mfERG Implicit Time Research Articles

Fixation stability and implication for multifocal electroretinography in patients with neovascular age-related macular degeneration after anti-VEGF treatment.

To quantify fixation stability in patients with neovascular age-related macular degeneration (nAMD) at baseline, 3 and 6months after anti-vascular endothelial growth factor (anti-VEGF) treatment and furthermore asses the implications of an unsteady fixation for multifocal electroretinography (mfERG) measurements. Fifty eyes of 50 nAMD patients receiving intravitreal anti-VEGF treatment with either bevacizumab or ranibizumab and eight eyes of eight control subjects were included. Fixation stability measurements were performed with the Eye-Link eyetracking system and the retinal area in degrees2 (deg2) containing the 68% most frequently used fixation points (RAF68) was calculated. MfERG P1 amplitude and implicit time were analyzed in six concentric rings and as a summed response. Patients were examined at baseline, 3 and 6months. Four different mfERG recordings were performed for the control subjects to mimic an involuntary unstable fixation: normal central fixation, 2.4°, 4.8°, and 7.1° fixation instability. For control subjects, a fixation instability of 2.4° (corresponding to the central hexagon) did not reduce mfERG ring amplitudes significantly, whereas 4.8° and 7.1° fixation instability reduced the amplitudes significantly in rings 1 and 2 (p < 0.001) as well as in the peripheral rings in the 7.1° instability condition (p < 0.001). Fixation stability improved non-significantly for patients at 3 and 6months. The size of the retinal area of fixation was at baseline, 3 and 6months negatively correlated to visual acuity (VA) (rbaseline = -0.65, r3 months = -0.60, and r6 months = -0.66 respectively, p < 0.001) and mfERG amplitudes of the three innermost rings (rbaseline = -0.29, p = 0.042, r3months = -0.43, p = 0.003 and r6months = -0.31, p = 0.042). The VA cutoff for a fixation area less than 5deg2 (approximately the central hexagon) was 65, 77, and 68 ETDRS letters (corresponding a maximal Snellen equivalent of 0.31) at baseline, 3 and 6months, respectively. MfERG amplitudes in recordings of nAMD patients are at substantial risk of being reduced due to poor fixation as a large number of patients may use a fixation area of more than 5deg2. Fixation monitoring during recording as well as interpretation of results should be performed with care, especially in patients with poor visual acuity.

Is multifocal electroretinography an early predictor of glaucoma?

To investigate the potential use of mfERG as an objective functional test that can express inner and outer retinal changes during the early stages of glaucoma. One hundred and twenty-six eyes of 126 patients were included. There were 30 healthy (Group 1), 28 glaucoma suspect (Group 2), 48 early glaucoma (Group 3), and 20 advanced glaucoma cases (Group 4). After complete ophthalmic examination, Humphrey visual field analysis and mfERG were performed. These examinations were performed three times at 6-month intervals, and only the last examination results were used for the analysis. Visual fields global indices and mfERG implicit time and amplitudes were evaluated and analyzed by ring system (central 5°, 5°-10°, 10°-15° and >15°). One-way ANOVA and ROC curve analysis were used for statistical analysis. There was no statistically (one-way ANOVA) significant differences in patient age between groups (p = 0.126). For all rings, we detected statistically significant differences for the mean implicit time (latency) of the N1, P1, and N2 components between the advanced glaucoma and control subjects and between the advanced glaucoma and glaucoma suspects. The N2 amplitudes were significantly decreased in all rings in the advanced glaucoma patients when compared with control subjects. The N2 amplitude was significantly different between healthy subjects (Group 1) and early glaucoma subjects (Group 3) in the central 2° and 2°-5° rings. We used MedClac ROC curve analysis to identify the best parameters for discriminating between control subjects (Group 1) and early glaucoma patients (Group 3). The N2 implicit time for the central 2° ring (p < 0.0001), N2 amplitude for the central 2° ring (p = 0.0001), P1 implicit time for the 2°-5° ring (p = 0.0001), N2 implicit time for the 2°-5° ring (p = 0.0003), and N2 amplitude for the 2°-5° ring (p = 0.001) had ≥0.7 AUC values and were the best parameters in the ROC curve analyses that included the VFA parameters Alterations of amplitudes and implicit times of N2 response in the central area may be able to detect glaucoma earlier than VFA. In addition, with progression to advanced glaucoma these changes can be significant in all retinal areas. Although implicit times of all mfERG components are significantly delayed in glaucoma, both delayed implicit time and decreased amplitude of N2 wave in the central area are effective predictors in early glaucoma diagnosis.

Retinal Vascular Fractals Correlate With Early Neurodegeneration in Patients With Type 2 Diabetes Mellitus.

To investigate the correlation between the retinal vascular fractal dimension (Fd) and neurodegenerative changes in patients with no or mild diabetic retinopathy (DR). In this cross-sectional study we examined 103 patients with type 2 diabetes mellitus (T2DM) with no or mild DR. In a randomly selected eye of each patient, Fd was calculated using SIVA-Fractal, a specialized semiautomatic software. Retinal neurodegeneration was evaluated by Topcon 3D OCT-2000 spectral-domain optical coherence tomography (OCT) and by a RETI-scan multifocal ERG (mf-ERG) system in rings one to six. Level of DR was determined by a single trained grader in seven-field fundus photos according to the Early Treatment Diabetic Retinopathy Study (ETDRS) scale. Mean age and duration of T2DM were 62.3 and 11.6 years, respectively; 46.6% were men. Mean Fd was 1.413 (range, 1.278-1.509) and ETDRS levels were 10 (42.7%), 20 (35.0%), and 35 (22.3%), respectively. Fd correlated inversely with mf-ERG implicit time of ring one (r = -0.25, P = 0.01) and present diabetic neuropathy (P = 0.02), and positively with OCT ganglion cell layer (GCL) thickness (r = 0.20, P = 0.04). In a multivariable linear regression model, Fd was associated with mf-ERG implicit time of ring one (coefficient -0.0021/ms, P = 0.040) and the presence of diabetic neuropathy (coefficient -0.0209 for neuropathy present versus absent, P = 0.041). In patients with T2DM and no or minimal DR, independent correlations were found between early vascular and neurogenic changes. Thus, retinal vascular fractal analysis might be considered as a tool to identify patients with early neurodegenerative retinal changes.

Impact of reticular pseudodrusen on microperimetry and multifocal electroretinography in intermediate age-related macular degeneration.

To examine the influence of reticular pseudodrusen (RPD) on retinal and visual function in intermediate AMD using multifocal electroretinography (mfERG) and microperimetry. In a prospective cross-sectional study, microperimetry and mfERG testing, followed by color fundus photography, near-infrared reflectance imaging and spectral-domain optical coherence tomography (SD-OCT) scans were performed in 120 eyes from 60 participants with bilateral intermediate AMD. The number of subfields with pigmentary changes and RPD within the central 3-mm diameter of the Early Treatment of Diabetic Retinopathy Study (ETDRS) grid and drusen cube root volume within the central 3-mm diameter was determined. The influence of these pathological features on microperimetry and mfERG in this region were examined. Microperimetric sensitivity was not significantly associated with the presence and extent of RPD (P = 0.068), but with drusen volume and extent of pigmentary changes (P < 0.001 for both). However, the presence and extent of RPD was independently and significantly associated with mfERG implicit time, along with drusen volume and the extent of pigmentary changes (P ≤ 0.023). The mfERG response amplitude was not significantly associated with the presence and extent of RPD (P = 0.130). The presence and extent of RPD was associated with functional changes on mfERG implicit time, but not mfERG response amplitude or microperimetry. These findings suggest that the presence of RPD in eyes with intermediate AMD has a significant influence on cone-mediated neuroretinal function, without a significant influence on mesopic visual function as determined on microperimetry.

Color vision and neuroretinal function in diabetes.

We investigate how type 2 diabetes (T2DM) and diabetic retinopathy (DR) affect color vision (CV) and mfERG implicit time (IT), whether CV and IT are correlated, and whether CV and IT abnormality classifications agree. Adams desaturated D-15 color test, mfERG, and fundus photographs were examined in 37 controls, 22 T2DM patients without DR (NoRet group), and 25 T2DM patients with DR (Ret group). Color confusion score (CCS) was calculated. ITs were averaged within the central 7 hexagons (central IT; ≤4.5°) and outside this area (peripheral IT; ≥4.5°). DR was within (DRIN) or outside (DROUT) of the central 7 hexagons. Group differences, percentages of abnormalities, correlations, and agreement were determined. CCS was greater in the NoRet (P=0.002) and Ret (P<0.0001) groups than in control group. CCS was abnormal in 3, 41, and 48% of eyes in the control, NoRet, and Ret groups, respectively. Ret group CV abnormalities were more frequent in DRIN than in DROUT subgroups (71 vs. 18%, respectively; P<0.0001). CCS and IT were correlated only in the Ret group, in both retinal zones (P≤0.028). Only in the Ret group did CCS and peripheral IT abnormality classifications agree (72%; P<0.05). CV is affected in patients with T2DM, even without DR. Central DR increases the likelihood of a CV deficit compared with non-central DR. mfERG IT averaged across central or peripheral retinal locations is less frequently abnormal than CV in the absence of DR, and these two measures are correlated only when DR is present.

Global flash multifocal electroretinogram: early detection of local functional changes and its correlations with optical coherence tomography and visual field tests in diabetic eyes

To investigate the correlations of the global flash multifocal electroretinogram (MOFO mfERG) with common clinical visual assessments--Humphrey perimetry and Stratus circumpapillary retinal nerve fiber layer (RNFL) thickness measurement in type II diabetic patients. Forty-two diabetic patients participated in the study: Ten were free from diabetic retinopathy (DR), while the remainder suffered from mild to moderate nonproliferative diabetic retinopathy. Fourteen age-matched controls were recruited for comparison. MOFO mfERG measurements were made under high- and low-contrast conditions. Humphrey central 30-2 perimetry and Stratus OCT circumpapillary RNFL thickness measurements were also performed. Correlations between local values of implicit time and amplitude of the mfERG components [direct component (DC) and induced component (IC)], and perimetric sensitivity and RNFL thickness were evaluated by mapping the localized responses for the three subject groups. MOFO mfERG was superior to perimetry and RNFL assessments in showing differences between the diabetic groups (with and without DR) and the controls. All the MOFO mfERG amplitudes (except IC amplitude at high contrast) correlated better with perimetry findings (Pearson's r ranged from 0.23 to 0.36, p < 0.01) than did the mfERG implicit time at both high and low contrasts across all subject groups. No consistent correlation was found between the mfERG and RNFL assessments for any group or contrast conditions. The responses of the local MOFO mfERG correlated with local perimetric sensitivity but not with RNFL thickness. Early functional changes in the diabetic retina seem to occur before morphological changes in the RNFL.

In diabetic eyes, multifocal ERG reflects differences in function between the nasal part and the temporal part of the macula

The purpose of the present study was to compare retinal function between the perifoveal nasal and perifoveal temporal areas of diabetic eyes using multifocalERG (mfERG). We included 36 eyes from 27 patients with diabetes (age 58 ± 14years; duration of diabetes 13 ± 9years; HbA(1c) 7.1 ± 1.8%) and a control group with 18 eyes from 18 healthy subjects (age 57 ± 11years). Retinal thickness was assessed with optical coherence tomography (OCT) in the perifoveal areas corresponding to the summed nasal and temporal inner and outer areas. MfERG amplitude and implicit time were recorded from corresponding areas. Diabetic eyes showed lower mfERG amplitude in the nasal area than in the temporal area (14 ± 6 vs 17 ± 7nV/deg(2); p < 0.0001) and longer implicit time (31 ± 3 vs 30 ± 3ms; p = 0.005). In the control group, there were no significant differences between the two areas. Diabetic eyes showed lower amplitude and longer implicit time in the nasal area than in the temporal, which might indicate that the nasal area is more vulnerable. These findings may be of importance for evaluation of diabetic maculopathy and outcome after laser treatment.

Central Retinal Function as Measured by the Multifocal Electroretinogram and Flicker Perimetry in Early Age-Related Macular Degeneration

To determine the retinal function in early age-related macular degeneration (AMD) assessed by the multifocal electroretinogram (mfERG) and flicker perimetry and to seek a relationship between local objective mfERG parameters and subjective flicker perimetry thresholds. mfERG and flicker perimetry were performed in 15 patients (15 eyes) with early AMD and 14 controls (14 eyes) of similar age. The mfERG P1 response amplitude density (nV/deg²) and P1 implicit time of the first-order kernel and the flicker thresholds of each concentric ring were analyzed. The relationship between individual mfERG responses and the corresponding individual flicker sensitivity outcomes was determined. The mfERG response amplitude of the central ring (ring 1) was significantly reduced in early AMD eyes compared with the controls (P = 0.009). No significant difference in mfERG amplitude between early AMD and control eyes was detected in the other rings. The mfERG implicit time was significantly increased in the early AMD eyes but only within the central four rings of 12°. A significant reduction in flicker sensitivity was also detected in early AMD eyes but only within the central 6°. There was a significant, moderate correlation (r = -0.477; P < 0.001) between local mfERG latency and flicker sensitivity from the same tested locations within the central 6°. There was a weak correlation (r = 0.200; P = 0.014) between mfERG amplitude and flicker sensitivity. Both mfERG and flicker perimetry show abnormal retinal function, but only in the very central macula, in early AMD. A novel relationship between mfERG and flicker sensitivity should enhance the clinical monitoring of disease progression.

Prediction, by Retinal Location, of the Onset of Diabetic Edema in Patients with Nonproliferative Diabetic Retinopathy

To formulate a model to predict the location of the onset of diabetic retinal edema (DE) in adults with diabetic retinopathy (DR), at risk for DE. In all, 46 eyes from 23 patients with DR were included. Subjects were followed semiannually until DE developed or the study concluded. The presence or absence of DE within the central 45 ° at the final visit was the outcome measure, and data from the prior visit were used as baseline. A logistic regression model was formulated to assess the relationship between DE development and: multifocal electroretinogram (mfERG) implicit time (IT) Z-score, mfERG amplitude (Amp) Z-score, sex, diabetes duration, diabetes type, blood glucose, HbA1c, age, systolic (SBP) and diastolic blood pressure, and grade of retinopathy. A total of 35 retinal zones were constructed from the mfERG elements and each was graded for DE. Data from 52 control subjects were used to calculate the maximum IT and minimum Amp Z-scores for each zone. Receiver operating characteristic curves from a fivefold cross-validation were used to determine the model's predictive properties. Edema developed in 5.2% of all retinal zones and in 35% of the eyes. The mfERG Amp, mfERG IT, SBP, and sex were together predictive of edema onset. Combined, these factors produce a model that has 84% sensitivity and 76% specificity. Together mfERG, SBP, and sex are good predictors of local edema in patients with DR. The model is a useful tool for assessing risk for edema development and a candidate measure to evaluate novel therapeutics directed at DE.

Multifocal Electroretinograms Predict Onset of Diabetic Retinopathy in Adult Patients with Diabetes

The authors' previous models predicted local formation of diabetic retinopathy (DR) in adults with diabetes and existing retinopathy. Here they derived a multivariate model for local prediction of DR onset in patients with no previous retinopathy. Seventy-eight eyes from 41 diabetes patients were tested annually for several years. The presence or absence of DR at the last study visit was the outcome measure, and measurements of risk factors from the previous visit were used for prediction. Logistic regression was used to assess the relationship between DR development and 7 factors: multifocal ERG (mfERG) implicit time (IT) Z-score, sex, diabetes duration, blood glucose, HbA1c, age, and diabetes type. Thirty-five retinal zones, spanning 45°, were constructed from the mfERG stimulus elements. The maximum IT Z-score for each zone was calculated based on data from 50 control subjects. ROC curve analysis, using fivefold cross-validation, was used to determine the model's predictive properties. Mild DR developed in 80 of 2730 retinal zones (3%) in 29 of 78 eyes (37%). Multivariate analysis showed mfERG IT to be predictive for DR development in a zone after adjusting for diabetes type. The multivariate model has a sensitivity of 80% and a specificity of 74%. mfERG IT is a good predictor of DR onset, 1 year later, in patients with diabetes without DR. It can be used to assess the risk for DR development in these patients and may be a valuable outcome measure in evaluation of novel prophylactic therapeutics directed at impeding DR.

Multifocal VEP (mfVEP) reveals abnormal neuronal delays in diabetes

This pilot study examined the diagnostic role of multifocal visually evoked potentials (mfVEP) in a small number of patients with diabetes. mfVEP, mfERG, and fundus photographs of both eyes of five patients with diabetes, three with nonproliferative diabetic retinopathy (NPDR) and two without NPDR were examined. Thirteen control subjects were also examined. Eighteen zones were constructed from the 60-element mfVEP stimulus array. mfVEP implicit time (IT) and amplitude (SNR) differences were tested between subject groups. We also examined whether there was a difference in function for patches with and without retinopathy in the NPDR group. Lastly, we compared mfVEP and mfERG results in the same patients. We found significant mfVEP IT differences between controls and all patients with diabetes, controls and diabetics without retinopathy, and between controls and diabetics with retinopathy. The subject groups did not differ significantly in terms of SNR. In the retinopathy group, ITs from zones with retinopathy were significantly longer than ITs from zones without retinopathy (P = 0.016). mfERG IT was more frequently abnormal than mfVEP IT. In addition, mfERG hexagons were twice as likely to be abnormal if the corresponding mfVEP zone was abnormal (P < 0.05). mfVEP implicit times are significantly delayed in patients with diabetes even when there is no retinopathy. These cortical response results are similar, albeit considerably less abnormal, than those previously reported for retinal (mfERG) responses in patients with diabetes. A correlation exists between the location of abnormal mfERG hexagons and abnormal mfVEP zones.

MfERG implicit time as a predictor of future diabetic retinopathy development

MfERG implicit time as a predictor of future diabetic retinopathy development

Analysis of multifocal electroretinography implicit times in the prediction of macular hole formation

Abstract Purpose Our aim was to investigate the predictive role of multifocal electroretinography (mfERG) by analyzing the implicit time changes in the fellow eye of patients with unilateral macular hole. Methods 80 eyes of 40 patients with unilateral macular hole were examined by mfERG (RetiScan, Roland Consult, Germany). Ring ratios of the multifocal electroretinograms were calculated by correlating the central rings’ implicit time with that of the peripheral ones (T1/T2, T1/T3, T1/T4 and T1/T5). After vitreoretinal surgery, during the follow‐up period of 24 months, in 13 of 40 cases macular hole formation was detected in the previously intact fellow eye by optical coherence tomography. Patients were divided into two groups according to this. The implicit time ring ratios of the two groups were compared. Results Surprisingly, although the implicit times showed no significant difference in the two groups, the ratios T1/T2, T1/T3, T1/T4 and T1/T5 were significantly lower in the eyes that later developed macular hole (1.08, 1.12, 1.14, 1.16) than those which remained intact (1.01, 1.03, 1.05, 1.07, respectively; p&lt;0,05). Conclusion By analyzing the mfERG implicit time, using ring ratios seems to be a more sensitive method in predicting macular hole formation in the fellow eye, than analyzing the implicit times alone. Lower values might forecast propensity for subsequent macular holes. These patients may require stricter follow‐up.

Local Diabetic Retinopathy Prediction by Multifocal ERG Delays over 3 Years

To derive and validate a model for use in predicting local retinal areas in which nonproliferative diabetic retinopathy (NPDR) lesions will develop over a 3-year period, by using primarily the implicit time (IT) of the multifocal electroretinogram (mfERG). Eighteen diabetic patients were examined at baseline and at three annual follow-ups. Ophthalmic examinations, including fundus photographs and mfERG testing, were performed at each visit. Thirty-five retinal zones were constructed from the 103-element stimulus array, and each zone was assigned the maximum IT z-score within it based on 30 age-similar control subjects. Logistic regression was used to investigate the development of retinopathy in relation to baseline mfERG IT delays and additional diabetic health variables. Receiver operating characteristic (ROC) curves were used to evaluate the models. Retinopathy developed in 77 of the 1208 retinal zones, of which 25 had recurring retinopathy. Multivariate analyses yielded baseline mfERG IT, duration of diabetes, and blood glucose concentration as the most important predictors of recurring retinopathy. mfERG ITs were not predictive of transient retinopathy. ROC curves based on the multivariate model for the prediction of recurring retinopathy resulted in an area under the curve of 0.95, sensitivity of 88%, and specificity of 98%. Ten-fold cross-validation confirmed the high sensitivity and specificity of the model. The development of recurring retinopathy over a 3-year period can be well predicted by using a multivariate model based on mfERG implicit time. Multifocal ERG delays are promising candidate measures for trials of novel therapeutics directed at preventing or slowing the progression of NPDR.

A multifocal electroretinogram model predicting the development of diabetic retinopathy.

The prevalence of diabetes has been accelerating at an alarming rate in the last decade; some describe it as an epidemic. Diabetic eye complications are the leading cause of blindness in adults aged 25-74 in the United States. Early diagnosis and development of effective preventatives and treatments of diabetic retinopathy are essential to save sight. We describe efforts to establish functional indicators of retinal health and predictors of diabetic retinopathy. These indicators and predictors will be needed as markers of the efficacy of new therapies. Clinical trials aimed at either prevention or early treatments will rely heavily on the discovery of sensitive methods to identify patients and retinal locations at risk, as well as to evaluate treatment effects. We report on recent success in revealing local functional changes of the retina with the multifocal electroretinogram (mfERG). This objective measure allows the simultaneous recording of responses from over 100 small retinal patches across the central 45 degrees field. We describe the sensitivity of mfERG implicit time measurement for revealing functional alterations of the retina in diabetes, the local correspondence between functional (mfERG) and structural (vascular) abnormalities in eyes with early nonproliferative retinopathy, and longitudinal studies to formulate models to predict the retinal sites of future retinopathic signs. A multivariate model including mfERG implicit time delays and 'person' risk factors achieved 86% sensitivity and 84% specificity for prediction of new retinopathy development over one year at specific locations in eyes with some retinopathy at baseline. A preliminary test of the model yielded very positive results. This model appears to be the first to predict, quantitatively, the retinal locations of new nonproliferative diabetic retinopathy development over a one-year period. In a separate study, the predictive power of a model was assessed over one- and two-year follow-ups. This permitted successful prediction of new retinopathy development in eyes with and without retinopathy at baseline. Finally, we briefly describe our current research efforts to (a) locally predict future sight-threatening diabetic macular edema, (b) investigate local retinal function change in adolescent patients with diabetes, and (c) better understand the physiological bases of the mfERG delays. The ability to predict the retinal locations of future retinopathy based on mfERG implicit time provides clinicians a powerful tool to screen, follow-up, and even consider early prophylactic treatment of the retinal tissue in diabetic patients. It also aids identification of 'at risk' populations for clinical trials of candidate therapies, which may greatly reduce their cost by decreasing the size of the needed sample and the duration of the trial.

Formulation and Evaluation of a Predictive Model to Identify the Sites of Future Diabetic Retinopathy

To formulate and test a model to predict the development of local patches of nonproliferative diabetic retinopathy (NPDR), based on multifocal electroretinogram (mfERG) implicit times and candidate diabetic risk factors. mfERGs and fundus photographs were obtained from 28 eyes of 28 diabetic patients during an initial and 12-month follow-up examination. mfERG implicit times were derived at 103 locations using a template-stretching method, and a z-score was calculated in comparison with 20 age-matched normal subjects. Thirty-five nonoverlapping retinal zones were constructed by grouping two to three adjacent stimulated locations, and each zone was assigned the maximum z-score within it. Zones containing initial retinopathy were excluded from further analysis. The probability that new retinopathy would develop in the remaining zones by the follow-up examination was modeled based on the mfERG implicit time z-score for the zone and other candidate diabetic risk factors determined during the initial visit. Data collected from four previously untested diabetic subjects and the other eye of eight previous subjects during their second year follow-up were used to test the predictive model. After 1 year, new retinopathy developed in 11 of the 12 NPDR eyes and 1 of the 16 eyes without initial retinopathy. After accounting for the correlation among zones within each eye, a predictive model was formulated with the variables mfERG implicit time, duration of diabetes, presence of retinopathy (NPDR or no retinopathy), and blood glucose level at initial visit. The area under the receiver operating characteristic (ROC) curve of this multivariate model is 0.90 (P <0.001). The predictive model has an expected sensitivity of 86% and a specificity of 84%, which was verified by the test data. The development of diabetic retinopathy over a 1-year period can be well predicted by a multivariate model. The inclusion of local mfERG implicit times allowed the model to identify the specific sites of future retinopathy.