Unique Characteristics of Two Types of Retinitis Pigmentosa Patients with Different Rod Sensitivities

Purpose To determine the psychophysical differences between two types of retinitis pigmentosa (RP) patients with different rod sensitivities.Methods Thirty-five RP patients with a visual acuity of 0.7 or better were classified by cone–rod perimetry into type 1, those with undetectable rod sensitivity, and type 2, those with measurable rod sensitivity. Their symptoms, age at onset of symptoms, cone and rod sensitivity, and full-field electroretinograms (ERGs) were compared.Results The age when the symptoms of night blindness were first noticed was 13.1 ± 3.3 years (mean ± SD) for type 1 and 34.5 ± 14.4 years for type 2 patients (P = 0.0001). One of nine type 1 patients (11%) and 10 of 26 type 2 patients (38%) did not have any symptoms of night blindness. The average rod sensitivity within the central 10° was 43.7 ± 12.0dB for type 2 patients with night blindness, and 54.8 ± 6.4dB for type 2 patients without night blindness (P = 0.014). One of nine (11%) type 1 patients and 9 of 23 (39%) type 2 patients had recordable ERGs (P = 0.13).Conclusions These findings indicate that the two types of RP patients, distinguished by their rod sensitivity, have different psychophysical characteristics of the visual system. The course of the disease process and the long-term prognosis for these two types of patients are different. Jpn J Ophthalmol 2005;49:114–120 © Japanese Ophthalmological Society 2005     

Klinische Befunde bei autosomal-rezessivem Syndrom der Blauzapfenhypersensitivität

Background. Intrafamilial variability of the syndrome of night blindness, maculopathy, and enhanced S-cone hypersensitivity was examined. Patients and methods. Siblings with a history of night blindness and reduced visual acuity were examined clinically, psychophysically, electroretinographically (ERG), and electro-oculographically (EOG). Results. The siblings had had night blindness since early childhood and reduced visual acuity since the age of 20 years. Ophthalmoscopy showed degenerative, pigmented changes and subretinal spots, while one sibling had cystic lesions in the fovea. Scotopic ERG showed no rod-driven responses, while large, slow waveforms were detected in response to bright flashes. Photopic ERG induced responses similar in time, amplitude, and configuration to those of the dark-adapted ERG. The b-wave configuration was unchanged in response to chromatic stimuli. However, photopic ERG was more sensitive to blue and white than to red stimuli. The light peak on EOG was reduced. Conclusions. The enhanced S-cone sensitivity syndrome was expressed to a different degree of severity and probably inherited in an autosomal recessive mode. These unusual ERG findings may be due to a depressed rod system and an increased number of S-cone photoreceptors, postreceptoral circuits, and S-cone sensitive ganglion cells.     

Night Blindness with Depolarizing Pattern of ON/OFF Response in Electroretinogram: A Case Report

Purpose: To present a patient who has night blindness with a depolarizing pattern of ON/OFF response by electroretinography (ERG). Case: A 43-year-old woman had had night blindness and poorly corrected visual acuity since childhood. Parental consanguinity was noted. The patient had suffered from mental retardation, epilepsy, and mild cerebellar ataxia. Corrected visual acuity was 20/30 in the right eye and 20/25 in the left. Goldmann perimetry showed no scotoma but slight depression with internal isoptors. No evidence for rod activity was observed by Goldmann–Weekers adaptometry. The ocular fundi appeared normal. Methods: Conventional full-field ERGs to scotopic (dim and bright flash) and photopic (bright flash and flicker) stimuli were recorded. Photopic ERG responses to long flash stimulation (200 ms) were also examined. Results: The scotopic responses to dim flash were non-recordable, while those to bright flash were severely reduced. The photopic responses to bright flash were decreased. The amplitudes of flicker responses also were significantly decreased, and the implicit times of those responses were prolonged. Although the amplitudes of a- and d-waves to long flash stimulation were reduced, those of the b-wave were within normal range. The implicit times of a-, b- and d-waves were significantly prolonged. The patient showed a normal rise for the photopic b-wave but lacked a normal falling slope after the b-wave peak. An OFF-response late-negativity was also noted. Conclusions: The abnormal ON/OFF response found in the patient could be diagnosed as depolarizing pattern, characterized by elevation of the plateau to a positive potential above the prestimulus baseline. Since the ERG waveforms and clinical features found in our patient were different from those in previous reports, her ERG findings might reflect another retinal physiological mechanism.     

Negative scotopic ERG and photopic ERG ON response impairment in a patient with normal dark adaptation

Purpose To present ocular findings in a patient who showed negative scotopic electroretinogram (ERG) and reduced ON response, but normal dark adaptation.Case An 18-year-old Japanese male patient who complained of severe asthenopia. His corrected visual acuities were 1.2 in both eyes. His fundi were normal. He had normal contrast sensitivity and normal dark adaptation.Methods The patients underwent ERG (including the standard protocol and photopic long flash recordings).Results The amplitudes of the rod ERG b-wave were reduced. The scotopic standard combined ERG response showed negative configuration. The photopic response to long flash revealed the reduced b-wave (ON response), while the amplitude of the first peak of the d-wave (OFF response) was within the normal range.Conclusions Postsynaptic abnormalities in both the rod and cone ON-pathways, which are often found in patients with night blindness, were suggested in the ERG findings, but the dark adaptation of our patient was normal. Neuromuscular evaluation of the patient and ophthalmological evaluation, including ERG, of his parents were normal. To our knowledge, the ophthalmological and electrophysiological findings of our patient cannot be attributed to any known clinical entity.     

Rod-driven focal macular electroretinogram

PURPOSE: To determine the stimulus conditions required to elicit rod-driven, focal macular electroretinograms (rod FMERGs). METHODS: A blue (lambda(max)=470 nm) stimulus, 5 degrees in size, was imaged at a luminance of 1.5 cd/m(2) on different regions of the human retina. Electroretinograms (ERGs) elicited by this stimulus were recorded from the light- and dark-adapted retina of four subjects without any ophthalmological abnormalities. A subject with cone dystrophy was also tested by this method. RESULTS: Stimulus luminance <==1.5 cd/m(2) did not elicit a response when it was imaged on the optic disc, but higher intensities elicited a small b-wave from stray light. When this stimulus was imaged on the macular area or the 15 degrees temporal retina, an ERG was elicited that had the shape of the full-field scotopic ERG. This stimulus with a luminance of 1.5 cd/m(2) did not elicit a response from stimulation of the macular area of a light-adapted retina but elicited a slow-rising positive b-wave after 30 minutes of dark adaptation. In a subject with cone dystrophy, focal rod response was elicited from the macula, despite no response under photopic conditions. CONCLUSION: We conclude that this stimulus will elicit a response that is derived exclusively from rods and is a focal response with no contribution from stray light.     

Congenital stationary night blindness and a "Schubert-Bornschein" type electrophysiology in a family with dominant inheritance

BACKGROUND/AIMS: To present the clinical, psychophysical, and electrophysiological characteristics of a family with dominantly inherited congenital stationary night blindness (CSNB). METHODS: Five affected family members from three generations were ascertained. Four affected individuals underwent ophthalmic examination and electrodiagnostic investigations. Three affected individuals also underwent scanning laser ophthalmoscopy and psychophysical testing. RESULTS: Affected individuals reported night blindness from an early age. Visual acuities were normal. Fundal appearances were normal apart from one older patient showing areas of peripheral chorioretinal atrophy. Autofluorescence images showed no gross abnormality. International Society for Clinical Electrophysiology of Vision (ISCEV) standard electroretinography (ERG) showed undetectable rod specific responses and electronegative maximal responses, but normal ISCEV cone responses. Additional S-cone specific ERG recordings were of reduced amplitude in all patients studied. There was no apparent rod component to the dark adaptation curve. Central 30 degrees thresholds were normal under photopic conditions but showed increased thresholds under scotopic conditions for both red and blue stimuli. CONCLUSION: Results from investigation of this family are consistent with an impairment of rod photoreceptor signalling. The ERG findings suggest an abnormality occurring after phototransduction with rod and S-cone pathway involvement. These findings differ from those rare families reported previously with dominant CSNB.     

显性遗传先天性静止性夜盲全视野明视ERG的分析

对同一家系11名显性遗传CSNB 患者进行全视野明视ERG 分析,发现8名患者出现异常,表现为:1.明视白光刺激的b 波峰时延长或振幅降低;2.白光刺激出现负电反应;3.对闪烁光刺激的反应振幅降低甚至无波。认为CSNB 的主要病损在视网膜杆体系统,但锥体系统也受到不同程度的损害。提出根据电生理和心理物理检查可将本病分为仅累及杆体系统的单纯型和杆体、锥体均受到损害的混合型。临床上这两种不同的亚型是CSNB 基因不同表现度的反映。     

Spontaneous occurrence of a potentially night blinding disorder in guinea pigs

Several hereditary retinal disorders such as retinitis pigmentosa and congenital stationary night blindness compromise, sometimes exclusively, the activity of the rod pathway. Unfortunately, there are few animal models of these disorders that could help us better understand the pathophysiological processes involved. The purpose of this report is to present a pedigree of guinea pigs where, as a result of a consanguineous mating and subsequent selective breeding, we developed a new and naturally occurring animal model of a rod disorder. Analysis of the retinal function with the electroretinogram reveals that the threshold for rod-mediated electroretinograms (ERGs) is significantly increased by more than 2 log-units compared to that of normal guinea pigs. Furthermore, in response to a suprathreshold stimulus, also delivered under scotopic condition, which yield a mixed cone-rod response in normal guinea pigs, the ERG waveform in our mutant guinea pigs is almost identical (amplitude and timing of a- and b-waves) to that evoked in photopic condition. The above would thus suggest either a structural (abnormal development or absence) or a functional deficiency of the rod photoreceptors. We believe that our pedigree possibly represents a new animal model of a night blinding disorder, and that this condition is inherited as an autosomal recessive trait in the guinea pig population.     

Scotopic versus photopic pattern onset-offset electroretinograms

We investigated the contribution of rods and cones to the human pattern electroretinogram to onset and offset checkerboards of different spatial frequency and wavelength in a 39° × 39° field. Under strictly scotopic conditions, there was a negative potential at onset and a positive potential at offset, whereas under photopic conditions, there was a positive potential at onset and a negative/positive potential at offset. Thus, the waveform to pattern onset (offset) was that of the luminance electroretinogram to decreasing (increasing) luminances. For pattern onset, the sensitivity difference 486–601 nm under scotopic and photopic conditions closely followed the luminosity function of rods and cones. The amplitude of the scotopic onset response increased with check size up to 3°30 and that of the photopic onset response, up to 30. With larger checks, the scotopic and photopic onset response markedly decreased. This indicates antagonistic center-surround organization of the receptive fields under both scotopic and photopic conditions. By contrast, the offset response monotonically increased with check size under scotopic and photopic conditions, which suggests a luminance component in the pattern electroretinogram. Consequently, the pattern electroretinogram to reversing checker-boards has to be regarded as a mixture of both pattern- (contrast) and luminance-specific components.     

Processing of scotopic increments and decrements

Rod and cone photoreceptors send their signals to ON- and OFF-retinal ganglion cells through different pathways in the primate retina. We hypothesized that increments and decrements of light may be processed differently by the rod-bipolar pathway because of the funneling of the rod signal through the rod bipolar cell. We tested this hypothesis using a psychophysical adaptation paradigm, which has provided evidence that photopic increments and decrements of light are processed by ON- and OFF-pathways in the human visual system. We had observers adapt to either a rapid-on or rapid-off sawtooth waveform, under both photopic and scotopic conditions. We then measured detection thresholds for one cycle of a rapid-on or rapid-off sawtooth stimulus. For photopic stimuli, sawtooth adaptation asymmetrically raised thresholds for test stimuli in a manner that depended on the polarity of the adaptation stimulus. For scotopic stimuli, thresholds were raised, but no significant selective adaptation effect was found. By repeating the photopic condition with sawtooth stimuli which had been filtered using an impulse response function derived for the rod system, we demonstrated that the lack of selective adaptation was not a consequence of the sluggish temporal response of the rod-bipolar pathway. We conclude instead that the reduced effectiveness of sawtooth adaptation is due to channeling of rod photoreceptor signals through the rod bipolar cell before reaching ON- and OFF-ganglion cells.     

The negative response of the flash electroretinogram in glaucoma

The existence of a negative ERG component following the b-wave has been known for a long time. Recently, in unilateral macaque experimental glaucoma, a negative response in flash electroretinograms under scotopic as well as photopic conditions has been shown to be greatly reduced or absent compared to the healthy fellow eye. The aim of this pilot study was to test whether a late negative electroretinogram component is reduced also in human glaucoma patients under different stimulus conditions. Dark-adapted ganzfeld flash electroretinograms were recorded after 30 min of dark using two test conditions, obtained as optimal in pilot studies on controls. Under the scotopic condition I white Xenon-flashes of intensity 0.53 Log photopic Td s were presented on a low white background of 1.38 Log scotopic Td. Under the more photopic condition II orange flashes of intensity –0.37 Log photopic Td s were presented on a blue-adapting background of 2.5 Log scotopic Td. Nine controls and 18 patients with advanced glaucoma were analyzed. The amplitude of the negative response was not significantly reduced in glaucoma patients (condition I: –28.5±23.7 V; condition II: –25.2±19.7 V) compared to controls (condition I: –41.4±36.6 V; condition II: –31.3±26.2 V). The peak latency of the responses under condition I and II did not differ significantly between patients and controls. Thus, the late negative electroretinogram component in ganzfeld flash electroretinograms obtained under scotopic and more photopic conditions does not seem to distinguish as easy between human controls and glaucoma patients as animal experiments suggest.     

Measuring contrast sensitivity in normal subjects with OPTEC® 6500: influence of age and glare

Background

The purpose of this study was to develop age-related curves for contrast sensitivity (CS) in normal subjects under day and night conditions with and without glare.

Methods

Sixty-one healthy eyes from 61 subjects were measured with the OPTEC® 6500 P under day and night conditions (luminance levels: 85 cd/m² and 3.0 cd/m² with and without glare; spatial frequencies: 1.5, 3, 6, 12 and 18 cycles/degree). A reliability analysis with five repeated measurements of six persons on 4 days was performed to examine the repeatability. The influence of age on contrast sensitivity, forward and backward scatter was examined by means of linear regression.

Results

Contrast sensitivity was significantly reduced under night conditions with glare, whereas glare had less influence under daylight illumination. Mean reliability coefficients are 0.87 (day), 0.77 (day with glare), 0.69 (night) and 0.81 (night with glare), which suggests sufficient retest reliability of the device. Regression analyses showed a highly significant influence of age, but the variance of the measurement values is not explained by age alone. The coefficients of determination for the regression of area under the log contrast sensitivity function (AULCSF) on age are 0.33 (photopic), 0.34 (photopic with glare), 0.29 (mesopic) and 0.36 (mesopic with glare, p?

Conclusion

A significant relationship between age, CS and scatter was confirmed in our study. The results provide baseline values for the examination of patients with different diseases in which contrast sensitivity is impaired (such as glaucoma, cataracts and amblyopia) and might be useful in studies of roadworthiness or in investigation of the impact of intraocular lenses.

     

'On' response defect in paraneoplastic night blindness with cutaneous malignant melanoma.

Response properties of rod and cone systems were assessed in a patient with an acquired form of night blindness associated with a metastatic cutaneous malignant melanoma. The night blindness, a sensation of shimmering lights, and selective reductions in the amplitudes of both rod and cone electroretinographic (ERG) b-waves were present before and after chemotherapy, confirming that this disorder was a paraneoplastic consequence of the melanoma rather than a response to chemotherapy. During ERG testing with flashes of extended duration, the cone b-wave abnormality was found to be a predominant loss of the cone ERG "on" response with relative preservation of the "off" response, similar to that observed in patients with congenital stationary night blindness. An impairment in signal transmission specific for retinal "on" pathways may be a primary defect in both of these forms of night blindness.     

Improvement of Scotopic Electroretinograms and Night Blindness with Recovery of Serum Zinc Levels

Background We sought to determine the cause of reduced scotopic and photopic electroretinograms (ERGs) and night blindness in a 46-year-old man with liver dysfunction but no history of alcoholism. Case A 46-year-old Japanese man with a complaint of visual difficulties in dim light for 1 month. Observations By electrophysiological investigation, the patient was found to have low levels of serum zinc and vitamin A on admission. The rod b wave was unrecordable, and the bright-flash ERGs were reduced, with the a wave > b wave. The amplitudes of the cone and 30-Hz flicker responses were also reduced, and their implicit times were prolonged. Three weeks after admission, the patient's serum zinc level recovered to normal levels, but his serum vitamin A level was still low. The symptoms of night blindness were gone, and the rod ERGs and single bright-flash responses were within normal limits. However, the cone ERGs and 30-Hz flicker responses were still depressed. Conclusions The recovery of scotopic function together with the recovery of zinc but not vitamin A levels suggests that the ERG changes were most likely related to low zinc levels.     

Infliximab exerts a dose-dependent effect on retinal safety in the albino rabbit

Purpose

To study whether the ERG and other clinical findings help to distinguish between advanced hydroxychloroquine (HCQ) retinopathy and pericentral or diffuse retinitis pigmentosa (RP) with similar fundus appearance.

Methods

We conducted a retrospective analysis of patients with advanced HCQ retinopathy (n = 11), pericentral RP (n = 8) and diffuse RP (n = 8). Pericentral RP was defined as having limited fundus damage and relatively normal flicker ERG time-to-peak. Diffuse RP had typical loss of the rod ERG and flicker timing delay. All patients showed reduced amplitude of the ISCEV responses in the full-field electroretinogram (ERG). Aspects of history, visual field results, fundus appearance, fundus autofluorescence and ocular coherence tomography were also compared.

Results

Relative to pericentral RP, patients with HCQ toxicity showed delayed flicker ERG time-to-peak and lower ERG amplitudes, particularly combined rod–cone responses. Relative to diffuse RP, most HCQ toxicity patients had some preserved rod ERG response, and there was no obvious predilection for rod over cone damage. In addition, patients with HCQ toxicity usually lacked markers of long-standing degeneration such as bone spicule figures or severe loss of peripheral field. History of familial disease and long-standing night blindness were specific to RP.

Conclusions

While the early signs of HCQ damage are typically regional in the posterior pole, advanced disease is characteristically diffuse (unlike pericentral RP). This is appropriate for a systemic toxin, as is the finding that rods and cones were both affected in the ERG to a similar degree (unlike genetic rod–cone dystrophies). For patients with severe HCQ exposure and some of our discriminatory findings, and no family history or prior night blindness, HCQ toxicity is a sufficient diagnosis without invoking a second rare disease (Occam’s razor).

     

Circadian variation in the electroretinogram and the presence of central melatonin

The light/dark cycle is the most important circadian clock synchronizer for mammals and humans. Circadian rhythms of dopamine and melatonin production in the retina have been reported to follow the light and dark cycle, but their impact on rod and cone functioning is not clear. The purpose of this study was to assess diurnal variations (morning vs. evening) in retinal function as measured with the photopic and scotopic electroretinogram (ERG). We also tried to correlate our results with the presence or absence of melatonin secretion in the saliva. Photopic and scotopic luminance–response functions were obtained in 29 participants at 11:00 (when melatonin should not be present) and 23:00 (when melatonin should be present). From the luminance–response function, Vmax, log K and slope parameters were derived. In scotopic condition, a significant increase of 6% in Vmax amplitude was observed in evening compared to morning (P = 0.03) along with a prolonged b-wave implicit time of 8% (P = 0.01) and an increase in rod sensitivity in evening compared to morning (P = 0.02). As expected, these changes in rod function were accompanied by a higher concentration of melatonin in saliva samples in the evening (P = 0.01). In photopic condition, only a prolonged a-wave implicit time of 5% was observed in evening when compared to morning (P = 0.02). Our findings suggest that the rod system is favored during night time, when circulating melatonin is present. Although statistically significant changes were observed, the day vs. night difference observed in the present study appears to be too small to impact significantly upon clinical assessment of retinal function.     

Oscillatory potentials and pattern electroretinogram: are they related?

The possible relationship between the pattern electroretinogram (ERG) and oscillatory potentials was investigated in two patients with night blindness. One patient had congenital stationary night blindness of Schubert-Bornschein type, and the other had Oguchi's disease. Both had normal visual acuity, normal mass photopic (cone) ERG and normal local macular ERG. In each patient, scotopic (rod) ERG after 20-minute dark adaptation was nonrecordable and the single bright flash ERG was of the negative type. The difference between the ERG pattern of the two patients was found in the oscillatory potentials. The patient with congenital stationary night blindness showed no oscillatory potentials, whereas the patient with Oguchi's disease had good oscillatory potentials. The pattern ERG in both patients was normal. Based on the data of these two patients, it was thought that the pattern ERG is not closely related to the oscillatory potentials and may have different mechanisms of generation.     

Two cases of retinal degeneration with an unusual form of electroretinogram

An unusual form of retinal degeneration is reported in 15-year-old girl and 11-year-old girl with different pedigrees, which resembles the cases reported by Gouras and associates (1983). The subjective symptoms in these patients included decreased visual acuity, photophobia, anomalous color vision and night blindness. Electroretinograms (ERGs) in these two patients were identical in substance and revealed drastic alterations in both photopic and scotopic functions. The stimulus versus intensity response curve in a single-flash ERG showed an unusual form. This peculiar supernormal response was elicited by bright stimuli although the stimulus threshold was extremely elevated.     

The incidence of negative ERG in clinical practice

Introduction: A negative electroretinogram (ERG) is one in which there is a selective reduction in amplitude of the b-wave, such that it does not exceed that of the a-wave. The purpose of this study was to determine the incidence and clinical causes of negative ERGs at a tertiary referral centre. In addition, interesting and previously unreported aetiologies are described. Patients and methods: Retrospective review of all ERGs done at Moorfields Eye Hospital from November 1995 to December 1998 under ISCEV standard conditions. Many patients had photopic ON- and OFF-response recording in addition to conventional ISCEV Standard ganzfeld ERG. Results: A total of 2,640 ERGs were performed during the study period. 128 cases (4.8%) showed a negative ERG. The causes, where a firm clinical diagnosis was possible, include X-linked juvenile retinoschisis, congenital stationary night blindness, central retinal artery occlusion, birdshot chorioretinopathy and melanoma-associated retinopathy (MAR). Unilateral negative ERG waveforms with normal fundal appearances were seen in 7 patients. Photopic ON- responses could be selectively affected. Conclusions: The incidence of negative ERGs over a 34-month period presenting to a large tertiary centre was almost 5%. The presence of a negative ERG may be instrumental in demonstrating the site of visual dysfunction, with many cases showing minimal or no fundus abnormality. ON- and OFF-response recording yielded additional information regarding photopic post-receptoral/phototransduction function.     

Photopic suppression of monkey's rod receptor potential,apparently by a cone-initiated lateral inhibition

The late RP (receptor potential) was isolated in macaque monkeys by clamping the retinal circulation at the optic disc, while maintaining the animal on light halothane anesthesia with well controlled arterial oxygenation. Just after its isolation the late RP from all retinal areas was pure cone in origin, when elicited by stimulus intensities well above cone threshold. This was shown by criteria of response form, and by spectral response curves. In the central fovea and parafovea these pure cone responses were well maintained. At constant photopic intensity, however, a slowly decaying rod contribution appeared in the late RP of the peripheral retina soon after clamping the retinal circulation. This was shown to result from hypoxia of the peripheral retina, and the response that appeared was shown of rod origin by criteria of response form, spectral response curves, its selective abolition by adaptation with white light, and its recovery rate after light adaptation. After its appearance by hypoxia, the rod late RP was present throughout the photopic intensity range. In another series of experiments the late RP was isolated by infusing pentobarbital into the vitreous humor. At concentrations just sufficient to isolate the late RP, responses to photopic intensities were pure cone. At higher concentrations a rod contribution appeared in both the response form and the spectral response curve, and this effect was reversible. With either method of isolating the late RP, a pure rod late RP could always be seen by lowering stimulus intensity into the scotopic range. Our results indicate that under normal physiological conditions, stimuli well above cone threshold do not elicit a rod response of saturated amplitude; instead, the rod late RP is completely suppressed. At photopic intensities where visual functions are mediated only by cones, the entire post-receptor pathway is thus cleared for carrying pure cone signals. This mechanism has advantages or implications for many aspects of photopic visual functions. It appears to result from a lateral inhibitory pathway initiated by cones and involving the horizontal cell as inhibitory interneuron, with this pathway being functionally interrupted by either hypoxia or pentobarbital.