The role of dark adaptation in understanding early AMD.

The main aim of the paper is to discuss current knowledge on how Age Related Macular Degeneration (AMD) affects Dark Adaptation (DA). The paper is divided into three parts. Firstly, we outline some of the molecular mechanisms that control DA. Secondly, we review the psychophysical issues and the corresponding analytical techniques. Finally, we characterise the link between slowed DA and the morphological abnormalities in early AMD. Historically, DA has been regarded as too cumbersome for widespread clinical application. Yet the technique is extremely useful; it is widely accepted that the psychophysically obtained slope of the second rod-mediated phase of the dark adaptation function is an accurate assay of photoreceptor pigment regeneration kinetics. Technological developments have prompted new ways of generating the DA curve, but analytical problems remain. A simple potential solution to these, based on the application of a novel fast mathematical algorithm, is presented. This allows the calculation of the parameters of the DA curve in real time. Improving current management of AMD will depend on identifying a satisfactory endpoint for evaluating future therapeutic strategies. This must be implemented before the onset of severe disease. Morphological changes progress too slowly to act as a satisfactory endpoint for new therapies whereas functional changes, such as those seen in DA, may have more potential in this regard. It is important to recognise, however, that the functional changes are not confined to rods and that building a mathematical model of the DA curve enables the separation of rod and cone dysfunction and allows more versatility in terms of the range of disease severity that can be monitored. Examples are presented that show how analysing the DA curve into its constituent components can improve our understanding of the morphological changes in early AMD.

The Light and the Dark of Early and Intermediate AMD: Cone- and Rod-Mediated Changes Are Linked to Fundus Photograph and FAF Abnormalities.

Purpose: The purpose of this paper is to describe the extent to which scotopic and photopic measures of visual function predict color fundus photograph (CFP) and fundus autofluorescence (FAF) changes in early and intermediate nonexudative AMD. Methods: Sixty-nine observers were recruited: 56 AMD patients (mean age, 73 ± 12.98 years) and 13 controls (mean age, 67.77 ± 9.72 years). A nonmydriatic retinal camera was used to obtain stereo fundus photographs and FAF images were recorded with a cSLO Heidelberg Spectralis HRA+OCT. Visual acuity (VA) was measured using an Early Treatment of Diabetic Retinopathy Study chart. Contrast sensitivity (CS) was assessed with a Pelli-Robson chart. Dark adaptation (DA) curves were recorded at 3° eccentricity using a PC-based technique. Analysis of these curves yielded five parameters: cone threshold (CT), cone time constant (CC), cone-rod break (α), slope of the second rod component (S2), and rod-rod break (ß). Results: Both cone and rod sensitivity recovery were grossly abnormal in the patients. The rod recovery slope (S2) most accurately predicted the fundus photograph-based grade and the FAF classification (ρ = 0.61 and ρ = 0.60, respectively; both P < 0.0001). CS showed a strong association with FAF (ρ = 0.50, P < 0.0001) and with fundus photograph-based grade (ρ = 0.38, P < 0.002). There was no correlation between VA and either imaging method. Conclusions: Dynamic, rod-based measures most accurately reflect the severity of early AMD. Although less specific to AMD than DA changes, static photopic abnormalities such as CS also correspond with morphologic changes. Assessment of function in early AMD should include dynamic rod- and cone-mediated measurements of sensitivity recovery.

Slowed Dark Adaptation in Early AMD: Dual Stimulus Reveals Scotopic and Photopic Abnormalities.

Purpose: The recovery of visual sensitivity after a photobleach in early AMD is slowed in rods but cones also may be abnormal. The purpose of this article was to test different stimulus locations to investigate cone function and its relation to rod abnormalities. Methods: Stimuli were presented at two locations, 3.0° and 5.5°, in the inferior visual field. Post photobleach dark adaptation (DA) curves from 50 early-AMD patients were compared with those from 15 healthy controls of similar age. Curves were characterized in terms of four parameters: ct, cone threshold; α, the transition point from cone to rod function; S2, the slope of the second rod-mediated component; and ß, the transition from the second to the third rod-mediated component. Results: There were strong location effects for the healthy group and the AMD group. Cone threshold was higher for the outer compared with the inner stimulus (P = 0.001), S2 was steeper for outer compared with inner (P < 0.001), α was shorter for outer (P = 0.004), and ß was shorter for outer than inner (P = 0.002). The high variance in the patient data, particularly for α and ß, explained the absence of a group*location interaction in the statistics. Conclusions: The data provide a novel perspective on abnormal cone- and rod-sensitivity recovery in early dry AMD. The comparison of pairs of DA curves from different locations highlights the involvement of cones in the underlying pathology of AMD. Dynamic measures of visual function are particularly sensitive to early AMD.

Slowed dark adaptation in older eyes; effect of location.

PURPOSE: The rate of rod sensitivity recovery following a photobleach is a basic measure of the integrity of the outer retina. Rods are selectively impaired in aging and many disorders of the retina, notably Age-Related Macular Degeneration (AMD). It is not known for certain whether the age-related deficit is a pan-retinal effect or if there are localised regions of impaired rod function. To address this important issue a dual arc stimulus was developed that samples sensitivity recovery in two retinal locations. METHODS: Arc-shaped stimuli were presented on a black CRT screen at two locations, in the inferior visual field. Following a bleach, which was localised to the stimuli, recovery of sensitivity was measured using a modified method of adjustment technique. Neutral density filters were used to extend the luminance range of the CRT. Sensitivity recovery functions were fitted by non-linear regression to a seven-parameter model. RESULTS: Pairs of sensitivity recovery functions were generated from the stimuli. The cone phases of these functions were identical. The slopes of the S2 sections of the curves were steeper for the outer stimuli for both young (p < 0.001) and older (p = 0.003) observers. The difference between the two was the same for the two groups. The α point was reached slightly earlier for the young observers and with the outer stimulus but neither of these effects reached statistical significance. The ß point occurred earlier for the outer stimuli and this effect was statistically significant only for the older group. CONCLUSIONS: The method places minimal demands on observers. The fact that rod sensitivity recovery is slowed in the older normal eye to the same extent in the two locations suggests that this deficit may be uniform across the retina. As there are localised losses in scotopic function in AMD, the technique is ideally suited to distinguishing impaired recovery dynamics due to normal ageing from those caused by disease.

Automated Measurement of Visual Acuity in Pediatric Ophthalmic Patients Using Principles of Game Design and Tablet Computers.

PURPOSE: To report on the utility of a computer tablet-based method for automated testing of visual acuity in children based on the principles of game design. We describe the testing procedure and present repeatability as well as agreement of the score with accepted visual acuity measures. DESIGN: Reliability and validity study. METHODS: Setting: Manchester Royal Eye Hospital Pediatric Ophthalmology Outpatients Department. PATIENT POPULATION: Total of 112 sequentially recruited patients. INTERVENTION: For each patient 1 eye was tested with the Mobile Assessment of Vision by intERactIve Computer for Children (MAVERIC-C) system, consisting of a software application running on a computer tablet, housed in a bespoke viewing chamber. The application elicited touch screen responses using a game design to encourage compliance and automatically acquire visual acuity scores of participating patients. Acuity was then assessed by an examiner with a standard chart-based near ETDRS acuity test before the MAVERIC-C assessment was repeated. MAIN OUTCOME MEASURE: Reliability of MAVERIC-C near visual acuity score and agreement of MAVERIC-C score with near ETDRS chart for visual acuity. RESULTS: Altogether, 106 children (95%) completed the MAVERIC-C system without assistance. The vision scores demonstrated satisfactory reliability, with test-retest VA scores having a mean difference of 0.001 (SD ±0.136) and limits of agreement of 2 SD (LOA) of ±0.267. Comparison with the near EDTRS chart showed agreement with a mean difference of -0.0879 (±0.106) with LOA of ±0.208. CONCLUSIONS: This study demonstrates promising utility for software using a game design to enable automated testing of acuity in children with ophthalmic disease in an objective and accurate manner.

Potential role for microfluctuations as a temporal directional cue to accommodation.

The goal was to revisit an important, yet unproven notion that accommodative microfluctuations facilitate the determination of direction (sign) of abrupt focus changes in the stimulus to accommodation. We contaminated the potential temporal cues from natural accommodative microfluctuations by presenting uncorrelated external (screen) temporal defocus noise that combined with the retinal image effects of natural microfluctuations. A polychromatic Maltese spoke pattern thus either modulated defocus at a combination of two temporal frequencies (on-screen noise condition) or was static (control condition). The on-screen conditions were combined with step changes in optical vergence that were randomized in direction and magnitude. Five subjects monocularly viewed stimuli through a Badal optical system in a Maxwellian view. An artificial 4-mm aperture was imaged at the entrance pupil of the eye. Wavefront aberrations were measured dynamically at 50 Hz using a custom Shack-Hartmann aberrometer. Dynamic changes in the Zernike defocus term with step changes in optical vergence were analyzed. We calculated the percentage of correct directional responses for 1, 2, and 3 D accommodative and disaccommodative step stimuli using preset criteria for latency, velocity, and persistence of the response. The on-screen noise condition reduced the percent-correct responses compared to the static stimulus, suggesting that this manipulation affected the detectability of the sign of the accommodative stimulus. Several possible reasons and implications of this result are discussed.

Development and testing of an automated computer tablet-based method for self-testing of high and low contrast near visual acuity in ophthalmic patients.

PURPOSE: Many eye diseases require on-going assessment for optimal management, creating an ever-increasing burden on patients and hospitals that could potentially be reduced through home vision monitoring. However, there is limited evidence for the utility of current applications and devices for this. To address this, we present a new automated, computer tablet-based method for self-testing near visual acuity (VA) for both high and low contrast targets. We report on its reliability and agreement with gold standard measures. METHODS: The Mobile Assessment of Vision by intERactIve Computer (MAVERIC) system consists of a calibrated computer tablet housed in a bespoke viewing chamber. Purpose-built software automatically elicits touch-screen responses from subjects to measure their near VA for either low or high contrast acuity. Near high contrast acuity was measured using both the MAVERIC system and a near Landolt C chart in one eye for 81 patients and low contrast acuity using the MAVERIC system and a 25 % contrast near EDTRS chart in one eye of a separate 95 patients. The MAVERIC near acuity was also retested after 20 min to evaluate repeatability. RESULTS: Repeatability of both high and low contrast MAVERIC acuity measures, and their agreement with the chart tests, was assessed using the Bland-Altman comparison method. One hundred and seventy-three patients (96 %) completed the self- testing MAVERIC system without formal assistance. The resulting MAVERIC vision demonstrated good repeatability and good agreement with the gold-standard near chart measures. CONCLUSIONS: This study demonstrates the potential utility of the MAVERIC system for patients with ophthalmic disease to self-test their high and low contrast VA. The technique has a high degree of reliability and agreement with gold standard chart based measurements.

The impact of higher-order aberrations on the strength of directional signals produced by accommodative microfluctuations.

It has been proposed that the accommodation system could perform contrast discrimination between the two dioptric extremes of accommodative microfluctuations to extract directional signals for reflex accommodation. Higher-order aberrations (HOAs) may have a significant influence on the strength of these contrast signals. Our goal was to compute the effect HOAs may have on contrast signals for stimuli within the upper defocus limit by comparing computed microcontrast fluctuations with psychophysical contrast increment thresholds (Bradley & Ohzawa, 1986). Wavefront aberrations were measured while subjects viewed a Maltese spoke stimulus monocularly. Computations were performed for accommodation or disaccommodation stimuli from a 3 Diopter (D) baseline. Microfluctuations were estimated from the standard deviation of the wavefronts over time at baseline. Through-focus Modulation Transfer, optical contrast increments (ΔC), and Weber fractions (ΔC/C) were derived from point spread functions computed from the wavefronts at baseline for 2 and 4 cycles per degree (cpd) components, with and without HOAs. The ΔCs thus computed from the wavefronts were compared with psychophysical contrast increment threshold data. Microfluctuations are potentially useful for extracting directional information for defocus values within 3 D, where contrast increments for the 2 or 4 cpd components exceed psychophysical thresholds. HOAs largely reduce contrast signals produced by microfluctuations, depending on the mean focus error, and their magnitude in individual subjects, and they may shrink the effective stimulus range for reflex accommodation. The upper defocus limit could therefore be constrained by discrimination of microcontrast fluctuations.

Optimisation and assessment of three modern touch screen tablet computers for clinical vision testing.

Technological advances have led to the development of powerful yet portable tablet computers whose touch-screen resolutions now permit the presentation of targets small enough to test the limits of normal visual acuity. Such devices have become ubiquitous in daily life and are moving into the clinical space. However, in order to produce clinically valid tests, it is important to identify the limits imposed by the screen characteristics, such as resolution, brightness uniformity, contrast linearity and the effect of viewing angle. Previously we have conducted such tests on the iPad 3. Here we extend our investigations to 2 other devices and outline a protocol for calibrating such screens, using standardised methods to measure the gamma function, warm up time, screen uniformity and the effects of viewing angle and screen reflections. We demonstrate that all three devices manifest typical gamma functions for voltage and luminance with warm up times of approximately 15 minutes. However, there were differences in homogeneity and reflectance among the displays. We suggest practical means to optimise quality of display for vision testing including screen calibration.

An assessment of a modern touch-screen tablet computer with reference to core physical characteristics necessary for clinical vision testing.

There are a multitude of applications using modern tablet computers for vision testing that are accessible to ophthalmology patients. While these may be of potential future benefit, they are often unsupported by scientific assessment. This report investigates the pertinent physical characteristics behind one of the most common highest specification tablet computers with regard to its capacity for vision testing. We demonstrate through plotting of a gamma curve that it is feasible to produce a precise programmable range of central luminance levels on the device, even with varying background luminance levels. It may not be possible to display very low levels of contrast, but carefully using the gamma curve information allows a reasonable range of contrast sensitivity to be tested. When the screen is first powered on, it may require up to 15 min for the luminance values to stabilize. Finally, luminance of objects varies towards the edge of the screen and when viewed at an angle. However, the resulting effective contrast of objects is less variable. Details of our assessments are important to developers, users and prescribers of tablet clinical vision tests. Without awareness of such findings, these tests may never reach satisfactory levels of clinical validity and reliability.

Effects of accommodation training on accommodation and depth of focus in an eye implanted with a crystalens intraocular lens.

PURPOSE: To investigate objective measures of the effects of accommodative training of a pseudophakic eye implanted with a Crystalens AT-52SE (eyeonics Inc) intraocular lens (IOL) on reading performance, accommodation, and depth of focus. METHODS: Objective dynamic measures of accommodation, pupil size, and depth of focus were quantified from wavefront measures before and after 1 week of accommodative training that began 29 months after implantation of an accommodating IOL in one patient. Depth of focus was estimated from 50% cut-off of peak performance levels for defocus curves that were computed from the image quality metric VSOTF based on ocular wavefront aberrations. RESULTS: The patient reported improved near vision reading performance after completing the training procedure. After training, there was a shift in conjugate focus in the hyperopic direction, yet the depth of focus increased significantly for near objects. Simulated retinal images and the calculated modulation transfer function of the eye both demonstrated improved quality for near vision after training. CONCLUSIONS: The subjective report of improved near vision after training was correlated with improvement of objective measures. Depth of focus increased for near objects with attempts to accommodate after training. This change was linked to increases in aberrations and pupil size and occurred despite the conjugate focus shifting in the hyperopic direction. These results demonstrate that accommodative training may be useful in improving near vision in patients with accommodating IOLs.

The oblique effect has an optical component: orientation-specific contrast thresholds after correction of high-order aberrations.

Most of the high-order aberrations of the eye are not circularly symmetric. Hence, while it is well known that human vision is subject to cortically based orientation preference in cell tuning, the optics of the eye might also introduce some orientational anisotropy. We tested this idea by measuring contrast sensitivity at different orientations of sine-wave gratings when viewing through a closed-loop adaptive optics phoropter. Under aberration-corrected conditions, mean contrast sensitivity improved for all observers by a factor of 1.8× to 5×. The detectability of some orientations improved more than others. As expected, this orientation-specific effect varied between individuals. The sensitivity benefits were accurately predicted from MTF model simulations, demonstrating that the observed effects reflected the individual's pattern of high-order aberrations. In one observer, the orientation-specific effects were substantial: an improvement of 8× at one orientation and 2× in another orientation. The experiments confirm that, for conditions that are not diffraction limited, the optics of the eye introduce rotational asymmetry to the luminance distribution on the retina and that this impacts vision, inducing orientational anisotropy. These results suggest that the traditional view of meridional anisotropy having an entirely neural origin may be true for diffraction-limited pupils but that viewing through larger pupils introduces an additional orientation-specific optical component to this phenomenon.

Higher-order aberrations produce orientation-specific notches in the defocused contrast sensitivity function.

Local minima or notches in the defocused contrast sensitivity function (CSF) have been linked to the aberrations of the eye. We use theoretical modeling of the effects of the aberrations to show these notches can be orientation-selective due to the effects of aberration terms such as coma and trefoil. Notches that changed with orientation were observed in the defocused CSF of four subjects. The measured CSFs were found to match well with theoretical predictions produced using the individual aberrations. Theoretical modeling highlighted orientation-specific differences in notches for both positive and negative blur. The results indicate that orientation is an important variable when testing for the functional effects of higher-order aberrations.

The importance of grating orientation in contrast sensitivity following refractive surgery.

Higher-order aberrations degrade visual performance when the pupil is large, particularly in eyes that have abnormally high amounts of aberrations, such as those that have undergone refractive surgery. Geometrical optics predicts that asymmetrical aberrations such as coma can produce orientation selective effects, much like uncorrected astigmatism. Coma is also one of the main aberrations to increase following refractive surgery. Orientation may therefore be an important parameter when testing grating based contrast sensitivity, particularly in refractive surgery patients. Contrast sensitivity to four orientations of a 12 cycles deg(-1) sine wave grating was measured in normals (n = 34) and refractive surgery patients (n = 12). In over a third of normal subjects the higher-order aberrations produced a significant orientation-specific change in contrast sensitivity (13 out of 34 eyes, p < 0.05). No significant differences existed in the aberrations between those that displayed orientation-selective changes and those that did not. In subjects who underwent refractive surgery those that displayed orientation selective changes had significantly higher amounts of overall aberrations and also higher amounts of primary coma than those that did not. These results indicate that grating orientation is an important factor when assessing the effects of higher-order aberrations on contrast sensitivity.

Contrast sensitivity based orientation changes in refractive surgery patients.

It is well known that refractive surgery leads to an increase in higher-order aberrations. These can cause problems such as glare, starburst and halos in vision, particularly in low light levels when the pupil is large. The overall wavefront aberration of the eye is typically non-circularly symmetric due to the presence of aberrations such as coma and trefoil. These asymmetries have been shown to induce orientation-selective effects in grating-based contrast sensitivity tests. Classically, contrast sensitivity is assumed to be independent of orientation and is measured at only one orientation. Examining more orientations may give a better indicator of visual performance when abnormal amounts of aberration are present. To examine this, contrast sensitivity through a dilated pupil was determined for four orientations of a 12 cycles deg(-1) sine wave grating in 12 subjects both before and after refractive surgery. Surgery produced orientation-selective changes in contrast sensitivity in most patients (9 out of 12, p < 0.05). The correlation between contrast sensitivity and higher-order aberrations was found to improve when several orientations were tested compared with data from only one orientation (combined orientations, r(2) = 0.46, p = 0.007; single orientation r(2) = 0.55, p < 0 .05 to r(2) = 0.09, p > 0.05). These results indicate that grating orientation is an important factor when investigating the link between visual performance and higher order aberrations.

Importance of grating orientation when monitoring contrast sensitivity before and after refractive surgery.

PURPOSE: To measure losses in contrast sensitivity at different orientations of grating stimuli in refractive surgery patients and show the importance of orientation when higher-order aberrations (HOAs) are altered. SETTING: Manchester Centre for Vision, Manchester Royal Eye Hospital, Manchester, United Kingdom. METHODS: Contrast sensitivity for sine-wave gratings of 12 cycles per degree was measured in 12 patients before and after different types of refractive surgery. Measurements were taken at 4 orientations with small (3.0 mm) and large (dilated) pupils using a binary search procedure. Higher-order aberrations were also measured. RESULTS: Changes in contrast sensitivity at different orientations were seen in patients before and after the surgery. All patients had significantly higher aberrations after surgery. Patients with increased amounts of postoperative HOAs were more likely to exhibit orientation effects. CONCLUSIONS: When contrast sensitivity is tested with gratings, it is advisable to measure more than 1 orientation. This particularly applies when root-mean-square error values are unusually high, such as in refractive surgery patients.