Tom Wright

Multifocal ERG Defects Associated with Insufficient Long-Term Glycemic Control in Adolescents with Type 1 Diabetes

PURPOSE To investigate the relationship between long-term glycemic control and localized neuroretinal function in adolescents with type 1 diabetes (T1D) without diabetic retinopathy (DR). METHODS Standard (103 hexagons) and slow-flash (61 hexagons) multifocal ERGs (standard mfERG and sf mfERG) were recorded in 48 patients and 45 control subjects. Hexagons with delayed responses were identified as abnormal. Negative binomial regression analysis was conducted with the number of abnormal hexagons as the outcome variable. Glycated hemoglobin (HbA(1c)) levels, time since diagnosis of T1D, age at diagnosis of T1D, age at testing, and sex were the covariates. Another model replacing HbA(1c) closest to the date of testing with a 1-year average was also generated. RESULTS There were more abnormal hexagons for mfOPs in patients than in control subjects (P = 0.005). There was no significant difference in the mean number of abnormal hexagons for standard mfERG responses between patients and control subjects (P = 0.11). Negative binomial regression analysis for the standard mfERG data demonstrated that a 1-unit increase in HbA(1c) was associated with an 80% increase in the number of abnormal hexagons (P = 0.002), when controlling for age at testing. Analysis using the 1-year HbA(1c) averages did not result in significant findings. CONCLUSIONS Poor long-term glycemic control is associated with an increase in areas of localized neuroretinal dysfunction in adolescents with T1D and no clinically visible DR. Stricter glucose control during the early stages of the disease may prevent neuroretinal dysfunction in this cohort.

Localizing functional damage in the neural retina of adolescents and young adults with type 1 diabetes.

PURPOSE It is unknown which regions of the retina are most susceptible to damage by diabetes mellitus. We hypothesized that the standard and slow-flash (sf-) multifocal electroretinogram (mfERG) will localize retinal regions of greatest vulnerability. METHODS A total of 55 adolescents and young adults with type 1 diabetes and without diabetic retinopathy (DR) or with mild nonproliferative DR and 54 typically-developing, age-similar control participants underwent mfERG and sf-mfERG testing. The amplitude and implicit time of the first order response of the standard mfERG and of three multifocal oscillatory potentials (mfOPs) of the sf-mfERG were compared between groups at the level of hexagons, quadrants, and rings using separate mixed model ANOVAs. Spatial mapping of the P values from post hoc pairwise comparisons illustrated patterns of retinal dysfunction. RESULTS Delays in mfERG implicit times were evident across the tested retinal areas in the diabetes group. Delays in sf-mfERG implicit times were found at different eccentricities for each mfOP in the diabetes group. The greatest delays were noted in the periphery for mfOP1, in the midperiphery for mfOP2, and in the macular region for mfOP3. There were no significant group differences in amplitude for the mfERG and sf-mfERG protocols. CONCLUSIONS Delays in mfERG and sf-mfERG responses suggest that the inner retina is particularly vulnerable to diabetes. Localizing regions of early dysfunction will help guide future studies to examine early structural damage associated with DR.

Oligocone trichromacy is part of the spectrum of CNGA3-related cone system disorders

Purpose: To report the rare observation of CNGA3 mutation as a cause of oligocone trichromacy (OT) and present phenotypic characteristics. Methods: A 20 year old male patient underwent ophthalmological evaluation including detailed color vision assessment using Ishihara pseudoisochromatic plates, American Optical Hardy Rand Rittler plates (HRR) and Mollon-Reffin Minimalist test (MRM). Optical coherence tomography (OCT), fundus autofluorescence (FAF), visual field assessment and electrophysiological testing was also performed. The patient’s DNA was sequenced for mutations in the coding sequence of CNGA3 and CNGB3 genes. Results: Best corrected visual acuity (BCVA) was 20/50 and 20/30 in the right and left eyes respectively. His color vision was normal to Ishihara, HRR and MRM tests. Fundus appearance, FAF, OCT and Goldmann visual fields (GVF) were all normal. Humphrey visual field analysis (HVF) demonstrated reduced sensitivity and paracentral scotomas (5–20°). The full-field electroretinogram (ERG) showed normal rod responses and severely reduced cone responses. The multifocal electroretinogram (mfERG) was non-recordable above noise. Compound heterozygous mutations in exon 8 of the CNGA3 coding sequence were identified; c.1070 A > G (Tyr357Cys; novel) and c.1694 C > T (Thr565Met). Allele-specific polymerase chain reaction confirmed that the mutations were located on separate alleles. No mutations were identified in CNGB3. Conclusion: This is the second reported case of CNGA3 associated OT. Mutations in CNGA3 have previously been associated with incomplete and complete achromatopsia. This report confirms that OT forms the mildest end of the spectrum of CNGA3 related diseases.

Blue Flash ERG PhNR Changes Associated with Poor Long-Term Glycemic Control in Adolescents with Type 1 Diabetes

PURPOSE To investigate the relationship between long-term glycemic control and photopic negative response (PhNR) changes in the blue flash ERG in adolescents with type 1 diabetes (T1D) without diabetic retinopathy (DR). METHODS After light adaptation, ERG responses to 1.60 cd·s/m(2) blue (420 nm) flashes (blue flash ERG) and 3.0 cd·s/m(2) white flashes (LA 3.0 ERG) were recorded in 22 patients (age range, 12 to 19 years) and 28 age-similar control subjects. The primary outcome measure was the amplitude of the PhNR. Secondary outcome measures were the amplitude and implicit time of the a-wave and b-wave. Multiple regression analyses were conducted with glycated hemoglobin (HbA(1c)) values and the time since diagnosis of T1D as covariates. RESULTS Blue flash ERG PhNR amplitudes were reduced (P = 0.005) in patients compared with control subjects. Multiple regression analysis demonstrated that a 1-unit increase in HbA(1c) was associated with a 15% decrease in the blue flash ERG PhNR amplitude (r = 0.61, P = 0.003). Compared with controls blue flash ERG a-waves (P = 0.03) and b-waves (P = 0.02) were delayed in patients but were not significantly associated with HbA(1c) or time since diagnosis of T1D. None of the ERG measures in the LA 3.0 ERG were significantly different in patients compared with controls. CONCLUSIONS Poorer long-term glycemic control is associated with worsening inner retinal dysfunction involving short-wavelength cone pathways of adolescents with T1D and no clinically visible DR. Future studies are warranted to determine whether changes in the blue flash ERG PhNR are a predictive marker of subclinical DR.

Cone-Photoreceptor Density in Adolescents With Type 1 Diabetes.

PURPOSE Changes to retinal structure and function occur in individuals with diabetes before the onset of diabetic retinopathy. It is still unclear if these changes initially affect vascular or neural retina, or if particular retinal areas are more susceptible than others. This paper examines the distribution of cone photoreceptor density in the retina of adolescents with type 1 diabetes. METHODS This cross-sectional prospective study includes 29 adolescents and young adults with type 1 diabetes and no diabetic retinopathy and 44 control participants recruited at the Hospital for Sick Children. Adaptive-optics enhanced retinal imaging of the cone photoreceptor mosaic was performed in four quadrants at an eccentricity of ∼7° from the fovea. After image registration and averaging, cone photoreceptors were counted and photoreceptor density was calculated. Analysis of variance with repeated measures was used to assess the differences in photoreceptor density between groups. RESULTS Cone density was similar in both control participants and participants with diabetes. There was a small effect of retinal hemisphere; participants with diabetes did not show the expected radial asymmetry observed in control participants. CONCLUSIONS Cone density in the parafoveal retina is not reduced in adolescents with type 1 diabetes.

Analysis of multifocal electroretinograms from a population with type 1 diabetes using partial least squares reveals spatial and temporal distribution of changes to retinal function

Spatial–temporal partial least squares (ST-PLS) is a multivariate statistical analysis that has improved the analysis of modern imaging techniques. Multifocal electroretinograms (mfERGs) contain a large amount of data, and averaging and grouping have been used to reduce the amount of data to levels that can be handled using traditional statistical methods. In contrast, using all acquired data points, ST-PLS enables statistically rigorous testing of changes in waveform shape and in the distributed signal related to retinal function. We hypothesise that ST-PLS will improve analysis of the mfERG. Two mfERG protocols, a 103 hexagon clinical protocol and a slow-flash mfERG (sf-mfERG) protocol, were recorded from an adolescent population with type 1 diabetes and an age similar control population. The standard mfERGs were analysed using a template-fitting algorithm and the sf-mfERG using a signal-to-noise measure. The results of these traditional analysis techniques are compared with those of the ST-PLS analysis. Traditional analysis of the mfERG recordings revealed changes between groups for implicit time but not amplitude; however, the spatial location of these changes could not be identified. In contrast, ST-PLS detected significant changes between groups and displayed the spatial location of these changes on the retinal map and the temporal location within the mfERG waveforms. ST-PLS confirmed that changes to diabetic retinal function occur before the onset of clinical pathology. In addition, it revealed two distinct patterns of change depending on whether the multifocal paradigm was optimised to target outer retinal function (photoreceptors) or middle/inner retinal function (collector cells).

Rod a-wave analysis using high intensity flashes adds information on rod system function in 25% of clinical ERG recordings.

PURPOSE To investigate whether rod a-wave analysis using high intensity flashes adds information above that obtained with standard ERG. METHODS A total of 2,396 eyes were recorded. Patient age was 2.4 months-84.6 years. RESULTS A-wave analysis of high intensity flashes provided additional information on rod system function in 25% of eyes recorded, most importantly in subjects with midretinal disease and artificially reduced rod responses. High intensity flashes also provided measurable responses for longitudinal monitoring in rod dystrophies with non-recordable rod ERGs. CONCLUSIONS Clinical ERG testing would benefit greatly from adding high intensity flashes to its standard testing conditions.

A comparison of signal detection techniques in the multifocal electroretinogram

A common task in the analysis of the multifocal electroretinogram (mfERG) is determining which retinal areas have preserved signal in recordings which are attenuated by the effects of disease. Several automated methods have been proposed for signal detection from multifocal recordings, but no systematic study has been published comparing the performance of each. This article compares the sensitivity and specificity of expert human scoring with three different automated methods of mfERG signal detection. Recordings from control subjects were artificially modified to simulate decrease in signal amplitudes (attenuation) as well as total signal loss. Human scorers were able to identify areas with preserved signal at both low and high attenuation levels with a high specificity (minimum 0.99), sensitivities ranged from 0.2 to 0.94. Automated methods based on template correlation performed better than chance at all attenuation levels, with a slide fit method having the best performance. Signal detection based on signal to noise ratio performed poorly. In conclusion automated methods of signal detection can be used to increase signal detection sensitivity in the mfERG.

Isolating visual evoked responses--comparing signal identification algorithms.

Purpose To compare signal identification algorithms for recording visual evoked potentials (VEP). Methods VEPs were recorded both in the presence and absence of a stimulus. Four algorithms were designed to estimate the probability that a recording contains a stimulus evoked signal, and to assign weights for use in a weighted average to isolate a final VEP. Algorithms were compared on their ability to identify trials containing VEPs; the signal-to-noise (SNR) ratios of the final VEP, and the number of trials required to isolate a VEP that was significantly different from background noise. Results All the algorithms isolated VEPs that did not differ significantly in timing or amplitude from those extracted using traditional ensemble averaging. All the studied algorithms were capable of identifying and assigning a significantly greater weight to trials containing visually evoked signals compared with trials containing only noise potentials (P < 0.01). The best performing algorithm produced a ninefold increase in the signal-to-noise of the extracted waveform. Discussion The present investigation provides empirical confirmation that computational signal identification algorithms can improve the detection of VEP signal embedded in noise. When combined with weighted averaging they can reduce the number of trials required for evaluation.