The rod-mediated multifocal electroretinogram in aging and in early age-related maculopathy

PURPOSE: To measure function with the rod-mediated multifocal electroretinogram (mfERG) in younger and older subjects with normal vision and with early age-related maculopathy (ARM). METHODS: Thirty subjects were studied: 10 healthy subjects with a mean age of 31 years (young group), 10 healthy subjects with a mean age of 71 years (old group), and 10 early ARM subjects with a mean age of 71 years (early ARM group). The influence of cataract was approximated by retesting five subjects of the young group through an 0.3 neutral density filter (ND filter group). We analyzed first-order N1P1-amplitude and P1-implicit time (P1-IT) mfERG responses and correlated them with funduscopic changes as defined by the Age-Related Eye Disease Study (AREDS) group. RESULTS: Averaged concentric ring P1-ITs were significantly delayed in the old (p = 0.02) and early ARM (p < 0.001) compared with the young group and in the early ARM group compared with the old and ND group (p < or = 0.01). There were no significant differences in N1P1-amplitudes between groups, but there was a significant location effect for all groups with highest mean amplitudes for the most peripheral ring of hexagons (p < 0.01). Significantly delayed overall P1-ITs (p < 0.05) were correlated with progressive funduscopic changes. CONCLUSIONS: Aging and early ARM affects the rod-mediated mfERG, and there is good correlation with funduscopic changes. Although a lens effect cannot be excluded, a neuronal transmission alteration at the postreceptoral level is suggested.     

Delays in rod-mediated dark adaptation in early age-related maculopathy.

OBJECTIVE: To determine whether there are disturbances in the rod-mediated kinetics of dark adaptation in early age-related maculopathy (ARM). DESIGN: Comparative, observational case series. PARTICIPANTS: Twenty older adults with early ARM as defined by one or more large (> 63 microm) drusen, focal hyperpigmentation, or both, but no choroidal neovascularization or geographic atrophy, and 16 adults in the same age range with none of these fundus features. All participants had 20/25 visual acuity or better in the tested eye. METHODS: Dark adaptation functions were measured using a modified Humphrey Field Analyzer (Zeiss Humphrey Systems, Dublin, CA) to assess the rate of rod-mediated sensitivity recovery at 12 degrees on the vertical meridian in the inferior visual field after exposure to the equivalent of a 98% bleach. Baseline (prebleach) scotopic sensitivity, visual acuity, contrast sensitivity, and photopic sensitivity were also measured. MAIN OUTCOME MEASURES: Rod-cone break; second and third components of rod-mediated dark adaptation; time to baseline sensitivity; and baseline (prebleach) scotopic sensitivity. RESULTS: Although their visual acuity was at least 20/25, patients with early ARM on average exhibited deficits in almost all rod-mediated parameters of dark adaptation as compared with age-similar healthy participants. For example, the rod-cone break was delayed approximately 10 minutes in early ARM patients as compared with healthy participants. Age-related maculopathy patients were more likely to fall outside the normal reference range for variables representing dark adaptation kinetics than for steady-state visual functions such as scotopic sensitivity. For example, 85% of ARM patients fell outside the normal reference range in at least one dark adaptation kinetic parameter, whereas only 25% of ARM patients fell outside the normal reference range for steady-state scotopic sensitivity. CONCLUSIONS: Rod-mediated kinetic parameters of dark adaptation, which reflect the sensitivity recovery of the visual cycle, are disrupted early in ARM pathogenesis.     

Post-receptoral contributions to the rat scotopic electroretinogram a-wave

The electroretinogram is a widely used objective measure of visual function. The best characterised feature of the full-field dark-adapted flash ERG, is the earliest corneal negativity, the a-wave, which primarily reflects photoreceptoral responses. However, recent studies in humans and primates show that there are post-receptoral contributions to the a-wave. It is not clear if such contributions exist in the rat a-wave. We consider this issue in the rat a-wave, using intravitreal application of pharmacological agents that isolate post-receptoral ON-pathways and OFF-pathways. In anaesthetised adult long Evans rats, we show that the ON-pathway (2-amino-4-phosphonobutyric acid, APB sensitive) makes negligible contribution to the a-wave. In contrast, CNQX (6-cyano-7-nitroquinoxaline-2,3-dione) or PDA (cis-piperidine-2,3-dicarboxylic acid) sensitive mechanisms modify the a-wave in two ways. First, for bright luminous energies, OFF-pathway inhibition (CNQX or PDA) results in a 22% reduction to the early phase of the leading edge of the a-wave up to 14 ms. Second, OFF-pathway inhibition removed a corneal negativity that resides between the a-wave trough and the b-wave onset.     

Recovery of rod-mediated a-wave during light-adaptation in mGluR6-deficient mice

The purpose of this study was to compare the a-waves of mGluR6-deficient mice (KO) to that of wild-type mice (WT), and to determine whether the light-adapted electroretinogram of the KO mice originate exclusively from cones. Dark-adapted a-waves were recorded under the same conditions from both types of mice. With a 96-cd/m(2) background, the a-wave from both types of mice showed a rapid recovery over a 50-min period. The analysis of the a-waves in KO mice indicated that the recovery was determined mainly by the rod component. The light-adapted b-wave of WT mice showed no corresponding recovery. We conclude that rod contribution must be considered in the analyses of the light-adapted a-waves of KO mice.     

Comparison of different high resolution multifocal electroretinogram recordings in patients with age-related maculopathy

AIM: to compare two different resolutions of multifocal electroretinogram recordings (MF-ERG) in patients with age-related macular degeneration (AMD). PATIENTS AND METHODS: in 20 eyes (14 patients) with early or late stages of AMD, MF-ERGs of 8 min duration were recorded using a low and a high resolution. The central 50 degrees of the retina were stimulated by 103 as well as by 241 stimulus elements. Results were compared with one another and with an age-matched control group. RESULTS: when response averages of equal eccentricity were analysed, amplitudes of the MF-ERG differed significantly from normal within the central 40 degrees. This held true for both low (103) and high (241) resolutions. Sixteen of 20 eyes also showed focal retinal dysfunction at both resolutions. In one case, the high resolution MF-ERGs could detect functional deficits that could not be seen with the lower resolution. However, due to a reduced signal-to-noise ratio three high resolution recordings could not be analysed. CONCLUSION: high resolution MF-ERG seems more sensitive than low resolution MF-ERG. However, the low resolution (103) MF-ERG is recommended for routine application in the clinic because of its better signal-to-noise ratio.     

Bull's-eye maculopathy and negative electroretinogram

The authors studied four patients with a bull's-eye maculopathy and otherwise normal fundus. A single-flash electroretinogram (ERG) with an intense white light stimulus in the dark showed a normal a-wave but reduced b-wave amplitude (negative ERG). Other findings common to all four patients were initially normal visual acuity, subsequent progressive decrease in visual acuity, mild to moderate deficiency of color vision, normal peripheral visual field, relatively well preserved cone ERG, normal 30-Hz flicker ERG, normal EOG, near emmetropia and selective involvement in males. Cone dystrophy, retinitis pigmentosa, congenital retinoschisis, congenital stationary night blindness, and Batten's disease were excluded. The correlation between this disease and benign concentric annular macular dystrophy is discussed.     

Cone-mediated multifocal electroretinogram in early age-related maculopathy and its relationships with subjective macular function tests

PURPOSE: To investigate the multifocal electroretinogram (mfERG) and subjective function in early age-related maculopathy (ARM). METHODS: Seventeen subjects with early ARM with visual acuity (VA) of 6/12 or better and 20 age-matched control subjects were examined. We assessed mfERGs, high and low contrast distance VA, near VA, low luminance VA, contrast sensitivity, saturated and desaturated Panel D-15 and visual fields (mean sensitivity). The mfERG responses were analysed by comparing central-overall (method 1) and superior-inferior (method 2) ratios. RESULTS: The mfERG did not discriminate between the groups whereas colour vision (tritan deficiency), contrast sensitivity, and high contrast and low contrast VA showed significantly reduced responses for the early ARM group compared with the control group (p < or = 0.01). The mfERG first-order kernel responses correlated significantly with the desaturated D-15 in both methods (r = -0.5, p < or = 0.05). Fundus grading was not correlated with the mfERG measures. CONCLUSIONS: Although the mfERG correlated significantly with the desaturated D-15 in early ARM, suggesting it operates at a sensitive level, it failed to discriminate between the control and ARM groups. In our sample, the subjective function measures were more sensitive than the mfERG measures.     

Effect of short-term, high-dose retinol on dark adaptation in aging and early age-related maculopathy

PURPOSE: To examine the effect of a short course of high-dose retinol (preformed vitamin A) on dark adaptation in older adults with normal retinal health or early age-related maculopathy (ARM). METHODS: The study design was a randomized, double-masked, placebo-controlled experiment. Adults > or = 50 years of age whose fundus photographs for the eye to be tested psychophysically fell within steps 1 to 9 of the Age-Related Eye Disease Study (AREDS) Grading System were randomly assigned to a 30-day course of 50,000 IU oral retinol or a placebo. At baseline and 30-day follow-up, dark adaptation was tested and the Low Luminance Questionnaire (LLQ), an instrument for assessing difficulty with vision in reduced lighting, was administered. Primary outcomes of interest were rod- and cone-mediated parameters of dark adaptation, with scores on the LLQ's six subscales as secondary outcomes. RESULTS: The sample consisted of 104 participants with 52 each in the intervention and placebo groups. There were no group differences in baseline variables. At 30-days, the dark-adaptation parameters of cone time-constant, cone threshold, rod-cone break, and rod threshold did not differ. The retinol intervention group had significantly larger (i.e., steeper) rod slopes, indicating faster sensitivity recovery, than did the placebo group (P = 0.0419). There were no group differences in scores on the LLQ subscales driving, extreme lighting, emotional distress, general lighting, or peripheral vision. The retinol group had a higher score by five points on the mobility subscale compared with the placebo group (P = 0.0141). Those who had the most self-reported change on the mobility subscale at day 30 were more likely to have greater change in the speed of dark adaptation, as indicated by the rod slope parameter (r = 0.24, P = 0.0141). CONCLUSIONS: A short-term, high-dose course of retinol increased the rate of rod-mediated dark adaptation in older adults who were in the early phases of ARM or were exhibiting normal retinal aging. These results are consistent with the hypothesis that depositions and other structural changes in the retinal pigment epithelium and Bruch's membrane in aging and early ARM cause a localized retinoid deficiency.     

A new component in the a-wave of the human cone electroretinogram

The human cone electroretinogram (ERG) to a full field flash has been examined on a rod saturating background (17,000 photopic trolands). With strong stimuli, a negative wavelet appears in the falling phase of the a-wave. This response has a latency of 10–12 milliseconds, about 6–8 milliseconds after the start of the a-wave and just before the rising phase of the corneal positive b-wave begins. We suggest that it may represent a hyperpolarizing response of second order retinal neurons.     

Telescopic scanning and age-related maculopathy

We report the management of various aspects of the care provided over a span of 12 years for a patient with age-related maculopathy (ARM). The use of a low-power telescope proved to be particularly helpful because, with it, she learned eccentric viewing and made best use of her remaining vision.     

Phototoxic drugs and age-related maculopathy

OBJECTIVES: To disclose a correlation between age-related macular degeneration (AMD) and long-lasting treatments with potentially phototoxic drugs. DESIGN: Case-control study. METHODS: The case group was made up of 90 randomized patients, 65 years old or older, with documented AMD, examined in 1998 and 1999. The M/F sex ratio was 0.54, and mean age 79.9 years. The control group was randomized with age- and sex-matched subjects. In both groups, we noted long-lasting oral treatment for hypertension, diabetes mellitus, epilepsy, hyperuricemia, and psychiatric pathologies. All the study group patients underwent a complete ophthalmological examination for visual acuity, contrast sensitivity, biomicroscopy, fundus color and red-free photographs, fluorescein and ICG angiographies. RESULTS: When the study group was compared with the control group, neovascular AMD was positively associated with thiazide diuretics (p<0.001). When the study group was analyzed alone, intake of one or several antihypertensive drugs was positively associated with occult neovascularization and mild to moderate visual loss (p=0.009). Only thiazide diuretic intake was positively associated with severe bilateral loss of vision (p=0.041) and extensive choroidal neovascularization with major subretinal hemorrhages (p=0.022). CONCLUSIONS: These findings suggest that severe neovascular AMD is associated with long-term thiazide diuretic treatment.     

Temporal response properties of the macular cone system: effect of normal aging and age-related maculopathy

PURPOSE: To evaluate the influence of aging and age-related maculopathy (ARM) on the temporal frequency response function (TFR) of macular focal electroretinography. METHODS: Macular (18 degrees ) focal electroretinograms (FERGs) in response to sinusoidal flicker, modulated at TFs between 3.7 and 52 Hz, were recorded from 13 young (age range, 14-29 years) and 9 old (age range, 55-80 years) healthy subjects and from 18 patients with ARM (stage 2 disease; age range, 55-80 years; visual acuity >/=0.4). Amplitude and phase of the Fourier-analyzed response fundamental (1F) and seconnd harmonic (2F) were measured. RESULTS: In young healthy subjects, mean 1F TFR showed a maximum amplitude at 41 Hz, a secondary peak at 3.7 Hz, a minimum at 8 Hz, and a high TF (32-52 Hz) roll-off. Mean 1F TFR of old, compared with young, healthy subjects showed amplitude enhancement at 10 to 14 Hz and a small loss at high TF. Mean 2F TFR of young and old healthy subjects had a maximum at 5.7 to 8 Hz and an attenuation beyond 10 Hz. Mean 1F and 2F TFRs of ARM patients were similar to those of old healthy subjects but were depressed in mean amplitude. FERG TFR changes of old healthy subjects and ARM patients were not mimicked by reducing stimulus retinal illuminance or modulation depth in young healthy subjects. CONCLUSIONS: FERG temporal properties are affected by normal aging and ARM. Because FERG TFR is shaped mainly by postreceptoral activity, the findings suggest that photoreceptor and postsynaptic dysfunction underlie aging- and ARM-related FERG changes.     

Empiric limits of rod photocurrent component underlying a-wave response in the electroretinogram

The corneally recorded rod photocurrent component (photoresponse) underlying the a-wave feature of the electroretinogram was analyzed. The results set empiric limits on critical photoresponse variables. Measurements were obtained from four normal adult subjects on a-wave amplitude, a-wave velocity, b-wave amplitude, b-wave implicit time and b-wave height above baseline. At high intensity, interference from the b-wave component was minimized and the amplitude of the saturated photoresponse component was approximated by the a-wave feature. At lower intensities, the a-wave feature represented progressively less of the underlying photoresponse amplitude. Photoresponse amplitude saturation was signaled by the abrupt slowing of the rate of decline of b-wave peak latency and occurred at an intensity about 2.5 log units above the first appearance of the b-wave. At the intensity of photoresponse saturation, the peak amplitude of the a-wave feature was only about 25% of the maximum amplitude of the underlying photoresponse component. A-wave leading edge velocity was found to increase up to 3 log units above the intensity of photoresponse amplitude saturation and to provide a good estimate of photoresponse velocity at higher intensities. A cascaded low-pass filter model with modifications to accommodate amplitude and timing nonlinearities was used to generate a set of probable underlying photoresponses from the analysis of a-wave amplitude and velocity. Movement of the a-wave leading edge to the left at higher intensities in algebraic combination with a static b-wave leading edge above the intensity of photoresponse amplitude saturation was found to explain the second rise of the b-wave amplitude function and the decline of b-wave amplitude above baseline at high intensities. This analysis provides a basis for modeling the underlying photoresponse on a biochemical level and for interpreting photoreceptor damage in disease states.Supported in part by a grant from the Ethel Brown Foerderer Foundation, Children's Hospital of Philadelphia, and by a grant from the Nina and Paul MacKall Trust.     

Evidence that a-wave latency of the electroretinogram is determined solely by photoreceptors

PURPOSE: To identify the retinal cells that determine the a-wave latency of rats. METHODS: Electroretinograms (ERGs) were recorded from the rod-dominated (0.85% cones) retinas of Long-Evans rats following an intravitreal injection of 1 microL of 40 mM 2-amino-4-phosphonobutyric acid to block the activity of the ON pathway of the second order retinal neurons. ERGs were also recorded following an intraperitoneal injection of sodium iodate to destroy the retinal pigment epithelial (RPE) cells. Damage to a large area of the retina was produced by constant light exposure, and focal damage to the retina was induced by argon laser photocoagulation. The effects of age and anesthesia level on the a-wave latency were also determined. RESULTS: Blocking the activity of the ON pathway of the second order retinal neurons did not alter the a-wave latency, and destroying the RPE cells also did not alter the a-wave latency. Damage to a large area of the retina resulted in prolonging the latency but focal retinal damage did not alter the a-wave latency. The a-wave latency was longer in young rat pups but was adult-like by 18 days. The level of anesthesia had no effect on the latency except at very deep stages. CONCLUSIONS: The a-wave latency is determined solely by the activity of the photoreceptors. A prolonged latency would indicate that the photoreceptors are damaged over a large area of the retina.     

叶黄素、玉米黄素与年龄相关性黄斑病变

叶黄素和玉米黄素是视网膜黄斑色素的主要成分。研究发现人类黄斑色素的水平较低是罹患年龄相关性黄斑病变（ARM）的危险因素。摄入一定剂量叶黄素和玉米黄素，可以增加视网膜黄斑色素密度，降低ARM的发病率，并且对视网膜功能也有保护作用。