “sloped” in depth. These problems have led to interest in a more anatomically correct measure of neuroretinal rim tissue. It has been suggested that “rim” should be defined as a ribbon-like surface whose width extends from BMO to the inner limiting membrane (ILM).4 The parameter minimum rim width (MRW) relative to BMO, also known as BMO-MRW, has been defined as the shortest distance between the BMO and the ILM within SDOCT scans, averaged around the disc.5,6 The radial scans can also be used to estimate the minimum rim area (MRA) through which the axons must pass.7 Minimum rim area attempts to adjust for the fact that MRW will be related to disc size and not just the number of axons. It has been shown that these new measures correlate better with function and with other structural measures than the previously used “horizontal” rim measurements.6,7 Peripapillary RNFLT is a measurement of predominantly neural tissue (the retinal ganglion cell axon bundles), made adjacent to the optic disc, typically approximately 1.7 mm from its center. For example, the circular scan used in this study is performed at a radius of 6° from the center of the optic disc as placed by the operator. By contrast, MRW is a measurement of the thickness of the neuroretinal rim tissue, and thus is contained within the optic disc. It has therefore been suggested that MRW may be more sensitive to conformational changes occurring within the ONH tissues such as the lamina cribrosa. It is possible that these aspects of glaucomatous ONH structural change occur separately from, and perhaps precede, retinal ganglion cell axon loss. In a nonhuman primate unilateral experimental glaucoma model, the onset of MRW change preceded the onset of RNFLT change.8 In a study comparing human eyes with open-angle glaucoma against healthy controls, for 95% specificity, the sensitivity of MRW was reported to be 81%, compared with 70% for RNFLT.6 While early detection of glaucomatous damage is clearly important, it is also important to be able to monitor eyes for subsequent change. To be useful for this task, the rate of change of a parameter must be sufficiently rapid to distinguish it from measurement noise. We have previously described the use of a longitudinal signal-to-noise ratio (LSNR) for this purpose.9 The principle is that the rate of change of a progressing eye should be a relatively large multiple of the variability. The aim of the LSNR technique is to determine how easy it is to distinguish change from variability, and a highly negative LSNR indicates that the eye is changing too rapidly for the change to be plausibly caused by variability alone. This formulation enables comparisons between parameters measured on different scales, and indeed using different instruments, if the same eyes and same testing dates are used for both. In this study, we use the LSNR to compare the abilities of MRW, MRA, and RNFLT to distinguish longitudinal change from variability.

Importance Minimal information exists regarding the long-term comparative effectiveness of telemedicine to provide diabetic retinopathy screening examinations. Objective To compare telemedicine to traditional eye examinations in their ability to provide diabetic retinopathy screening examinations. Design, Setting, and Participants From August 1, 2006, through September 31, 2009, 567 participants with diabetes were randomized and followed up to 5 years of follow-up (last date of patient follow-up occurred on August 6, 2012) as part of a multicenter randomized clinical trial with an intent to treat analysis. We assigned participants to telemedicine with a nonmydriatic camera in a primary care medical clinic (n = 296) or traditional surveillance with an eye care professional (n = 271). Two years after enrollment, we offered telemedicine to all participants. Main Outcomes and Measures Percentage of participants receiving annual diabetic retinopathy screening examinations, percentage of eyes with worsening diabetic retinopathy during the follow-up period using a validated scale from stage 0 (none) to stage 4 (proliferative diabetic retinopathy), and percentage of telemedicine participants who would require referral to an eye care professional for follow-up care using a cutoff of moderate diabetic retinopathy or worse, the presence of macular edema, or an unable-to-determine result for retinopathy or macular edema. Results The telemedicine group was more likely to receive a diabetic retinopathy screening examination when compared with the traditional surveillance group during the 6-month or less (94.6% [280/296] vs 43.9% [119/271]; 95% CI, 46.6%-54.8%; P P Conclusions and Relevance Telemedicine increased the percentage of diabetic retinopathy screening examinations, most participants did not require referral to an eye care professional, and diabetic retinopathy levels were generally stable during the study period. This finding suggests that primary care clinics can use telemedicine to screen for diabetic retinopathy and monitor for disease worsening over a long period. Trial Registration clinicaltrials.gov Identifier:NCT01364129

Automated perimetry uses a 3.5 log unit (35dB) range of stimulus contrasts to assess function within the visual field. Using 'Size III' stimuli (0.43°), presenting stimuli within the highest 15dB of available contrast may not increase the response probability at locations damaged by glaucoma, due to retinal ganglion cell response saturation. This experiment examines the effect of instead using 'Size V' (1.72°) stimuli.Luminance increment thresholds for circular spot stimuli of each stimulus size were measured in 35 participants (mean deviation -20.9 to -3.4 dB, ages 52-87) using the method of constant stimuli, at four locations per participant. Frequency-of-seeing curves were fit at each size and location, with three free parameters: mean, standard deviation, and asymptotic maximum response probability. These were used to estimate the contrasts to which each participant would respond on 25% of presentations (Using segmented orthogonal regression, the maximum observed response probabilities for size III stimuli began to decline atThe lower limit of the reliable stimulus range did not differ significantly between stimulus sizes. However, more locations remained within the reliable stimulus range when using the size V stimulus.Size V stimuli enable reliable clinical testing later into the glaucomatous disease process.

We have shown previously that a nonlinear exponential model fits longitudinal series of mean deviation (MD) better than a linear model. This study extends that work to investigate the mode (linear versus nonlinear) of change for pointwise sensitivities.Data from 475 eyes of 244 clinically managed participants were analyzed. Sensitivity estimates at each test location were fitted using two-level linear and nonlinear mixed effects models. Sensitivity on the last test date was forecast using a model fit from the earlier test dates in the series. The means of the absolute prediction errors were compared to assess accuracy, and the root means square (RMS) of the prediction errors were compared to assess precision.Overall, the exponential model provided a significantly better fit (An exponential model may more accurately track pointwise VF change, at locations damaged by glaucoma. This was more noticeable in the upper hemifield where the VF changed more rapidly. However, linear and exponential models were similar in their ability to forecast future VF status.The VF progression appears to accelerate in early glaucoma patients.

Purpose Studies in glaucoma patients show that standard automated perimetry results increase in variability as sensitivity decreases. However, the reasons for this change are unclear. This study presents the principle of Divergent Dysfunction as a possible explanation for this change in variability, and incorporates it into a model that can be used to simulate perimetry. Methods A computer program was written to simulate visual field test results based on the model, using a Full Threshold testing strategy. The validity of the simulation was tested by comparing it with normal sensitivity values, and with test–retest data from 63 participants evaluated five times each over the course of 1 month. The effect on the simulated data of varying parameters of the model was investigated, such as changing the magnitude of variability and the percentages of false positive and negative responses. Results The correlation between subject and simulated test–retest data was 0.987. Several factors were found to affect the sensitivity–variability relationship for the simulated data, most notably the rate of sensitivity decline, the percentage of false positives, and the starting luminance of the test procedure. Conclusions The principle of Divergent Dysfunction presented here provides a plausible explanation for the sensitivity–variability relationship for standard automated perimetry in glaucomatous eyes. The model and resultant simulation program aim to provide an intuitive demonstration of the principle, which can also be used to examine the effectiveness of different testing strategies. These findings have great implications for future clinical research.

To test whether the minimum rim area assessed by spectral domain optical coherence tomography (SD-OCT), based on the shortest distance from the Bruch membrane opening (BMO) to the inner limiting membrane, corresponds more closely to retinal nerve fiber layer (RNFL) thickness and visual field mean deviation (MD) than current rim measures in early glaucoma.Prospective cross-sectional study.We studied 221 participants with non-endstage glaucoma or high-risk ocular hypertension and performed standard automated perimetry. We received SD-OCT and confocal scanning laser ophthalmoscopy (CSLO) scans on the same day. Rim area measured by CSLO was compared with 3 SD-OCT rim measures from radial B-scans: horizontal rim area between BMO and inner limiting membrane within the BMO plane; mean minimum rim width (BMO-MRW); and minimum rim area (BMO-MRA) optimized within sectors and then summed. Correlations between these measures and either MD from perimetry or RNFL thickness from SD-OCT were compared using the Steiger test.RNFL thickness was better correlated with BMO-MRA (r = 0.676) or BMO-MRW (r = 0.680) than with either CSLO rim area (r = 0.330, P0.001) or horizontal rim area (r = 0.482, P0.001). MD was better correlated with BMO-MRA (r = 0.534) or BMO-MRW (r = 0.546) than with either CSLO rim area (r = 0.321, P0.001) or horizontal rim area (0.403, P0.001). The correlation between MD and RNFL thickness was r = 0.646.Minimum rim measurements from SD-OCT are significantly better correlated to both RNFL thickness and MD than rim measurements within the BMO plane or based on the clinical disc margin. They provide new structural parameters for both diagnostic and research purposes in glaucoma.