Photopic ERG Research Articles

Retinoschisin (RS1), the Protein Encoded by the X-linked Retinoschisis Gene, Is Anchored to the Surface of Retinal Photoreceptor and Bipolar Cells through Its Interactions with a Na/K ATPase-SARM1 Complex

Retinoschisin or RS1 is a discoidin domain-containing protein encoded by the gene responsible for X-linked retinoschisis (XLRS), an early onset macular degeneration characterized by a splitting of the retina. Retinoschisin, expressed and secreted from photoreceptors and bipolar cells as a homo-octameric complex, associates with the surface of these cells where it serves to maintain the cellular organization of the retina and the photoreceptor-bipolar synaptic structure. To gain insight into the role of retinoschisin in retinal cell adhesion and the pathogenesis of XLRS, we have investigated membrane components in retinal extracts that interact with retinoschisin. Unlike the discoidin domain-containing blood coagulation proteins Factor V and Factor VIII, retinoschisin did not bind to phospholipids or retinal lipids reconstituted into unilamellar vesicles or immobilized on microtiter plates. Instead, co-immunoprecipitation studies together with mass spectrometric-based proteomics and Western blotting showed that retinoschisin is associated with a complex consisting of Na/K ATPase (alpha3, beta2 isoforms) and the sterile alpha and TIR motif-containing protein SARM1. Double labeling studies for immunofluorescence microscopy confirmed the co-localization of retinoschisin with Na/K ATPase and SARM1 in photoreceptors and bipolar cells of retina tissue. We conclude that retinoschisin binds to Na/K ATPase on photoreceptor and bipolar cells. This interaction may be part of a novel SARM1-mediated cell signaling pathway required for the maintenance of retinal cell organization and photoreceptor-bipolar synaptic structure.

Mathematical analysis of the cone ERG photopic hill: Clinical applications

Abstract Purpose: With brighter stimuli, the photopic ERG b‐wave increases to a maximal value and then decreases to a plateau, a feature known as the Photopic Hill (PH). Recently, a mathematical model combining a Gaussian (GF) and a Logistic Growth (LGF) functions was developed to fit the PH (Hamilton et al., Vision Research, in press). We examined if this equation could help us sort out selected retinopathies. Methods: We compared PHs (background: 30 cd.m‐2; intensities: ‐0.8 to 2.84 log cd.sec.m‐2) obtained from normals (N=40) and patients (N=20) affected with Congenital Stationary Night Blindness (CSNB), Congenital Postreceptoral Cone Pathway Anomaly (CPCPA) and Retinitis Pigmentosa (RP) with the GL ratio [GL= Gb / (Gb+Vbmax)] were Gb and Vbmax represent the amplitude of the Gaussian and logistic (Vbmax) functions respectively. Results: The normal GL ratio is 0.60 ± 0.08 (mean ± 1SD) compared to ≈1.0 in CSNB (almost pure GF) and 0.32±0.08 in CPCP [reduced GF (p<.05) and normal LF (p>.05)] patients. Six of the 8 RP patients had a GL ratio above 0.5 (mean GL= 0.70 ± 0.19) and 2 below (0.28 and 0.41). Of interest, while in some retinopathies, a decline in Gb and Vbmax occurred with disease progression (longitudinal and transversal comparisons), it did not always modify the GL ratio. Conclusions: Human PH can be dissected into two distinct and concomitant phenomena each represented by its own equation. Altghough the retinal origin of the GF and LGF awaits to be confirmed, use of this mathematical approach appears to add valuable information that will further refine the diagnosis of retinal disorders affecting the photopic (cone) pathway. Supported by CIHR and Réseau Vision.

Clinical management of congenital achromatopsia

Abstract Purpose: Describe the long term follow‐up of children affected by congenital achromatopsia (CA). CA is a rare recessive inherited vision disorder (1:50000) and includes two clinical categories: complete CA and incomplete CA. Methods: Fourteen children (9 M, 5 F) were followed‐up and a rehabilitation individual program was carried out.The assessment included: far and near visual acuity (Teller, Lea Symbols, Snellen Charts),refraction, color vision (Farnsworth, Ishihara, Montessori), contrast sensitivity, visual field, slit lamp examination, fundus ophthalmoscopy, electrophysiologic tests (photopic, scotopic and flicker ERG and VEPs) and genetic examination. Results: Early onset of nystagmus, low vision and photophobia are first clinical manifestations of CA. The differential diagnosis includes Leber Amaurosis, and congenital nystagmus and albinism.Visual acuity in our patients is around 1/10 and it is worse for near. Refractive errors showed a distribution toward hyperopia (50%) and emmetropia (35%). Macular hypoplasia is present in all cases and electrophysiology showed a reduced or absent photopic ERG, while scotopic system appears normal. Conclusions: Due to abnormal or totally absent cone function, which lead to macular hypoplasia, CA shows reduced visual acuity, absent/severely impaired color vision, nystagmus and photophobia. Low vision aids such as telescopic systems and magnification devices along with OCR/ICR software were prescribed after a carefully evaluation. Spectral filters were early prescribed to reduce photophobia and improve vision.The molecular analysis may confirm the diagnosis and give genetic couseling to the family. An early detection of CA is underlined by the importance to carry out a complete and precocious rehabilitative approach.

Is AZOOR an autoimmune disease?

Abstract Purpose: Acute zonal occult outer retinopathy (AZOOR) is one of the "white dot syndromes" a clinically heterogeneous group of inflammatory chorioretinopathies. The etiology is not yet clear. Methods: We present a 50 years female patient with a prior history of migraine. She experienced progressive visual loss and visual field defects in the last 3 years. Preceding each episode she experienced blue flickering photopsias. Results: Visual acuity was 0,3 in the right eye and 0,6 in the left eye. Biomicroscopy showed a normal anterior segment, fundus exam revealed pigment epithelial atrophy more pronounced in the worse eye. Electrophysiology showed a marked reduction in the photopic ERG in the more affected eye. MRI demonstrated multiple white matter lesions including a corpus callosum location. Lumbar puncture showed oligoclonal bands. Further tests demonstrated hearing impairment.Therapy was instituted during the three years course of the disease with steroids, immune suppressants and plasmapheresis with visual loss being progressive. New photopsia is currently present. Conclusions: The etiology of AZOOR remains unclear. With our patient being one of the few described in the literature with concomitant multiple sclerosis, the question remains on whether there is an underlying common process of inflammatory autoimmune reactions. Whether treatment is possible, remains to be evaluated.

Which color vision test should be used in progressive cone dystrophy?

Abstract Purpose: The early manifestation of progressive cone dystrophy (COD) can remain unrecognized due to the relatively normal macular appearance. Color vision testing can be very useful as a first diagnostic step. The many available color vision tests have different benefits and shortcomings. We aimed to identify which test would be preferred to use in a clinical setting as a first step towards diagnosis of COD. Methods: We compared patients (n=18) derived from the ophthalmogenetic unit of Erasmus Medical Center and University Medical Center Nijmegen, with various levels of cone dysfunction. Golden Standard for diagnosis of COD was a diminished photopic ERG and a relative central scotoma on Goldmann perimetry. Controls (n=33) were patients from these clinics with other diagnoses or healthy companions of COD patients. We estimated sensitivity and specificity of the Ishihara test, Lanthony Desaturated and Saturated Panel D15 test, the Hardy‐Rand‐Rittler (HRR) pseudo‐isochromatic plates, and the Nagel anomaloscope. We analyzed sensitivity, specificity and the predictive value with receiver operating characteristic curve (ROC). Results: The HRR test had the highest sensitivity and specificity for protan and deutan axes. HRR and Ishihara had the highest predictive value. Lanthony Panel D15 test did not have an additional predictive value for severe color vision defects. The Nagel anomaloscope was not reliable due to low specificity. Its results showed high variations among both healthy and afflicted individuals. Conclusions: The HRR test was the most useful for COD. This test had the highest sensitivity in detecting early dysfunction of all three cone types, and it adequately quantifies the level of cone dysfunction in the course of the disease.

Eccentricity-dependent changes in local onset and offset responses in patients with progressive cone dystrophy

Shinoda and colleagues hypothesized that patients with cone dystrophy (CD) might suffer from a selective ON-system deficit, based on the local nature of the disease [Shinoda, K, Ohde, H, Inoue, R, Ishida, S, Mashima, Y, & Oguchi, Y (2002). ON-pathway disturbance in two siblings. Acta Ophthalmologica Scandinavica, 80, 219–223]. The purpose of the current study was to test this hypothesis by examining onset and offset responses as a function of eccentricity in a group of patients with CD using long-duration LED stimuli. Nine patients with CD participated in this study (mean age of 36.1 years and visual acuity ⩾20/200). For this study, the following measures were obtained: Humphrey threshold visual fields, standard multifocal ERGs (mfERGs) as well as mfERGs to long duration stimuli recorded using the Retiscan stimulator (Roland Instruments). This display contained 61 scaled hexagons and the LEDs were on for 100 ms (180 cd/m 2) and off for 100 ms. In addition, standard full-field photopic and flicker ERGs using Ganzfeld stimulation were obtained. For the control subjects, the onset responses were larger than the offset responses at all eccentricities; whereas for the patients, there was overlap between the amplitudes of the onset and offset responses. For the patients, the amplitude ratios (relative to the control data) indicated that the difference between the onset and offset responses was greatest for the central-most ring and this difference decreased with increasing eccentricity. For the onset responses, Humphrey thresholds and mfERG amplitudes, performance was poorest for the center ring and best for the most peripheral ring; for the offset responses, the opposite pattern of results was obtained. The differences in the pattern of results in the long duration mfERG data are consistent with a selective loss of the onset responses in our patient population.

Antioxidants slow photoreceptor cell death in mouse models of retinitis pigmentosa

Retinitis pigmentosa (RP) is a heterogeneous group of diseases in which one of a wide variety of mutations selectively causes rod photoreceptor cell death. After rods die, cone photoreceptors gradually die resulting in blindness. Antioxidants reduce cone cell death in rd1/rd1 mice indicating that cones die from oxidative damage in that model of rapidly progressive RP. In this study, we sought to determine if this observation could be generalized to models of other types of RP, rd10/rd10 mice, a model of more slowly progressive recessive RP, and Q344ter mice, a model of rapidly progressive dominant RP. Compared to appropriate vehicle-treated controls, rd10/rd10 and Q344ter mice treated between P18 and P35 with a mixture of antioxidants previously found to be effective in rd1/rd1 mice showed significantly greater cone survival. Antioxidant-treated rd10/rd10 mice showed preservation of cone function as shown by a significant increase in photopic ERG b-wave amplitudes, and surprisingly showed temporary preservation of scotopic a-wave amplitudes, prolonged rod survival, and slowed depletion of rhodopsin mRNA. These data suggest that oxidative damage contributes to cone cell death regardless of the disease causing mutation that leads to the demise of rods, and that in more slowly progressive rod degenerations, oxidative damage may also contribute to rod cell death. Protection from oxidative damage may be a broadly applicable treatment strategy in RP.

Negative ERGs in mucopolysaccharidoses (MPS) Hurler–Scheie (I-H/S) and Hurler (I-H)-syndromes

The configuration and progression of the ERG in two children with mucopolysaccharidosis (MPS) I H/S (Hurler-Scheie syndrome) and MPS I H (Hurler syndrome) is described. Physical examination, biochemical analysis, ophthalmic examination and electroretinography were performed. The Hurler-Scheie patient (case 1) showed negative scotopic but normal photopic ERGs, which remained unchanged over 2 years. The Hurler patient (case 2) showed negative scotopic and photopic ERGs which did not alter after bone marrow transplantation (BMT). One year after BMT, further b-wave amplitude reduction had caused the ERGs to become more negative. The electronegative configuration of the ERGs suggests that, in these cases of MPS, the primary retinal abnormality in MPS I may be faulty synaptic transmission from photoreceptors to more proximal elements, deficient bipolar responsivity, or Muller cell disease. Further degradation with time suggests the defect to be progressive with BMT causing little or no improvement. In the Hurler-Scheie syndrome case, the defect appears to spare the cone system and to show little or no progression.

Effect of spatial frequency of stimulus on focal macular ERGs in monkeys

To determine the effect of the spatial frequency of a small grating stimulus centered on the macula on the focal macular ERGs (fmacERGs) of monkeys. fmacERGs were recorded from eight eyes of four adult monkeys (Macaca fuscata). The spatial frequency of the stimulus was changed from 0.25 to 8 cycles/degree. The luminance of the light bars was 10 cd/m(2), and the contrast was 95%. The stimulus was flashed on and off with an on duration of 100 ms and an off duration of 150 ms (4 Hz). The stimulus was centered on the fovea and subtended 12.7 degrees at the cornea. The luminance of the steady light-adapting background was 3.5 cd/m(2). The location of the stimulus on the retina was monitored throughout the recordings. The effects of the spatial frequency of the stimulus on the amplitudes and implicit times of the a-waves, b-waves, and oscillatory potentials (OPs) were determined. fmacERGs were also recorded following intravitreal tetrodotoxin (TTX). The amplitudes of the a- and b-waves did not change with changes in the spatial frequency of the stimulus. The OPs, on the other hand, responded best to the lowest spatial frequency, and the OPs after the first two were attenuated at intermediate and higher frequencies (Wilcoxon signed-rank test: P < 0.05). TTX reduced all OP wavelets in monkeys. The OPs of the photopic macular ERGs are affected by the spatial frequency of the stimulus and are reduced by TTX, consistent with their being generated by inner retinal neurons.

Ames Waltzer Deaf Mice Have Reduced Electroretinogram Amplitudes and Complex Alternative Splicing ofPcdh15Transcripts

Mutations of PCDH15, the gene encoding protocadherin 15, cause either nonsyndromic deafness DFNB23 or Usher syndrome type 1F (USH1F) in humans and deafness with balance problems in Ames waltzer (av) mice. Persons with USH1 usually begin to exhibit signs of retinitis pigmentosa (RP) in early adolescence, but av mice are reported to have functional retinas. In this study, the auditory, visual and molecular biological phenotype of Pcdh15av-5J and Pcdh15av-Jfb mice is characterized, and their usefulness as animal models of USH1 is evaluated. Hearing thresholds of mice between 6 and 10 weeks of age were measured by auditory brain stem response (ABR). Immunohistochemistry and histology were used to examine the effect of homozygosity of Pcdh15av-5J on stereocilia bundles of inner ear hair cells and on the photoreceptor cells of the retina. Scotopic and photopic Ganzfeld ERGs were recorded from homozygous Pcdh15av-5J and Pcdh15av-Jfb mice at different ages. Heterozygous littermates served as control subjects. Measurements of the width of the outer nuclear layer (ONL) and the length of rod photoreceptor outer segment (ROS) were made. Homozygous Pcdh15av-5J mice have profound hearing loss and disorganized stereocilia bundles of inner ear hair cells. Compared with heterozygous littermates, homozygous Pcdh15av-5J and Pcdh15av-Jfb mutant mice had scotopic ERG amplitudes consistently reduced by approximately 40% at all light intensities. The b-to-a-wave ratio confirmed that the a- and b-waves were reduced proportionally in homozygous mutant mice. Histologic measurements of retinal sections revealed no significant differences in either the ONL width or the ROS length as a function of genotype. The protocadherin 15 labeling pattern with antisera PB303 in the retina of both heterozygous and homozygous Pcdh15av-5J mice was indistinguishable from the wild type. Wild-type Pcdh15 have many alternatively spliced isoforms. A novel isoform was found in the retina of homozygous Pcdh15av-5J mice, which appears to circumvent the effect of the mutant allele (IVS14-2A-->G), which causes skipping of exon 14, a shift in the translation reading frame and a premature stop codon in exon 15. Pcdh15(av-5J) and Pcdh15(av-Jfb) mice do not faithfully mimic the RP found in USH1 due to mutations of PCDH15, but have significantly attenuated ERG function in the absence of histologic change. The decline in ERG amplitude with a preserved b-to-a-wave ratio suggests a role for Pcdh15 in retinal function and/or generation of the ERG potentials. Understanding the molecular mechanism by which av mice circumvent degeneration of the retina might offer insights into potential therapies for USH1.

ON- and OFF-response of the photopic electroretinogram in relation to stimulus characteristics

The aim of this study was to explore the effect of stimulus duration, stimulus intensity, stimulus wavelength and background luminance on the amplitude and waveform of the ON- (b-wave) and OFF- (d-wave) response of the photopic ERG. The following parameters were used in this study: stimulus duration from 5 to 200 ms, the flash intensities from 0.4 to 2.1 log cd s/m2, the background luminance from 20 to 50 cd/m2 and stimulus wavelengths 460, 508 and 667 nm. Prolonging the stimulus duration from 75 to 200 ms did not influence the amplitudes of a-, b- and d-waves significantly. Higher stimulus intensities (1.9 log cd s/m2) broadened the b-wave and increased variability of its implicit time. With a brighter background (50 cd/m2) the b-wave did not broaden and its optimal amplitude was preserved. Stimuli of longer wavelengths (667 nm) significantly reduced the d-wave amplitude. Our results suggest that high intensities and longer wavelengths (red) may not be suitable stimulus parameters in the routine clinical ON- and OFF-response recording.

The Gradient of Retinal Functional Changes during Acute Intraocular Pressure Elevation

To characterize retinal function during a period of acutely elevated intraocular pressure (IOP) across a wide range of IOPs, including those typically observed in animals with experimental glaucoma. Unilateral elevation of IOP was achieved manometrically in adult Brown Norway rats (nine experimental groups; n=4-7 in each; 10-100 mmHg and sham control). Full-field ERGs were recorded simultaneously from treated and control eyes, beginning 75 minutes after IOP elevation. Scotopic ERG stimuli were brief white flashes (-6.1 to 2.7 log cd-s/m2). Photopic ERGs were recorded (1.2-2.7 log cd-s/m2) after 15 minutes of light adaptation (150 cd/m2). Relative amplitude (treated/control, %) of ERG components versus IOP was described with a cumulative normal function. Resting IOP was 12.1 +/- 2.8 mmHg and mean femoral artery pressure was 97.6 +/- 10.7 mmHg. ERG components showed a graded effect dependent on IOP. Systematic delays in the timing of the scotopic threshold response (STR) and photopic b-wave were observed between IOPs of 30 and 40 mmHg. Analysis of amplitudes revealed that the negative STR component (nSTR) and the photopic OPs were the most sensitive to acute IOP elevation. These components were first significantly affected at 50 mmHg, whereas all parameters of middle and outer retinal function (scotopic P2 and P3) remained normal. The nSTR and photopic OPs declined by 50% at IOP <61 mmHg. The scotopic P2, OPs, and positive STR (pSTR) had intermediate sensitivity, such that they were reduced by 50% at IOPs between 61 and 66 mmHg. Scotopic P2 amplitude, but not sensitivity, was significantly reduced by 60 mmHg. At 60 and 70 mm Hg, the decline in P2 amplitude was not attributable to changes in photoreceptor response (P3) amplitude or sensitivity. The least sensitive component was the scotopic a-wave (RmP3) showing a 50% reduction at an IOP of 71 mmHg. During acute IOP elevation, functional changes progress from the proximal to the distal retina. Alterations in ganglion-cell-related ERG potentials occurred at IOPs (30-50 mmHg) commonly observed in rat experimental glaucoma models. Nonspecific functional changes were observed at acute IOP above 50 mmHg, suggesting that IOP should be maintained below this level in experimental glaucoma models if selective ganglion cell injury is to be sought. Repeated IOP spikes above this level may cause permanent, nonspecific damage, perhaps via ischemic mechanisms. Thus, IOP should be monitored frequently in these models.

Splicing site mutation of D19S418 in PRPF-31 gene and its phenotypic characters with autosomal dominant retinitis pigmentosa

To evaluate the disease-causing gene and phenotypic characters of a large family with autosomal dominant retinitis pigmentosa (adRP). Disease status and associated ocular abnormalities of eight patients and six unaffected members who represent different generations of this family were assessed by measurement of visual psychophysics, full-field and multifocal electrophysiology (ERG and mfERG) and funds fluorescent angiography (FFA). The DNA samples of nineteen patients and fifteen unaffected individuals in this family were examined by Genome scanning, linkage analysis and mutation detection to identify coding sequence changes. A case with variable, early onset night blindness before 10 years and visual field loss in their teens was found. Macular dystrophy, progressing to a retinitis pigmentosa phenotype was demonstrated in most adult cases. Both a-wave and b-wave amplitudes of photopic and scotopic full-field ERG were marked reduced and nearly non-detectable, demonstrating severe damage of photoreceptor systems. There were two obligate gene carriers in the family which remained asymptomatic in the clinical. But one of them was found with a minimal RP characteristic and the other was normal by examination of fundus and ERG. An unreported splicing site mutation (IVS5-1G > A) was identified in intron 5- acceptor site of PRPF-31 gene on chromosome 19. ERG and molecular genetic findings were consistent with the reclassification of this disease as an autosomal dominant RP. It is a novel splicing site mutation that IVS5-1G > A of D19S418 site in PRFP31, the relative phenotypes by which main displayed type I/diffuse has variable expressivity and complex phenotype.

Monocromatismo de conos azules ligado a X: Una familia afecta

A family affected by X-linked blue cone monochromatism is presented. There are 4 male affected individuals and 9 female carriers. The diagnosis of blue cone monochromatism is based on severely affected color vision with preserved blue function, poor visual acuity, nystagmus, nearly absent photopic ERG, and a family pedigree compatible with X-linked inheritance. The female carriers showed normal visual function and ocular motility. It is important to be familiar with non progressive cone dysgenesis in order to make a genetic diagnosis of the illnesses in this group.

Luminance dependence of neural components that underlies the primate photopic electroretinogram.

At lower stimulus intensities, the amplitude of the photopic flash ERG b-wave increases with increasing stimulus intensities, but then plateaus and decreases at higher stimulus intensities (the "photopic hill"). The purpose of this study was to determine the mechanism underlying this unusual phenomenon. Five adult monkeys (Macaca mulatta and M. fascicularis) were studied. Stimuli were obtained from xenon strobe flashes, and the intensity was reduced by neutral-density filters in 0.4-log unit steps. N-methyl-D-aspartic acid and tetrodotoxin citrate (NMDA+TTX) were used to suppress inner retinal activities and L-2 amino-4-phosphonobutyric acid (APB) and cis-2,3 piperidine dicarboxylic acid (PDA) to block postreceptoral ON- and OFF-pathway activities. The postsynaptic ON- and OFF-components were isolated by subtracting the postdrug ERGs from the predrug ERGs. The intensity-response curve of the photopic b-wave obtained after the intravitreal injection of TTX+NMDA had the same shape as a photopic hill, suggesting that the contribution from the inner retinal neurons to the photopic hill is not significant. At low and intermediate intensities, the photopic b-wave was mainly shaped by the overlapping of two positive peaks from the ON- and OFF-components. However, the amplitude of the positive peak from the ON-component became smaller and broader at higher stimulus intensities. In addition, the timing of the positive peak of the OFF-component was gradually delayed with increasing intensities. After APB+PDA, the remaining cone photoreceptor component contributed only to the negative a-wave at all stimulus intensities. The photopic hill in the primate ERG results mainly from two factors: the reduction of the ON-component amplitude at higher intensities and the delay in the positive peak of the OFF-component at higher intensities.

Longitudinal changes in photopic OPs occurring with vigabatrin treatment.

Vigabatrin (gamma-vinyl-GABA) is an antiepileptic drug successful in the management of infantile spasms. Photopic ERGs were tested in children followed longitudinally before and during vigabatrin treatment. Subjects were 26 infants (age range 1.5-24 months, median 7.6 months) on vigabatrin treatment who had been tested on multiple visits (two to four visits; mean, three visits). Eighteen of these were assessed initially before starting vigabatrin therapy and eight were assessed within 1 week of initiation of the drug. ERGs were recorded at 6-month intervals. Standard ISCEV protocol with Burian-Allen bipolar contact-lens electrodes (standard flash 2.0 cd.s/m2) was used. Although ISCEV standards were followed, a higher flash intensity (set at 3.6 cd.s/m2) was chosen for single-flash cone assessment to provide a better definition of OPs. Photopic OPs were divided into categories of early OPs and late OP (OP4). Responses were compared with age corrected limits extrapolated from our lab control database. Results showed differential effects of vigabatrin on the summed early OP amplitudes versus the late OP (OP4) and cone b-wave amplitude. The early OPs showed significant decrease (p = 0.0005, repeated measures analysis of variance) after 6 months and remained decreased for the duration of treatment. There was no significant change seen in the late OP. The cone b-wave amplitude showed initial increase (p = 0.04) after 6 months, followed by a decrease after 18 months; a trend similar to that of the late OP. Early photopic OPs were disrupted more than the late OP, suggesting relative deficit in the ON (depolarizing) retinal pathways.

Regional variations in local contributions to the primate photopic flash ERG: revealed using the slow-sequence mfERG.

To determine the variations with eccentricity of the primate photopic ERG and to separate contributions by different retinal cells by using intravitreal pharmacologic agents. Slow-sequence multifocal (mf)ERGs were obtained from 19 anesthetized adult rhesus monkeys and 5 normal human subjects. Recordings in monkeys were obtained before and after injections of tetrodotoxin citrate (TTX) to block sodium-dependent spiking; TTX+N-methyl-D-aspartic acid (NMDA)+picrotoxin (PTX) or gamma-aminobutyric acid (GABA) to block all inner retinal activity; L-2 amino-4-phosphonobutyric acid (APB) to block the On-pathway; and cis-2, 3 piperidine dicarboxylic acid (PDA) to block the Off-pathway and the otherwise unblocked inner retinal activity. The stimulus consisted of 103 equal-sized hexagons within 17 degrees of the fovea; every 200 ms (15 frames), each hexagon had a 50% chance of remaining at 20 cd/m(2) or increasing briefly to 4.7 cd-s/m(2). Oscillatory potentials (OPs; 90-300 Hz) were extracted. The slow-sequence mfERG summed over the stimulated area looked similar to a standard photopic, full-field ERG, with a- and b-waves and OPs. OPs in the foveal and temporal retina were larger than in the nasal retina. This nasotemporal asymmetry was removed by TTX, and the OPs were eliminated, either by blocking inner retina activity or by blocking the On-pathway. The summed mfERG waveform, including OPs, was shaped mainly by the more peripheral retinal regions. The foveal b-wave peak occurred about 5 to 6 ms later than in the periphery, with the depolarizing peak of the On-pathway/bipolar contribution occurring earlier than the depolarizing peak of the Off contribution at all eccentricities. The a-wave was composed of a small photoreceptor contribution and postreceptoral portion originating from hyperpolarizing neurons. The variations in the primate photopic ERG with eccentricity are due to spike-driven oscillatory activity that is more prominent in central and temporal retina than in nasal retina and to the slower timing of all responses in the central, compared with the peripheral, retina. The full-field, photopic ERG most closely resembles the mfERG responses to stimulation of peripheral regions.

The photopic ERG luminance-response function (photopic hill): method of analysis and clinical application

With progressively brighter stimuli, the amplitude of the photopic b-wave first increases, briefly saturates and then decreases gradually to reach a plateau, where the amplitude of the b-wave equals that of the a-wave; a phenomenon previously presented as the photopic hill. The unique presentation of this luminance-response function seriously complicates its analysis with curve fitting equations such as that of Naka–Rushton used for scotopic electroretinogram. We report a method of analysis of the photopic hill based on easily identifiable and reproducible features of the ascending and descending limbs of this function. The clinical usefulness of these parameters is illustrated with selected cases of retinal disorders.

RDH5 gene mutations and electroretinogram in fundus albipunctatus with or without macular dystrophy: RDH5 mutations and ERG in fundus albipunctatus.

The aim of this study was to analyze the RDH5 gene in patients with fundus albipunctatus with and without macular dystrophy, and correlate the identified mutations with the electrophysiological results. Twenty-one patients from 19 unrelated Japanese families with fundus albipunctatus were examined. Ten unrelated patients had macular dystrophy. In 18 patients, either a homozygous or a compound heterozygous mutation in the RDH5 gene was identified. The bright-flash, mixed rod-cone ERG had a negative configuration with reduced a-wave amplitudes after a short period of dark-adaptation (20 or 30 min). After a prolonged dark-adaptation period (2 or 3 h), the waveform attained normal amplitudes in patients without macular dystrophy but the a-waves were still subnormal in patients with macular dystrophy. The photopic ERG responses were significantly reduced in patients with macular dystrophy, indicating that they also had cone dystrophy. The photopic ERGs were reduced in only some of the patients without macular dystrophy. In patients without macular dystrophy, the scotopic b-wave amplitudes were nonrecordable or significantly reduced after a short dark-adaptation period but then improved to normal levels. However, they did not fully recover in some patients with macular dystrophy. Three patients with macular dystrophy in whom a RDH5 gene mutation could not be detected by our routine method had atypical ERG responses. We conclude that RDH5 gene mutations cause a progressive cone dystrophy or macular dystrophy as well as night blindness. The clinical phenotype including electrophysiological responses varied among patients with the RDH5 gene mutations.

The human photopic ERG luminance-response function: Analysis, interpretation and application

The human photopic ERG luminance-response function: Analysis, interpretation and application