Assessment of Time Lag Between Blood Flow, Retinal Nerve Fiber Layer Thickness and Visual Field Sensitivity Changes in Glaucoma.

Purpose: This study investigates the temporal relationship between blood flow changes and alterations in retinal nerve fiber layer thickness (RNFLT) and mean deviation (MD) in individuals with glaucoma. Methods: Blood flow, measured by mean blur rate in optic nerve head vessels (MBRv) and tissues (MBRt) using laser speckle flowgraphy (LSFG)-NAVI, was analyzed using structural equation models (SEMs). SEMs assessed whether the previous rate of one parameter predicted the current rate of the other parameter, adjusted for its own rate in the previous time interval. Data from 345 eyes of 174 participants were gathered from visits every six months. Results: Rates of change of both MBRv and MBRt were significantly predicted by their own rate in the previous time interval and by the rate of change of MD in the previous time interval (P < 0.001 and P = 0.043, respectively), but not by the rate of MD in the concurrent interval (P = 0.947 and P = 0.549), implying that changes in MD precede changes in blood flow. Rates of change of RNFLT were predicted by their own previous rate and the rate of change of MBRv and MBRt in either the previous interval (P = 0.002 and P = 0.008) or the concurrent interval (P = 0.001 and P = 0.018), suggesting that MBR may change before RNFLT. Conclusions: The evidence supports a temporal sequence where MD changes precede blood flow changes, which, in turn, may precede alterations in RNFLT.

The Temporal Relation Between Rates of Retinal Nerve Fiber Layer and Minimum Rim Width Changes in Glaucoma.

Purpose: This study aims to determine whether OCT-derived rates of change in minimum rim width (MRW) are associated with and can potentially predict corresponding alterations in retinal nerve fiber layer thickness (RNFLT) in people with glaucoma. Methods: The rates of change between six-monthly visits were taken from 568 eyes of 278 participants in the P3 Study. Structural equation models (SEM) assessed whether one parameter was predicted by the concurrent or previous rate of the other parameter, after adjusting for its own rate in the previous time interval. Root mean square error of approximation (RMSEA, with 90% confidence intervals [CI]), Tucker Lewis index (TLI) and the comparative fit index (CFI) assessed goodness of fit. Results: Models without a time lag provided a better fit for the data (RMSEA = 0.101 [CI, 0.089, 0.113]), compared to a model featuring a time lag in RNFLT (RMSEA = 0.114 [CI, 0.102, 0.126]) or MRW (RMSEA = 0.114 [CI, 0.102, 0.127]). The SEMs indicated that rates for both MRW and RNFLT were predicted by their own rate in the previous time interval and by the other measure's change in the concurrent time interval (P > 0.001 for all). No evidence of a clinically significant time lag for either parameter was determined. Conclusions: MRW and RNFLT exhibit concurrent changes over time in patients with glaucoma, with no clinically significant time lag determined. Translational Relevance: RNFLT may be more useful than MRW in early glaucoma assessment because of its previously reported lower variability and reduced sensitivity to intraocular pressure changes.

Quality of Reporting Electronic Health Record Data in Glaucoma: A Systematic Literature Review.

TOPIC: Assessing Reporting Standards in Glaucoma Studies Utilizing Electronic Health Records (EHR) CLINICAL RELEVANCE: Glaucoma's significance, underscored by its status as a leading cause of irreversible blindness worldwide, necessitates reliable research findings. This study evaluates adherence to the CODE-EHR Framework in glaucoma studies using EHR, aiming to improve clinical care and patient outcomes. METHODS: A systematic review, following PRISMA guidelines (PROSPERO CRD42023430025), identified relevant studies (January 2022-May 2023) in MEDLINE, EMBASE, CINAHL, and Web of Science. Eligible studies, using EHR data from clinical institutions for glaucoma research, were assessed for study design, participant characteristics, EHR data, and sources. Quality appraisal used the CODE-EHR Framework, focusing on data construction, linkage, fitness for purpose, disease and outcome definitions, analysis, and ethics and governance. RESULTS: Of 31 identified studies, predominant EHR sources were hospitals and clinical warehouses. Commonly reported elements included age, gender, glaucoma diagnosis, and intraocular pressure. Only 16% fully adhered to CODE-EHR Framework's minimum standards, with none meeting preferred standards. While statistical analysis and ethical considerations were relatively well-addressed, areas such as EHR data management and study design showed room for improvement. Patient and public involvement, and acknowledgment of data linkage processes, data security and storage reporting were often missed. CONCLUSION: Adherence to CODE-EHR Framework's standards in EHR-based studies of glaucoma can be improved upon. Standardised reporting of EHR data is essential to ensure the reliability of research, facilitating its translation into clinical practice and improving healthcare decision-making for better patient outcomes.

Test-Retest Variability and Discriminatory Power of Measurements From Microperimetry and Dark Adaptation Assessment in People With Intermediate Age-Related Macular Degeneration - A MACUSTAR Study Report.

Purpose: The purpose of this study was to assess test-retest variability and discriminatory power of measures from macular integrity assessment (S-MAIA) and AdaptDx. Methods: This is a cross-sectional study of 167 people with intermediate age-related macular degeneration (iAMD), no AMD (controls; n = 54), early AMD (n = 28), and late AMD (n = 41), recruited across 18 European ophthalmology centers. Repeat measures of mesopic and scotopic S-MAIA average (mean) threshold (MMAT decibels [dB] and SMAT [dB]) and rod intercept time (RIT [mins]) at 2 visits 14 (±7) days apart were recorded. Repeat measures were assessed by Bland-Altman analysis, intra-class correlation coefficients (ICCs) and variability ratios. Secondary analysis assessed the area under the receiver operating characteristic curves (AUC) to determine the ability to distinguish people as having no AMD, early AMD, or iAMD. Results: Data were available for 128, 131, and 103 iAMD participants for the mesopic and scotopic S-MAIA and AdaptDx, respectively. MMAT and SMAT demonstrate similar test-retest variability in iAMD (95% confidence interval [CI] ICC of 0.79-0.89 and 0.78-0.89, respectively). ICCs were worse in RIT (95% CI ICC = 0.55-0.77). All tests had equivalent AUCs (approximately 70%) distinguishing between subjects with iAMD and controls, whereas early AMD was indistinguishable from iAMD on all measures (AUC = <55%). A learning effect was not seen in these assessments under the operating procedures used. Conclusions: MMAT, SMAT, and RIT have adequate test-retest variability and are all moderately good at separating people with iAMD from controls. Translational Relevance: Expected levels of test-retest variability and discriminatory power of the AdaptDx and MAIA devices in a clinical study setting must be considered when designing future trials for people with AMD.

Assessment of the Classification of Age-Related Macular Degeneration Severity from the Northern Ireland Sensory Ageing Study Using a Measure of Dark Adaptation.

Purpose: To assess the differences in rod-mediated dark adaptation (RMDA) between different grades of age-related macular degeneration (AMD) severity using an OCT-based criterion compared with those of AMD severity using the Beckman color fundus photography (CFP)-based classification and to assess the association between the presence of subretinal drusenoid deposits (SDDs) and RMDA at different grades of AMD severity using an OCT-based classification. Design: Cross-sectional study. Participants: Participants from the Northern Ireland Sensory Ageing study (Queen's University Belfast). Methods: Complete RMDA (rod-intercept time [RIT]) data, CFP, and spectral-domain OCT images were extracted. Participants were stratified into 4 Beckman groups (omitting late-stage AMD) and 3 OCT-based groups. The presence and stage of SDDs were identified using OCT. Main Outcome Measures: Rod-intercept time data (age-corrected). Results: Data from 459 participants (median [interquartile range] age, 65 [59-71] years) were stratified by both the classifications. Subretinal drusenoid deposits were detected in 109 eyes. The median (interquartile range) RMDA for the Beckman classification (Beckman 0-3, with 3 being intermediate age-related macular degeneration [iAMD]) groups was 6.0 (4.5-8.7), 6.6 (4.7-10.5), 5.7 (4.4-7.4), and 13.2 (6-21.1) minutes, respectively. OCT classifications OCT0-OCT2 yielded different median (interquartile range) values: 5.8 (4.5-8.5), 8.4 (5.2-13.3), and 11.1 (5.3-20.1) minutes, respectively. After correcting for age, eyes in Beckman 3 (iAMD) had statistically significantly worse RMDA than eyes in the other Beckman groups (P ≤ 0.005 for all), with no statistically significant differences between the other Beckman groups. Similarly, after age correction, eyes in OCT2 had worse RMDA than eyes in OCT0 (P ≤ 0.001) and OCT1 (P < 0.01); however, there was no statistically significant difference between eyes in OCT0 and eyes in OCT1 (P = 0.195). The presence of SDDs was associated with worse RMDA in OCT2 (P < 0.01) but not in OCT1 (P = 0.285). Conclusions: Eyes with a structural definition of iAMD have delayed RMDA, regardless of whether a CFP- or OCT-based criterion is used. In this study, after correcting for age, the RMDA did not differ between groups of eyes defined to have early AMD or normal aging, regardless of the classification. The presence of SDDs has some effect on RMDA at different grades of AMD severity.

Repeatability and Discriminatory Power of Chart-Based Visual Function Tests in Individuals With Age-Related Macular Degeneration: A MACUSTAR Study Report.

Importance: There is a need for validated clinical end points that are reliably able to quantify potential therapeutic effects of future treatments targeting age-related macular degeneration (AMD) before the onset of serious visual impairment. Objective: To assess the reliability and discriminatory power of 5 simple chart-based visual function (VF) tests as potential measures for clinical trial end points with regulatory and patient-access intention in intermediate AMD (iAMD). Design, Setting, and Participants: This international noninterventional study took place at 18 tertiary ophthalmology departments across Europe. Participants were recruited between April 2018 and March 2020 and were identified during routine clinical review. Participants with no AMD and early AMD were recruited from hospital staff, friends, and family of participants with AMD and via referrals from community ophthalmologists and optometrists. The repeatability and discriminatory power of 5 simple chart-based assessments of VF (best-corrected visual acuity [BCVA], low-luminance visual acuity [LLVA], Moorfields Acuity Test [MAT], Pelli-Robson Contrast Sensitivity [CS], and International Reading Speed Test [IReST]) were assessed in a repeated-measures design. VF assessments were performed on day 0 and day 14. Participants with early AMD, iAMD, late AMD, and no AMD were recruited. Main Outcomes and Measures: Intraclass correlation coefficients (ICCs) and Bland-Altman 95% limits of agreement (LoA) were computed to assess repeatability. Area under the receiver operating characteristic curves (AUCs) determined the discriminatory ability of all measures to classify individuals as having no AMD or iAMD and to differentiate iAMD from its neighboring disease states. Results: A total of 301 participants (mean [SD] age, 71 [7] years; 187 female participants [62.1%]) were included in the study. Thirty-four participants (11.3%) had early AMD, 168 (55.8%) had iAMD, 43 (14.3%) had late AMD, and 56 (18.6%) had no AMD. ICCs for all VF measures ranged between 0.88 and 0.96 when all participants were considered, indicating good to excellent repeatability. All measures displayed excellent discrimination between iAMD and late AMD (AUC, 0.92-0.99). Early AMD was indistinguishable from iAMD on all measures (AUC, 0.54-0.64). CS afforded the best discrimination between no AMD and iAMD (AUC, 0.77). Under the same conditions, BCVA, LLVA, and MAT were fair discriminators (AUC, 0.69-0.71), and IReST had poor discrimination (AUC, 0.57-0.61). Conclusions and Relevance: BCVA, LLVA, MAT, CS, and IReST had adequate repeatability in this multicenter, multiexaminer setting but limited power to discriminate between no AMD and iAMD. The prognostic power of these variables to predict conversion from iAMD to late AMD is being examined in the ongoing longitudinal part of the MACUSTAR study.

Optimising assessment of dark adaptation data using time to event analysis.

In age-related macular degeneration (AMD) research, dark adaptation has been found to be a promising functional measurement. In more severe cases of AMD, dark adaptation cannot always be recorded within a maximum allowed time for the test (~ 20-30 min). These data are recorded either as censored data-points (data capped at the maximum test time) or as an estimated recovery time based on the trend observed from the data recorded within the maximum recording time. Therefore, dark adaptation data can have unusual attributes that may not be handled by standard statistical techniques. Here we show time-to-event analysis is a more powerful method for analysis of rod-intercept time data in measuring dark adaptation. For example, at 80% power (at α = 0.05) sample sizes were estimated to be 20 and 61 with uncapped (uncensored) and capped (censored) data using a standard t-test; these values improved to 12 and 38 when using the proposed time-to-event analysis. Our method can accommodate both skewed data and censored data points and offers the advantage of significantly reducing sample sizes when planning studies where this functional test is an outcome measure. The latter is important because designing trials and studies more efficiently equates to newer treatments likely being examined more efficiently.

Evidence for Structural and Functional Damage of the Inner Retina in Diabetes With No Diabetic Retinopathy.

Purpose: To provide structural and functional evidence of inner retinal loss in diabetes prior to vascular changes and interpret the structure-function relationship in the context of an established neural model. Methods: Data from one eye of 505 participants (134 with diabetes and no clinically evident vascular alterations of the retina) were included in this analysis. The data were collected as part of a large population-based study. Functional tests included best-corrected visual acuity, Pelli-Robson contrast sensitivity, mesopic microperimetry, and frequency doubling technology perimetry (FDT). Macular optical coherence tomography volume scans were collected for all participants. To interpret the structure-function relationship in the context of a neural model, ganglion cell layer (GCL) thickness was converted to local ganglion cell (GC) counts. Results: The GCL and inner plexiform layer were significantly thinner in participants with diabetes (P < 0.05), with no significant differences in the macular retinal nerve fiber layer or the outer retina. All functional tests except microperimetry showed a significant loss in diabetic patients (P < 0.05). Both FDT and microperimetry showed a significant relationship with the GC count (P < 0.05), consistent with predictions from a neural model for partial summation conditions. However, the FDT captured additional significant damage (P = 0.03) unexplained by the structural loss. Conclusions: Functional and structural measurements support early neuronal loss in diabetes. The structure-function relationship follows the predictions from an established neural model. Functional tests could be improved to operate in total summation conditions in the macula, becoming more sensitive to early loss.

Determinants of Test Variability in Scotopic Microperimetry: Effects of Dark Adaptation and Test Indices.

Purpose: To test the effect of different dark adaptation conditions and reliability indices on the variability of two color scotopic microperimetry. Methods: We analyzed data from 22 consecutive visually healthy adults. Scotopic microperimetry was performed (Macular Integrity Assessment microperimeter, CenterVue, Padua, Italy) with two wavelength stimuli, cyan (505 nm) and red (627 nm), after a dark adaptation time of 10, 20, or 30 minutes. All tests were repeated twice to measure test-retest variability with Bland-Altman plots. We also provide a method to more accurately quantify the false-positive (FP) responses based on response data (button pressing) from the device, similar to FP responses used in standard static perimetry. Data on fixation stability (95% bivariate contour ellipse area) and blind spot responses were also extracted. Their relationship with measured sensitivity (in decibels) and test-retest variability was quantified through linear mixed effect models. Results: Dark adaptation had a significant effect on the sensitivity (dB) measured with the cyan stimulus (P < 0.001), but no effect on the red stimulus. Of the three metrics, the novel FP responses showed the best association with test-retest variability and was the only predictor consistently significant for all tests (P < 0.01). Conclusions: Dark adaptation protocols should be carefully standardized for scotopic testing, especially if a cyan stimulus is used. The proposed FP responses should be used to assess reliability of microperimetry examinations instead of other metrics. Translational Relevance: We developed a method to calculate a more accurate estimate of the FP responses using data available to all researchers, generalizable to all Macular Integrity Assessment microperimeter tests.

Are Current Methods of Measuring Dark Adaptation Effective in Detecting the Onset and Progression of Age-Related Macular Degeneration? A Systematic Literature Review.

INTRODUCTION: Dark adaptation (DA) has been proposed as a possible functional biomarker for age-related macular degeneration (AMD). In this systematic review we aim to evaluate current methodology used to assess DA in people with AMD, the evidence of precision in detecting the onset and progression of AMD, and the relationship between DA and other functional and structural measures. METHODS: MEDLINE, EMBASE, CINAHL, AMED, PsycINFO, PsycARTICLES were searched for studies published between January 2006 and January 2020 that assessed DA in people with AMD. Details of eligible studies including study design, characteristics of study population and outcomes were recorded. All included studies underwent quality appraisal using approved critical appraisal tools. This systematic review follows PRISMA guidelines (PROSPERO registration number: CRD42019129486). RESULTS: Forty-eight studies were eligible for inclusion, reporting a variety of instruments and protocols to assess different DA parameters. Twenty of these studies used the AdaptDx (MacuLogix, Hummelstown, PA, USA) instrument and assessed rod-intercept time (RIT). Most of these reported that RIT was delayed in people with AMD and this delay worsened with AMD severity. Four studies, involving 533 participants, reported estimates of diagnostic performance of AdaptDx to separate people with AMD from visually healthy controls. DA has been compared to other measures of visual function, patient-reported outcome measures (PROMs) and structural measures. Ten studies specifically considered evidence that the presence of certain structural abnormalities was associated with impaired DA in AMD. CONCLUSIONS: This systematic review indicates overwhelming evidence of reasonable quality for an association between impaired DA and AMD. Data on the repeatability and reproducibility of DA measurement are sparse. There is evidence that structural abnormalities such as reticular drusen are associated with prolongation of DA time. Fewer studies have explored an association between DA and other measures of visual function or PROMs. We found no studies that had compared DA with performance-based measures.

Novel computer-based assessments of everyday visual function in people with age-related macular degeneration.

PURPOSE: To test the hypothesis that the performance in novel computer-based tasks of everyday visual function worsens with disease severity in people with non-neovascular age-related macular degeneration. METHODS: Participants with and without non-neovascular age-related macular degeneration (≥60 years, minimum logMAR binocular visual acuity 0.7) performed a series of standard visual function tests and two novel computer-based tasks. In a visual search task, participants had to locate an image of a single real-world object within an array of 49 distractor images. Next, in a series of simulated dynamic driving scenes, participants were asked to identify one or two approaching real-world road signs and then select these road signs from four options. Outcome measures were median response times and total correct responses. RESULTS: Forty-nine participants had no macular disease (n = 11), early/intermediate age-related macular degeneration (n = 16) or geographic atrophy (n = 22). Groups were age-similar with median (interquartile range) logMAR visual acuity of 0.00 (-0.08,0.12), 0.13 (-0.08,0.70) and 0.32 (0.12,0.70) respectively. Median (interquartile range) visual search response times were 1.9 (1.0,2.4), 1.8 (1.1,3.7) and 2.4 (1.2,6.0) seconds respectively. Median (interquartile range) road sign response times (single road signs) were 1.2 (0.4,1.7), 1.5 (0.9,2.8) and 1.8 (1.0,5.5) seconds respectively. Median (interquartile range) road sign response times (double road signs) were 1.7 (0.7,2.4), 2.3 (1.2,3.1) and 2.5 (1.7,6) seconds respectively. Participants with geographic atrophy recorded slower response times in all tasks and over 50% performed outside the normative limit for task performance. There were no significant differences between groups in total correct responses across all tasks. CONCLUSIONS: In a novel computer-based assessment, people with increasing severity of age-related macular degeneration take longer to perform visual search of everyday objects and take longer to identify road signs than those with no age-related macular degeneration. These novel assessments could be useful as patient-relevant, secondary outcomes for clinical trials.

Structure-Function Analysis in Macular Drusen With Mesopic and Scotopic Microperimetry.

Purpose: To investigate the structure-function relationship in eyes with drusen with mesopic and scotopic microperimetry. Methods: We analyzed structural and functional data from 43 eyes with drusen. Functional data were acquired with mesopic and scotopic two-color (red and cyan) microperimetry. Normative values were calculated using data from 56 healthy eyes. Structural measurements were green autofluorescence and dense macular optical coherence tomography scans. The latter were used to calculate the retinal pigment epithelium elevation (RPE-E) and the photoreceptor reflectivity ratio (PRR). The pointwise structure-function relationship was measured with linear mixed models having the log-transformed structural parameters as predictors and the sensitivity loss (SL, deviation from normal) as the response variable. Results: In the univariable analysis, the structural predictors were all significantly correlated (P < 0.05) with the SL in the mesopic and scotopic tests. In a multivariable model, mesopic microperimetry yielded the best structure-function relationship. All predictors were significant (P < 0.05), but the predictive power was weak (best R2 = 0.09). The relationship was improved when analyzing locations with abnormal RPE-E (best R2 = 0.18). Conclusions: Mesopic microperimetry shows better structure-function relationship compared to scotopic microperimetry; the relationship is weak, likely due to the early functional damage and the small number of tested locations affected by drusen. The relationship is stronger when locations with drusen are isolated for the mesopic and scotopic cyan test. Translational Relevance: These results could be useful to devise integrated structure-function methods to detect disease progression in intermediate age-related macular degeneration.