MACUSTAR: Development and Clinical Validation of Functional, Structural, and Patient-Reported Endpoints in Intermediate Age-Related Macular Degeneration.

PURPOSE: Currently, no outcome measures are clinically validated and accepted as clinical endpoints by regulatory agencies for drug development in intermediate age-related macular degeneration (iAMD). The MACUSTAR Consortium, a public-private research group funded by the European Innovative Medicines Initiative intends to close this gap. PROCEDURES: Development of study protocol and statistical analysis plan including predictive modelling of multimodal endpoints based on a review of the literature and expert consensus. RESULTS: This observational study consists of a cross-sectional and a longitudinal part. Functional outcome measures assessed under low contrast and low luminance have the potential to detect progression of visual deficit within iAMD and to late AMD. Structural outcome measures will be multimodal and investigate topographical relationships with function. Current patient-reported outcome measures (PROMs) are not acceptable to regulators and may not capture the functional deficit specific to iAMD with needed precision, justifying development of novel PROMs for iAMD. The total sample size will be n = 750, consisting mainly of subjects with iAMD (n = 600). CONCLUSIONS: As clinical endpoints currently accepted by regulators cannot detect functional loss or patient-relevant impact in iAMD, we will clinically validate novel candidate endpoints for iAMD.

Effect of varying skin surface electrode position on electroretinogram responses recorded using a handheld stimulating and recording system.

PURPOSE: A handheld device (the RETeval system, LKC Technologies) aims to increase the ease of electroretinogram (ERG) recording by using specially designed skin electrodes, rather than corneal electrodes. We explored effects of electrode position on response parameters recorded using this device. METHODS: Healthy adult twins were recruited from the TwinsUK cohort and underwent recording of light-adapted flicker ERGs (corresponding to international standard stimuli). In Group 1, skin electrodes were placed in a "comfortable" position, which was up to 20 mm below the lid margin. For subsequent participants (Group 2), the electrode was positioned 2 mm from the lid margin as recommended by the manufacturer. Amplitudes and peak times (averaged from both eyes) were compared between groups after age-matching and inclusion of only one twin per pair. Light-adapted flicker and flash ERGs were recorded for an additional 10 healthy subjects in two consecutive recording sessions: in the test eye, electrode position was varied from 2 to 10-20 mm below the lid margin between sessions; in the fellow (control) eye, the electrode was 2 mm below the lid margin throughout. Amplitudes and peak times (test eye normalised to control eye) were compared for the two sessions. RESULTS: Including one twin per pair, and age-matching yielded 28 individuals per group. Flicker ERG amplitudes were significantly lower for Group 1 than Group 2 participants (p = 0.0024). However, mean peak times did not differ between groups (p = 0.54). For the subjects in whom electrode position was changed between recording sessions, flash and flicker amplitudes were significantly lower when positioned further from the lid margin (p < 0.005), but peak times were similar (p > 0.5). CONCLUSIONS: Moving the skin electrodes further from the lid margin significantly reduces response amplitudes, highlighting the importance of consistent electrode positioning. However, this does not significantly affect peak times. Thus, it may be feasible to adopt a more comfortable position in participants who cannot tolerate the recommended position if analysis is restricted to peak time parameters.

The effect of non-neovascular age-related macular degeneration on face recognition performance.

PURPOSE: There is a well-established research base surrounding face recognition in patients with age-related macular degeneration (AMD). However, much of this existing research does not differentiate between results obtained for 'wet' AMD and 'dry' AMD. Here, we test the hypothesis that face recognition performance is worse in patients with dry AMD compared with visually healthy peers. METHODS: Patients (>60 years of age, logMAR binocular visual acuity 0.7 or better) with dry AMD of varying severity and visually healthy age-related peers (controls) completed a modified version of the Cambridge Face Memory Test (CFMT). Percentage of correctly identified faces was used as an outcome measure for performance for each participant. A 90% normative reference limit was generated from the distribution of CFMT scores recorded in the visually healthy controls. Scores for AMD participants were then specifically compared to this limit, and comparisons between average scores in the AMD severity groups were investigated. RESULTS: Thirty patients (median [interquartile range] age of 76 [70, 79] years) and 34 controls (median age of 70 [64, 75] years) were examined. Four, seventeen and nine patients were classified as having early, intermediate and late AMD (geographic atrophy) respectively. Five (17%) patients recorded a face recognition performance worse than the 90% limit (Fisher's exact test, p = 0.46) set by controls; four of these had geographic atrophy. Patients with geographic atrophy identified fewer faces on average (±SD) (61% ± 22%) than those with early and intermediate AMD (75 ± 11%) and controls (74% ± 11%). CONCLUSIONS: People with dry AMD may not suffer from problems with face recognition until the disease is in its later stages; those with late AMD (geographic atrophy) are likely to have difficulty recognising faces. The results from this study should influence the management and expectations of patients with dry AMD in both community practice and hospital clinics.

Nutritional and smoking advice recalled by patients attending a UK age-related macular degeneration clinic.

Background: Age-related macular degeneration (AMD) is responsible for half of registered visual impairment in the UK. The Royal College of Ophthalmologists recommends providing guidance to people with AMD regarding smoking, diet, and nutritional supplements. The aim of this study was to investigate lifestyle advice recalled by patients with neovascular AMD (nAMD). Methods: The study took place at a UK hospital outpatients' clinic. Eligible patients with unilateral nAMD were presented with a survey about lifestyle advice provision. Results: Of 248 respondents, only 39.9% remembered receiving advice regarding diet at the hospital. Only 24.2% of respondents recalled receiving advice regarding nutritional supplements, and only 19.8% of respondents started taking daily supplements as a result of their AMD. The most prevalent reason for not taking supplements amongst those advised to do so was lack of understanding of how it would help their eyes. Nearly 13% of the sample reported currently smoking, 53.1% of which reported that they were advised to stop smoking when diagnosed with AMD. Conclusion: The findings suggest that it would be beneficial to review the provision of lifestyle advice to patients attending AMD outpatients' clinics, and to consider whether advice is being provided in an optimal format for later recall.

Seeing it differently: self-reported description of vision loss in dry age-related macular degeneration.

PURPOSE: A realistic description of visual symptoms associated with dry age-related macular degeneration (AMD) is important for raising awareness of the condition and educating patients. This study aimed to develop a set of descriptors for dry AMD and examine the realism of images currently and frequently used to show visual symptoms of the condition. METHODS: Volunteers with dry AMD with a range of disease severity were given an eye examination and were asked to describe visual symptoms of their condition in a conversational interview. Participants were also asked to comment on a photograph typically used to portray the visual symptoms of AMD. Interviews were audio recorded, transcribed and subjected to content analysis. RESULTS: Twenty-nine participants were interviewed. Median (interquartile range [IQR]) age was 75 (70, 79) years. Median (IQR) binocular visual acuity (VA) and Pelli-Robson contrast sensitivity (CS) was 0.2 (0.18, 0.36) logMAR and 1.65 (1.50, 1.95) log CS respectively. Three, 17 and nine patients had early, intermediate and late (geographic atrophy, GA) AMD, respectively. The most frequently reported descriptor group was blur (n = 13) followed by missing (n = 10) and distortion (n = 7). We chose the most popular image used to portray the visual symptoms of dry AMD based on an internet search and showed this to 21 participants. Sixteen participants (76% [95% confidence interval 53-92%]), including three out of the seven people with geographic atrophy, unequivocally rejected the realism of the image. CONCLUSIONS: People with dry AMD use a wide range of descriptors for their visual experience. Visual symptoms of dry AMD as portrayed by commonly shown images were not the experience of most people in this study.

Measurement of cone dark adaptation: a comparison of four psychophysical methods.

PURPOSE: Dark adaptometry is an important clinical tool for the diagnosis of a range of conditions, including age-related macular degeneration. In order to identify the most robust, clinically applicable technique for the measurement of cone dark adaptation, the repeatability and agreement of four psychophysical methods were assessed. METHODS: Data were obtained from 31 healthy adults on two occasions, using four psychophysical methods. Participants' pupils were dilated, and 96 % of cone photopigment was bleached before threshold was monitored in the dark using one of the techniques, selected at random. This procedure was repeated for each of the remaining methods. An exponential recovery function was fitted to all threshold recovery data. The coefficient of repeatability (CoR) was calculated to assess the repeatability of the methods, and a repeated-measures analysis of variance was used to compare mean recovery parameters. RESULTS: All four methods demonstrated a similar level of intersession repeatability for measurement of cone recovery, yielding CoRs between 1.18 and 1.56 min. There were no statistically significant differences in estimates of mean time constant of cone recovery (cone τ) between the four methods (p = 0.488); however, significant differences between initial and final cone thresholds were reported (p < 0.005). CONCLUSIONS: All of the techniques were capable of monitoring the rapid changes in visual threshold that occur during cone dark adaptation, and the repeatability of the techniques was similar. This indicates that despite the respective advantages and disadvantages of these psychophysical techniques, all four methods would be suitable for measuring cone dark adaptation in clinical practice.

An evaluation of two candidate functional biomarkers for AMD.

PURPOSE: To evaluate the intersession repeatability of the Colour Assessment and Diagnosis (CAD) test and a novel 14-Hz flicker test in a population of healthy participants to provide benchmark data for their use as functional biomarkers for age-related macular degeneration (AMD). METHODS: Visual function was assessed using both techniques in 30 healthy adults (mean [standard deviation] age 36.3 [14.1] years) on two separate days. Intersession repeatability of RG and YB CAD thresholds and 14-Hz flicker thresholds was assessed by determining their coefficient of repeatability (CoR). RESULTS: The CoR was calculated to be 0.39 CAD units (17.0%) for RG thresholds, 0.43 CAD units (31.1%) for YB thresholds, and 0.015 (53.4%) for 14-Hz flicker contrast thresholds. On average, thresholds improved by 4.72% (RG), 6.33% (YB), and 13.3% (14-Hz flicker) between visits 1 and 2, suggesting a small but consistent learning effect. The CoR for all parameters was relatively small compared to the mean thresholds obtained (RG: mean 2.27 [4.58], CoR 0.39; YB: mean 1.37 [0.55], CoR 0.43; 14-Hz flicker: mean 0.028 [0.01], CoR 0.015). CONCLUSIONS: This study has described the repeatability of the CAD and 14-Hz flicker tests. These data can help clinicians decide if the results from repeated measures are of clinical significance. Despite pretest training, there was some evidence of a learning effect. Therefore, clinical trials using these techniques should ensure training is sufficient to minimize these effects.

A new slit lamp-based technique for anterior chamber angle estimation.

PURPOSE: To design and test a new noninvasive method for anterior chamber angle (ACA) estimation based on the slit lamp that is accessible to all eye-care professionals. METHODS: A new technique (slit lamp anterior chamber estimation [SLACE]) that aims to overcome some of the limitations of the van Herick procedure was designed. The technique, which only requires a slit lamp, was applied to estimate the ACA of 50 participants (100 eyes) using two different slit lamp models, and results were compared with gonioscopy as the clinical standard. RESULTS: The Spearman nonparametric correlation between ACA values as determined by gonioscopy and SLACE were 0.81 (p < 0.001) and 0.79 (p < 0.001) for each slit lamp. Sensitivity values of 100 and 87.5% and specificity values of 75 and 81.2%, depending on the slit lamp used, were obtained for the SLACE technique as compared with gonioscopy (Spaeth classification). CONCLUSIONS: The SLACE technique, when compared with gonioscopy, displayed good accuracy in the detection of narrow angles, and it may be useful for eye-care clinicians without access to expensive alternative equipment or those who cannot perform gonioscopy because of legal constraints regarding the use of diagnostic drugs.

How effective is eccentric viewing training? A systematic literature review.

PURPOSE: The global prevalence of age-related macular degeneration and associated central vision loss is rising. Central vision loss hinders the performance of many activities of daily living. Adaptive strategies such as eccentric viewing and steady eye strategy may be used to compensate for central vision loss. In order to establish the potential of these rehabilitation strategies, this systematic review evaluates current literature regarding the effectiveness of eccentric viewing and steady eye strategy training in people with central vision loss. RESULTS: The search strategies identified 2605 publications, 36 of which met the inclusion criteria for the review, but only three of which were randomised controlled trials. This literature shows that eccentric viewing and steady eye strategy training can improve near visual acuity, reading speed, and performance of activities of daily living in people with central vision loss. However, there was insufficient literature to establish a relationship between training and distance visual acuity or quality of life. There is no conclusive evidence to show that a particular model of eccentric viewing training is superior to another, little clear evidence of a relationship between participant characteristics and training outcomes and no data regarding the cost effectiveness of training. CONCLUSION: This report highlights the need for further robust research to establish the true potential and cost effectiveness of eccentric viewing and steady eye strategy training as a rehabilitation strategy for individuals with central vision loss.

The effect of pre-adapting light intensity on dark adaptation in early age-related macular degeneration.

BACKGROUND: This study aimed to identify the pre-adapting light intensity that generated the maximum separation in the parameters of dark adaptation between participants with early age-related macular degeneration (AMD) and healthy control participants in the minimum recording time. METHODS: Cone dark adaptation was monitored in 10 participants with early AMD and 10 age-matched controls after exposure to three pre-adapting light intensities, using an achromatic annulus (12° radius) centred on the fovea. Threshold recovery data were modelled, and the time constant of cone recovery (τ), final cone threshold, and time to rod-cone-break (RCB) were determined. The diagnostic potential of these parameters at all pre-adapting intensities was evaluated by constructing receiver operating characteristic (ROC) curves. RESULTS: There were significant differences between those with early AMD and healthy controls in cone τ and time to RCB (p < 0.05) at all pre-adapting 'bleaching' intensities. ROC curves showed that the diagnostic potential of dark adaptometry was high following exposure to all three pre-adapting intensities, generating an area under the curve in excess of 0.87 ± 0.08 for cone τ and time to RCB for all conditions. CONCLUSIONS: Dark adaptation was shown to be highly diagnostic for early AMD across a range of pre-adapting light intensities, and therefore, the lower pre-adapting intensities evaluated in this study may be used to expedite dark adaptation measurement in the clinic without compromising the integrity of the data obtained. This study reinforces the suggestion that cone and rod dark adaptation are good candidate biomarkers for early AMD.

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.

Aging and cone dark adaptation.

PURPOSE: Following exposure to a bright light that bleaches a significant portion of photopigment, the eyes take several minutes to regain sensitivity. This slow process, known as dark adaptation, is impaired in patients with age-related macular degeneration and is an important candidate biomarker for this disease. The aim of this study was to evaluate the effect of age on cone dark adaptation. METHODS: Data were obtained from 41 healthy adults aged between 20 and 83 years. Pupils were dilated and 96% of cone photopigment was "bleached," before threshold was monitored continuously for 5 min in the dark, using a 4° diameter achromatic spot centered on the fovea. Threshold recovery data were modeled, and the time constant of cone recovery (τ), initial cone thresholds, and final cone thresholds were determined. Regression analysis was used to determine the relationship between age and cone dark adaptation parameters. RESULTS: Cone τ increased by 16.4 s/decade of life, indicating a progressive slowing of dark adaptation with increasing age. This change in cone τ throughout adulthood was significant (p < 0.0005). There was no significant relationship between increasing age and initial cone threshold (p = 0.84) or final cone threshold (p = 0.82). CONCLUSIONS: Our results provide evidence for age-related slowing of cone dark adaptation after a full bleach in healthy adults, which is likely to contribute to visual difficulties when moving from bright to dim photopic light levels. We propose that the sensitivity and specificity of cone τ as a biomarker for early age-related macular disease could be improved by taking into account the significant age-related decline in this parameter.

What Advice Is Currently Given to Patients with Age-Related Macular Degeneration (AMD) by Eyecare Practitioners, and How Effective Is It at Bringing about a Change in Lifestyle? A Systematic Review.

There is currently no treatment for early/intermediate Age-related Macular Degeneration (AMD) but Eye Care Professionals (ECPs) are recommended to advise patients about modifiable lifestyle factors, including dietary changes, that can slow disease progression. The aim of this review was to understand advice currently given to patients with AMD by ECPs and to evaluate evidence regarding patient compliance. A systematic review was conducted of literature published in electronic databases: CINAHL, MEDLINE, PsycINFO, PyscARTICLES, EMBASE, AMED. Methods followed PRISMA guidelines (PROSPERO registration number: CRD42020223724). Twenty-four reports were eligible for inclusion, 12 focused on ECP experience, 7 on patient experience, and 6 on impact of advice (one paper reported on the ECP and patient experience). Studies reported that a substantial proportion of patients did not recall receiving lifestyle modification advice from their ECP (57.95%, range 2-95% across patient based studies). Practitioners were most likely to provide advice about nutritional supplements (80%, range 67-93% across ECP studies), and least likely about smoking (44%, range 28-71% across ECP studies), however supplements advised did not always comply with evidence-based guidelines. The main reason for patients not following lifestyle advice was lack of provision by the ECP (54.5%, range 21-94% across studies on the impact of advice). The review highlighted a need for more studies to understand patient preferences for receiving advice and research on ECP perceived barriers to advice provision.

Electrophysiological Assessment in Birdshot Chorioretinopathy: Flicker Electroretinograms Recorded With a Handheld Device.

Purpose: The flicker electroretinogram (ERG) is a sensitive indicator of retinal dysfunction in birdshot chorioretinopathy (BCR). We explored recordings from a handheld device in BCR, comparing these with conventional recordings in the same patients and with handheld ERGs from healthy individuals. Methods: Non-mydriatic flicker ERGs, using the handheld RETeval system (LKC Technologies), were recorded with skin electrodes at two centers. At one center (group 1), the stimuli (85 Td·s, 850 Td background) delivered retinal illuminance equivalent to international standards; at the other center (group 2), a different protocol was used (32 Td·s, no background). Patients also underwent international standard flicker ERG recordings with conventional electrodes following mydriasis. Portable ERGs from patients were also compared with those from healthy individuals. Results: Thirty-two patients with BCR (mean age ± SD, 56.4 ± 11.3 years) underwent recordings. Portable and standard ERG parameters correlated strongly (r > 0.75, P < 0.01) in both groups. Limits of agreement for peak times were tighter in group 1 (n = 21; -4.3 to +2.0 ms [right eyes], -3.9 to 1.5 ms [left eyes]) than in group 2 (n = 11; -3.4 to +6.9 ms [right eyes], -4.8 to +9.0 ms [left eyes]). Compared with healthy controls (n = 66 and n = 90 for groups 1 and 2, respectively), patients with BCR showed smaller mean amplitudes and longer peak times. Conclusions: Portable ERGs correlated strongly with conventional recordings, suggesting potential in rapid assessment of cone system function in office settings. Translational Relevance: Flicker ERGs, known to be useful in BCR, can be obtained rapidly with a portable device with skin electrodes and natural pupils.

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.

The repeatability of the Goldmann-Weekers adaptometer for measuring cone adaptation.

To assess the inter-session repeatability of the Goldmann-Weekers adaptometer for the measurement of cone dark adaptation in a population of healthy subjects. Data were obtained from 31 healthy adults (mean age 21.5 ± 2.5) on 2 days. At each visit, pupils were dilated and a 96% bleach of cone photopigment was administered to the test eye before threshold was monitored continuously for 5 min in the dark using the Goldmann-Weekers adaptometer. A single exponential function was fitted to the threshold recovery data on a least squares basis. The coefficient of repeatability (CoR) was calculated to assess the repeatability of the time constant of recovery (τ), initial threshold and final threshold. Cone dark adaptation functions were successfully recorded from all subjects on both visits. The CoR was 79.48 s for τ, 0.71 log cdm(-2) for the initial threshold, and 0.58 log cdm(-2) for the final threshold. Paired samples t-tests showed that there were no significant differences between visits for any of the parameters assesed. Although the Goldmann-Weekers adaptometer was capable of monitoring the rapid changes in threshold that occur during cone dark adaptation, the CoR for τ was relatively large compared to the mean recovery time constants (126.48 ± 40.33 and 119.94 ± 33.25 s at the first and second visits, respectively). This indicates that the Goldmann-Weekers adaptometer is unlikely to be a useful instrument to chart changes in an individual's vision over time.

The effect of bleach duration and age on the ERG photostress test.

BACKGROUND: The ERG photostress test assesses the recovery of the focal 41 Hz ERG following exposure to a bright light that bleaches a significant proportion of photopigment. The aims of this study were: 1) to compare the repeatability of the ERG photostress test recovery time constant following long and short duration light exposure, and 2) to determine the effect of age on the ERG photostress test recovery time constant. METHODS: Focal 41 Hz ERGs were recorded from 23 participants (age range 20-71 years) at 20-second intervals for 5 minutes following either a short-duration (photoflash) or long-duration (equilibrium) light exposure. After a 5-minute wash-out period, the procedure was repeated using the second bleach modality. The time constant of cone recovery was determined by fitting an exponential model to the amplitude recovery data. The whole procedure was repeated on a second occasion. The co-efficient of repeatability (CoR) was calculated for each bleaching technique. The relationship between the time constant of recovery and age was investigated (Pearson's correlation coefficient). RESULTS: The time constant of recovery following an equilibrium bleach was more repeatable than recovery following a photoflash (CoR = 85s and 184s respectively). Eight trials (from seven participants) failed to show a reduction in amplitude following the photoflash, suggesting that a blink or fixation loss had occurred. All participants were reliably light-adapted by the equilibrium bleach. For the equilibrium bleach data, the time constant of recovery increased with age at a rate of 27 seconds per decade. CONCLUSIONS: The equilibrium bleach was more reliable and repeatable than the photoflash. Increasing participant age was shown to result in a lengthening of the recovery time constant, of a magnitude comparable to previously published psychophysical data.

Topography of cone dark adaptation deficits in age-related maculopathy.

PURPOSE: Despite widespread agreement that dark adaptation is abnormal in age-related maculopathy (ARM), the optimal retinal location for detection of this deficit is unclear. We quantified the diagnostic potential of cone dark adaptation as a function of retinal eccentricity and compared this with the diagnostic potential of the time to the rod-cone-break (RCB). METHODS: Cone dark adaptation was monitored after an 80% cone photopigment bleach in 10 subjects with ARM and 10 age-matched controls, using four achromatic annuli (0.5, 2, 7, and 12° radius) centered on the fovea. Threshold recovery data were modeled and the time constant of cone recovery (τ), final cone threshold, and time to RCB were determined. Diagnostic potential was evaluated by constructing receiver operating characteristic curves for these parameters. RESULTS: Cone τ was significantly longer for the ARM group at 2, 7, and 12°. The greatest difference between groups was observed at 12° from fixation. At this location, the mean τ was 3.49 (±2.02) min and 0.64 (±0.38) min for ARM and control subjects, respectively (p = 0.002), and time to RCB was 17.68 (±5.37) min and 9.05 (±2.11) min for ARM and control subjects, respectively (p = 0.001). Correspondingly, receiver operating characteristic curves showed that the diagnostic potential of dark adaptometry is greatest for stimuli presented 12° from fixation; for cone τ, the area under the curve = 0.99 ± 0.02 and for time to RCB, area under the curve = 0.96 ± 0.04. CONCLUSIONS: This study has shown cone-mediated dark adaptation to be significantly impaired in ARM. Our results provide compelling evidence in support of the diagnostic potential of cone dark adaptation and the use of annular stimuli at 12°. The observation that cone τ is highly diagnostic at this eccentricity is significant clinically because this parameter may be quantified within a few minutes.

How is the risk of being diagnosed with referable diabetic retinopathy affected by failure to attend diabetes eye screening appointments?

BACKGROUND/AIMS: This study examines the anecdotal impression that in diabetes eye screening there is a relationship between number of consecutive missed screening appointments and the incidence of referable retinopathy at the next screening appointment that is attended. METHODS: A retrospective observational audit was conducted of data from 62,067 people who were due for annual diabetes eye screening in the North East London Diabetes Eye Screening Programme between January 2010 and January 2017, and who had missed at least one screening appointment within that time. RESULTS: Missing 5 consecutive screening appointments increased the incidence of referable retinopathy from a programme average of 4% up to 15%. The incidence of referable retinopathy in people missing 10 or more consecutive appointments was ~20%. There was an association between younger age, male gender, type I disease, and being of African ethnicity with increasing number of missed appointments. CONCLUSIONS: There was a strong association between the number of missed appointments and the proportion of patients showing referable retinopathy at the next visit. Approaches to reduce the number of missed appointments may help to reduce the incidence of referable retinopathy. These may be targeted at those showing the greatest non-attendance behaviour in the current 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.