Multifocal electroretinography in diabetic retinopathy and diabetic macular edema.

In this review article, we first present a brief overview of the vascular and neural components of diabetic retinopathy. Next, the multifocal electroretinogram (mfERG) technique, which can map neuroretinal function noninvasively, is described. Findings in diabetic retinal disease using the mfERG are reviewed. We then describe the progress that has been made to predict the onset and progression of diabetic retinopathy and edema in specific retinal locations, using quantitative models based on the mfERG. Finally, we consider the implications for the future of these predictive models.

Differences in neuroretinal function between adult males and females.

PURPOSE: To determine whether neuroretinal function differs in healthy adult males and females younger and older than 50 years. METHODS: This study included one eye from each of 50 normal subjects (29 females and 21 males). Neuroretinal function was assessed using first-order P1 implicit times (ITs) and N1-P1 amplitudes (AMPs) obtained from photopic multifocal electroretinograms. To assess local differences, retinal maps of local IT and (separately) AMP averages were constructed for each subject group. To examine global differences, each subject's 103 ITs and (separately) AMPs were also averaged to create whole-eye averages. Subsequently, retinal maps and whole-eye averages of one subject group were compared with those of another. RESULTS: In subjects younger than 50 years, neuroretinal function differed significantly between the males and females: local ITs were significantly shorter at 83 of 103 tested retinal locations, and whole-eye IT averages were shorter (p = 0.015) in the males compared with the females. In contrast, no analysis indicated that the males and females older than 50 years were significantly different. A subanalysis showed that the females who reported a hysterectomy (n = 5) had the longest whole-eye ITs of all subject groups (p ≤ 0.0013). In the females who did not report a hysterectomy, neuroretinal function was worse in the females older than 50 years compared with the females younger than 50 years: local ITs were significantly longer at 62 of 103 retinal locations tested, and whole-eye IT averages tended to be greater (p = 0.04). Conversely, ITs were not statistically different between the younger and older males. N1-P1 amplitudes did not differ between the sexes. CONCLUSIONS: Multifocal electroretinogram IT differs between males and females, depending on the age group and hysterectomy status.

Early neural and vascular changes in the adolescent type 1 and type 2 diabetic retina.

PURPOSE: This cross-sectional study examines the existence and frequency of functional and structural abnormalities in the adolescent Type 1 diabetic retina. We also compare the results with those of adolescents with Type 2 diabetes. METHODS: Thirty-two adolescents with Type 1 diabetes (5.7 ± 3.6 years; mean duration ± SD), 15 with Type 2 diabetes (2.1 ± 1.3 years), and 26 age-matched control subjects were examined. Multifocal electroretinogram responses from 103 retinal regions were recorded. Optical coherence tomography was used to measure retinal thickness. Vascular diameter around the optic nerve was also assessed. RESULTS: Nine of the 32 (28%) adolescents with Type 1 diabetes and 6 of the 15 (40%) with Type 2 diabetes had significant multifocal electroretinogram implicit time delays compared with 2 of the 26 controls (8%). Retinal thicknesses in both patient groups were significantly (P ≤ 0.01) thinner than controls. The Type 2 group also showed significant (P ≤ 0.03) retinal venular dilation (235.8 ± 5.9 µm) compared with controls (219.6 ± 4.0 µm). CONCLUSION: The present study illustrates that subtle but significant functional and structural changes occur very early in Type 1 diabetes. Adolescents with Type 2 diabetes appear to be more affected than those with Type 1 diabetes. Further longitudinal examination of the etiology and progression of these abnormalities is warranted.

Blood pressure, vessel caliber, and retinal thickness in diabetes.

PURPOSE: In this study, we examine the association of blood pressure (BP), retinal thickness (RT), and vessel caliber in patients with type 2 diabetes and high HbA1c (elevated long-term blood glucose) with or without mild or moderate nonproliferative diabetic retinopathy (NPDR). METHODS: Forty-three patients with type 2 diabetes and high HbA1c measures (23 without NPDR and 20 with mild to moderate NPDR) and 22 age-matched nondiabetic controls participated. The BP, RT (Stratus OCT3), fundus photography, and HbA1c were measured. Correlations between BP, HbA1c, vessel caliber, and RT were evaluated. RESULTS: Diastolic BP (DBP) is positively and significantly associated with RT in patients with NPDR (p < 0.02). Blood pressure was not associated with RT in patients without NPDR (p = 0.83). There is an association between higher HbA1c and higher DBP within the NPDR group (p < 0.02). Furthermore, HbA1c modifies the slope of the relationship between DBP and RT in NPDR patients. Greater venule diameters and loss of the correlation between decreased arteriole size and increased systolic blood pressure, seen in controls, were observed in patients with and without NPDR. CONCLUSIONS: The results of this study show that HbA1c and BP together have an impact on RT measures of patients with DR. These measures should be considered when evaluating RT in patients with DR both clinically and in future optical coherence tomography studies on this population.

Subclinical capillary changes in non-proliferative diabetic retinopathy.

PURPOSE: To establish adaptive optics scanning laser ophthalmoscopy as a method to detect and characterize microscopic signs of diabetic retinopathy in capillaries and cone photoreceptors in the parafovea. METHODS: Recently, adaptive optics scanning laser ophthalmoscope (AOSLO) has enabled noninvasive assessment of photoreceptors, capillaries, and leukocytes in the retinas of live human subjects. Repeated application of AOSLO imaging along with comparison to fluorescein angiography was used to track individual capillaries near the foveal avascular zone (FAZ) from one eye affected with severe non-proliferative diabetic retinopathy. Fluorescein angiography was used to identify clinical signs of diabetic retinopathy, such as microaneurysms and intraretinal microvascular abnormalities, and corresponding regions were imaged and assessed using the AOSLO. In addition, the structural integrity of photoreceptors and the spatial distribution of leukocytes around the parafoveal capillary network were quantitatively assessed. RESULTS: Capillaries and cone photoreceptors were visualized using the AOSLO without the use of injected contrast agents. Although the majority of capillaries were stable over a period of 16 months, one capillary at the edge of the FAZ dropped out, leading to a small but significant increase in FAZ size. Longitudinal assessment of the capillaries also showed microaneurysm formation and disappearance as well as the formation of tiny capillary bends similar in appearance to intraretinal microvascular abnormalities. The leukocytes in the capillary network were found to preferentially travel through the same routes in all four visits, suggesting that these channels are robust against small changes to the surrounding capillaries. In this eye, cone photoreceptor spacing was increased in the fovea when compared with normal data but stable across all visits. CONCLUSIONS: AOSLO imaging can be used to longitudinally track capillaries, leukocytes, and photoreceptors in diabetic retinopathy. Capillary changes that can be detected include dropout of individual capillaries as well as formation and disappearance of microaneurysms.

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.

Reproducibility of the mfERG between instruments.

PURPOSE: First, to examine both the reproducibility of the multifocal electroretinogram (mfERG) recorded on different versions of the same instrument, and the repeatability of the mfERG recorded on a single instrument using two different amplifiers. Second, to demonstrate a means by which multicenter and longitudinal studies that use more than one recording instrument can compare and combine data effectively. METHODS: Three different amplifiers and two mfERG setups, one using VERIS 4.3 software (mfERG1) and another using VERIS Pro 5.2 software (mfERG2), were evaluated. A total of 73 subjects with normal vision were tested in three groups. Group 1 (n = 42) was recorded using two amplifiers in parallel on mfERG1. Group 2 (n = 52) was recorded on mfERG2 using a single amplifier. Group 3 was a subgroup of 21 subjects from groups 1 and 2 that were tested sequentially on both instruments. A fourth group of 26 subjects with diabetes were also recorded using the two parallel amplifiers on mfERG1. P1 implicit times and N1-P1 amplitudes of the 103 local first order mfERGs were measured, and the differences between the instruments and amplifiers were evaluated as raw scores and Z-scores based on normative data. Measurements of individual responses and measurements averaged over the 103 responses were analyzed. RESULTS: Simultaneous recordings made on mfERG1 with the two different amplifiers showed differences in implicit times but similar amplitudes. There was a mean implicit time difference of 2.5 ms between the amplifiers but conversion to Z-scores improved their agreement. Recordings made on different days with the two instruments produced similar but more variable results, with amplitudes differing between them more than implicit times. For local response implicit times, the 95% confidence interval of the difference between instruments was approximately +/-1 Z-score (+/-0.9 ms) in either direction. For local response amplitude, it was approximately +/-1.6 Z-scores (+/-0.3 microV). CONCLUSIONS: Different amplifiers can yield quite different mfERG P1 implicit times, even with identical band-pass settings. However, the reproducibility of mfERG Z-scores across recording instrumentation is relatively high. Comparison of data across systems and laboratories, necessary for multicenter or longitudinal investigations, is facilitated if raw data are converted into Z-scores based on normative data.

Adolescents with Type 2 diabetes: early indications of focal retinal neuropathy, retinal thinning, and venular dilation.

PURPOSE: The eye provides a unique window into the neural and vascular health of a patient with diabetes. The present study is the first of its kind to examine the neural retinal function, structure, and retinal vascular health in adolescents with Type 2 diabetes. METHODS: Focal neural responses from 103 discrete retinal regions of the eye were tested using multifocal electroretinography. Optical coherence tomography was utilized to measure retinal thickness. Digital fundus photographs were examined for the presence of retinopathy and to measure vascular caliber using retinal vessel analysis. Fifteen adolescents diagnosed with Type 2 diabetes, aged 13 to 21 years with a mean diabetes duration of 2.1 +/- 1.3 years, were tested. Twenty-six age-matched control subjects were also tested. RESULTS: Multifocal electroretinograms of the Type 2 diabetic group were significantly (P = 0.03) delayed by 0.49 milliseconds. The diabetic group also showed significant (both; P < or = 0.03) retinal thinning (10.3 microm) and significant venular dilation (16.2 microm). CONCLUSION: The present study shows early indications of focal retinal neuropathy, retinal thinning, and venular dilation in adolescents with Type 2 diabetes. Early detection of functional and structural changes will hopefully aid in the prevention of permanent damage or further functional loss.

OCT reveals regional differences in macular thickness with age.

PURPOSE: To assist identification of macular thickness abnormalities by optical coherence tomography (OCT), we use techniques that improve spatial localization across the retina to establish any age-related retinal thickness changes in healthy eyes. METHODS: Retinal thickness was measured in 30 eyes of 30 healthy subjects aged 13 to 69 years. Using Stratus OCT 3, 12 radial scans centered at the foveola were acquired and points between scans were interpolated to create a topographic map of the central 20 degrees . The thickness map was divided into 37 hexagonal regions. A mean retinal thickness for each hexagon was computed. Retinal thickness vs. age was evaluated for the entire scanned area, five anatomical regions, and within individual hexagons. The retinal nerve fiber layer (RNFL) contribution to total retinal thinning was analyzed in the papillomacular region. RESULTS: There was a small but significant thinning of the overall macular area with increasing age (2.7 mum/decade; p = 0.027). Comparing the 10 youngest subjects (age 13 to 27 years) with the 10 oldest (age 51 to 68 years), retinal thicknesses in the temporal, superior, inferior, and foveal regions were not significantly different. However, the two age groups differed significantly in retinal thickness in the nasal region (p < 0.008). Across all subjects, retinal thickness in this region was linearly correlated with age, decreasing by 4.1 mum/decade (p < 0.002). Approximately 43% of the retinal thinning in the nasal region was attributed to RNFL loss. CONCLUSIONS: The method of OCT acquisition and analysis used in this study allows for greater spatial localization of change in retinal thickness associated with aging or pathological processes. Based on the results of this study, the macula thins with increasing age but does so nonuniformly. The greatest amount of thinning occurs nasal to the fovea. RNFL loss accounts for much, but not all the thinning in this area.

Local diabetic retinopathy prediction by multifocal ERG delays over 3 years.

PURPOSE: 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). METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Association between multifocal ERG implicit time delays and adaptation in patients with diabetes.

PURPOSE: Local first-order multifocal electroretinogram (mfERG) implicit time (K1-IT) delays have proved to be important and predictive indicators of retinal function in diabetes. To better understand the nature of these delays, the authors examined the spatial association between K1-IT and second-order amplitudes (K2-SNR; a measure of adaptation) in diabetic and control subjects. METHODS: The authors studied K1-IT, K1 amplitude, and K2-SNRs of responses from 35 retinal zones. These were recorded from 20 diabetic patients without retinopathy, 20 patients with mild to moderate nonproliferative diabetic retinopathy (NPDR), and 30 healthy control subjects. The K1-IT and K2-SNR measurements were then adjusted according to normative and subject median values to reduce or remove the effects of retinal location, intersubject differences, and abnormally small K1 amplitudes. RESULTS: There was no significant association between K1-IT and K2-SNR in the control group (P > 0.05) and only a marginal association in the NoRet group (P = 0.05). In contrast, longer K1-ITs were significantly associated with reduced K2-SNRs in NPDR subjects (P < 0.01). In the NPDR eyes, zones without retinopathic lesions showed a significant association between K1-IT and K2-SNR (P < 0.01). CONCLUSIONS: The results suggest that an association between longer K1-IT and reduced K2-SNR (abnormal adaptation) develops after the appearance of NPDR, but this association does not depend on the presence of colocalized retinopathic lesions.

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.

Male-female differences in diabetic retinopathy?

The purpose of this paper is to review male-female differences in the incidence and prevalence of diabetes and diabetic retinopathy. These differences will be established primarily through results from our present research and a review of related literature. Previously, we have demonstrated that neuroretinal dysfunction can be used to predict the location of future retinopathy up to three years before it is manifest. Our current research suggests that, for type 2 diabetes, the normal differences in neuroretinal function between nondiabetic males and females under 50 years of age are altered in patients with type 2 diabetes. Furthermore, local neuroretinal function in type 2 diabetes is more abnormal in adult males compared with adult females. The literature also suggests that there are male-female differences in the occurrence of diabetes. In adolescence, the incidence of type 1 diabetes is greater in males, whereas in type 2 diabetes, the incidence is greater in females. This excess of females in type 2 diabetes shifts to a more equal incidence between the two sexes in adults. In addition, advanced retinopathy in type 1 diabetes appears to be more common in males, and the presence and severity of diabetic retinopathy at the time of diagnosis in type 2 diabetes appears to be more associated with male sex. Although the reasons for male-female differences identified in this review are unknown, sex appears to be a significant factor in certain aspects of diabetes incidence and diabetic retinopathy.

Retinal function in normal and diabetic eyes mapped with the slow flash multifocal electroretinogram.

PURPOSE: It has been suggested that late components of the standard multifocal electroretinogram (mfERG) are preferentially affected by diabetes mellitus. The slow-flash (sf-)mfERG stimulates with flashes separated by dark periods, facilitating interpretation of late first-order response components compared with standard multifocal stimulation. Retinal function and response component changes were examined using the sf-mfERG in diabetic subjects with and without diabetic retinopathy. METHODS: Eighteen control subjects, 12 diabetic patients without retinopathy and 17 diabetic patients with nonproliferative diabetic retinopathy (NPDR), were tested monocularly. A total of 103 areas of the central 45 degrees were stimulated by pseudorandom 100-cd/m2 flashes separated by at least 53.3 ms. Major components and the amplitude of the first-order sf-mfERGs were examined. Each subject's N1, P1, and N2 implicit times (ITs) and scalar product amplitudes (SPs) were measured at all 103 retinal locations and converted into z-scores based on the control values. Abnormalities were defined as z-scores greater than 2.33 (P < 0.01). RESULTS: Local functional abnormalities were found in both the diabetic patients with NPDR and in those without retinal disease. In both groups of diabetic patients, most abnormalities occurred more frequently in the inferior retina. Later components (P1 and N2) of the local sf-mfERGs were not preferentially affected by diabetes. The local SP and P1 IT measures distinguished the subject groups better than N1 IT and N2 IT. CONCLUSIONS: Local functional retinal abnormalities in diabetic persons with or without NPDR can be detected and mapped by the sf-mfERG. Diabetes and NPDR do not, however, preferentially affect the late P1 and N2 response components.

Selective loss of an oscillatory component from temporal retinal multifocal ERG responses in glaucoma.

PURPOSE: To evaluate electrophysiologic function in glaucoma by using a new stimulus designed to enhance ganglion cell and optic nerve head component (ONHC) contributions to multifocal electroretinogram (mfERG) responses. METHODS: mfERGs of 16 individuals with glaucoma (POAG) and 18 normal control subjects were recorded and analyzed with a VER imaging system. The stimulus had three frames inserted between each m-sequence step: a full-field dark frame (1.0 cd/m(2)), a full-field flash (200 cd/m(2)), and another dark frame. Multifocal flashes were 100 cd/m(2). The stimulus subtended approximately 40 degrees total diameter and contained 103 scaled hexagonal elements. Signals were obtained using Burian-Allen bipolar electrodes, amplified x10(6), band-pass filtered at 10 to 300 Hz, and sampled at 1200 Hz. RESULTS: Local first-order responses (kernels) consisted of a direct component (DC) followed by an induced component (IC). Nasal-temporal response asymmetries in normal eyes were most easily observed in the IC. A small but distinct oscillation in the ICs of temporal retinal responses distinguished them from nasal IC waveforms. In individuals with glaucoma, there was less asymmetry between nasal and temporal responses, mostly because of the reduction of the oscillation in the temporal retinal ICs. The amplitude of this oscillation was 4.4 +/- 2.1 nV/deg(2) in the control group and 1.8 +/- 1.2 nV/deg(2) in the glaucoma group (P < 0.0001). Amplitude and latency measures of other response features were not significantly different from normal. Amplitude of the IC oscillation was not correlated with age in either the normal or glaucoma groups. In a group of normal subjects retested 3 months later, the average test-retest repeatability was +/-12%. CONCLUSIONS: Selective loss of an oscillatory feature from IC responses in glaucoma may represent abnormalities in the inner plexiform layer of the temporal retina, where classic oscillatory potentials (OPs) are thought to arise. However, evidence suggests that this effect may also be due in part to loss of the ONHC.

Multifocal electroretinogram delays predict sites of subsequent diabetic retinopathy.

PURPOSE: To examine the potential of abnormal mfERGs to predict the development of diabetic retinopathy at corresponding retinal locations 1 year later. METHODS: One eye of 11 diabetic patients with nonproliferative diabetic retinopathy (NPDR) and 11 diabetic patients without retinopathy were retested 12 months after initial testing. At each time, mfERGs were recorded from 103 retinal locations, and fundus photographs were taken within 1 month of each recording. Local mfERG implicit times were measured and their z-scores were calculated based on results obtained from 20 age-matched control subjects. mfERG abnormalities were defined as z-scores of 2 or more for implicit time and z-scores of -2 or less for amplitude (P < or = 0.023). mfERG z-scores were mapped onto fundus photographs, and the relationship between baseline abnormal z-scores and new retinopathy at follow-up was examined. RESULTS: New retinopathy developed in 7 of the eyes with NPDR after 1 year. In these eyes, 70% of the mfERGs in areas of new retinopathy had abnormal implicit times at baseline. In contrast, only 24% of the responses in regions that remained retinopathy free were abnormal at baseline. Relative risk of development of new retinopathy over 1 year in the areas with abnormal baseline mfERG implicit times was approximately 21 times greater than that in the areas with normal baseline mfERGs (odds ratio = 31.4; P < 0.001). Eyes without initial retinopathy did not develop new retinopathy within the study period, although 4 of these 11 eyes had abnormal implicit times at baseline. mfERG implicit times tended to be more delayed at follow-up than at baseline in NPDR eyes, but not in eyes without retinopathy and control eyes. mfERG amplitudes had no predictive power. CONCLUSIONS: Localized functional abnormalities of the retina reflected by mfERG delays often precede the onset of new structural signs of diabetic retinopathy. Those functional abnormalities predict the local sites of new retinopathy observed 1 year later.

Local multifocal oscillatory potential abnormalities in diabetes and early diabetic retinopathy.

PURPOSE: To study retinal dysfunction in diabetes and early nonproliferative diabetic retinopathy (NPDR) using a new method to analyze local multifocal electroretinogram oscillatory potentials (mfOPs). METHODS: One eye of each of 26 normal subjects, 16 diabetic subjects without retinopathy (NoR), and 16 diabetic subjects with early NPDR was examined. Slow-flash multifocal electroretinograms (sf-mfERGs) were recorded from the central 45 degrees, and stereo fundus photographs of the diabetic eyes were taken. The first-order (K1), induced first-order (K1i), and second-order (K2) response components were extracted from each retinal location, and K1i and K2 were added to create Ks2. Responses from 35 contiguous areas were digitally filtered 90 to 225 Hz to isolate the mfOPs. The signal-to-noise ratio (SNR) of the mfOPs was calculated, and abnormality was defined as SNR below the fifth percentile of the normal subjects. RESULTS: Combining the K1i and K2 components to form Ks2 before isolation of the mfOPs by digital filtering increased the SNR. Mean Ks2 and K1 mfOP SNRs were abnormal in 25% and 19% of the NoR eyes, respectively, and both were abnormal in 62% of the NPDR eyes. The retinal distributions of the local Ks2 and K1 mfOP abnormalities overlapped, but they differed. Furthermore, local Ks2 mfOP abnormalities were preferentially associated with retinal sites containing NPDR but K1 mfOP abnormalities were not. CONCLUSIONS: The cells that contribute to the generation of local mfOPs are affected by diabetes and, to a greater degree, by early NPDR. The results suggest that fast adaptive mechanisms influencing the mfOPs are most abnormal at retinal sites containing NPDR.

Formulation and evaluation of a predictive model to identify the sites of future diabetic retinopathy.

PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Multifocal electroretinogram and short-wavelength automated perimetry measures in diabetic eyes with little or no retinopathy.

OBJECTIVE: To compare severity and locations of abnormalities detected by the multifocal electroretinogram (mfERG) and short-wavelength automated perimetry (SWAP) in diabetic eyes with early or no retinopathy. METHODS: One eye from each of 22 patients with diabetes mellitus who had early retinopathy and 18 patients with diabetes mellitus who had no retinopathy were tested on mfERG and SWAP. The mfERG implicit times were interpolated based on SWAP stimulus locations and compared with normative values obtained from 30 age-similar control subjects. The SWAP total threshold deviations were analyzed using an age-based control data set from 255 healthy subjects. The z scores of both measures were derived to allow measurement comparisons. RESULTS: Most responses for the 2 measurements were subnormal in both groups with diabetes mellitus. The 2 measurements showed a similar number of significant abnormalities (z score >/=2), about 40% and 20% of responses for diabetic patients with retinopathy and diabetic patients with no retinopathy, respectively. Local mfERG and SWAP results showed some spatial agreement for subjects with retinopathy (r = -0.38, P<.001) but not for those with no retinopathy. CONCLUSIONS: Both mfERG and SWAP are sensitive measurements of diabetic dysfunction, even prior to retinopathy. The lack of spatial correspondence between mfERG and SWAP abnormalities in diabetic patients with no retinopathy reflects overlapping, but different, retinal anomalies in early diabetic eye disease.

Assessment of macular function using the SKILL Card in adults with type 2 diabetes mellitus.

PURPOSE: To evaluate the impact of reduced contrast and reduced luminance on visual acuity (VA) using the Smith-Kettlewell Institute Low Luminance (SKILL) Card in patients with type 2 diabetes mellitus (T2DM). METHODS: We studied adults aged 27 to 65 years, 32 with T2DM and no retinopathy (NoRet group), 22 with T2DM and nonproliferative diabetic retinopathy (NPDR group), and 38 healthy control subjects. Monocular high-contrast (SKILL light) and low-contrast, low-luminance (SKILL dark) near visual acuities were tested. The SKILL score was calculated as the difference between dark chart and light chart acuities and was corrected for age. Contrast sensitivity (CS) was also measured. Subject group differences were examined using ANOVA and Tukey honestly significant difference test. Receiver operating characteristic curve analysis was used to assess the ability of the SKILL Card and CS to discriminate the subject groups. RESULTS: The SKILL score and CS were significantly worse in both diabetes groups compared with the controls (P < 0.01). SKILL scores in the NPDR group were poorest (highest) and significantly worse than those in the NoRet group (P < 0.05). SKILL scores discriminated NPDR and NoRet patients from the controls with high accuracy (99% and 88%, respectively), which was significantly (P < 0.03) better than CS (78% and 74%, respectively). CONCLUSIONS: The SKILL Card demonstrated vision function changes in diabetes even in the absence of clinically evident retinopathy. Diabetic retinopathy led to a further increase in the SKILL score, while high-contrast VA remained unchanged.