Optic neuropathy following simulation of orbital hemorrhage in the nonhuman primate.

The goal of the study was to determine, using a nonhuman primate (NHP) model, the minimum duration of elevated intraocular pressure (IOP) (induced by an inflated catheter) necessary to produce significant visual system deficits. In Old World monkeys (Macaca mulatta), a catheter was placed retrobulbarly in one orbit and inflated with saline for either 180 min (10 monkeys) or 240 min (six monkeys subjects). Baseline color fundus photographs, monochromatic photography, fluorescein angiography, and IOP measurements were performed preoperatively and at either 2, 4, or 6 weeks postoperatively on both eyes of each monkey prior to killing and histological analysis. Optic neuropathy was demonstrated in eight of these NHPs. In the two most severe cases (240 min inflation condition), complete nerve fiber atrophy with central retinal artery occlusion was observed. Sector nerve fiber atrophy, extending from the temporal disc to beyond the macula, was noted in the other six monkeys, five of which were in the 180 min inflation condition. Thus, optic neuropathy, sufficient to produce visual loss, was noted following increased IOP (> or = 50 mm Hg) for 180 min or 240 min. These data emphasize the need for timely intervention to mitigate the potential detrimental effects of retrobulbar hemorrhage when it occurs in humans.

Nimodipine, a centrally active calcium antagonist, exerts a beneficial effect on contrast sensitivity in patients with normal-tension glaucoma and in control subjects.

BACKGROUND/PURPOSE: The use of calcium antagonists in patients with normal-tension glaucoma (NTG) currently is under investigation. The aim of this study is to evaluate the effect of an acute dose of oral nimodipine, a centrally active calcium antagonist, on spatial contrast sensitivity in patients with NTG and in age-matched control subjects. METHODS: Spatial contrast sensitivity was measured using the Pelli-Robson and the Vistech 6000 charts in 14 patients with NTG and in 17 control subjects. Testing was performed at baseline and at two subsequent sessions. Measurements were recorded 2 hours after oral administration of either nimodipine or placebo in a randomized, double-masked manner. Data were analyzed using unpaired, two-tailed Student's t test for between-group comparisons and repeated measures analysis of variance for within-group comparisons. RESULTS: Using the Pelli-Robson charts, baseline contrast sensitivity was significantly lower in patients with NTG compared with control subjects (P < 0.05, unpaired Student's t test). There was a significant increase in log contrast sensitivity after administration of nimodipine compared with baseline and placebo in patients with NTG (baseline, 1.39 +/- 0.38; placebo, 1.41 +/- 0.40; nimodipine, 1.51 +/- 0.39) and in control subjects (baseline, 1.62 +/- 0.11; placebo, 1.64 +/- 0.10; nimodipine, 1.81 +/- 0.14) (P < 0.05, repeated measures analysis of variance). A similar trend was observed using the Vistech charts. CONCLUSION: These results suggest that central visual function as measured by Pelli-Robson and Vistech contrast sensitivity is impaired in eyes with NTG. An acute, oral administration of nimodipine, a calcium antagonist, improved contrast sensitivity in patients with NTG and in control subjects. The mechanism of this improvement is not fully understood. Further studies are needed to evaluate the effect of long-term administration in glaucoma.

Development of electroretinogram and rod phototransduction response in human infants.

PURPOSE: To describe and analyze developmental change from birth through maturity of human electroretinogram (ERG) response, especially in terms of rod phototransduction as represented in the ERG a-wave. METHODS: Electroretinograms were recorded from 16 human infants from 5 to 270 days of age, two children 1.9 and 3.4 years of age, and 13 older subjects between 10 and 43 years of age. A range of full-field, white-light flashes up to intensities sufficient to saturate a-wave and b-wave amplitudes and a-wave rate-of-rise was used. The a-wave leading edge, the a-wave and b-wave amplitudes, and the b/a-wave ratio at maximum intensity were analyzed using a model of the activation steps of the G-protein phototransduction cascade. This model, applied to a-waves, provides three parameters interpretable in terms of rod phototransduction: amax (a-wave maximum amplitude, proportional to circulating dark current), A' (estimated constant of transduction amplification), and t'eff (sum of brief delays associated with the cascade steps). RESULTS: Both amax and bmax (maximum b-wave amplitude) increased rapidly from birth. bmax reached apparently mature values by approximately 6 months, but amax, and thus (b/a)max (b/a ratio at maximum intensity), did not reach mature values until sometime after the third or fourth year. Similarly, A' was immature at birth at approximately 25% to 50% of adult levels at intensities below rate-of-rise saturation. For the youngest infants, rate-of-rise saturation appeared to occur at lower effective isomerizations per rod compared to that of the adult. Following a time course similar to that of amax, full maturity for A' probably was not reached before 5 years of age. CONCLUSIONS: Results from the a-wave analysis are consistent with immaturities in the rod photoreceptors early in life. The difference from those of the adult may be explained by lower neonatal concentrations in one or more of the transduction substrates, decreased outer segment length, and, possibly, decreased density of some membrane proteins mediating the cationic dark current. Early adultlike b-wave amplitudes suggest early maturity for the inner retinal elements (rod bipolar and Müller cells) underlying b-wave response, compared to the photoreceptors.

Modified ERG-jet contact lens electrodes for use in infants and toddlers.

A simple modification of the standard ERG-jet contact lens recording electrode for use in infants and small children was developed. A small Plexiglas cylinder is fixed to the front surface of the electrode, which prevents lid closure and facilitates handling. Sedation or general anesthesia is rarely needed. Waveforms obtained with the modified electrode appear comparable to those obtained with standard electroretinogram electrodes.

An animal model of visual loss from orbital hemorrhage.

Intraorbital hemorrhage may arise spontaneously or following orbital or periorbital surgery or trauma and may be associated with visual loss or impairment. This project was designed to evaluate the ophthalmic effects and underlying mechanism(s) associated with visual impairment secondary to intraorbital hemorrhage. An experimental surgical procedure was developed to simulate intraorbital hemorrhage. A reversible state of unilateral visual loss secondary to acutely increased intraorbital volume was induced and maintained under general anesthesia for either 90, 120, or 180 min duration in nine adult nonhuman primates (NHPs) (Macaca arctoides). Color funduscopic photography, i.v. fluorescein angiography, electrophysiological testing, and tonometry were obtained during baseline, experimental, and follow-up procedures. The globes and optic nerves were obtained for histopathologic evaluation. One of three animals in the 180 min experimental group exhibited clinical and histopathological changes of optic neuropathy 6 weeks after the experimental procedure. Optic neuropathy is one of several proposed etiologies for producing visual loss secondary to intraorbital hemorrhage. This study offers a reliable, safe, and reversible technique to study the effects of acutely increased intraorbital volume in nonhuman primates. The animal model described may be useful for evaluating mechanism(s) involved with visual impairment in other acquired optic neuropathies.

Analysis of ERG a-wave amplification and kinetics in terms of the G-protein cascade of phototransduction.

PURPOSE: To test rigorously the hypothesis that the a-wave of the electroretinogram (ERG) is proportional to the rod photocurrent by examining the applicability to a-waves of a recent model of the activation steps in the G-protein cascade of phototransduction. METHODS: ERGs were recorded in response to flashes of graded intensity, from six dark-adapted normal subjects and from two patients, one with retinitis pigmentosa (RP) and one with cone retinal dystrophy with rod involvement (CRD). The a-wave portions of the responses were analyzed with a model of the activation steps of the G-protein cascade. The model is characterized by a parameter, A, the amplification constant, with units of s-2 (per photoisomerization), which may be expressed as the product of physical and biochemical parameters of the transduction cascade. RESULTS: Each a-wave family was well described by the model. For the six normal subjects, we obtained A approximately 7 s-2, about 100-fold greater than in isolated amphibian rods at 22 degrees C, but close to the value for isolated primate rods. For the patient with RP, the maximum a-wave amplitude (amax) was considerably reduced, but the amplification constant was normal (A = 7.5 s-2). In contrast, the patient with CRD had a nearly normal amax but had an amplification constant about sixfold lower than normal (A = 1.1 s-2). CONCLUSIONS: The authors conclude that the a-wave is a direct reflection of the rod photo-current and that the rising phase kinetics are accurately described by a simple model of the G-protein cascade. They show that the small volume of the human rod outer segment is crucial to the achievement of high amplification, and they show how their observations constrain the possible pathologies of phototransduction in patients with retinal disease.

The visual-evoked response in infants with central visual impairment.

We studied ten children with central visual impairment with a known neurologic defect and an abnormal visual-evoked response who had results of repeat electrophysiologic testing evaluated at the Children's Hospital of Philadelphia from December 1989 through July 1991. Central visual impairment is defined as poor visual function with a normal anterior visual pathway. Age at first examination ranged from 5 to 48 months with a followup of two to 31 months. Repeat visual-evoked response testing showed improvement in seven patients and no change in three. Grating acuity as measured by the Teller acuity card procedure, performed in nine of ten patients, improved in seven, showed no change in one, and declined in one. We found a potentially favorable prognosis for those infants with central visual impairment, despite an initially abnormal visual-evoked response. We used a clinical approach to this disorder to improve diagnostic categorization and prognostic capabilities in central visual impairment.

Do tinted lenses improve the reading performance of dyslexic children? A cohort study.

The use of tinted lenses as a method to improve reading skills in children with dyslexia has been a controversial issue in recent years. The purpose of the present study was to determine if tinted lenses cause a measurable improvement in the reading performance of dyslexic children. Twenty-four children aged 8 to 12 years participated in the study. Dyslexia was diagnosed in all children by psychological evaluation, and these children underwent an ophthalmic evaluation for inclusion into the study. Participants were graded for speed and accuracy as they read through spectacle frames that contained red-, blue-, yellow-, and green-tinted lenses, a neutral-density lens, and empty frames. All lenses for each subject were of the same density level, with subjects alternately distributed to one of two densities tested (0.12 or 0.30 log units). Each child was asked to select the lens condition that subjectively improved reading ability at the conclusion of testing. One-way analysis of variance of reading performance showed neither improvement nor deterioration attributable to lens color or density when applied to error rates (F = 1.73, P = .14 for a density of 0.12; F = 0.28, P = .92 for a density of 0.30) or to reading rates (F = 0.98, P = .44 for a density of 0.12; F = 0.81, P = .55 for a density of 0.30). In addition, the lens condition that was subjectively preferred by each child did not correlate with actual reading performance (chi 2 = 3.83, not significant; 11.07 needed for significance at P = .05).

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.

Electroretinogram interpretation in central retinal vein occlusion.

The authors report electroretinogram (ERG) data from the initial clinic visit of 39 patients with central retinal vein occlusion (CRVO). No patient had signs of neovascular complications or had received treatment at the time of the ERG examination. Area under the receiver operating characteristic (ROC) curve was used to compare effectiveness of the 4 ERG parameters (Rmax, Log K, b/a wave ratio, and 30 Hz implicit time) in separating those patients who went on to iris neovascularization from those who did not. Rmax is the maximum saturated b-wave amplitude and Log K is the half saturation constant of the Naka-Rushton curve fit to the intensity response data. Discriminant scores, derived using multiple discriminant analysis, were calculated for the total patient groups, CRVO eye alone, and intereye difference. These scores also were compared with the four individual ERG parameters using ROC analysis. Parameters based on amplitude of ERG response, Rmax, and b/a wave ratio are as effective predictors of neovascular response as those interpreted as indicators of retinal sensitivity, such as 30Hz implicit time or Log K. The authors present evidence that loss of b-wave amplitude is not necessarily associated with irreversible loss of inner retinal function.

Electroretinogram b-wave implicit time and b/a wave ratio as a function of intensity in central retinal vein occlusion.

The ability of electroretinogram (ERG) b-wave implicit time and b/a wave ratio to predict iris neovascular response was analyzed as a function of stimulus intensity over a 3.6 log unit intensity range in 39 patients with central retinal vein occlusion (CRVO). Predictive power for CRVO patients was evaluated using ROC area at intensities of 1.23, 1.83, 2.43, and 3.03 effective log quanta/rod, where reliable data for both parameters were obtainable from most patients. The relative predictive power of b-wave implicit time and b/a wave ratio were shown to vary with stimulus intensity. The predictive power of b-wave implicit time, as measured by ROC area, declined to below significance at high intensity (above 1.83 log quanta/rod), while b/a wave ratio performed best at middle intensities (1.83 and 2.43 log quanta/rod) and not as well at high and low intensities. Further analysis of statistical behavior of both ERG parameters was obtained from the t statistic. Insight into the mechanism influencing predictive power of b-wave implicit time was derived from measurements on normal adults and CRVO patients with response data taken at high intensities. These results suggest that an optimal stimulus intensity range can be found for these ERG parameters in the evaluation of CRVO.

Temporal contrast sensitivity loss in primary open-angle glaucoma and glaucoma suspects.

The need for more sensitive tests for the early detection of compromised visual function in glaucoma is established by anatomic and psychophysical evidence of damage occurring to optic nerve fibers in eyes with normal visual fields. The results are reported of temporal frequency testing on 51 glaucoma suspects without visual field loss in either eye, 52 glaucoma patients with visual field deficits in the tested eye, and 11 normal subjects. Modulation transfer functions were obtained using a sinusoidally flickering 5 degrees spatially uniform white field viewed with central fixation and plotted at six frequencies from 5-30 Hz. The results showed a frequency-specific sensitivity loss centered at 15 Hz and a nonfrequency-specific mean sensitivity loss, that was greater, on average, in glaucoma patients than in suspects. Sensitivity losses of both kinds were seen in most glaucoma patients, but only in a minority of glaucoma suspects. About 12% of suspects were indistinguishable from the lowest performing one third of these glaucoma patients. A smaller number of suspects appeared to form a second mode in the frequency distribution for temporal sensitivity at 15 and 25 Hz. In patients with glaucoma, age was found to be a significant factor associated with the magnitude of mean sensitivity loss. Age was not a significant factor contributing to sensitivity loss in individual suspect data as measured by regression analysis, but it contributed to a small and consistent sensitivity loss across frequency for group-averaged data in those older than 55 years of age.

Electroretinogram parameters at presentation as predictors of rubeosis in central retinal vein occlusion patients.

This report evaluates the prognostic value of parametric electroretinography (ERG) techniques in the development of rubeosis in central retinal vein occlusion (CRVO). An ERG protocol was followed on the initial clinic visit for 21 CRVO patients. None of these patients had neovascular complications or any treatment before the ERG examination. The ERG data were used to define an intensity-response (I-R) function, b-wave to a-wave peak ratio (b/a-wave ratio), and 30-Hz b-wave implicit time. A Naka-Rushton function was fitted to the I-R data to obtain values for maximum saturated response (Rmax) and for the log of the half-saturation intensity (log K). The authors' results show that ERG parameters relating both to the effective number of responding retinal elements and to the sensitivity of responding elements have significant prognostic value. Unexpectedly high predictive values were found for the Rmax and b/a ratio, parameters thought to correlate with the effective number of responding elements, compared with log K and 30-Hz implicit time, parameters thought to relate more closely to retinal ischemia. A multiple discriminant analysis, combining information from these ERG parameters, allowed separation of CRVO patients in whom rubeosis would develop from those in whom it would not, with a false-positive rate of only 14%.

Selective loss of pattern discrimination in early glaucoma.

A new perimetric pattern discrimination test was compared with conventional automated perimetry (Humphrey program 30-2 or Octopus program 32) in glaucoma patients, glaucoma suspects, and control subjects. The new test is based on the rationale that a greater percentage of retinal ganglion cells should be needed to detect a stimulus by its shape, or pattern, than by its brightness. The pattern discrimination stimulus was apatch of nonrandom dots embedded in a surrounding random dot field of the same average density. Pattern discrimination thresholds were measured by changing the degree of regularity, or coherence, of the stimulus dots. The fully coherent target was a static, 1-s duration, 20 x 20-dot checkerboard. Using a criterion-free relative operating characteristic analysis, we estimated the ability of both the pattern discrimination and conventional tests to distinguish the normal data distribution from the suspect and glaucoma distributions. The pattern discrimination test appeared to produce separations greater than conventional perimetry for glaucoma suspects and separations equivalent to conventional perimetry for glaucoma patients.

Influence of serial practice on Farnsworth-Munsell 100-hue scores: the learning effect.

Clinical application of the Farnsworth-Munsell 100-hue test may be compromised by uncontrolled sources of psychophysical fluctuation such as a serial practice effect. Although the literature does not report a substantial practice effect for the 100-hue test, we have measured significant improvement in performance extending over at least four test repetitions for a group of twenty-six normal naive subjects. Analysis of test taking strategy identified the most likely source of improvement as cognitive in nature and not related to the availability of the peripheral color signal. An extended training procedure was devised to minimize the serial practice effect which included intensive instruction with illustrations of correct and incorrect cap sequences and practice with verbal feedback on performance using a subset of ten 100-hue caps. Administration of the pretest training was found to minimize the practice effect in an additional group of thirty initially naive subjects. Using pretest training, we were also able to record consistent 100-hue intensity-response functions over five illumination levels.

Age covariance between 100-Hue color scores and quantitative perimetry in primary open angle glaucoma.

Color vision tests have shown promise as an early indicator of optic nerve compromise in primary open angle glaucoma (POAG). In this context, it is of interest to know how well color test performance correlates with an accepted measure of glaucomatous optic nerve damage, such as is provided by quantitative static perimetry. We found correlation values for 96 glaucoma suspects (ocular hypertensive patients) and 110 patients with POAG. No significant correlation values were found for the suspect group when age correction was applied to the color variable. Similarly, for the patients with POAG, age correction of the color test scores reduced all age group correlation values below significance, except for the age group 60 to 69 years. These findings conflict with another recent study reporting significant correlation between Farnsworth-Munsell 100-hue color test scores and visual field performance for glaucoma suspects but which did not correct for age. We interpreted our results for the glaucoma suspects and patients with glaucoma to indicate some independence of mechanisms responsible for early color loss compared with visual field loss.

Improved color test results with large-field viewing in dichromats.

Standard methods for screening color vision defects may be expected to underestimate a color defective's complete chromatic discrimination abilities because the viewing field is confined to the fovea (central 2 degrees). Large-field (8 degrees) Farnsworth-Munsell 100-hue and dichotomous (D-15) tests were constructed. The 100-hue test, along with its small-field counterpart, was administered to five deuteranopes (green defectives) and four protanopes (red defectives). The D-15 small- and large-field tests were given to these same subjects with the addition of two deuteranopes and one protanope. Both deuteranopes and protanopes showed marked improvement on the large-field D-15 and 100-hue tests. This improvement in performance for large-field over small-field viewing is consistent with color-matching data, which show large-field trichromacy in observers who have been demonstrated to be small-field red-green dichromats. These results suggest that tests confined to central fovea viewing provide an incomplete functional description of the color vision of an appreciable number of classic dichromats.

Developmental aspects in the assessment of visual function in young children.

The developmental aspects in the assessment of visual acuity in the preverbal child have been reviewed. Several investigative techniques indicate that visual acuity of infants increases significantly between birth and age 6 months. Transient oculomotor deviation in infancy must be differentiated from pathologic ocular conditions. Changes in refraction of the developing eye that occur normally and as a result of an ocular disorder must be recognized and managed early in the infant's life.

What do color blind children really see? Guidelines for clinical prescreening based on recent findings.

Recent research on classical red-green blind observers has shown that complete dichromacy may be present only under conditions where the viewing angle is small. For viewing angles greater than about 4 degrees, both rods and an anomalous cone have been shown to underlie a weak form of trichromacy. The conditions for rod or anomalous cone mediation of this trichromacy have also been shown to depend on the overall viewing luminance. These data taken together prompt a rethinking of the classical view of red-green dichromacy and lead to new considerations of the color discrimination performance of dichromatic candidates. In this paper we review the recent research on the presence of trichromatic abilities in classical dichromats and we relate these findings to the needs of the clinician, especially in the screening of young children.