Marcus A. Bearse

Imaging localized retinal dysfunction with the multifocal electroretinogram.

Conventional electroretinographic techniques do not permit efficient mapping of retinal responsiveness for the detection of small dysfunctional areas. This study explores the application of a new technique that makes such mapping possible. It utilizes a multifocal electroretinogram technique based on binary m sequences that simultaneously tests a large number of small retinal areas by multiplexing their responses onto a single signal derived from the human cornea. The focal responses are subsequently extracted for the derivation of high-resolution maps that characterize retinal responsiveness. The required recording times are short enough to make such testing feasible in the clinic. In this study we demonstrate the high sensitivity of the technique by mapping a small area that has been partially bleached by a strobe flash in a normal retina and by mapping dysfunctional areas in three patients with different, well-documented retinal pathologies. The results suggest that the multifocal electroretinogram has the potential to become a valuable clinical tool.

The optic nerve head component of the human ERG

The local responses of the multifocal ERG reveal continuous changes in the second order waveforms from the nasal to the temporal retina. Scrutiny of these changes suggests the presence of an additive component whose latency increases with the distance of the stimulus from the optic nerve head. This observation led to the hypothesis of a contributing source in the vicinity of the optic nerve head whose signal is delayed in proportion to the fiber length from the stimulated retinal patch to the nerve head. The hypothesis was tested with two independent methods. In Method 1, a set of different local response waveforms was approximated by two fixed components whose relative latency was allowed to vary and the fit of this two component model was evaluated. In Method 2, two signals were derived simultaneously using different placements for the reference electrode. The placements were selected to produce a different ratio of the signal contributions from the retina and the nerve head in the two recording channels. The signals were then combined at a ratio that canceled the retinal component. Method 1 yielded an excellent fit of the two component model. Waveforms and latencies of the hypothetical optic nerve head component derived from the two methods agree well with each other. The local latencies also agree with the propagation delays measured in the nerve fiber layer of the monkey retina. In combination, these findings provide strong evidence for a signal source near the optic nerve head.

Adolescents with Type 2 Diabetes: Early Indications of Focal Retinal Neuropathy, Retinal Thinning and Venular Dilation

Purpose: The eye provides a unique window into the neural and vascular health of a patient with diabetes. The present study is the first of its kind to examine the neural retinal function, structure, and retinal vascular health in adolescents with Type 2 diabetes. Methods: Focal neural responses from 103 discrete retinal regions of the eye were tested using multifocal electroretinography. Optical coherence tomography was utilized to measure retinal thickness. Digital fundus photographs were examined for the presence of retinopathy and to measure vascular caliber using retinal vessel analysis. Fifteen adolescents diagnosed with Type 2 diabetes, aged 13 to 21 years with a mean diabetes duration of 2.1 ± 1.3 years, were tested. Twenty-six age-matched control subjects were also tested. Results: Multifocal electroretinograms of the Type 2 diabetic group were significantly (P = 0.03) delayed by 0.49 milliseconds. The diabetic group also showed significant (both; P ≤ 0.03) retinal thinning (10.3 &mgr;m) and significant venular dilation (16.2 &mgr;m). Conclusion: The present study shows early indications of focal retinal neuropathy, retinal thinning, and venular dilation in adolescents with Type 2 diabetes. Early detection of functional and structural changes will hopefully aid in the prevention of permanent damage or further functional loss.

The optic nerve head component of the monkey's (Macaca mulatta) multifocal electroretinogram (mERG).

To search for an optic nerve head component (ONHC) in the monkeys (Macaca mulatta) multifocal electroretinogram (mERG), mERGs from three animals were recorded with different electrode configurations. A component with a latency that varied with distance from the optic nerve head was easily identified by eye in recordings from the speculum of a Burian-Allen electrode referenced to a DTL on the unstimulated eye. This component was reasonably well isolated by subtracting a weighted version of a Burian-Allen bipolar recording or by employing the extraction algorithm of Sutter and Bearse (1999, Vision Research, 39, 419-436). The waveform of this component resembles the ONHC reported for the human mERG.

Distribution of oscillatory components in the central retina

This study examines the characteristics and the naso-temporal asymmetries of the higher-order oscillatory components of the multifocal electroretinogram (mERG). The magnitude of the mERG asymmetry and the mechanisms which produce it have not been studied previously. We recorded the mERG from seven normal observers using slow multifocal flicker and response filtering of 10–300 Hz. This permitted, without additional filtering, examination of the dominant first order component and the oscillation-rich components in the first and second order kernels. The oscillatory components in the two kernels had multiple peaks separated by about 6.8 ms, similar to those of conventional oscillatory potentials. Naso-temporal asymmetry of the three response components was analyzed in three groups (concentric rings around the fovea) spanning 1.5–10 deg of retinal eccentricity. The oscillation-rich components were, on average, approximately 14% larger in amplitude in the temporal retina than in corresponding nasal locations (p < 0.05) while the dominant first order component was not asymmetrically distributed. We tested the hypothesis that the asymmetry could be modeled as a combination of a retinal component (RC) and an optic nerve head component (ONHC) which varies in latency as a function of distance from the optic disc. We found that both oscillatory components and the dominant first order response could be decomposed into RCs and ONHCs that are symmetrically distributed. Thus, it appears that the naso-temporal asymmetries of the oscillation-rich components are produced primarily by the relative alignment and enhancement of RC and ONHC wavelets in the temporal retina, and misalignment and partial cancellation in the nasal retina.

Early neural and vascular changes in the adolescent type 1 and type 2 diabetic retina.

Purpose: This cross-sectional study examines the existence and frequency of functional and structural abnormalities in the adolescent Type 1 diabetic retina. We also compare the results with those of adolescents with Type 2 diabetes. Methods: Thirty-two adolescents with Type 1 diabetes (5.7 ± 3.6 years; mean duration ± SD), 15 with Type 2 diabetes (2.1 ± 1.3 years), and 26 age-matched control subjects were examined. Multifocal electroretinogram responses from 103 retinal regions were recorded. Optical coherence tomography was used to measure retinal thickness. Vascular diameter around the optic nerve was also assessed. Results: Nine of the 32 (28%) adolescents with Type 1 diabetes and 6 of the 15 (40%) with Type 2 diabetes had significant multifocal electroretinogram implicit time delays compared with 2 of the 26 controls (8%). Retinal thicknesses in both patient groups were significantly (P ≤ 0.01) thinner than controls. The Type 2 group also showed significant (P ≤ 0.03) retinal venular dilation (235.8 ± 5.9 μm) compared with controls (219.6 ± 4.0 μm). Conclusion: The present study illustrates that subtle but significant functional and structural changes occur very early in Type 1 diabetes. Adolescents with Type 2 diabetes appear to be more affected than those with Type 1 diabetes. Further longitudinal examination of the etiology and progression of these abnormalities is warranted.

Towards optimal filtering of “standard” multifocal electroretinogram (mfERG) recordings: findings in normal and diabetic subjects

Aims: To study the effects of two commonly used pre-amplifier filtering bandwidths on normal multifocal electroretinogram (mfERG) responses and their comparative abilities to detect retinal disease. Methods: 103 standard mfERGs were recorded simultaneously in two channels with different pre-amplifier settings (10–100 Hz and 10–300 Hz) from one eye of each of 20 normal subjects, 17 diabetics with non-proliferative diabetic retinopathy (NPDR), and 12 diabetics without retinopathy. Signal to noise ratios (SNR) of the normal subjects’ first order mfERGs were compared between channels. All subjects’ amplitudes and implicit times were derived using a “template stretching” method. For comparison, implicit time was also measured using a “template sliding” method. mfERG amplitudes and implicit times were compared between the channels and among subject groups. Results: Normal mean amplitudes and implicit times were similar for the two channels. However, normal 10–100 Hz recordings had significantly higher SNR and lower intersubject variability than 10–300 Hz recordings. In NPDR, the 10–100 Hz channel identified significantly more implicit time and amplitude abnormalities. In the diabetics without retinopathy, 10–100 Hz filtering identified significantly more implicit time abnormalities than 10–300 Hz filtering. For both filter settings, diabetic implicit times were more often abnormal than amplitudes. The 10–100 Hz channel was superior for both implicit time measurements. Conclusion: Standard mfERGs recorded from normal eyes and filtered 10–100 Hz contain less noise, higher SNR, and less intersubject variability than those filtered at 10–300 Hz. This underlies the finding that the 10–100 Hz filter setting identifies more retinal dysfunction than the 10–300 Hz setting.

OCT reveals regional differences in macular thickness with age.

Purpose. To assist identification of macular thickness abnormalities by optical coherence tomography (OCT), we use techniques that improve spatial localization across the retina to establish any age-related retinal thickness changes in healthy eyes. Methods. Retinal thickness was measured in 30 eyes of 30 healthy subjects aged 13 to 69 years. Using Stratus OCT 3, 12 radial scans centered at the foveola were acquired and points between scans were interpolated to create a topographic map of the central 20°. The thickness map was divided into 37 hexagonal regions. A mean retinal thickness for each hexagon was computed. Retinal thickness vs. age was evaluated for the entire scanned area, five anatomical regions, and within individual hexagons. The retinal nerve fiber layer (RNFL) contribution to total retinal thinning was analyzed in the papillomacular region. Results. There was a small but significant thinning of the overall macular area with increasing age (2.7 &mgr;m/decade; p = 0.027). Comparing the 10 youngest subjects (age 13 to 27 years) with the 10 oldest (age 51 to 68 years), retinal thicknesses in the temporal, superior, inferior, and foveal regions were not significantly different. However, the two age groups differed significantly in retinal thickness in the nasal region (p < 0.008). Across all subjects, retinal thickness in this region was linearly correlated with age, decreasing by 4.1 &mgr;m/decade (p < 0.002). Approximately 43% of the retinal thinning in the nasal region was attributed to RNFL loss. Conclusions. The method of OCT acquisition and analysis used in this study allows for greater spatial localization of change in retinal thickness associated with aging or pathological processes. Based on the results of this study, the macula thins with increasing age but does so nonuniformly. The greatest amount of thinning occurs nasal to the fovea. RNFL loss accounts for much, but not all the thinning in this area.

Differences in neuroretinal function between adult males and females.

Purpose To determine whether neuroretinal function differs in healthy adult males and females younger and older than 50 years. Methods This study included one eye from each of 50 normal subjects (29 females and 21 males). Neuroretinal function was assessed using first-order P1 implicit times (ITs) and N1-P1 amplitudes (AMPs) obtained from photopic multifocal electroretinograms. To assess local differences, retinal maps of local IT and (separately) AMP averages were constructed for each subject group. To examine global differences, each subject’s 103 ITs and (separately) AMPs were also averaged to create whole-eye averages. Subsequently, retinal maps and whole-eye averages of one subject group were compared with those of another. Results In subjects younger than 50 years, neuroretinal function differed significantly between the males and females: local ITs were significantly shorter at 83 of 103 tested retinal locations, and whole-eye IT averages were shorter (p = 0.015) in the females compared with the males. In contrast, no analysis indicated that the males and females older than 50 years were significantly different. A subanalysis showed that the females who reported a hysterectomy (n = 5) had the longest whole-eye ITs of all subject groups (p ⩽ 0.0013). In the females who did not report a hysterectomy, neuroretinal function was worse in the females older than 50 years compared with the females younger than 50 years: local ITs were significantly longer at 62 of 103 retinal locations tested, and whole-eye IT averages tended to be greater (p = 0.04). Conversely, ITs were not statistically different between the younger and older males. N1-P1 amplitudes did not differ between the sexes. Conclusions Multifocal electroretinogram IT differs between males and females, depending on the age group and hysterectomy status.