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Purpose: To investigate whether there is a significant correlation between the photopic negative response (PhNR) of the electroretinogram (ERG) and retinal nerve fiber layer thickness and optic disc topography in glaucomatous eyes., Methods: Ninety-nine eyes of 53 patients with open-angle glaucoma (OAG) and 30 eyes of 28 normal volunteers were studied. Photopic ERGs were elicited by red stimuli (644 nm, 1600 cd/m(2)) on a blue background (470 nm, 40 cd/m(2)). The mean deviation (MD) of the visual field was obtained by static visual field analyses. The topography of the optic nerve head was determined by confocal scanning laser ophthalmoscopy. The retinal nerve fiber layer thickness (RNFLT) around the optic nerve head was measured with a scanning laser polarimeter., Results: The amplitude of the PhNR and the PhNR/b-wave ratio decreased with an increase in visual field defects. The logarithmic values of the PhNR amplitude and PhNR/b-wave amplitude ratio were significantly correlated with the MD better than the linear values. The PhNR amplitude and PhNR/b-wave amplitude ratio were significantly correlated with the RNFLT and the rim area of the optic disc and with the cup/disc area ratio. These correlations were higher when expressed linearly than when stated logarithmically. The sensitivity and specificity were 77% and 90% for the PhNR amplitude and 70% and 87% for the PhNR/b-wave amplitude ratio when the optimal cutoff values were used. Although the a-wave amplitude correlated with the MD, the a-wave amplitudes of most of the patients fell within the normal range. The correlation between the b-wave amplitude and MD was not significant., Conclusions: The PhNR amplitudes correlate with the decrease in function and morphology of retinal neurons in eyes with OAG. The linear relationship between the PhNR and the structural parameters indicates that inner retinal function declines proportionately with neural loss in eyes with glaucoma.

Purpose: This study tests whether cones in the rhodopsin-mutant transgenic P23H-3 retina are damaged by ambient light and whether subsequent light restriction allows repair of damaged cones., Methods: P23H-3 rats were raised in scotopic cyclic (12 hours of 5 lux, 12 hours of dark) ambient light. At postnatal day 90 to 130, some were transferred to photopic conditions (12 hours of 300 lux, 12 hours of dark) for 1 week and then returned to scotopic conditions for up to 5 weeks. Photoreceptor function was assessed by the dark-adapted flash-evoked electroretinogram, using a two-flash paradigm to isolate the cone response. Outer-segment structure was demonstrated by immunohistochemistry for cone and rod opsins and by electron microscopy., Results: Exposure for 1 week to photopic ambient light reduced the cone b-wave, the rod b-wave, and the rod a-wave by 40% to 60% and caused shortening and disorganization of cone and rod outer segments. Restoration of scotopic conditions for 2 to 5 weeks allowed partial recovery of the cone b-wave and the rod a- and b-waves, and regrowth of outer segments., Conclusions: Modest increases in ambient light cause rapid and significantly reversible loss of cone and rod function in the P23H-3 retina. The reduction and recovery of cone function are associated with shortening and regrowth of outer segments. Because the P23H mutation affects a protein expressed specifically in rods, this study emphasizes the close dependence of cones on rod function. It also demonstrates the capacity of cones and rods to repair their structure and regain function.

Purpose: To define rod and cone function further in terms of visual cycle mechanism, the retinal phenotype resulting from Rpe65 (retinoid isomerase I) deficiency in Nrl(-)(/)(-) mice having a single class of photoreceptors resembling wild-type cones was characterized and outcomes of retinoid supplementation evaluated., Methods: Rpe65(-)(/)(-)/Nrl(-)(/)(-) mice were generated by breeding Rpe65(-)(/)(-) and Nrl(-)(/)(-) strains. Retinal histology, protein expression, retinoid content, and electroretinographic (ERG) responses were evaluated before and after treatment with 11-cis retinal by intraperitoneal injection. Results Retinas of young Rpe65(-)(/-)/Nrl(-)(/-) mice exhibited normal lamination, but lacked intact photoreceptor outer segments at all ages examined. Rpe65, Nrl, and rhodopsin were not detected, and S-opsin and M/L-opsin levels were reduced. Retinyl esters were the only retinoids present. In contrast, Nrl(-)(/)(-) mice exhibited decreased levels of retinaldehydes and retinyl esters, and elevated levels of retinols. ERG responses were elicited from Rpe65(-)(/-)/Nrl(-)(/-) mice only at the two highest intensities over a 4-log-unit range. Significant retinal thinning and outer nuclear layer loss occurred in Rpe65(-)(/-)/Nrl(-)(/-) mice with aging. Administration of exogenous 11-cis retinal did not rescue retinal morphology or markedly improve ERG responses., Conclusions: The findings provide clarification of reported cone loss of function in Rpe65(-)(/-)/Nrl(-)(/-) mice, now showing that chromophore absence results in destabilized cone outer segments and rapid retinal degeneration. The data support the view that rod-dominant retinas do not have a cone-specific mechanism for 11-cis retinal synthesis and have potential significance for therapeutic strategies for rescue of cone-rich retinal regions affected by disease in the aging human population.

Purpose: A cathode-ray-tube (CRT) monitor-based technique was used to isolate clinically significant components of dark adaptation. The utility of the technique in identifying adaptation abnormalities in eyes with age-related maculopathy (ARM) is described., Methods: A CRT dark adaptometer was developed to assess cone and rod recovery after photopigment bleach. The following measures were obtained: cone recovery rate (R(c); in decades per minute) and absolute threshold (Tf(c); log candelas per square meter), rod recovery rate (R(r); decades per minute), and rod-cone transition (rod-cone break [RCB], in minutes). These components were isolated by appropriately selecting stimulus size, stimulus location, pigment bleach, and test duration and by coupling the CRT with judiciously selected neutral-density (ND) filters. The protocol was developed by using 5 young observers and was tested on 27 subjects with ARM in the study eye and 22 age-matched control subjects., Results: The parameters necessary for effective isolation of cone and early phase rod dark adaptation were a 2.6 ND filter (for a standard CRT monitor, 0.08-80 cd . m(-2) luminance output); a 4 degrees foveated, 200-ms, achromatic spot; approximately 30% pigment bleaching; and a 30-minute test duration. These settings returned obvious rod and cone recovery curves in control and ARM eyes that were compatible with conventional test methods and identified 93% of participants with ARM as having delayed dynamics in at least one of the parameters. Cone recovery dynamics were significantly slower in the ARM group when compared with age-matched control subjects (R(c), 0.99 +/- 0.35 vs. 2.63 +/- 0.61 decades . min(-1), P < 0.0001). Three of the 27 eyes with ARM did not achieve RCB during the allowed duration (30 minutes). The remaining eyes with ARM (n = 24) exhibited a significant delay in rod recovery (R(r)(,) ARM, 0.16 +/- 0.03 vs. controls, 0.22 +/- 0.02 decades . min(-1), P < 0.0001) and the average time to RCB (+/-SD) in the ARM group was significantly longer than in the control subjects (19.12 +/- 5.17 minutes vs. 10.40 +/- 2.49 minutes, P < 0.0001)., Conclusions: The CRT dark-adaptation technique described in this article is an effective test for identifying abnormalities in cone and rod recovery. Slowed cone and rod recovery and a delayed RCB were evident in the eyes with ARM. The test method is potentially useful for clinical intervention trials in which ARM progression is monitored.

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.

Purpose: To characterize progressive changes of retinal ganglion cell (RGC) function and intraocular pressure (IOP) in the DBA/2J mouse model of spontaneous glaucoma., Methods: Serial pattern electroretinograms (PERGs) and IOPs measures were obtained from both eyes of 32 anesthetized DBA/2J mice over an age range of 2 to 12 months at 1-month intervals. Cone-driven flash-ERGs (FERGs) were also recorded. The endpoint was defined as the age at which the PERG amplitude reached the noise level in at least one eye. At that point, both eyes were histologically processed to evaluate the thickness of the retinal fiber layer (RNFL)., Results: IOP increased moderately between 2 and 6 months ( approximately 14-17 mm Hg) and then more steeply, until it leveled off at approximately 28 mm Hg by 9 to 11 months. The mean PERG amplitude decreased progressively after 3 months of age to reach the noise level (85% reduction of normal amplitude) at approximately 9 to 12 months in different animals. When the PERG was at noise level, the RNFL showed a relatively smaller reduction (40%) in normal thickness. The FERG displayed minor changes throughout the observation period. IOP and PERG changes were highly correlated (r(2) = 0.51, P < 0.001)., Conclusions: Results indicate that inner retina function in DBA/2J mice progressively decreases after 3 months of age, and it is nearly abolished by 10 to 11 months, whereas outer retina function shows little change and the RNFL thickness is relatively spared. This result suggests that surviving RGCs may not be functional. Progression of inner retinal dysfunction is strongly associated with increased IOP.

Purpose: To evaluate the diagnostic potential of the electroretinogram (ERG) photostress test and the focal cone ERG in age-related maculopathy (ARM)., Methods: The cohort comprised 31 patients with ARM and 27 age-matched control subjects. The ERG photostress test was used to monitor cone adaptation after intense light adaptation. Focal 41- and 5-Hz cone ERGs were recorded monocularly (central 20 degrees) to assess steady state retinal function. Univariate analysis identified electrophysiological parameters that differed between groups, and receiver operating characteristic (ROC) curves were constructed to assess their diagnostic potential. Logistic regression analysis determined the diagnostic potential of a model incorporating several independent predictors of ARM., Results: The rate of recovery of the ERG photostress test was reduced (recovery was slower) in subjects with ARM. The parameter exhibited good diagnostic potential (P = 0.002, area under ROC curve = 0.74). The implicit times of the 5-Hz (a-wave, P = 0.002; b-wave, P < 0.001) and the 41-Hz (P < 0.001) focal cone ERGs were increased, and the 41-Hz focal cone ERG amplitude (P = 0.003) and focal to full-field amplitude ratio (P = 0.001) were reduced in the ARM group. Logistic regression analysis identified three independent predictors of ARM, including the rate of recovery of the ERG photostress test., Conclusions: Early ARM has a marked effect on the kinetics of cone adaptation. The clinical application of the ERG photostress test increases the sensitivity and specificity of a model for the diagnosis of ARM. Improved assessment of the functional integrity of the central retina will facilitate early diagnosis and evaluation of therapeutic interventions.

Behavioral experiments in humans with a rare genetic mutation that compromises the function of alpha-transducin (Galpha the alpha-subunit of the G-protein in the primary cone phototransduction cascade) reveal a residual cone response only viable at high light levels and at low temporal frequencies. It has three characteristic properties. First, it limits temporal frequency sensitivity to the equivalent of a simple first order reaction with a time constant of approximately 140 ms. Second, it delays the visual response by an amount that is also consistent with such a reaction. Third, it causes temporal acuity to be linearly related to the logarithm of the amount of bleached pigment. We suggest that these properties are consistent with the residual function depending on a sluggishly generated cone photobleaching product, which we tentatively identify as a cone metarhodopsin. By activating the transduction cascade, this bleaching product mimics the effects of real light and is therefore one of the molecular origins of "background equivalence," the long-established observation that the aftereffects of photopigment bleaches and the effects of real background lights are equivalent. Alternative explanations for the residual cone response include the possibilities that there is a secondary phototransduction mechanism that bypasses alpha-transduction, or that the truncated alpha-transduction that results from the mutation retains some minimal functionality.

Purpose: To report a novel mouse model of achromatopsia with a cpfl3 mutation found in the ALS/LtJ strain., Methods: The effects of a cpfl3 mutation were documented using fundus photography, electroretinography (ERG), and histopathology. Genetic analysis was performed using linkage studies and PCR gene identification., Results: Homozygous cpfl3 mice had poor cone-mediated responses on ERG at 3 weeks that became undetectable by 9 months. Rod-mediated waveforms were initially normal, but declined with age. Microscopy of the retinas revealed progressive vacuolization of the photoreceptor outer segments. Immunocytochemistry with cone-specific markers showed progressive loss of labeling for alpha-transducin, but the cone outer segments in the oldest mice examined remained intact and positive with peanut agglutinin (PNA). The cpfl3 mapped to mouse chromosome 3 at the same location as human GNAT2, known to cause achromatopsia. Sequence analysis revealed a missense mutation due to a single base pair substitution in exon 6 in cpfl3., Conclusions: The Gnat2(cpfl3) mutation leads to cone dysfunction and the progressive loss of cone alpha-transducin immunolabeling. Despite a poor cone ERG signal and loss of cone alpha-transducin label, the cones survive at 14 weeks as demonstrated by PNA staining. This mouse model of achromatopsia will be useful in the study of the development, pathophysiology, and treatment of achromatopsia and other cone degenerations. The gene symbol for the cpfl3 mutation has been changed to Gnat2(cpfl3).

Purpose: To determine whether the magnitude of transient tritanopia (TT) differs between migraine and control groups. TT is a retinal phenomenon characterized by a paradoxical reduction in sensitivity to short-wavelength (purple) stimuli after extinction of long-wavelength (yellow) adapting displays. A group difference in the magnitude of TT would provide evidence for a retinal contribution to the S-cone-specific color-processing abnormalities that have been reported in migraine., Methods: Thirty-two migraineurs and 32 age- and sex-matched control participants were tested with a four-alternative, forced-choice procedure to determine S-cone increment and decrement detection thresholds before and after adaptation to a long-wavelength (yellow) display and a neutral (white) display. Migraine history, migraine triggers, and pattern sensitivity were also assessed., Results: Both groups' detection thresholds for increment (purple) S-cone stimuli were increased after extinction of the long-wavelength adapting display compared with the neutral display, demonstrating TT. This loss of sensitivity was significantly greater in the migraine group. In contrast, loss of sensitivity to decrement (yellow) S-cone stimuli was less marked and did not differ between the groups. The magnitude of TT correlated positively with indices of pattern sensitivity and susceptibility to visually triggered migraines but not with migraine history., Conclusions: These results demonstrate that abnormalities in a specific retinal circuit contribute to decreased short-wavelength sensitivity after adaptation in migraine. As thresholds did not correlate with indices of migraine history, it is unlikely that this finding reflects cumulative damage induced by repeated migraine episodes.

Purpose: To examine the relationship between short-wavelength-sensitive (SWS) resolution acuity and epidemiologically defined stages of early age-related maculopathy (ARM)., Methods: Subjects consisted of 88 adults aged 51 to 87 years. Psychophysical testing was undertaken in only one eye of each subject (the study eye). All study eyes had a LogMAR acuity of 0.30 (20/40 Snellen) or better. SWS and achromatic grating resolution acuity were measured at 6 degrees eccentricity from the fovea. Stereoscopic color fundus photographs centered on the macula were taken on both eyes of each subject and were graded using the Wisconsin Age-Related Maculopathy Grading System (WARMGS). After grading, features of ARM were combined to assign a severity stage from 0 to 5 using the methods described by the Rotterdam Eye Study. Relationships between visual function, study eye ARM stage, and fellow eye status were examined with the use of standard statistical analysis., Results: Although SWS resolution acuity was significantly reduced in eyes classified as having any ARM compared with eyes classified as having no ARM (P = 0.002), there was no relationship between the severity of functional deficits and the morphologic severity from stage 1 to stage 4. On reassigning subject eyes to a revised severity staging (stage 0, stages 1 to 4 combined, and stage 5), SWS acuity was significantly different among these three groups (P < 0.001). No significant relationship was found between achromatic resolution acuity and ARM staging. The status of the fellow eye (advanced macular degeneration present or absent) was not significantly related to visual function in the study eye., Conclusions: Significant functional deficits in SWS resolution acuity were found in eyes with ARM features, but the severity of functional loss did not correlate well with the currently accepted method of assigning a morphologic severity stage. Longitudinal studies may reveal further information on the relationships between functional deficits, ARM status, disease progression, and outcome.

Purpose: To characterize rod and cone distribution, organization, and phagocytosis in the diurnal mouse-like rodent Arvicanthis ansorgei., Methods: Retinas of adult A. ansorgei were processed for histology, electron microscopy and immunohistochemistry using rod- and mouse cone-specific antibodies. For phagocytosis studies, retinas were sampled every 3 hours under a 12-hour light-dark cycle and processed for double-label immunohistochemistry. The number of phagosomes in the retinal pigmented epithelium were quantified with a morphometric system., Results: A. ansorgei retinas were composed of 33% cones and 67% rods, approximately 10 times more cones than mice and rats. Cones were arranged in two cell layers at the scleral surface, distributed uniformly across the entire retina. Cone arrestin was distributed throughout the dark-adapted cones, from outer segments to synapses, whereas short- and mid-wavelength cone opsins were restricted to outer segments. Short-wavelength cone density was mapped in wholemounted retinas, in a significantly higher number in the central region. Rhodopsin immunopositive (rod) phagosomes showed a small peak late in the dark phase, then a large burst 1 to 2 hours after light onset, after decreasing to low baseline levels by 12 AM. Mid-wavelength cone opsin immunopositive (cone) phagosomes were 10 times less numerous than rods, and demonstrated a broad peak 1 to 2 hours after light onset., Conclusions: The diurnal rodent A. ansorgei possesses a large number of cones, organized in a strict anatomic array. Rod and cone outer segment phagocytosis and shedding can be monitored simultaneously and show similar profiles but different amplitudes. This species may constitute a valuable novel animal model for investigating cone pathophysiology.

We compared the visual detection thresholds for cone-isolating stimuli of trichromats (those with normal color vision) with those of X-linked dichromats, who lack either the long-wavelength-sensitive (L) cones (protanopes) or middle-wavelength-sensitive (M) cones (deuteranopes). At low (1 Hz) temporal frequencies, dichromats have significantly higher (twofold) thresholds for all colored stimuli than trichromats; whereas at high (16 Hz) temporal frequencies, they perform as well or better than trichromats. The advantages of dichromats in detecting high temporally modulated targets can be related to an increased number, through replacement, of the remaining L- or M-cone type. However, their disadvantages in detecting low temporally modulated targets, even in directions of color space where their increased number of cone photoreceptors might be expected to be beneficial, are best explained in terms of the loss of L-M cone opponency and the inability of the visual pathways to reorganize to allow the detection of low-frequency luminance modulation.

Purpose: A prior study showed that some patients with fundus albipunctatus (FA) have severely reduced full-field cone ERGs. The purpose of this study was to investigate the frequency of cone dysfunction and to determine the cause of the reduced full-field cone ERGs in patients with FA and whether the rod system is affected in patients with FA., Methods: Sixteen consecutive patients with FA (from 1993 to 2003; eight males, eight females; mean age, 25.4 years) with an RDH5 gene mutation were studied. The amplitudes and implicit times of the standard cone ERGs in the patients with FA were compared to those obtained from normal subjects (n = 55). The a-waves of cone ERGs were also elicited by a bright flash and were fitted to a mathematical model of the a-wave. Rod ERG responses were elicited by dim blue flashes after 3 hours of dark adaptation., Results: The amplitude of the b-wave of the cone ERG in the FA group varied considerably from within the normal limits to markedly decreased. Six of 16 patients with FA had b-wave amplitudes that were smaller than the lowest limit of the control subjects. The degree of cone dysfunction tended to be more severe in older patients. The analysis of the cone a-wave demonstrated that R(m) (maximal response amplitude) in the patients with FA with reduced standard cone ERGs was significantly smaller than that in control subjects. Rod ERGs were also reduced in the patients with FA who had reduced cone ERGs., Conclusions: In patients with FA, 38% had extensive cone dysfunction. The reduced full-field cone ERGs were mainly due to the loss of cone photoreceptors, and the rod system was also affected in some patients.

Purpose: To investigate the onset of retinal neural dysfunction in the streptozotocin (STZ)-induced diatebic rat., Methods: A cohort of 20 Sprague-Dawley rats were randomly assigned to treatment (STZ 50 mg/kg, n = 10) and control (citrate buffer, n = 10) groups and observed for 12 weeks. Diabetes was confirmed by blood glucose (>15 mmol/L) and HBA(1c) (>7.0%). Treated animals received 2 to 3 U insulin daily. Retinal function was monitored using paired-flash electroretinograms (ERGs) at baseline and various time points between 2 days and 12 weeks after treatment, to allow isolation of rod and cone components. Protocols compared photoreceptor and inner retinal responses (rod and cone) at each time point., Results: Losses in the function of rod photoreceptors and the inner retina were seen 2 days after STZ injection, with recovery in some components by 4 weeks and a secondary loss of function at 12 weeks. Some inner retinal responses (cone response and rod oscillatory potentials (OPs) remained consistently depressed over the entire 12 weeks., Conclusions: Retinal neural dysfunction was observed as early as 2 days after STZ injection. These acute changes reflect either STZ toxicity or hyperglycemia as a result of pancreatic compromise. Consistent loss over the 12 weeks of the cone response and OPs suggests a vulnerability of the inner retina to STZ-related effects. The 12-week losses in function of retinal neurons are consistent with a generalized diabetic neuropathy, since impaired function developed simultaneously in both inner and outer retinal neurons.

Purpose: To determine the molecular basis for phenotypic variability in a three-generation consanguineous family containing a single individual with complete achromatopsia and three individuals with progressive cone dystrophy., Methods: Four affected individuals underwent ophthalmic examination, electrophysiological assessment, color fundus photography, and psychophysical testing. Blood samples were obtained for DNA extraction and mutation screening of the cone-specific cGMP-gated (CNG) channel protein gene CNGB3 was undertaken., Results: The clinical findings in one family member were consistent with a diagnosis of complete achromatopsia, with nystagmus, photophobia, and poor visual acuity from early infancy and complete color-blindness, normal fundi, and absent cone responses with normal rod responses on electroretinography (ERG). Mutation analysis revealed her to be homozygous for the common CNGB3 achromatopsia mutation, 1148delC (Thr383fs). In contrast, the three other symptomatic individuals in the family had findings consistent with progressive cone dystrophy. Their visual problems began later in childhood (ranging from 3 to 14 years of age) and there was evidence of progressive deterioration in cone function. All three had a marked tritanopic color vision defect and fundoscopy revealed bilateral macular atrophy. Electrophysiological testing of these three subjects demonstrated clear evidence of progressive deterioration of cone responses over time; rod responses were normal. All three individuals with this progressive phenotype were found to be compound heterozygotes for the 1148delC (Thr383fs) frameshift mutation and a novel Arg403Gln missense mutation in CNGB3., Conclusions: Mutations in CNGB3, which have been shown to cause achromatopsia, are now shown to be associated with autosomal recessive progressive cone dystrophy. In this study, a novel Arg403Gln mutation was identified, located in the middle of the pore domain of the cone CNG cation channel beta-subunit, which when associated with the nonsense mutation Thr383fs, resulted in progressive cone dystrophy.

Purpose: To determine the extent of rod and cone photoreceptor dysfunction in patients with cone dystrophy using psychophysical and electrophysiological tests., Methods: Ten patients with cone dystrophy participated. Rod and cone system psychophysical thresholds were measured as a function of retinal eccentricity. Bright-flash full-field electroretinograms were obtained under dark-adapted (rod-mediated) and light-adapted (cone-mediated) conditions. The a-wave data were fitted with a model based on photopigment transduction to obtain values for log Rmax (maximum response) and log S (sensitivity). b-Wave parameters were also examined by fitting a nonlinear, saturating function (the Naka-Rushton equation) to the rod-mediated responses. Oscillatory potentials were measured to the cone-mediated high-intensity flashes., Results: On average, the rod-mediated psychophysical thresholds were elevated by 0.5 log unit. These threshold elevations did not differ significantly with retinal eccentricity. In contrast, cone-mediated psychophysical thresholds were elevated up to 3.0 log units. Threshold elevation was greatest in the central retinal locations. For rod-mediated conditions, the a-wave Rmax parameter was significantly reduced in three patients; the a-wave log S parameter was within normal limits. The rod-mediated b-wave Rmax parameter was reduced in six patients; log k was abnormal in one patient. For cone-mediated conditions, the a-wave Rmax parameter was reduced in six patients and the a-wave log S parameter was reduced in two patients. The cone system oscillatory potentials were abnormal in nine patients., Conclusions: Patients with cone dystrophy show different patterns of psychophysical rod versus cone system sensitivity losses with retinal eccentricity. The full-field electrophysiological data indicate that most of the patients had abnormal cone photoreceptor function. Some patients also showed rod photoreceptor abnormalities. The rod system changes were smaller than the cone system changes.

Purpose: To describe the electrophysiological, histologic, and hereditary features of a naturally occurring rat model of cone function loss., Methods: Dark- and light-adapted electroretinograms (ERGs) were used to evaluate retinal function. The thickness and architecture of the retina were observed by light microscopy. The cone density was investigated by wholemount immunocytochemistry. The inheritance pattern was defined by mating with control female rats., Results: In affected rats, light-adapted ERGs were nearly absent, whereas dark-adapted responses were of normal amplitude with delays in b-wave implicit time. Overall retinal structure was normal at the light microscopic level. There was no difference in cone density between control and affected rats. The cone function abnormality is inherited as an X-linked trait., Conclusions: A spontaneous rat mutant was identified that has markedly affected cone function, whereas rod-mediated function is largely spared. The presence of the normal number of cone outer segments indicates that the defect does not involve cone photoreceptor degeneration. This rat model provides a model of X-linked cone dysfunction, and may also be used to examine aspects of rod-mediated visual function in the rat. Further studies are needed to identify the gene that is involved.

Purpose: To investigate whether there is significant selective reduction in short-wavelength-sensitive (SWS) ganglion cell density in early to moderate glaucoma., Methods: Peripheral achromatic resolution acuity (an indirect measure of the underlying midget ganglion cell density) and peripheral chromatic resolution acuity under conditions of blue cone isolation (an indirect measure of the underlying small bistratified ganglion cell density) were measured at 13 degrees eccentricity in four oblique meridians in 15 eyes (mean age, 64.6 +/- 9.6 years) with early to moderate glaucoma. The results from the subjects with glaucoma were compared with those in a group of 17 age-matched normal eyes (mean age, 62.5 +/- 6.6 years)., Results: Mean achromatic resolution acuity across the four locations was significantly lower in the subjects with glaucoma than in the normal subjects (2.92 vs. 4.01 cyc/deg). Mean chromatic resolution acuity across the four locations was also significantly lower in the subjects with glaucoma than the normal subjects (0.78 vs. 0.99 cyc/deg). There was no selective loss of mean SWS acuity in the subjects with glaucoma. Individual location analysis revealed that the chromatic-achromatic resolution ratio was not significantly different in the subjects with glaucoma who had early glaucomatous damage when compared with the normal subjects. The chromatic-achromatic resolution ratio was lower than normal at certain locations in certain individuals with early glaucoma., Conclusions: The results indicate that there is no evidence of significant selective reduction in global SWS ganglion cell density in early to moderate glaucoma. However, there may be selective loss of SWS ganglion cell density at individual locations in individual eyes.

Purpose: Carriers of X-linked retinitis pigmentosa (XLRP) frequently show prolonged implicit times of the flicker electroretinogram (ERG). This study tested the hypothesis that a preferential response attenuation within the cone depolarizing (ON) bipolar cell (DBC) pathway is a major contributing factor., Methods: Light-adapted, full-field ERGs were recorded from 10 XLRP carriers and 12 visually normal control subjects. Fundamental amplitudes and phases of ERG responses to sinusoidally flickering stimuli at temporal frequencies ranging from 8 to 96 Hz were analyzed within the framework of a recent vector summation model of the cone system ERG to test for evidence of a response attenuation within the DBC pathway. In addition, ERG responses to sawtooth flicker were examined for a reduced b- to d-wave amplitude ratio, indicative of ON pathway dysfunction., Results: The carriers' fundamental response phases at 32 Hz correlated significantly with their log ratios of response amplitudes at 32 versus 12 Hz (r = 0.89, P < 0.001) and with their log b- to d-wave amplitude ratios (r = 0.71, P < 0.05), both of which were used as indices of response attenuation within the DBC pathway. A control experiment demonstrated that a reduced sensitivity of cone phototransduction made at most only a minimal contribution to the timing changes in the carriers' flicker ERG responses., Conclusions: The overall pattern of results indicates that a preferential response attenuation within the DBC pathway is the primary source of timing changes in the flicker ERGs of these carriers of XLRP. These findings illustrate the value of analyzing ERG responses to flickering stimuli at multiple temporal frequencies to evaluate mechanisms of disease action in photoreceptor degenerations.

Purpose: To evaluate cone visual function of subjects with age-related maculopathy (ARM)., Methods: Cone thresholds in 16 patients with ARM and 14 age-matched control subjects were compared. All subjects had visual acuity of 6/12 or better in the studied eye. A range of contrast thresholds were measured to evaluate diverse aspects of cone visual function under steady state conditions (spatiotemporal, color and luminance, and photopic sensitivity) or after bleaching (adaptation dynamics)., Results: ARM produced a diffuse loss across all cone steady state visual functions in 31% to 44% of subjects. The adaptation time constant of cone recovery was significantly prolonged in most (69%) ARM eyes. A cross-correlational analysis found adaptational kinetics to be independent of other steady state losses, with cone photopigment regeneration being the most affected visual function in ARM (chi(2) = 4.03, P < 0.05)., Conclusions: The results show that cone-adaptational kinetics are affected in ARM more so than are steady state thresholds. Given that cone recovery is easy to examine in a clinical setting, this test may provide a useful index of photopic function in patients with ARM.

Purpose: To evaluate regional cone dysfunction in retinitis pigmentosa (RP) by recording focal electroretinograms (FERGs) from the central and paracentral retinal regions and to correlate the FERG with perimetric sensitivity losses., Methods: Twenty-three typical patients with RP (age, 18-65 years; visual acuity, 20/100 to 20/20; kinetic visual field by size II/4e, 20-40 degrees ) and eight age-matched control subjects were evaluated. FERGs were recorded in response to either a central (eccentricity, 0-2.25 degrees ) or a paracentral annular (2.25-9 degrees ) field, presented on a light-adapting background. Fields' luminances (mean: 80 cd/m(2)) were sinusoidally modulated at different temporal frequencies (TFs; 10.3, 14, 21, 32, 41, and 52 Hz). Amplitude and phase of the responses' fundamental harmonic (1F) were measured. Perimetric sensitivity was measured by a visual field perimeter. For each patient, mean sensitivity losses were calculated for both the central (0-2.25 degrees ) and paracentral (2.25-9 degrees ) regions., Results: On average, central and paracentral FERGs of patients with RP were reduced in amplitude (P

Purpose: Findings in a previous study have shown that the retina of newborn rats exposed to hyperoxia during the first days of life sustain permanent functional (as determined with the rod ERG) and structural (as determined with histology) damage that appears to be determined by the level of retinal maturity reached at the time of oxygen exposure-the retinas of rat pups being more susceptible to hyperoxic shock during the second week of life than during the first week. Given that the cone ERG has been shown to mature later than the rod ERG, the purpose of the present study was to examine whether cone responses also demonstrates a similar maturational susceptibility to postnatal hyperoxia. Also examined was whether the oscillatory potentials (OPs) were affected by postnatal hyperoxia., Methods: Newborn rats were exposed to hyperoxia during selected postnatal day intervals either initiated at birth (early-onset exposure) or at a later postnatal age (late-onset exposure). Photopic and scotopic (mixed cone-rod) electroretinograms were recorded at 30 days., Results: Data analysis reveals that photopic and scotopic responses (b-wave and OPs) demonstrated a similar maturational susceptibility to postnatal hyperoxia, in which exposure regimens initiated during the second week of life were most detrimental to retinal function. The results also revealed a temporal window of enhanced oxygen susceptibility at approximately postnatal day 10. The duration of this window was longer when estimated with the scotopic responses, but the extent of the functional damage was more pronounced when estimated with the photopic signals. Finally, compared with the b-wave, the OPs, especially the short-latency OPs, were proportionally more affected., Conclusions: The results suggest that cone function is significantly more susceptible to postnatal hyperoxia than rod function, and the OPs appear to be the most susceptible ERG components, thus suggesting a differential susceptibility to oxygen toxicity of the different retinal components. However, despite a clear demonstration of its existence, the exact nature of the temporal window of enhanced oxygen susceptibility as well as a possible equivalence in other animal models of oxygen induced retinopathy, including the human form (retinopathy of prematurity), remains to be determined.

Purpose: To compare the patterns of local cone and rod system impairment in patients with progressive cone dystrophy (CD) using psychophysical and electrophysiological techniques., Methods: Local cone system function was assessed by measuring cone system thresholds (visual fields) and cone-mediated multifocal electroretinograms (mfERGs). Rod system function was assessed by measuring rod system thresholds (visual fields) and rod-mediated mfERGs. The results in a group of eight patients with CD were compared with those in an age-similar control group., Results: All the patients had abnormal cone system visual field thresholds and cone-mediated mfERGs. Cone system psychophysical thresholds were elevated for targets presented within the central 10 degrees, but were within normal limits for targets at peripheral locations. Cone-mediated mfERG measures of amplitude scale and time scale were abnormal for most of the hexagons tested. Most of the rod-mediated psychophysical thresholds and mfERGs were within normal limits. Rod system losses tended to be patchy and scattered throughout the area tested., Conclusions: There was poor correspondence among local measures of cone and rod system losses in these patients with CD. The results suggest that the spatial pattern of cone system losses in this disease differs from the spatial pattern of rod system losses.

Purpose: To establish the basis for an ON-pathway abnormality of the cone system in melanoma-associated retinopathy (MAR) through analysis of the electroretinogram (ERG) and visual evoked potential (VEP)., Methods: Two patients with MAR syndrome whose sera produced immunolabeling of retinal bipolar cells participated in the study. Full-field ERGs were recorded in response to brief flashes, to rapid-on and rapid-off sawtooth stimuli at a temporal frequency of 8 Hz, and to sine-wave stimuli at temporal frequencies ranging from 8 to 96 Hz. Fundamental responses to the sine-wave stimuli were evaluated within the context of a vector-summation model of the depolarizing bipolar cell (DBC) and hyperpolarizing bipolar cell (HBC) contributions to the response fundamental. VEPs were recorded to the onset of luminance increments and decrements that had contrasts of 10%, 20%, and 50%. The patients' results were compared with those of age-similar control subjects., Results: The patients with MAR showed abnormal ERG responses to luminance increments, consisting of a marked attenuation of the initial portion of the b-wave, but their ERG responses to luminance decrements were normal in amplitude and timing. The ERG temporal response functions of the patients with MAR had normal amplitudes at frequencies of 32 Hz and higher, with a constant phase lag across these frequencies, but larger-than-normal amplitudes at frequencies below 32 Hz, and a phase lead at 8 Hz. Their VEP responses showed a marked delay to increments but only a minimal delay to decrements., Conclusions: Within the context of the vector-summation model, the ERG findings in the patients with MAR are more consistent with an attenuation of the DBC contribution to the ERG response than with a DBC response delay. The delayed VEP responses of the patients with MAR to luminance increments may represent a late response of the OFF system to increment onset.

Purpose: To determine the ability of oxygen supplementation to ameliorate the effects of retinal detachment in a cone-dominated retina., Methods: Retinal detachments were created in the right eyes of ground squirrels and the animals immediately placed in normoxic (room air) or hyperoxic (70% oxygen) conditions for 3 days. The retinas were sampled from different regions and investigated morphologically or immunocytochemically by light or confocal microscopy. Agarose embedded sections were immunostained with antibody probes to cytochrome oxidase, synaptophysin, medium-to-long wavelength-sensitive (M/L) cone opsin, rod opsin, excitatory amino acid transporter 1 (EAAT1), glutamate synthetase (GS), cellular retinaldehyde-binding protein (CRALBP), and peanut agglutinin (PNA) lectin. Retinal wholemounts were labeled with PNA and antibodies to short (S)-wavelength-sensitive cone opsin and rod opsin. Cell death was examined using a TUNEL assay on agarose sections or using toluidine blue staining on semithin sections., Results: The percentage of dying cells relative to the total nuclei in the photoreceptor layer was significantly reduced, and the total number of nuclei was greater in hyperoxic animals. Triple labeling using TUNEL, anti-M/L cone opsin and anti-rod opsin showed that hyperoxia had a remarkable effect both on the reduction of cone cell death and the maintenance of the overall structure of cone photoreceptors. Analysis of the retinal wholemounts demonstrated the preservation of PNA, S-cone, and rod opsin antibody labeling in the detachments maintained in hyperoxic conditions. Although the disruption of cytochrome oxidase and synaptophysin was seen in normoxic animals, there was minimal disruption in hyperoxic animals. Labeling with anti-EAAT1, anti-GS, and anti-CRALBP was increased in the Müller cells of normoxic animals with detachments, but was decreased in the hyperoxic animals., Conclusions: Hyperoxia prevents the degeneration of both rods and cones in retinas heavily dominated by cones and mitigates the effect of detachment on Müller cell reactivity. The current results suggest that the rescue of cones is not secondary to that of rods.

Purpose: Individuals with X-linked retinoschisis (XLRS) show a comparatively greater reduction of the ON response than the OFF response of the electroretinogram (ERG) of the cone system. At high temporal frequencies, they also show a marked attenuation of the flicker ERG that has been attributed to an abnormal cone photoreceptor response. The purpose of this study was to determine whether the high-frequency response attenuation contributes to the abnormal ERG ON response in XLRS., Methods: Light-adapted ERGs were recorded from three patients with XLRS and from three control subjects, by using rapid-on and rapid-off sawtooth flicker to emphasize ON and OFF responses, respectively, and by using low-pass sawtooth flicker, from which the high temporal frequencies had been removed to mimic the high-frequency attenuation in XLRS., Results: For the control subjects, removing the high stimulus frequencies reduced the amplitude of the b-wave component of the ON response but had little effect on the amplitude of the d-wave component of the OFF response. In the patients with XLRS, the b-wave component of the ON response was already diminished using the full sawtooth stimulus, and removing the higher stimulus frequencies had no further effect. Patients' ERG responses to the 16-Hz stimulus fundamental alone were also abnormal, in that an initial response component normally present in the ERG was absent., Conclusions: The overall pattern of findings indicates that two factors contribute to the preferential ON-response deficit in XLRS: first, a high-frequency attenuation of the cone photoreceptor response that effectively produces a low-pass stimulus for the postreceptoral pathway and that affects the ON response more than the OFF response and, second, a relatively greater attenuation of the ON- than of the OFF-bipolar cell response that is evident in the aberrant response to the sawtooth fundamental.

Purpose: To compare the sensitivity of the photopic negative response (PhNR) from the shortwave (S)-sensitive and the long (L)- and medium (M)-wave-sensitive cone electroretinograms (ERGs), with the pattern electroretinogram (PERG) in the early stages of primary open-angle glaucoma (POAG)., Methods: Eighteen patients under treatment for diagnosed POAG and 19 normal control subjects were investigated. S-cone ERGs were elicited using adaptation to 650-nm light to suppress L-cone activity, and substitution between 450 nm and 535 nm to silence M-cone response at luminances higher than rod saturation. PhNRs from the L&M-cone pathways were elicited by a 200-msec pulse of red light (650 nm) on a continuous blue (450 nm) background. PERGs were recorded in accordance with the International Society for Clinical Electrophysiology of Vision (ISCEV) standard., Results: Each method showed a statistically significant difference in the two groups. The S-cone PhNR was the most sensitive test and provided the most statistically significant results, with the largest area enclosed by the receiver operating characteristic (ROC) curve., Conclusions: The findings indicate that all three types of ERG may be useful in glaucoma investigation. The L- and M-cone PhNRs may have a role in monitoring established glaucoma. The previously reported high sensitivity of the PERG was confirmed. Extensive diffuse damage to S-cone bipolar and bistratified ganglion cells appears to occur at a very early stage in POAG, owing to a pressure-related mechanism, and the S-cone PhNR was the most sensitive test. It may in future have an important role in diagnosis and monitoring of early glaucoma. Further investigation of this possibility is recommended.

Purpose: To study the dynamics of the long (L)- and middle (M)-wavelength-sensitive cone-driven pathways and their interactions in patients with Stargardt's macular dystrophy-fundus flavimaculatus (SMD-FF) and to correlate them with other clinical parameters and individual genotypes., Methods: Forty-seven patients with SMD-FF participated in the study. In addition to standard 30-Hz flicker electroretinograms (30-Hz fERG), ERG responses were measured to stimuli that modulated exclusively the L or the M cones (L/M cones) or the two simultaneously. Blood samples were screened for mutations in the 50 exons of the ABCA4 gene., Results: Patients with SMD-FF did not show a decrease in the mean L/M-cone-driven ERG sensitivity, but there was a significant increase in the interindividual variability. The mean L-/M-cone weighting ratio was normal. However, the L-cone-driven ERG was significantly phase delayed, whereas the M-cone-driven ERG was significantly phase advanced. These phase changes were significantly correlated with disease duration. The amplitude and implicit time of the standard 30-Hz fERG both correlated significantly with the L/M-cone-driven ERG sensitivity and with the phase difference between the L/M-cone-driven ERGs, indicating the complex origin of the standard 30-Hz fERG. Probable disease-associated mutations in the ABCA4 gene were found in 40 of 45 patients, suggesting that they form a genetically fairly uniform SMD-FF study group. There was no correlation between the genotype and the L/M-cone-driven ERGS:, Conclusions: The changes in L/M-cone-driven ERG sensitivity and phase possibly represent two independent disease processes. The phase changes are similar to those found in patients with retinitis pigmentosa and possibly are a general feature of retinal dystrophies.

Purpose: The purpose of this study was to evaluate the hypothesis that the reduced b-wave to a-wave ratio of the brief-flash electroretinogram (ERG) of the cone system typically observed in X-linked retinoschisis (XLRS) represents a relatively greater deficit in the ON response (response to light onset) than the OFF response (response to light offset). A second purpose was to investigate the use of sawtooth flicker as a stimulus for eliciting ERG ON and OFF responses., Methods: Light-adapted, full-field ERGs were recorded in six patients with XLRS and six age-similar control subjects in response to 8-Hz rapid-on and rapid-off sawtooth flicker to emphasize ON and OFF responses, respectively. ERG responses were analyzed in terms of the amplitudes and implicit times of the a-wave, b-wave, and d-wave components., Results: There was no significant difference between the patients with XLRS and the control subjects for either the amplitude of the a-wave of the ON response or the amplitude of the d-wave of the OFF response. However, the amplitude of the b-wave of the ON response was reduced significantly in the patients with XLRS, resulting in a significantly reduced b-wave to d-wave ratio. The patients' implicit times were increased significantly for all waveform components., Conclusions: The reduced b-wave to d-wave ratio of the ERG of the cone system in these patients with XLRS is consistent with a relative dysfunction of the cone ON bipolar cell pathway in this disorder. The results show further that sawtooth flicker is a promising stimulus for eliciting well-defined ERG waveforms that can provide a quantitative assessment of the properties of ON and OFF responses in retinal disease.

Purpose: To evaluate in glaucomatous eyes the photopic electroretinogram (ERG) negative response (PhNR), a component that follows the b-wave peak and is thought to be correlated with inner retinal activity., Methods: Eleven patients with open-angle glaucoma (OAG) and moderate field loss (Humphrey 30-2 [Humphrey Instruments, San Leandro, CA] mean deviation < or = -6 dB), eight with ocular hypertension (OHT), and eight age-matched normal subjects were tested. Optic discs of patients and control subjects were evaluated by confocal scanning laser ophthalmoscopy. ERGs were recorded to long-duration stimuli (250 msec) of photopic luminance (78 candelas [cd] /m2), presented in the macular region (12 degrees x 12 degrees field size) on a steady, adapting background. Amplitudes of the a-wave and b-wave and the PhNR were measured. Pattern reversal ERGs to 30-minute checkerboards were also recorded from patients and control subjects., Results: Compared with control subjects, patients with OAG showed reduced PhNR (average reduction: 62%, P < 0.01), but normal a- and b-wave amplitudes. In patients with OHT, PhNR and a- and b-wave amplitudes did not differ from control values. In individual patients with OAG, PhNR amplitudes were correlated positively with pattern ERG amplitudes (r = 0.80; P < 0.01) and central (12 degrees) perimetric mean deviations (r = 0.68; P < 0.05) and negatively with cup-to-disc area ratios (r = -0.79; P < 0.01) and cup shape measures (r = -0.78; P < 0.01)., Conclusions: Similar to that found in monkeys with experimentally induced glaucoma, the PhNR is selectively altered in human glaucoma. The correlation between PhNR losses and clinical parameter abnormalities suggests that this component depends on inner retina integrity and may be of clinical value for detecting glaucomatous damage.

Purpose: To evaluate retinal, cone-mediated flicker sensitivity (CFS) in age-related maculopathy (ARM) by quantifying response gain and threshold of the focal electroretinogram (FERG) to flicker modulation., Methods: Nineteen patients with ARM (visual acuity > or =20/30) and 11 age-matched control subjects were examined. Twelve patients had less than 20 soft drusen in the macular region and no hyper-/hypopigmentation (early lesion), whereas seven had more than 20 soft drusen and/or focal hyper-/hypopigmentation (advanced lesion). Macular (18 degree ) FERGs were elicited by a sinusoidally flickering (41 Hz) uniform field (on a light-adapting background) whose modulation depth was varied between 16.5% and 94%. Amplitude and phase of the response's fundamental harmonic were measured., Results: In both control subjects and patients with ARM, log FERG amplitude increased with log stimulus modulation depth with a straight line (power law) relation. However, the slope (or gain) of the function was, on average, steeper in control subjects than in patients with either early or advanced lesions. Mean FERG threshold, estimated from the value of the log modulation depth that yielded a criterion response, did not differ between control subjects and patients with early lesions but was increased (0.35 log units) compared with control subjects in those with advanced lesions. In both patient groups, but not in control subjects, mean FERG phase tended to delay with decreasing stimulus modulation depth., Conclusions: Retinal CFS losses can be detected in ARM by evaluating the FERG as a function of flicker modulation depth. Reduced response gain and phase delays, with normal thresholds, are associated with early lesions. Increased response thresholds, in addition to gain and phase abnormalities, may reflect more advanced lesions. Evaluating CFS by FERG may directly document different stages of macular dysfunction in ARM.

Purpose: To resolve the discrepancy between nonrecordable full-field short wavelength cone electroretinograms (S-cone ERGs) and the presence of normal color vision in patients with the complete type of congenital stationary night blindness (CSNB1)., Methods: Conventional white-on-white (W-W) perimetry, blue-on-yellow (B-Y) perimetry, and the Farnsworth-Munsell 100-hue test were performed in five patients with CSNB1. Diagnosis of CSNB1 was made by clinical and electrophysiological examinations. Twelve normal, age-matched control subjects and an additional 7 normal, highly myopic subjects were tested., Results: Color vision was normal in all the CSNB1 patients by the Farnsworth-Munsell 100-hue test. B-Y perimetry demonstrated that blue cone sensitivity in CSNB1 was normal in the fixation area, but the mean sensitivities of the entire 60 degrees field, the central 0 degrees-to-15 degrees, and 15 degrees-to-30 degrees ring were significantly decreased compared with the normal and myopic subjects. The sensitivity difference between 15 degrees-to-30 degrees and 0 degrees-to-15 degrees in B-Y perimetry increased significantly in CSNB1 compared with both normal and myopic control subjects., Conclusions: Our perimetric results demonstrated that the S-cone function in CSNB1 is preserved only in the fovea and becomes abnormal toward the peripheral retina. This accounts for the normal color vision that tests mainly foveal function and the nonrecordable S-cone ERGs that arise mainly from peripheral retina.

Purpose: To investigate the topography of cone electroretinographic (ERG) responses in the enhanced S cone syndrome (ESCS)., Methods: A 19-year-old female with ESCS who was one of the original cases defining the syndrome was studied. Full-field, focal (Maculoscope) and multifocal (VERIS) ERGs were performed using white light. Multifocal ERG responses were also generated with red and blue stimuli and with a slow m-sequence to elicit off-responses. Results were analyzed by averaging data in rings at increasing eccentricity from the fovea and compared to data recorded identically from a normal subject., Results: The full-field ERG from this patient showed typ ical large slow photopic waveforms and was unchanged from recordings made 9 years earlier. The focal ERG showed signals of borderline low amplitude from the fovea with the multifocal ERG, the ESCS responses from the central macula had a relatively normal waveform, and those 9 degrees to 20 degrees from fixation showed the prolonged wave-form that characterizes the full-field ERG. Responses were larger to blue light than red light in ESCS in both center and periphery. The central ESCS responses were relatively normal in timing to both red and blue light, whereas the peripheral ESCS responses were markedly delayed to both. Off-responses were seen in ESCS only near the foveal center., Conclusions: The marked differences between central and peripheral ERG responses in ESCS suggest that there are different distributions of S, L, and M cones in these regions and that S cones may feed into different neural pathways in the center and periphery. It was postulated that in ESCS, S cones may partially replace L and M cones centrally and feed into the usual S cone pathways. In the periphery, however, there is little L and M cone b-wave activity in ESCS, and S cones may usurp both the space and neural pathways of the rods.

Purpose: To find out how the different cone types contribute to the electroretinogram (ERG) by quantifying the contribution of the signal pathways originating in the long (L-) and the middle (M-) wavelength-sensitive cones to the total ERG response amplitude and phase., Methods: ERG response amplitudes and phases were measured to cone-isolating stimuli and to different combinations of L- and M-cone modulation. Conditions were chosen to exclude any contribution of the short wavelength-sensitive (S-) cones. The sensitivity of the ERG to the L and the M cones was defined as the cone contrast gain., Results: In the present paper, a model is provided that describes the ERG contrast gains and ERG thresholds in dichromats and color normal trichromats. For the X-chromosome-linked dichromats, the contrast gains of only one cone type (either the L or the M cones) sufficed to describe the ERG thresholds for all stimulus conditions. Data suggest that the M-cone contrast gains of protanopes are larger than the L-cone contrast gains of deuteranopes. The response thresholds of the trichromats are modeled by assuming a vector summation of signals originating in the L and the M cones. Their L- and M-cone contrast gains are close to a linear interpolation of the data obtained from the dichromats. Nearly all trichromats had larger L- than M-cone contrast gains. Data from a large population of trichromats were examined to study the individual variations in cone weightings and in the phases of the cone pathway responses., Conclusions: The data strongly suggest that the missing cone type in dichromats is replaced by the remaining cone type. The mean L-cone to M-cone weighting ratio in trichromats was found to be approximately 4:1. But there is a substantial interindividual variability between trichromats. The response phases of the L- and the M-cone pathways can be reliably quantified using the response phases to the cone-isolating stimuli or using a vector addition of L- and M-cone signals.

Purpose: To determine whether the rod and cone photoreceptors are affected in patients with diabetic retinopathy., Methods: Twelve patients with diabetes and varying levels of retinopathy and nine age-similar control observers participated in this study. Two-color (500 versus 650 nm) dark-adapted thresholds were measured as a function of retinal eccentricity. Full-field flash electroretinograms were obtained using brief, high-intensity flashes. Dark-adapted rod-isolated (Wratten 47B filter) and light-adapted cone-isolated (Wratten 26 filter) electroretinographic responses were measured as a function of flash intensity. The a-wave data were fitted with a model based on photopigment transduction to obtain values for the parameters of Rmax (the maximal response) and log S (sensitivity). Standard clinical 30-Hz flicker electroretinographic responses were also measured., Results: Psychophysically measured dark-adapted thresholds were elevated primarily at eccentricities of 5 degrees and 10 degrees from the fovea. Analysis of rod and cone a-wave data showed that Rmax was normal in most of the patients, but log S was reduced. Analysis of b-wave and oscillatory potential parameters showed rod and cone postreceptoral abnormalities, including changes in the rod-isolated semisaturation constant (log k), cone-mediated 30-Hz flicker, and cone-isolated oscillatory potentials. The electrophysiological results were not significantly correlated with blood glucose or glycosylated hemoglobin level., Conclusions: The results provide evidence for rod and cone receptoral and postreceptoral deficits in patients with diabetic retinopathy. The photoreceptor changes are primarily in the log S (sensitivity) parameter and are attributed to transduction abnormalities.

Purpose: To study results of foveal cone electroretinography (ERG) in patients with nonproliferative diabetic retinopathy (NPDR), with and without clinically significant macular edema (CSME)., Methods: Electroretinograms of foveal cones were elicited, with a dual-beam stimulator-ophthalmoscope, from 18 consecutive patients with bilateral NPDR and unilateral CSME., Results: Analysis of resulting data revealed that mean amplitude was significantly lower in eyes with CSME and in eyes without CSME., compared with that in normal eyes. Mean implicit time was significantly longer in eyes with CSME compared with that in normal eyes, but in eyes of diabetic patients without CSME., mean implicit time was the same as that in normal eyes. Amplitudes were directly correlated and implicit times were inversely correlated with best-corrected Snellen visual acuity in eyes with and without CSME. Eyes with CSME had significantly lower amplitudes and longer implicit times than their fellow eyes without CSME. In addition, eyes with NPDR, with or without CSME, did not exhibit the normal rise in amplitude with increasing duration of light exposure., Conclusions: Electroretinographic findings showed abnormalities in foveal cone responses in eyes with NPDR, particularly in the presence of CSME. These results may support a functional role for outer retinal dysfunction in patients with diabetic retinopathy and loss of central vision.

Purpose: To determine whether specific chromatic pathways are selectively affected by short-term variations in blood glucose levels in observers with and without diabetes., Methods: Ten subjects with diabetes, all with type 1 diabetes and no retinopathy, and eight age-similar normal subjects were tested. Cortical visually evoked potentials (VEPs) in response to stimuli designed to selectively activate the short-wavelength-sensitive (S) or long- and middle-wavelength-sensitive (LM) chromatic (isoluminant) pathways or the achromatic pathway were recorded over a period of several hours. Capillary blood glucose also was measured repeatedly over the same period. The relation between VEP latency and blood glucose was determined., Results: The S-pathway VEP latency was correlated significantly with blood glucose in a slight majority (6/10) of persons with diabetes; S-pathway latency was longer at higher blood glucose levels. This association between S-pathway latency and blood glucose was not dependent on the pattern of blood glucose variation over time (i.e., significant correlations between blood glucose and latency were observed in persons for whom blood glucose increased, decreased, or rose and then fell over time). No dependence on blood glucose was observed for LM- or achromatic-pathway VEP latency in subjects with diabetes., Conclusions: Acute variations in blood glucose of subjects with diabetes over hours selectively affect the function of the short-wavelength-sensitive chromatic pathway. The findings are discussed within the context of known mechanisms by which elevated glucose affects cellular metabolism with a time course consistent with the transient nature of the effect observed.

Purpose: To determine the functional defects in two male patients with progressive cone dystrophy and hybrid L-M cone pigment genes., Methods: Clinical evaluation, standard electroretinography, and electrooculography were performed in two affected patients and two family members. Measurements of spectral sensitivity and transient tritanopia were made in both patients., Results: In the patients, visual acuity varied between 20/50 and 20/100. The electroretinogram showed reduced flicker responses. When light adapted, a-wave amplitudes were borderline, but b-wave amplitudes were reduced severely. Electroretinography with chromatic stimuli showed a difference between well-preserved responses to green and markedly reduced responses to red stimuli. Spectral sensitivity measurement revealed a lack of L (long-wavelength sensitive; red) cone function and normal function of the S (short-wavelength sensitive; blue) and M (middle-wavelength sensitive; green) cones. Transient tritanopia was abnormal, indicating a severe disturbance of cone-cone interaction., Conclusions: Progressive cone dystrophy with predominant dysfunction of L cones exists in both patients. The cone dystrophy may be caused by a rearrangement of the X-chromosome pigment gene array that is associated with the deletion of L-cone sequences and the formation of hybrid L-M cone pigment genes. It cannot be excluded, however, that both patients have protanopia and that cone dystrophy developed because of other causes.

Purpose: To understand the sites of macular dysfunction in retinitis pigmentosa by evaluating focal electroretinogram (FERG) fundamental and second harmonic components, which are dominated by the activity of the outer and inner retina, respectively., Methods: FERGs were recorded in response to a uniform field (9 degrees x 9 degrees) flickered sinusoidally at either 8 Hz or 32 Hz. The fundamental components of the responses to both the 8-Hz and 32-Hz stimuli and the second harmonic of the response to the 8-Hz stimulus were measured in their amplitudes and phases. Normal subjects (n = 17), as well as patients with typical retinitis pigmentosa (n = 22), cone dystrophy (CD, n = 7) and X-linked congenital retinoschisis (XLR, n = 5) served as subjects. The fundamental (32-Hz)-second harmonic (8 Hz) amplitude ratio was taken as an index of the relative function of outer-inner layers of the macula., Results: Compared to controls, patients with retinitis pigmentosa showed losses of both FERG fundamental and second harmonic and an increase of the fundamental-second harmonic ratio. Patients with CD also showed losses of both fundamental and second harmonic, but the fundamental-second harmonic ratio was normal. Patients with XLR had a selective loss of the second harmonic, resulting in an increased fundamental-second harmonic ratio. On average, the fundamental-second harmonic ratio of patients with retinitis pigmentosa tended to increase with age., Conclusions: The results suggest that in retinitis pigmentosa, both receptoral and postreceptoral sites contribute to macular dysfunction. This differs from CD and XLR, where losses appear more selective for the outer and the inner retina. Postreceptoral losses in retinitis pigmentosa may become larger with increasing age.

Purpose: Although impaired color vision and ERG changes have been detected in carriers of blue-cone monochromatism (BCM), no eye movement abnormalities have been identified. Quantitative eye movements of three obligate carriers of BCM were analyzed., Methods: Horizontal and vertical eye movements of three obligate carriers of two families with BCM with visual acuity of 20/20 or better were recorded using the magnetic search coil technique. Subjects were examined fixing in primary and eccentric gaze and during horizontal and vertical smooth pursuit at 20 degrees, 40 degrees, and 80 degrees per second., Results: All carriers displayed fixation instability. In two subjects, fine-amplitude upbeat, jerk-type nystagmus was detected. Reduced pursuit gain was found in the carriers. The third subject had small downbeat nystagmus., Conclusion: Abnormal eye movements are described for the first time in carriers of BCM. The nystagmus is clearly distinct from congenital or latent nystagmus and is similar to the nystagmus reported in BCM. Because all carriers had excellent visual acuity, in BCM, nystagmus is intrinsic to the disease and can appear independently of the visual defect.

Purpose: To determine whether short-wavelength-sensitive (S-) cones are more severely damaged in patients with retinitis pigmentosa than long-wavelength-sensitive (L-) and middle-wavelength-sensitive (M-) cones. To determine whether there are differences in the amount of S-cone damage in patients with dominant versus nondominant inheritance patterns. To accomplish these goals with methods that provide information not furnished by previous studies with two-color increment thresholds., Methods: Acuity mediated by the S-cones was measured in 56 patients with retinitis pigmentosa, and the electroretinogram (ERG) generated by the S-cones was measured in 11 of these patients. Mixed L- and M-cone acuity, mixed L- and M-cone ERGs, and clinical full-field rod and cone ERGs were obtained for all patients. Data for both dominant and nondominant patient groups were compared with data from age-matched normal subjects., Results: Only the nondominant group had reduced S-cone acuity, and 43% of patients in this group had selective reduction of S-cone acuity. In this particular sample the dominant and nondominant groups were comparable in clinical full-field ERG parameters and mixed L- and M-cone acuity, so the difference in S-cone acuities is not due to the dominant group having less advanced retinal degeneration. All 11 patients tested had reduced S-cone ERGs, 6 with significantly greater loss in the S-cone ERG than in the mixed L- and M-cone ERG., Conclusions: These data provide evidence that retinitis pigmentosa can produce greater loss of S-cones than L- and M-cones, and that this selective loss is primarily seen in patients with nondominant forms of retinitis pigmentosa.