Cone A-wave Research Articles

The photopic negative response of the flash electroretinogram in retinal vein occlusion

The photopic negative response (PhNR) has recently been shown to be severely affected in central retinal artery occlusion (CRAO), despite relative preservation of the cone b-wave compared to that in the healthy unaffected fellow eye. The aim of this study was to test how the PhNR of the flash electroretinogram (ERG) is affected in human retinal vein occlusion. PhNR was elicited with red stimuli (1 cd s/m2, 5 cd s/m2, and 7 cd s/m2 with 4 ms duration) and blue background (10 cd/m2). Standard Ganzfeld flash ERG was produced according to the ISCEV standard for the clinical electroretinogram (2004). Sixteen patients with central retinal vein occlusion (CRVO), 14 patients with branch retinal vein occlusion (BRVO), and 16 controls were analyzed. The amplitude of the PhNRs was significantly smaller in the CRVO and BRVO eyes than those in the unaffected fellow or control eyes (p = 0.000). There was a significantly greater reduction of PhNR amplitudes than that of other waves including the OPs, rod b-wave, combined a-wave and b-wave, cone a-wave and b-wave, and 30 Hz flicker ERG. Thus, PhNR amplitude in retinal vein occlusion is severely affected. There is a potential role for PhNR in assessing inner retinal damage and evaluating the effect of treatment.

Origin of electroretinogram amplitude growth during light adaptation in pigmented rats

We assessed the growth of the rat photopic electroretinogram (ERG) during light adaptation and the mechanisms underlying this process. Full field ERG responses were recorded from anesthetized adult Brown-Norway rats at each minute for 20 min of light adaptation (backgrounds: 1.8, 2.1, 2.4 log scotopic cd m(-2)). The rat photopic b-wave amplitude increased with duration of light adaptation and its width at 33% maximal amplitude narrowed (by approximately 40 ms). These effects peaked 12-15 min after background onset. The narrowing of the b-wave reflected steepening of the b-wave recovery phase, with little change in the rising phase. OP amplitudes grew in proportion to the b-wave. Inhibition of inner retinal responses using TTX resulted in a greater relative growth of b-wave and OP amplitude compared with fellow control eyes, and delayed the change in recovery phase by approximately 5 min. Inhibition of all ionotropic glutamate receptors with CNQX/D-AP7 delayed both rising and recovery phases equally (approximately 12 ms) without altering b-wave width or the time course of adaptation changes. These outcomes suggest that inner retinal light responses are not directly responsible for b-wave amplitude growth, but may contribute to the change in its recovery phase during adaptation. A TTX-sensitive mechanism may help to hasten this process. The cone a-wave was isolated using PDA/L-AP4 or CNQX/L-AP4. A-wave amplitude (35 ms after stimulus onset) also increased with time during light adaptation and reached a maximum (130 +/- 29% above baseline) 12-15 min after background onset. B-wave amplitude growth in fellow control eyes closely followed the course and relative magnitude of cone a-wave amplitude growth. Hence, the increase of the cone response during light adaptation is sufficient to explain b-wave amplitude growth.

Phenotypic Characterization of a Large Family With RP10 Autosomal-Dominant Retinitis Pigmentosa: An Asp226Asn Mutation in the IMPDH1 Gene

To evaluate the clinical features associated with the RP10 form of autosomal-dominant retinitis pigmentosa in 11 affected members of various ages from one family with a defined IMPDH1 mutation (Asp226Asn). Prospective, observational case series. Visual function assessment included visual acuity, color vision, visual field, dark adaptometry, full-field electroretinography (ffERG), and multifocal electroretinography (mfERG). Ophthalmologic examinations, fundus photography, and optical coherence tomographic scans were also performed. Blood samples were obtained to screen for basic immune function. Visual acuity was slightly reduced in the teenage years and substantially reduced in association with cystoid macular edema (CME) at all ages. Color defects were observed in three patients (one teen, two adults). Dark-adapted thresholds were elevated. Visual fields were markedly constricted by age 40 (<or=20 degrees). Rod and cone a-wave and b-wave ffERG responses were small or nondetectable by age 20, with greater rod than cone loss at all ages. The normal to significantly delayed ffERG cone b-wave implicit times in different patients were explained by their mfERG implicit times from the central retina. The amplification factors (log S) and recovery kinetics derived from the full-field rod a-waves were normal. Optical coherence tomography revealed subretinal fluid accumulation in the majority of eyes. Cystoid macular edema was diagnosed in four patients. No unusual immunologic findings were noted. The Asp226Asn mutation is associated with a severe, early-onset form of retinal degeneration in members of this family.

Rod and Cone a-Waves in Central Retinal Vein Occlusion

To evaluate rod and cone a-waves in cases with unilateral central retinal vein occlusion (CRVO). Scotopic and photopic flash electroretinograms (ERGs) were recorded in seven patients aged 54-84 with unilateral hemorrhagic CRVO. Rod and cone a-waves were analyzed using photoreceptor models, and Rm(p3) (maximum a-wave amplitude) and S (sensitivity) were calculated. Decreased rod log S was found in all seven cases, and decreased cone log S was found in five cases. In only one case, rod log S in the fellow eye was decreased. The alterations in rod and cone log Rm(p3) were smaller than those in rod and cone log S. Of three cases in which ERGs could be recorded again after a certain follow-up period, rod log S and cone logS became larger in two cases and smaller in one case. The change in the phototransduction cascade was confirmed not only in rods but also in cones in five of our seven cases of CRVO. The ERG findings might reflect the functional change in the photoreceptor layer after the onset of CRVO.

Electroretinographic Monitoring in Birdshot Chorioretinopathy

To evaluate electroretinography (ERG) during long-term follow-up in birdshot chorioretinopathy (BCR). Retrospective, comparative interventional case series. University subspecialty clinic. Twenty-three HLA-A29-positive patients with BCR and 40 normal control subjects. INTERVENTION PROCEDURE: Patients were monitored with ERG approximately annually. Treatment was according to best medical judgment. main outcome measures: Baseline ERG values, vision, and ERG values during observed and treated intervals. Median age of patients was 52 years, and 19 patients were untreated at baseline. Eighty-two ERGs were performed. Eighteen patients had more than one ERG; mean follow-up of these patients was 40.2 months +/- 31.2, median 23 months. At baseline, several ERG parameters were statistically reduced compared with control subjects when adjusted for age. The combined rod-cone and cone b/a wave ratios did not differ from control subjects (P = .45 and 0.14). Scotopic rod and combined rod-cone b-wave amplitudes were statistically correlated with baseline vision, as were implicit times for the combined rod-cone a-wave, cone a-wave, and cone flicker b-wave. Median visual acuity was 20/25 and did not change during follow-up. Most ERG parameters showed marked worsening during observed intervals. During treated intervals, the ERG declined at a rate consistent with aging. Many ERG parameters in patients with BCR greatly differ from control subjects, correlate with vision, and worsen during observation. Selected patients may show improvement in ERG with treatment. The cone b-wave flicker implicit time was most often associated with clinically important measures such as vision, duration of symptoms, and deviation from normalcy.

Cone and Rod Dysfunction in Fundus Albipunctatus withRDH5Mutation: An Electrophysiological Study

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. 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. 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. 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.

PIII and Derived PII Analysis in a Patient with Retinal Dysfunction with Supernormal Scotopic ERG

To present electroretinographic (ERG) findings in a patient with retinal dysfunction with supernormal scotopic ERG, and to analyze rod and cone PIII components and rod inner nuclear layer (derived PII) responses. A Japanese 11-year-old girl complained of poor visual acuity. There was no parental consanguinity in her family. The corrected visual acuity was 0.7 in both eyes. No abnormal finding was observed in both fundi. The patient underwent full-field ERGs. Rod and cone a-waves were analyzed using photoreceptor models. The derived PII responses were analyzed using a technique described by Hood and Birch. In the photopic ERG, responses to single flash and 30-Hz flicker were attenuated. In the scotopic ERG, b-wave was supernormal in amplitude in response to intense flashes, but smaller than normal and markedly delayed over a lower range of flash intensities. By the PIII analysis, phototransductions (values of S) of both rod and cone were remarkably decreased. The derived PII responses for this patient were larger than the responses for normal subjects, and the onset of the PII responses in this patient are significantly delayed compared to those in normal subjects. The ophthalmological findings in this patient are consistent with previous publications of this disease. Although it has been reported that the sites of disease action were beyond the outer segment (values of S were within the normal range), our results suggest that photoreceptors could be involved in sites of disease action in at least some patients with this disease.

Disturbed visual system function in methionine synthase deficiency

Isolated functional methionine synthase deficiency occurs in the cblE and cblG defects of methylcobalamin metabolism and is one of a number of causes of severely elevated plasma homocysteine. Clinical features are predominantly of a neurological nature but also include functional restriction of the visual system manifesting as loss of visual acuity and nystagmus. As yet, the origin and pathogenesis of impaired vision have not been explained. We investigated a patient who was proven by complementation analysis in cultured fibroblasts to belong to the cblG complementation group. Ganzfeld electroretinograms (ERG) and flash visual evoked potentials (VEP) were recorded over a period of 4 years. Amplitudes of all International Society for Clinical Electrophysiology of Vision (ISCEV) standard responses were below normal. The greatest reductions were of rod response to 24 microV, of standard combined response (SC) b-wave to 120 microV, of oscillatory potentials (OP) to 5 microV, of cone response b-wave to 35 microV, and of 30 Hz flicker response to 8 microV. Except for SC and cone a-waves at age 2.5 and 3.5 years, as well as cone b-wave at 3.5 years, amplitudes remained at a subnormal level at follow-up examinations. Implicit times were slightly prolonged (SC b-wave 6 ms, OPs 2 ms, cone b-wave 2 ms, 30 Hz flicker 4 ms) or fell within the normal range. Responses of the flash VEP were severely deformed but reproducible. This is the first report of detailed investigations of the visual system in a patient with isolated methionine synthase deficiency. Reduced oscillatory potentials suggest microvascular damage to the retina through homocysteine. Decreased photoreceptor function as well as ganglion cell loss as indicated by pathological flash VEPs may reflect a cytotoxic impact of homocysteine on neurons of the visual pathway.

Predominant loss of the photopic negative response in central retinal artery occlusion

Purpose To determine how the photopic negative response (PhNR) is affected in central retinal artery occlusion (CRAO). Design Observational case series. Methods Seven patients with unilateral CRAO were included. Full-field scotopic and photopic electroretinograms (ERGs) including the PhNR were recorded. Each ERG amplitude in the affected eye was expressed as a percentage of amplitude of the corresponding wave in the unaffected eye. Results Mean of the PhNR amplitude was reduced to 12.3 ± 11.7% of that of unaffected eyes whereas the cone b-wave amplitude was attenuated to only 73.4 ± 30.4%. This reduction of the PhNR amplitude was more significant than that of other waves including the rod b-wave, maximum a-wave and b-wave, cone a-wave and b-wave, and 30 Hz flicker ERG ( P < .005). Conclusions The PhNR was severely affected in CRAO despite relative preservation of the cone b-wave, implicating massive loss of ganglion cells and their axons.

Cone and rod ERG phototransduction parameters in retinitis pigmentosa.

To analyze cone and rod phototransduction parameters from ERG a-waves in patients with RP and to determine the relationships among these parameters, age, and mode of inheritance. Sets of four white flashes (3.2-4.4 log scotopic troland [scot td-s]) were presented in the dark. The same stimuli were later presented against a rod-saturating background and the generated cone a-waves were subtracted from the dark-adapted responses to produce rod-only a-waves. The rod-only and cone a-waves were fit with computational models. Of 418 consecutive patients with retinitis pigmentosa (RP), cone a-waves were quantifiable in 136 (33%), whereas rod a-waves were quantifiable in 125 (30%). Cone R(max) (maximum response) and cone S (sensitivity) parameters were significantly below normal in all RP subgroups. Cone R(max) was lower in XlRP than in other forms of inheritance (P < 0.05). Cone S was abnormal in 77.9% of all patients with RP and in 96.8% of those with XlRP. More than 95% of the rod R(max) values were abnormal, whereas rod S was abnormal in 61.6% of these patients. The efficiency of cone phototransduction appears to be affected in all forms of RP, even in some patients in whom the sensitivity of rod phototransduction is normal. In this cross-sectional sample, there was no evidence that transduction efficiency decreased with increasing age of the patient. The X-linked mode of inheritance is associated with greater abnormalities in cone and rod photoreceptor function at a younger age compared with the other modes of inheritance.

Rod and cone a-waves in three cases of bietti crystalline chorioretinal dystrophy

PURPOSE: To estimate retinal function in Bietti crystalline chorioretinal dystrophy using the electroretinogram. METHODS: In this observational case series, the scotopic and photopic electroretinograms in three Japanese female patients (case 1, 55 years old; case 2, 56 years old; case 3, 47 years old) who showed bilateral crystalline retinal deposits but no corneal deposits were recorded. The rod and cone a-waves were analyzed by using the method described by Hood and Birch (1995, 1997). The parameters Rm p3 (maximum a-wave amplitude) and S (sensitivity) were calculated. RESULTS: In case 1, the rod Rm p3 was decreased in both eyes. The rod S in the right eye was within the normal range, but that in the left eye was significantly reduced. Although the cone Rm p3 was decreased, the cone S was within the normal range. In case 2, the rod and cone Rm p3 was reduced, but the rod and cone S was within the normal range in both eyes. In case 3, the rod and cone Rm p3 and S were within the normal range. CONCLUSIONS: Electroretinograms illustrated different disease stages, however, no eye with normal Rm p3 and decreased S was found in rods and cones. In the early stages of this disease, decreased numbers of photoreceptors and/or outer segment shortening may be present while phototransduction remains normal. As the damage to the retina progresses, phototransduction becomes severely affected. Because reduced cone S was not observed in our cases, cones may be less involved than rods in this disease.

The contribution of cone responses to rat electroretinograms.

The contribution of rods and cones to the scotopic electroretinogram (ERG) of small animals is unclear, with a recent report suggesting that the mouse has no cone a-wave. The present study considered the contribution of cones to the ERG of the rat. Dark-adapted Long Evans rats (n = 4) had ERG signals collected following a single flash, which stimulated rods and cones (mixed response), or a twin-fash paradigm (short interstimulus interval, 1 s), which isolated cone responses. Rod signals were derived by digital subtraction of the cone signal from the mixed rod/cone ERG. The rat a-wave was found to be dominated by rod responses but cone responses contributed substantially (45%) to post-receptoral waveforms (b-wave) at higher light levels.

An alternative phototransduction model for human rod and cone ERG a-waves: normal parameters and variation with age.

A quantitative description of the activation reactions in the cGMP phototransduction cascade has been recently developed [Lamb & Pugh (1992). Journal of Physiology, 449, 719-758]. When applied to the human electroretinogram a-wave, the widely used simplified form of this model provides a good description of all waveforms except those elicited with very high energy stimuli. The basis for these misfits at high energies is explored in the current study and an alternative model of phototransduction is derived that retains the quantitative aspects but avoids certain simplifying assumptions previously made. The new model describes well both rod- and cone-isolated a-waves over a large range of stimulus energies extending up to those that cause significant bleaching. To facilitate clinical application of this methodology, a short test protocol is developed and normal data for rod and cone transduction parameters are provided over a wide age range. In the sample of normal subjects studied, maximum amplitude of rod and cone a-waves and sensitivity of the cone a-wave do not change with age. An age-related decline in rod a-wave sensitivity is present and it is greater than that expected from pre-retinal absorption alone.

Phototransduction in human cones measured using the a-wave of the ERG

To study human cone phototransduction, the a-wave of the ERG was recorded from color normals, dichromats, and patients with retinitis pigmentosa. A model of the activation phase of phototransduction, previously fitted to responses from single rods and the rod a-wave, was modified and fitted to the human cone a-wave. The modified model fits the cone a-wave well and allows questions about human cone phototransduction to be addressed. In particular, we conclude that: (1) the amplification of the activation phase of human cone transduction is comparable to that of the human rods. (2) Steady lights have relatively little effect on the amplification of cone transduction. (3) The normal a-wave elicited by red flashes is dominated by the L cones, consistent with a ratio of L:M cones of > 1. (4) Retinitis pigmentosa caused by mutations of the rhodopsin gene can affect cone phototransduction. Finally, a simpler computational expression is shown to approximate the modified model's responses.

Enhanced S cone syndrome: Evidence for an abnormally large number of S cones

The cellular basis of the hypersensitivity of the S (blue) cone system in patients with enhanced S cone syndrome was examined by analyzing ERGs from three patients. The patients had large a-waves in response to the blue and white flashes. These a-waves were shown to be driven nearly entirely by the S cones. Although these S cone a-waves were 4–6 times the size of the normal L/M cone a-wave, they are of the same form, and could be quantitatively described with the same model previously shown to fit cone a-waves. We propose that the retina of these patients has many more S cones than the normal retina and that these cones replace some of the normal L/M cones and many of the rods.

ATTENUATING EFFECTS OF DIAZEPAM ON THE ELECTRORETINOGRAM OF NORMAL HUMANS

Response/log I curves were obtained under conditions of dark-and light-adaptation in seven normal male volunteers. For each subject, a baseline electroretinogram (ERG) was recorded. In the same afternoon, a second ERG was obtained after 0.05 mg/kg diazepam, and a third ERG was recorded following 0.10 mg/kg diazepam. Under conditions of dark-adaptation, the following dose-dependent changes were identified: 1) Diazepam attenuated the rod b-wave peak amplitude and increased its implicit time; 2) The dark-adapted longer wavelength cone a-wave and 'blue cone' b-wave showed an increased implicit time; 3) All oscillatory potentials showed an increased implicit time. Under conditions of light-adaptation, dose-dependent decreases in peak amplitude and delays in implicit time were observed for the a- and b-waves. The effects of diazepam on the human ERG were more profound under conditions of light- than dark-adaptation.