Kenneth R. Alexander

Rate of Visual Field Loss in Retinitis Pigmentosa

PURPOSE The authors quantitate the rate of visual field loss in patients with retinitis pigmentosa as it relates to different clinical field phenotypes. PATIENTS AND METHODS Goldmann visual fields were obtained with target V4e in 77 patients and with target II4e in 71 patients who had either isolated or various genetic types of retinitis pigmentosa and who met certain entrance criteria. The visual fields were categorized into five distinct clinical field phenotypes on the basis of their pattern of field loss. Mixed-model methods for the analysis of longitudinal data were used to model the natural logarithm of the visual field area as a function of patient age and clinical field phenotype. The average half-life (time over which half of the remaining field area would be lost) of the visual field area for each phenotype was computed from the results of this analysis. Visual field data were not analyzed for patients with a normal clinical field phenotype (type 1). RESULTS Independent of the field phenotype, average half-life values were 7.3 years for target V4e and 6.8 years for target II4e, which were not statistically different (P = 0.16). Visual fields with partial or complete midperipheral ring scotomas (type 2) and those with only a residual central field (type 4) had a half-life of 9.5 and 9.4 years, respectively, for target V4e, and 8.9 and 8.0 years, respectively, for target II4e. Patients with partial peripheral restriction (type 5) lost visual fields with a half-life of 9.5 years for target V4e and 7.3 years for target II4e. None of these differences in the half-lives between the different phenotypes were statistically significant for either targets V4e or II4e. Fields with a residual central area and remaining temporal and/or nasal islands (type 3) had a half-life of 4.8 years for target V4e and 6.0 years for target II4e. The differences in half-lives between type 3 and each of the other field phenotypes were statistically significant for the V4e target, but not for the II4e target. CONCLUSIONS The results of this study can be useful for counseling patients with retinitis pigmentosa and various visual field phenotypes as to their potential rate of visual field loss.

Human macular pigment assessed by imaging fundus reflectometry

A computerized, television-based, imaging fundus reflectometer was used to obtain estimates of the spatial distribution of macular pigment (xanthophylls) from seven normal subjects. Digitized images of the bleached macula of each subject were acquired at illuminating wavelengths from 462 to 697 nm. An analysis of spectral reflectances indicated that differences in short-wavelength reflectance between the foveal center and parafovea were influenced by spatial variations in melanin and oxyhemoglobin absorption as well as by the distribution of macular pigment. To provide an estimate of the spatial distribution of macular pigment alone, we have corrected fundus images obtained at 462 nm for the effect of melanin and oxyhemoglobin absorption. The spatial variation in macular pigment double density across the horizontal and vertical meridians of the retina was well described by Gaussian functions. The peak double densities for the individual subjects ranged from 0.22 to 0.45 and the standard deviations of the Gaussian functions averaged approx. 1 degree.

Spatial-frequency characteristics of letter identification

To investigate the spatial-frequency components that govern letter identification we compared contrast thresholds for three types of visual stimulus (1) standard Sloan letters, (2) Sloan letters that were spatially bandpass filtered by cosine log filters, and (3) D6 patterns (sixth spatial derivatives of Gaussians). Stimuli were presented on a gray-scale display screen of a Macintosh computer-based testing system at temporal frequencies primarily of 2 and 16 Hz. Contrast thresholds were measured in two subjects with normal visual acuity with use of forced-choice staircases. Contrast sensitivity functions for standard Sloan letters and D6 patterns were comparable at a temporal frequency of 16 Hz but differed systematically at a temporal frequency of 2 Hz. The measurement of contrast sensitivity for cosine log filtered letters presented at a temporal frequency of 2 Hz indicated that the object spatial frequency of maximum sensitivity shifted to lower frequencies as letter size decreased, whereas the retinal spatial frequency of maximum sensitivity remained relatively constant. When letters were spatially bandpass filtered at a peak object spatial frequency of 2.5 cycles/letter, then contrast sensitivity functions for letter identification were equivalent to those for D6 patterns at both temporal frequencies. These results suggest that spatially filtered letters may provide a more appropriate test of visual function than do standard letter optotypes.

Rayleigh discriminations in young human infants

The capacity of young infants to discriminate 3 x 3 degrees broadband red or 550 nm green squares from a 589 nm yellow surround was tested by means of the forced-choice preferential looking technique. All 3-month olds, about 3/4 of the 2-month olds, and just under half of the one-month-olds could make at least one of these discriminations. Taken together with other known properties of infant color vision, the failures of discrimination shown by the younger infants are more readily modeled as immaturities of neural processing than as an absence of anomaly of LWS or MWS cones.

Comparison of contrast sensitivity, visual acuity, and Humphrey visual field testing in patients with glaucoma.

BackgroundDespite their normal or near-normal Snellen visual acuity, patients with glaucoma often complain of “poor” vision. ObjectiveTo investigate the relationship between large-letter contrast sensitivity, high-contrast visual acuity, and visual field defects in patients with glaucoma who have 20/40 or better visual acuity. DesignProspective, cross-sectional case series. Patients and MethodsWe evaluated 250 eyes of 144 subjects from the Glaucoma Service at the University of Illinois at Chicago College of Medicine. Subjects with a diagnosis of glaucoma, suspected glaucoma, or ocular hypertension who met the 20/40 or better vision requirement were recruited. Visual acuity was measured using the rear-illuminated Lighthouse Visual Acuity Chart at 4 m. Contrast sensitivity was measured using the Pelli-Robson Chart in a front-illuminated box with even luminance across the chart. Visual fields of the patients were measured using the 24–2 full-threshold program on the Humphrey Visual Field Analyzer. ResultsA significant correlation (r = 0.57, P < 0.001, n = 127) was found between the visual field mean deviations and the contrast sensitivity scores. The correlation (r = −0.322, P < 0.001, n = 127) was less between the visual field mean deviation and the log MAR visual acuity values, as was the correlation between the contrast sensitivity scores and log MAR visual acuity values (r = −0.370, P < 0.001, n = 127). In the subgroup of patients with chronic open-angle glaucoma, the correlation between the mean visual field deviation and the contrast sensitivity score was higher at 0.689 (P ≤ 0.001, n = 62). ConclusionsReduced contrast sensitivity is significantly correlated with visual field losses in patients with glaucoma and a visual acuity of 20/40 or better. The study data support the conclusion that, compared with visual acuity, the disease process preferentially affects contrast sensitivity. In our previous work, contrast sensitivity was shown to be more related than visual acuity to real-world function in patients with early glaucomatous changes.

Rod-cone interaction in flicker perimetry.

We have assessed the influence of the rod system on cone flicker sensitivity during flicker perimetry. For temporal frequencies above 18 Hz extrafoveal cone-mediated flicker thresholds for a white test stimulus are as much as 1.5 log units lower when measured against a large background light that saturates the rods than when measured in darkness. Following a Ganzfeld bleach extrafoveal cone flicker thresholds are at their minimum once the cones have recovered their sensitivity, but then thresholds rise as the rods begin to recover from the bleach. Our results indicate that the flicker sensitivity of the extrafoveal cone system at high temporal frequencies is influenced by the rods surrounding the flickering test stimulus. The rods reduce flicker sensitivity maximally in the dark adapted state, and their suppressive influence is minimised only by strong rod bleaches or by large backgrounds that saturate the rod system.

Properties of the human cone system electroretinogram during light adaptation

Changes in the response characteristics of the flash electroretinogram (ERG) of the human cone system were studied during the time course of adaptation to a cone-isolating ganzfeld background. During light adaptation, the amplitudes of the b- and i-waves increased, while the implicit time of the b-wave decreased. The amplitude of the a-wave and the implicit times of the a- and i-waves did not change systematically during light adaptation. Luminance-response functions for b-wave amplitude were obtained at discrete times following background onset and were analyzed using the hyperbolic equation R/R(max) = L(n)/(L(n) + K(n)). The increase in b-wave amplitude was characterized by increases in R(max), K, and n. The decrease in b-wave implicit time was of a similar magnitude at all flash luminances. The amplitude increase of the i-wave only occurred at moderate flash luminances. The results provide a basis for optimizing the clinical recording of cone-isolated single-flash ERGs.

Rod and Cone Dysfunction in Carriers of X-linked Retinitis Pigmentosa

Carriers of X-linked retinitis pigmentosa were studied using electroretinographic and psychophysical procedures. Under both dark- and light-adapted (cone-isolated) conditions, electroretinogram (ERG) a-waves of carriers were reduced in amplitude but normal in implicit time, whereas b-waves were reduced in amplitude and delayed in implicit time. Reductions in b-wave amplitudes of the carriers as a group were equivalent for the rod and cone systems. Luminance-response functions for both dark-adapted and cone-isolated b-waves were fit by the Naka-Rushton equation and demonstrated a selective reduction of Rmax; the semi-saturation constant (K) and the slope parameter (n) were normal. Electroretinograms recorded using the brightest stimulus flashes were most effective at distinguishing carriers from normals. Absolute thresholds of the carriers were elevated significantly across the central 40 degrees of the visual field. As a group, the threshold elevations of the carriers were approximately equal for the rod and cone systems.

Delayed Rod Dark Adaptation in Patients with Stargardt's Disease

Twelve patients with Stargardts dystrophy were each found to have a prolongation in rod dark adaptation. All had a normal rate of recovery during the early portion of rod dark adaptation but a selective prolongation of the later segment of rod recovery. This observation was apparent in patients with limited fundus flecks and those with extensive fundus flecks, whether or not a dark choroid was observed and independent of the presence or absence of an atrophic-appearing macular lesion. A defect within retinal pigment epithelial cells of an enzyme or intracellular transport mechanism involved in the visual pigment regeneration cycle could account for these findings.

Autoantibodies in Melanoma-Associated Retinopathy Target TRPM1 Cation Channels of Retinal ON Bipolar Cells

Melanoma-associated retinopathy (MAR) is characterized by night blindness, photopsias, and a selective reduction of the electroretinogram b-wave. In certain cases, the serum contains autoantibodies that react with ON bipolar cells, but the target of these autoantibodies has not been identified. Here we show that the primary target of autoantibodies produced in MAR patients with reduced b-wave is the TRPM1 cation channel, the newly identified transduction channel in ON bipolar cells. Sera from two well characterized MAR patients, but not from a control subject, stained human embryonic kidney cells transfected with the TRPM1 gene, and Western blots probed with these MAR sera showed the expected band size (∼180 kDa). Staining of mouse and primate retina with MAR sera revealed immunoreactivity in all types of ON bipolar cells. Similar to staining for TRPM1, staining with the MAR sera was strong in dendritic tips and somas and was weak or absent in axon terminals. This staining colocalized with GFP in Grm6-GFP transgenic mice, where GFP is expressed in all and only ON bipolar cells, and also colocalized with Gαo, a marker for all types of ON bipolar cells. The staining in ON bipolar cells was confirmed to be specific to TRPM1 because MAR serum did not stain these cells in a Trpm1−/− mouse. Evidence suggests that the recognized epitope is likely intracellular, and the sera can be internalized by retinal cells. We conclude that the vision of at least some patients with MAR is compromised due to autoantibody-mediated inactivation of the TRPM1 channel.