Electroretinographic changes in eyes of patients with BRCA1 gene mutation

AIM: To assess the retinal function in BRCA1 gene mutation carriers and to evaluate the clinical significance of its potential alterations. PATIENTS AND METHODS: Flash electroretinogram (ERG) was studied in 15 unaffected patients (30 eyes) with constitutional BRCA1 gene mutation. Routine ophthalmological examination was additionally performed in the oldest, unaffected 15 patients and in 15 breast cancer patients being carriers of BRCA1 mutation. RESULTS: In ERGs, in the maximal response, a-wave (p < 0.03) and b-wave (p < 0.05) amplitudes were reduced. In the cone single-flash response, the amplitude of a-wave (p < 0.007) was also reduced. In the oscillatory potentials (OPs), increased amplitude of OP2 (p < 0.03), and increased latencies of OP3 (p < 0.0009) and OP4 (p < 0.03) were obtained. BRCA1 carriers even at old age or after treatment of breast cancer have not presented increased frequency of abnormalities detectable by routine ophthalmological examination. CONCLUSION: It can be hypothesized that dysfunction of rods, cones and inner retinal layers is present in asymptomatic carriers of BRCA1 gene mutation; however, this does not have clinical consequences.     

Visual field constriction and electrophysiological changes associated with vigabatrin

Purpose: We investigated functional, morphological and electrophysiological changes in patients under anti-epileptic therapy with vigabatrin (VGB), a GABA aminotransferase inhibitor. Methods: 20 epileptic patients treated with vigabatrin (age range 25–66 years) were enrolled in this study. The referrals were made by the treating neurologist, based on suspected or known visual field changes in these patients. Two patients had vigabatrin monotherapy, 18 patients were treated with vigabatrin in combination with other antiepileptic drugs. None of the patients reported visual complaints. Patients were examined with psychophysical tests including colour vision (Farnsworth D15), dark adaptation threshold, Goldmann visual fields and Tuebingen Automated Perimetry (90°). A Ganzfeld ERG and an EOG following the ISCEV standard protocol were also obtained. Additionally, all patients were examined with the VERIS multifocal ERG including recordings of multifocal oscillatory potentials. Results: Visual acuity, anterior and posterior segments, colour vision and dark adaptation thresholds were normal in all patients. Of 20 patients, 18 presented visual field constriction. All patients with visual field defects revealed altered oscillatory potentials waveforms in the ERG, especially in those patients with marked visual field defects. Multifocal oscillatory potentials were also delayed in those patients. In some patients a delayed cone single flash response (6/20), a reduced mERG amplitude (12/20) and a reduced Arden ratio (9/20) were found. Conclusions: The present data indicate an effect of vigabatrin on the inner retinal layers. Since abnormalities of the oscillatory potentials were seen in all patients with visual field defects a dysfunction of GABA-ergic retinal cell transmission might be assumed.     

Abnormal focal macular electroretinograms in eyes with idiopathic epimacular membrane.

PURPOSE: To study the functional state of the retina beneath an epimacular membrane by means of focal macular electroretinography. METHODS: Focal macular electroretinograms of 30 consecutive patients (age 25 to 75 years) with unilateral idiopathic epimacular membrane were recorded prospectively. The amplitudes and implicit times of the a and b waves and the oscillatory potentials (O1, O2, O3) recorded from the eye with idiopathic epimacular membrane were compared with those of the normal fellow eye. RESULTS: There was a statistically significant reduction in the amplitude of the a wave (P < .001), the b wave (P < .001), and the oscillatory potentials (O1 + O2 + O3; P < .001) of the affected eyes. The reduction of the b-wave amplitude was significantly greater than that of the a wave, resulting in a lower b/a wave ratio (P = .003) in the affected eyes. The reduction in the amplitude of the oscillatory potentials was significantly greater than that of the other two components (P < .001). The implicit times were significantly prolonged for the a wave (P < .001), the b wave (P = .004), and 03 (P < .001). There was a significant correlation between relative b-wave amplitude (affected/normal fellow eye) and the visual acuity (r = -0.50, P = .007). These findings were similar to those we reported for eyes with aphakic cystoid macular edema. CONCLUSIONS: The focal macular electroretinograms in eyes with epimacular membrane disclosed abnormalities that were similar to those of eyes with cystoid macular edema. This suggests that the epimacular membrane probably induced damage to the neurons in the inner retinal layers. Dysfunction of these neurons is one possible cause of visual impairment in this disease.     

Oscillatory potentials as predictors to amplitude and peak time of the photopic b-wave of the human electroretinogram

The oscillatory potentials are viewed by many as small oscillations of a highfrequency domain that ride on the b-wave of the electroretinogram. A study of electroretinograms and oscillatory potentials performed in 25 normal subjects was undertaken to substantiate my claim that oscillatory potentials are fast retinal potentials that are integrated to form the b-wave. The prominence of the OPs on the ascending limb of the b-wave was found to be only weakly correlated (r = –0.37) to the amplitude of the oscillatory potentials (measured in the 100–1000 Hz recordings). There was, however, a high correlation (r = 0.78) between the prominence of the oscillatory potentials and their frequency domain as determined by the peak-to-peak timing. Furthermore, the peak-to-peak timing of the oscillatory potentials was highly correlated with the b-wave peak time (r = 0.86) as well as with the a-wave trough to b-wave peak time (r = 0.90), while the amplitude of the oscillatory potentials was correlated to the amplitude of the b-wave (r = 0.78). Interestingly, when combining the amplitude of the oscillatory potentials with the time interval between oscillatory potentials 2 and 3 and 3 and 4, a higher correlation (r = 0.88) was found with the b-wave amplitude. The latter finding would support my claim that the b-wave represents an integration (amplitude as a function of time) of the oscillatory potentials.     

Retinal dysfunction in eyes of patients with BRCA1 gene mutation

PURPOSE: To assess the retinal function in BRCA1 gene mutation carriers. MATERIAL AND METHODS: Thirty unaffected patients (60 eyes) with constitutional BRCA1 gene mutation were studied. Flash ERG recordings were performed in accordance with the International Society for Clinical Electrophysiology of Vision (ISCEV) standards. RESULTS: In ERGs, in the maximal response, amplitude of a-wave (p<0.02) was reduced. In the cone single- flash response, the amplitude of a-wave (p<0.04) was also reduced. In the scotopic oscillatory potentials (OPs), we noted: increased amplitude of OP2 (p<0.0006), increased index of OP amplitude (01+02+03+04) (p<0.04), and increased latencies of OP1 (<0.05) and OP3 (p<0.004) and OP4 (p<0.03). CONCLUSIONS: Slight dysfunction of rods, cones and inner retinal layers is present in asymptomatic carriers of BRCA1 gene mutation.     

Reduction of oscillatory potentials and photopic negative response in patients with autosomal dominant optic atrophy with OPA1 mutations

PURPOSE: To study the electroretinographic (ERG) findings in patients with autosomal dominant optic atrophy (ADOA) with OPA1 mutations. METHODS: Eight ADOA patients (age range, 24-55 years; mean, 41 years) with OPA1 mutations were studied. In addition to routine ophthalmological tests, full-field ERGs including the rod response, mixed rod-cone response, oscillatory potentials (OPs), single-flash cone response, and photopic negative response (PhNR) were recorded and compared with those from 25 age-matched controls. The correlation between the ERG data and averaged retinal nerve fiber layer (RNFL) thickness around the optic disk measured by optical coherent tomography, mean deviation of the static perimetry (Humphrey 30-2 program), or corrected visual acuity was also examined. RESULTS: Amplitudes of the PhNR and OPs, both of which are believed to originate from inner retinal layers, were significantly smaller in ADOA patients than in control subjects (P < 0.01). Amplitudes of other ERG components were not statistically different in the two groups. OP amplitude was inversely correlated with the patient's age. The RNFL was thinner and the retinal sensitivities obtained by static perimetry were lower in ADOA patients, but these values were not correlated with the amplitude of PhNR or OPs. CONCLUSIONS: These results suggested that there are functional impairments not only in the ganglion cell layer but also in the inner nuclear and plexiform layers, including the amacrine cells of ADOA patients with OPA1 mutations.     

Effects of intravenous L-acetylcarnitine on retinal oscillatory potentials

L-acetylcarnitine is a compound with cholinergic properties and putative action on the visual system and the glucose metabolism. Ten healthy, emmertropic volunteers (age range: 21 to 28 years) were studied. Each subject was administered 5, 10, and 30 mg/kg acute intravenous doses of L-acetylcarnitine and matching placebo. Retinal oscillatory potentials to full-field flash stimulation were recorded before and 30, 60, and 120 min after administration. A systematic reduction of the implicit time of the P2 and N2 oscillatory potential components was observed after administration of the 10 and 30 mg/kg doses: significant changes were not evident at the 5 mg dose or after placebo. The latency reduction was significantly correlated with the postdrug increment of the L-acetylcarnitine plasma concentration. No other systematic modification in latency of amplitude was observed.The results were presented in part at the XXV I.S.C.E.V. Symposium, Sarasota (Florida), April 26–30, 1987.     

Maturation of the photopic b-wave and oscillatory potentials of the electroretinogram in the neonatal rabbit

We examined the ontogenesis of the b-wave of the rabbit electroretinogram (ERG) in light adaptation and looked at the contribution of the oscillatory potentials (OPs) to the waveform at each stage of development. Recordings were obtained weekly from 2 to 5 weeks of age in six rabbits and every other day during the second week of life in six others. Comparative analysis of the ERGs showed a changing peak time and amplitude of the photopic b-wave with increasing age, consistent with the development of new components corresponding to the OPs. The results illustrate the importance of the OPs in determining both the amplitude and peak time of the photopic b-wave in the maturing rabbit.     

Aging effects on vernier hyperacuity: a function of oscillation rate but not target contrast.

PURPOSE: Most previous studies have shown static vernier acuity for high-contrast targets to be largely unaffected by aging; those examining adult age differences on oscillatory displacement thresholds have consistently reported marked age deficits. The goals of this study were to (1) measure the age deficit on oscillatory discrimination beyond that attributable to any change in spatial discrimination by using the same target configuration for both task types and (2) determine whether an age-related change in the contrast response of the visual system contributes to age differences on static or oscillatory discrimination. METHODS: The displacement thresholds of young and old observers for a vernier task configuration were determined at two target contrast levels (0.08 and 0.64) for static and oscillating targets (2 and 6 Hz) RESULTS: No age differences were seen on static displacement thresholds at either high or low contrast. A marked age deficit that emerged when oscillation was increased was unrelated to target contrast or observer contrast sensitivity. CONCLUSIONS: Age-related declines in oscillatory discrimination beyond those attributable to spatial discrimination do not appear to be attributable to optical factors nor to a decline in the contrast response of the senescent visual system. These findings are discussed in terms of a functional decline in the magnocellular pathway, or "neural entropy," possibly due to random cell loss.     

Electroretinographic evaluation in adult diabetics

In cross-sectional fashion, we recorded the maximal combined response and 30-Hz flicker responses in 178 adult diabetics and 40 normal controls according to the recommendations of the International Society of Clinical Electrophysiology of Vision. The oscillatory potentials were extracted from the maximal combined response by high-pass filtering. The clear media and attached retina were criteria for inclusion in this study. The data were statistically analyzed with the expectation that this procedure may provide a new feature that could have some clinical significance. Timing delays occurred more frequently than amplitude reductions in the maximal combined response and flicker responses, while amplitude reductions were more common in the first and second oscillatory potentials. The hypernormal b-wave amplitude was rare. The summed amplitude of the oscillatory potentials was highly correlated with the total power of the oscillatory potentials (the frequency domain). A reduction of the second oscillatory potential amplitude was more common than a reduction of the summed amplitude or total power. The electroretinographic component that demonstrates retinal dysfunction in the earlier stage may be a valuable indicator. In the early stage, a delay in the a-wave time and a reduction in the second oscillatory potential amplitude were the most frequent abnormalities: analysis of variance demonstrated that the summed amplitude of the oscillatory potentials and second oscillatory potential amplitude and time were the most sensitive measures of the diabetic retina. Hence, the second oscillatory potential amplitude may be the most sensitive and valuable indicator representing a quantitative measure of overall retinal dysfunction.     

Recording the oscillatory potentials of the electroretinogram with the DTL electrode

Suprathreshold photopic oscillatory potentials recorded with a DTL electrode were compared to those obtained with a Lovac corneal electrode. The overall oscillatory potential response (sum of oscillatory potentials) recorded with the DTL electrode was half of that obtained with the Lovac electrode. However, there was no evidence of a selective attenuation (or amplification) of any given oscillatory potential with the DTL electrode. Similarly, the oscillatory potential relative amplitude ratios and the peak times of the oscillatory potentials were identical for both electrodes. Our findings clearly indicate that the DTL electrode is adequate to record the high-frequency oscillatory potentials. Given the low cost and ease of use, as well as the disposable nature of the DTL electrode, we believe that electroretinographic specialists should seriously consider a wider utilization.     

The effects of vigabatrin on electrophysiology and visual fields in epileptics: a controlled study with a discussion of possible mechanisms

Purpose: To compare the visual electrophysiology and visual fields of patients taking vigabatrin to those of a control group of epileptics on other anti-epileptic drugs (AEDs). Methods: Fourteen epileptics treated with vigabatrin and 10 control patients treated with other AEDs underwent ERG and EOG. Goldmann visual fields were performed and analysed using standard software to measure areas contained within I4e isopters. Results: The cone and rod b-waves of the ERG, the oscillatory potential amplitudes and Arden indices were reduced in vigabatrin-treated subjects and the oscillatory potentials delayed. The Arden indices were reduced due to an increased dark trough. The areas contained within the I4e isopter of vigabatrin treated subjects were reduced compared to the control group and these areas correlated well with oscillatory potential amplitudes and b-wave amplitudes in the vigabatrin group only. Conclusions:The use of vigabatrin is associated with a reduction of the ERG cone b-wave amplitude and oscillatory potentials which correlates with visual field loss. The Arden ratio is reduced in subjects taking vigabatrin but may recover after cessation. However, visual loss may persist in the presence of a recovered EOG. These findings suggest further effects of the drug than those mediated by GABA receptors, and support the contention that the cause of the field loss may be at least in part due to retinal effects. Possible mechanisms are discussed.     

Reduced amplitude of oscillatory potentials in female carriers of X-linked recessive congenital stationary night blindness

We studied the electroretinograms of 12 female carriers in eight families with X-linked recessive congenital stationary night blindness. Forty-two normal eyes served as controls. The age and refractive error of the normal eyes were matched to those of the female carriers. We found the amplitude of the oscillatory potentials (01 + 02 + 03 + 04) in carriers was statistically smaller than in normal eyes. Seventeen of 22 eyes of carriers were more than +/- 2 S.D. away from normal, and the mean value was statistically lower than normal (P less than .001). The peak time of oscillatory potentials, and the amplitude of the a-, b-, scotopic b-, and photopic b-waves were all within the normal range. The selective abnormality of the amplitude of the oscillatory potentials is a new finding in female carriers in X-linked recessive congenital stationary night blindness.     

Electroretinogram changes after scleral buckling surgery of retinal detachment

Objective To observe changes in visual function after a single scleral buckling surgery for rhegmatogenous retinal detachment (RD) by using ERG (electroretinogram). Methods One eye from 56 patients with rhegmatogenous RD was chosen. Forty-three corresponding normal fellow eyes from these patients were chosen as controls. Single scleral buckling surgery was carried out and a full-field ERG was performed before the surgery, and 1 and 6 months after surgery. Results The mean amplitude of ERG decreased and the latency (except for the a-wave) was delayed in the eye with a retinal detachment, and wavelets of the oscillatory potential decreased or were completely lacking. One month after surgery, the amplitudes of the a and b waves were noticeably improved (except for the 30 Hz flicker responses), but the latency (except for the a-wave) was still delayed. The ratio of b/a (mixed response) increased 1 month after surgery, with no further changes thereafter. The amplitude of the scotopic b wave was 58.1% of the control eyes, while the 30 Hz flicker responses was only 45.8% of controls; the difference between the two responses was significant (P < 0.001). The number of oscillatory potential wavelets increased, but the total amplitude of the oscillatory potentials did not exhibit any obvious changes during the follow-up period (P = 0.20). In the 41 patients whose detachment involved the macula preoperatively, the amplitude of the 30 Hz flicker responses improved significantly after surgery (P = 0.037). Six months after the operation, the wave amplitudes were not significantly different from 1 month after surgery, but there was a tendency toward a decrease in the latency. Conclusions After reattachment of the retina, visual function showed dramatic improvement 1 month after the surgery. The postreceptoral responses recovered more than the a-wave. The rod system recovered more quickly and completely than the cone system during the follow-up period. The incomplete recovery observed by using ERGs indicates that there is irreversible damage that likely occurs following retinal detachment and surgery.     

Oscillatory potentials, macular recovery time, and diabetic retinopathy through 3 years of intensified insulin treatment

Forty-five diabetic patients, 18 to 45 years of age, with mild or no retinopathy, were randomly assigned to continuous subcutaneous insulin infusion (CSII), multiple injections (Mls), and conventional insulin treatment (CIT). The effects of near-normoglycemia (CSII and MI) on oscillatory potentials (electroretinography [ERG]) and macular recovery time (nyctometry) were studied prospectively for 41 months. Before randomization, the amplitudes of oscillatory potentials were negatively correlated to age (P = 0.002) and positively correlated to the diameter of retinal veins (P less than 0.05). Men had shorter macular recovery time than women (P = 0.03). Nyctometry and oscillatory potentials were not related to mean blood glucose values, glycosylated hemoglobin (HbA1), retinopathy, blood pressure levels, or duration of diabetes. Changes in metabolic control (MI and CSII; P less than 0.01) and in microaneurysms and hemorrhages (CSII and CIT) during the study did not affect oscillatory potentials or nyctometry. Soft exudates (15 patients) and proliferative retinopathy (1 patient) transiently developed with MI and CSII regimens. No changes in oscillatory potentials or nyctometry were observed and no pretreatment characteristics of these parameters predicted the occurrence of these ischemic lesions. At the stage of proliferation, however, lowered amplitudes of oscillatory potentials and lengthened macular recovery time were observed.     

Vigabatrin; its effect on the electrophysiology of vision

Vigabatrin is known to induce visual field defects in approximately one third of patients treated with the drug. It is apparent from electrophysiological studies that the cause of this defect is at retinal level probably as a result of the build up of GABA. Studies of electrophysiological retinal parameters such as the EOG and photopic, scotopic and 30-Hz flicker ERG have revealed changes in Arden Index, photopic a and b wave latency and amplitude, changes in oscillatory potentials, and changes in latency and amplitude of the 30Hz response. However, many of these changes such as the Arden Index, oscillatory potentials, latency and amplitude of photopic b wave appear to be related to current anti-epileptic drug treatment rather than visual field defects. Certain parameters, particularly the amplitude of the 30-Hz flicker response, do appear to correlate with the severity of the field defect. Paediatric patients treated with the drug at age 9 years or below cannot reliably perform visual field perimetry. To identify these patients a special VEP H-Stimulus has been developed to produce separate responses from central and peripheral field stimulation by alternating at slightly separate rates. Forty-five healthy children between ages 3 and 10 years have been used to develop a normal database. This technique has a sensitivity of 75% and a specificity of 87.5% in identifying the field defect and may be used in children with epilepsy from age 3 upwards.     

Correlation of an exercise-induced increase in systemic circulation with neural retinal function in humans

Although the effects of physical exertion on intraocular pressure and systemic blood pressure are well established, the retinal response to such physiologic stress has not been examined. We studied the effect of short-term intense exercise on the principal waves in the scotopic and photopic flash electroretinograms, as well as the lower-amplitude oscillatory potentials. Sixteen healthy volunteers between 20 and 30 years of age participated in this experiment. The electroretinograms and oscillatory potentials were recorded with a Nicolet CA-1000 clinical averager, using DTL-type fiber electrodes. All retinal potentials were taken immediately before and after a minimum 20-min period of stationary bicycling that increased the heart rate to about 140 beats per minute. The electroretinograms were recorded from eyes with dilated pupils, 10 min after white-light adaptation of the right eye, and 30 min after dark adaptation of the left eye. Red flashes and dim white flashes were used to elicit photopic and scotopic electroretinograms, respectively. While no changes were recorded for any of the electroretinogram components recorded under photopic conditions, the amplitude of OP5 was decreased and the implicit time of OP4 was delayed after exercise for scotopic conditions. We concluded that exercise caused component-specific changes in the scotopic oscillatory potentials. Since it is well known that oscillatory potentials are vulnerable to ischemia, scotopic oscillatory potentials may be used as simple noninvasive indices of the reactivity of the retinal vascular autoregulatory system during exercise.     

Electrophysiological findings in anterior ischemic optic neuropathy

Electroretinograms (ERG), oscillatory potentials (OP) and pattern reversal visual evoked potentials (VEP) were performed in nine patients (mean age 66 years) with unilateral long-standing anterior ischemic optic neuropathy (AION) and in an age matched control group. Normal ERGs but bilateral impaired OPs were observed in virtually all AION affected patients. Regardless of visual acuity, VEP amplitude reduction was found in all eyes with AION and in controlateral eyes of patients with associated systemic conditions such as diabetes mellitus, arterial hypertension and atherosclerosis. A normal latency of VEP was found bilaterally in AION affected patients; however no correlation between VEP latency and visual acuity or fields could be established. Our results seem to indicate moderate ischemic damage to the retina and to the axons of the optic pathways in patients with AION.     

Methodologic dependence of electroretinogram oscillatory potential amplitudes

The International Society for Clinical Electrophysiology of Vision (ISCEV) protocol for eliciting oscillatory potentials uses a considerably lower flash intensity and a different preconditioning stimulus than the only oscillatory potential protocol used to predict progression of diabetic retinopathy. To determine if the ISCEV protocol will be useful in predicting progression of diabetic retinopathy, summed oscillatory potential amplitudes were measured by both protocols in a population of diabetics. Summed oscillatory potential amplitudes measured by the ISCEV protocol, although smaller, are highly correlated with the summed oscillatory potential amplitudes measured with the higher-intensity flash. Thus, summed oscillatory potential amplitudes measured with the ISCEV protocol should be useful in predicting outcome in diabetic retinopathy. Different signal processing filters used to extract oscillatory potentials from the electroretinogram waveform have a small, but significant, effect on summed oscillatory potential amplitude. Use of the caliper-square method or the summed peak-to-trough method for measuring oscillatory potential heights had an insignificant effect on measured oscillatory potential amplitude.Abbreviation FIR finite impulse response     

The influence of adaptation on the oscillatory potentials of the human electroretinogram

The influence of adaptation on the oscillatory potentials of the human electroretinogram was studied in the domains of frequency and time. The amplitude of OP1 to OP4, the summed amplitude of OP1 to OP4, as well as the area, decreased from dark adaptation to light adaptation. With increasing intensities of background illumination, they increased slightly and appeared to decrease with the strongest background illumination. The implicit time of oscillatory potentials 3 and 4 increased with stronger background illumination and decreased with the strongest background illumination. The results of the dominant frequency and the total power of the OPs correspond to the results in the time domain. The dominant power decreased from dark adaptation into light adaptation and did not show any systematic changes with increasing intensity of background illumination.Abbreviations BG background illumination - OP oscillatory potential