Clinical value, normative retinal sensitivity values, and intrasession repeatability using a combined spectral domain optical coherence tomography/scanning laser ophthalmoscope microperimeter.

PURPOSE: To establish normative values for macular light sensitivity and to determine the intrasession fluctuation of perimetric responses using the OPKO/OTI microperimeter. METHODS: A total of 32 visually normal subjects participated in the study. A standardized grid pattern was used for testing, which consisted of 28 points arranged concentrically in three circles that occupied an area of 11° (in diameter) within the central macula. Each subject participated in at least two tests. Parameters evaluated included: overall mean macular sensitivity for test 1 and 2, overall difference in mean macular sensitivity between tests, and the mean sensitivity for each circle. The relationship between sensitivity and age was also examined. RESULTS: The overall median sensitivity for test 1 was 16.8 decibels (dB) and for test 2 was 16.9 dB. The median sensitivities for test 1 and test 2 were not significantly different (P = 0.72). The mean intrasession sensitivity difference was 0.13 dB. The variability of the sensitivity difference between tests decreased as mean sensitivity increased. The sensitivity values averaged across the two tests for inner, middle, and outer circles ranged from 14.3 to 18.8 dB (median value of 16.9 dB), 13.8-18.3 dB (median value of 17.2 dB), and 11.3-18.3 dB (median value of 16.6 dB), respectively. Linear regression analysis showed a 0.5 dB sensitivity loss for each decade of life. CONCLUSION: We documented a narrow range of intrasession fluctuation using the OPKO/OTI microperimeter. The establishment of normative sensitivity values will facilitate monitoring the loss of macular visual function in patients with retinal disease.

Rod phototransduction in transgenic mice expressing a mutant opsin gene.

Rod-mediated electroretinograms (ERG's) were recorded from transgenic mice expressing a mouse opsin gene with three point mutations (V20G, P23H, and P27L; termed VPP mice) and from normal littermates. The leading edge of the alpha wave was analyzed in relation to a computational model of rod phototransduction [J. Physiol. 499, 719 (1992)], in which values for the maximum response (RmP3), transduction gain (S), and transduction delay (td) are derived from alpha-wave data. VPP mice exhibited an age-related decrease in RmP3. This decrease was consistent with reductions in the number of rod photoreceptors and in the length of rod outer segments observed in previous histological studies of the VPP retina. Values of S determined for the VPP mice were within the normal range, consistent with a normal amplification of the visual signal in VPP rods. At high stimulus intensities, both normal and VPP mice exhibited a decrease in S, which may reflect depletion of a phototransduction substrate at these stimulus levels. We examined the recovery of the alpha wave after a bright conditioning flash by measuring the rod alpha-wave response to a probe flash presented at varying times after the conditioning stimulus. In both normal and VPP mice a fourfold (0.6-log-unit) increase in conditioning stimulus intensity increased both T50%, the period required for half-maximal recovery, and tau, the exponential time constant describing recovery. However, the increases in T50% and tau were significantly greater in VPP mice, indicating an abnormally slow recovery of the flash response in VPP rods.

Sites of cone system sensitivity loss in retinitis pigmentosa.

PURPOSE: To examine the sites of cone sensitivity loss in patients with retinitis pigmentosa by comparing focal electroretinographic and psychophysical modulation thresholds. METHODS: Both psychophysical and electrophysiologic increment threshold curves were obtained in retinitis pigmentosa patients and a group of age-matched, normally-sighted adults. RESULTS: The majority of the retinitis pigmentosa data could be accounted for by a vertical displacement of the normal curve. The retinitis pigmentosa patients showed similar patterns of cone sensitivity losses using both techniques. CONCLUSIONS: The combined electrophysiologic and psychophysical results provide support for an outer retina locus for these cone sensitivity losses. The data suggest that these deficits may be caused by a spatially independent loss of cone photoreceptors with normal adaptation properties in the remaining photoreceptors.

Maculopathy caused by intra-arterially administered cisplatin and intravenously administered carmustine.

Eight patients with malignant gliomas were monitored with clinical examinations to study the effects of the combination of intravenous administration of carmustine and infraophthalmic intra-arterial administration of cisplatin on retinal and optic nerve function. Three patients developed a severe macular retinal pigment abnormality in the eye ipsilateral to the intra-arterial infusion. Electrophysiologic studies disclosed no evidence of a generalized disturbance in the photoreceptors, middle retinal layers, or retinal pigment epithelium. In contrast to previous studies involving patients whose visual loss was caused by vaso-occlusive lesions in the retina and optic nerve, our study involved patients with clinically significant maculopathy, that was not vascular in origin and that developed after treatment with carmustine and cisplatin. We suggest that the deficit may result from a localized retinal pigment disturbance in the macula.

Human VEP contrast modulation sensitivity: separation of magno- and parvocellular components.

Human cortical visual evoked potentials (VEPs) were retrieved in real time (without averaging). The stimuli were sinusoidal gratings whose contrast was temporally modulated about some mean value. Electrophysiologically determined contrast modulation thresholds were measured at standing contrast over the range from 2.5% to 50%, defining an increment threshold function. Increment threshold functions were obtained under two different spatio-temporal stimulus conditions identified as "sustained" (4 c/deg grating modulated at 1.5 Hz) and "transient" (1 c/deg grating modulated at 20 Hz). Under each of these conditions, threshold responses were retrieved at both the fundamental and second harmonic of the contrast modulation frequency. Under "sustained" conditions log increment threshold responses and the fundamental the second harmonic of the modulation frequency were similar to those at the fundamental except for a saturation effect (i.e., above a mean contrast of 25% there was little further reduction in modulation sensitivity). There was no contrast gain control under "transient" stimulus conditions. In other words, the same absolute amount of contrast change produced threshold responses for all mean levels up to 25%. This was true at both the fundamental and second harmonic of the modulation frequency. Stimulus differences produce striking differences in the electrophysiologically inferred increment threshold function for grating contrast, but fundamental and second harmonic evoked responses reflect processes with similar increment threshold behavior.

The clinical utility of visual-evoked potential acuity testing.

We assessed the clinical utility of objectively measured acuity using visual-evoked potentials. The technique was first standardized in normal emmetropic subjects and then applied to uncorrected myopic subjects. We found that visual-evoked potential acuity could accurately indicate Snellen acuity in emmetropia and corrected myopia; however, the two measures were highly correlated only in those uncorrected myopic subjects with visual acuities of 20/100 or better. In subjects with poorer than 20/200 uncorrected visual acuity caused by myopia, estimates of visual-evoked potential acuity could not be obtained. The correlation between these two measures of visual acuity was also lower in patients with decreased Snellen acuity attributable to retinal or ocular disease. We found that patients with unexplainable claims of decreased visual acuity could be diagnosed as having functional visual loss based on objective visual-evoked potential acuities.

Pattern electroretinogram threshold does not show contrast adaptation.

Pattern electroretinogram (PERG) thresholds were examined using a swept contrast stimulus method. Stimulus contrast was either continuously changed (swept) from high to low (descending sweep), or from low to high (ascending sweep). Visual evoked potential (VEP) contrast threshold was higher when measured using descending sweeps than when using ascending sweeps. This VEP threshold difference has been attributed to cortical adaptation. Although previous work has reported changes in the PERG amplitude as a function of pre-exposure, we have found no analogous effect on the PERG threshold.

Cone function in congenital nyctalopia.

A patient with congenital stationary night blindness (CSNB) (Schubert-Bornschein type) transmitted as an autosomal recessive trait was studied with several tests of electrical function as well as a variety of psychophysical procedures. Comparison of the patient's present findings with those obtained 23 years earlier showed that while rod thresholds have remained the same, cone sensitivity has decreased. Subjective flicker thresholds obtained following a bleach were unchanged during the course of dark adaptation. The absence of rod-cone interaction, together with an absent scotopic b-wave, implies that the defect is in the mid-retinal layers. Further, the absence of oscillatory potentials in the photopic electroretinogram (ERG) suggests that the interplexiform cell may be implicated in some manner. The focal ERG of the CSNB patient showed normal amplitude and normal phase delays, supporting the idea that the focal ERG samples primarily cone photoreceptor activity.

Contrast sensitivity of the human pattern electroretinogram.

Contrast thresholds for the pattern electroretinogram (PERG) were measured using lock-in amplifier retrieval of the retinal signal and a swept contrast display. Contrast sensitivity functions (CSF) developed from these PERG contrast thresholds were compared with those established psychophysically under identical stimulus conditions. Whereas the PERG CSF showed a band-pass characteristic across temporal frequency, the psychophysical CSF (and a temporal CSF developed from visual evoked potential contrast thresholds) had a low-pass pattern. Across spatial frequency, the PERG and psychophysical CSFs had similar shapes, although the PERG CSF peaked at a lower spatial frequency than the psychophysical CSF.

Evaluating macular function using the focal ERG.

A stimulus consisting of 96 red LEDs mounted in the rear of a ganzfeld bowl was used to elicit focal electroretinograms (FERG) from the central 9 degrees of the retina in human subjects. The luminance of the stimulus was driven sinusoidally at frequencies from 10-60 Hz. The temporal responsiveness and response phase lags of normal subjects and patients with retinal disease were measured. Normal subjects produced maximum amplitude FERG responses to stimuli between 30-40 Hz. Patients with retinitis pigmentosa showed a low-pass pattern of amplitude loss, with an additional frequency independent loss in sensitivity in those with poorer visual acuity. Patients with macular degeneration showed general amplitude loss associated with a relative sparing of the mid-temporal frequencies. The response phase lags in both patient groups were not significantly different from the normals. These findings point to a loss in temporal responsiveness accompanied by a secondary loss of sensitivity in these heredoretinal degenerations.

Objective assessment of temporal modulation transfer functions using the focal ERG.

Temporal modulation transfer functions (MTF's) were recorded from the macula of nine normal subjects using focal electroretinography (FERG). An array of light emitting diodes (LED's) was used to experimentally manipulate stimulus temporal frequency, modulation depth, and mean luminance values. Two techniques were used to derive FERG modulation thresholds at several temporal frequencies: conventional averaging with extrapolation to a criterion amplitude, and a swept stimulus lock-in retrieval method. These two methods produced comparable results. The electrophysiologically derived MTF's were similar in shape to those obtained psychophysically. Six patients with retinal disease were also examined; all patients showed sensitivity losses which were most marked at the higher frequencies. Such losses tended to be greater in patients with poorer visual acuity.

A rapid evoked potential index of cortical adaptation.

Contrast thresholds and acuity limits were measured in 4 observers with the swept visual evoked potential (VEP) technique. In this technique, grating contrast or grating spatial frequency is electronically varied while the subject's evoked response is retrieved in real time (without averaging). Contrast or spatial frequency variation make the stimulus vary in intensity; zero VEP response amplitude indicates the threshold intensity. Large shifts occur in the indicated threshold when stimulus sweep direction is reversed. Thresholds are always relatively elevated when the run begins with the strongest stimulus value. These shifts do not have a technical origin in the delay of the instrument (Nelson et al. 1984b). Here, it is shown that the shifts are due to orientation and spatial frequency selective adaptation, probably of cortical origin. Measureable adaptation is produced by momentary exposure to contrasts as low as 1.25%; nearly maximum adaptation (0.6 log units) is reached with 20% contrast. These findings support the concept of a contrast gain control mechanism in visual cortex, and pose practical problems for visual assessment with the evoked potential.

Lock-in techniques for the swept stimulus evoked potential.

We discuss the use of synchronous-demodulation (lock-in) techniques for evoked potential retrieval. Application to electronically swept visual displays is emphasized. These techniques permit a visual threshold to be specified in 20 s, but their application to visual assessment requires careful consideration of several problems, notably alleged delay in the instrumentation, specification of the baseline response level, and the nature of EEG interference. In addition, since stimulus waveform information is lost in all lock-in methods, questions concerning what activity is contributing to the measured response must be answered. A technique addressing these issues and combining phase-sensitive detection and vector computation is presented.

The assessment of evoked potential contrast thresholds using real-time retrieval.

Electrophysiologic contrast sensitivity functions (CSF) have been estimated using lock-in amplifier signal retrieval of the visually evoked response (VER). These CSFs were compared with CSFs obtained psychophysically using the same stimulus conditions. The two measures of contrast sensitivity behave similarly in response to variations of temporal and spatial frequency. The major advantage of using real-time retrieval is speed. Threshold for a single spatiotemporal condition can be estimated in as little as 20 sec, making the application of electrophysiologic contrast sensitivity testing feasible for clinical populations.

Contrast sensitivity loss in multiple sclerosis. Selectivity by eye, orientation, and spatial frequency measured with the evoked potential.

Multiple sclerosis can produce highly selective losses in visual function. Psychophysical studies have demonstrated contrast sensitivity deficits for spatial frequencies or for stimulus orientations. Using real-time lock-in retrieval of the visual evoked potential, the authors measured contrast sensitivity in 15 cases with probable or definite multiple sclerosis and acuities of 20/40 or better. Sine-wave grating contrast threshold determinations for three spatial frequencies (1, 4, and 8 cycles/deg) and four orientations (0, 45, 90, and 135 deg) revealed contrast deficits in at least one spatial frequency and orientation in every case. In most cases the visual losses were spotty or multifocal, and not the same in both eyes. Some cases with highly selective patterns of orientation or spatial frequency losses were observed and are discussed in terms of involvement of cortical functional architecture in the disease.

Spatiotemporal conditions which elicit or abolish the oblique effect in man: direct measurement with swept evoked potential.

Reversing sine wave gratings were electronically swept in spatial frequency and contrast. The acuity limits and contrast thresholds of 4 observers were inferred from evoked potential stimulus-response functions elicited by these stimuli and retrieved with a quadrature lock-in amplifier. The evoked potential functions, linearized in the case of contrast by increasing contrast logarithmically with time, were extrapolated to the point of zero response. This point provides an electrophysiologically defined threshold value for acuity and for contrast. An oblique effect (superior sensitivity for HV-oriented gratings) could reliably be demonstrated in both acuity and contrast threshold performance. This oblique effect could readily be abolished under low spatial/high temporal frequency conditions. The findings are discussed in terms of shifting relative strengths of X and Y contributions to the steady-state evoked potential.

The 20/20 eye in multiple sclerosis.

Using clinical and electrophysiologic measures, we evaluated the visual pathway of patients who had multiple sclerosis, 20/20 Snellen acuity, and no history of optic neuritis. Delayed latencies were found in the transient visual evoked potentials (VEPs) of 38% of the patients, and interocular latency differences were abnormal in 67%. Contrast VEPs were abnormal in 46%. Psychophysical determinations of contrast sensitivity were abnormal in 78%. Only 17% of the patients had dyschromatopsia, 36% had afferent pupillary abnormalities, and 59% had optic nerve pallor or nerve fiber layer loss. Psychophysical contrast evaluations and VEP studies were superior to other clinical evaluations in demonstrating visual dysfunction in these patients.

Recording the pattern electroretinogram: a cautionary note.

It is possible to record a pattern electroretinogram (PERG) of near normal amplitude in a situation when the eye containing the active electrode is occluded. Because PERG recording requires high amplification and sensitive signal retrieval techniques, the electrode in the occluded eye records a distant potential from the unoccluded eye. Referencing the active electrode to an ipsilateral ear diminishes, but does not eliminate the referred PERG potential. Such unlooked for interaction may provide misleading data in situations where binocular viewing is used because of poor vision in one eye; therefore, occlusion of the eye not being tested should be undertaken whenever possible.