Foveal avascular zone size and mfERG metrics in diabetes and prediabetes: a pilot study of the relationship between structure and function.

PURPOSE: Previous studies have demonstrated functional and structural retinal changes in type 2 diabetes (T2DM). However, less is understood in prediabetes, which is an important precursor to T2DM. Here, we evaluate the microvasculature structure of the foveal avascular zone (FAZ) and how it is correlated with retinal function as measured by the multifocal electroretinogram (mfERG) across levels of glucose dysfunction to uncover how T2DM and prediabetes alter this structure-function relationship. METHODS: 33 subjects were included: 9 controls, 12 prediabetes, 12 T2DM with no retinopathy or edema. Subjects were aged 30-70 years, had BCVA of 20/25 or better, and had no confounding ocular conditions. Blood was collected via fingerstick to determine Hemoglobin A1c (HbA1c), which was used along with previous diagnosis, to determine study grouping. Optical coherence tomography angiography (OCTA) was used to analyze the FAZ area and was corrected for refractive error. FAZ area was measured by hand using the Heidelberg Spectralis software. mfERG (VERIS 6.3) metrics implicit time (IT) and amplitude were evaluated in the foveal region, macular region, and averaged over the posterior pole of the right eye. Regression analysis was performed between each study group parameter to determine relationships, and t tests with corrections were used to compare groups. RESULTS: FAZ area (superficial plexus) was negatively correlated with mfERG posterior pole amplitude (p < 0.01, R2 = 0.30), foveal amp (p = 0.02 R2 = 0.17) and macular amplitude (p = 0.02 R2 = 0.18) across all 33 study subjects. FAZ and mfERG metrics were not significantly different between study groups in this cohort except for IT, which was more delayed in the diabetes group compared to other groups. CONCLUSION: FAZ area is correlated with mfERG amplitudes but not IT. This suggests a link between the structural metrics and retinal function. Longitudinal follow-up work would be helpful to determine the timing of these changes in prediabetes.

Fundus motion during mfERG testing.

PURPOSE: The purpose of this study was to assess eye movements during a multifocal ERG (mfERG) recording. This study evaluated the relationship between bivariate contour ellipse areas (BCEAs), mfERG amplitudes (Amps) and mfERG implicit times (ITs) with repeat testing and experienced subjects. METHODS: Thirty subjects were selected (15 experienced to ocular procedures and 15 novices). All were confirmed to have healthy retinas and at least 20/25 vision. MfERGs with a stimulus near 100% contrast and 4-min m-sequence were recorded on two different days using our common clinical technique, which did not constrain the head. VERIS with fundus monitoring system was used for recording with a Burian-Allen electrode. An external camera captured the fundus during each mfERG recording. The optic nerve head position was tracked in each video using a custom algorithm in order to determine BCEAs. Each subject performed one mfERG on two different days. MfERGs were analyzed for Amps and ITs for the fovea and whole eye. RESULTS: There was no correlation between the mfERG metrics and BCEAs with repeat testing. There were also no differences between the experienced and novice subjects for mfERG Amps, ITs or BCEAs. Eye movements between visits were highly correlated (multiple r = 0.67). BCEAs were larger during mfERGs (1.04 ± 0.8 deg2) than those observed in previous literature using brief viewing tasks (< 0.3 deg2). The proportion of time spent fixating within 1.0 and 2.0 degrees of the central hexagon was 68 and 93%, respectively. CONCLUSIONS: This study is the first to evaluate the stability of the retina while recording a mfERG in healthy subjects and indicates that the center of fixation during a mfERG stays within the central hexagon. Eye stability during an initial recording is the best indicator of stability on the second recording. The amount of movement during these recordings did not seem to affect the mfERG Amps or ITs. These data suggest clinical confidence with mfERGs when recording novice patients.

Case Report: Long-term Structural and Functional Effects of Ethambutol Optic Neuropathy.

SIGNIFICANCE: This case report demonstrates reduction in the retinal nerve fiber layer (RNFL) thickness and an abnormal electroretinogram after toxic optic neuropathy from ethambutol, more than 1 year after improvements in visual acuity (VA) and visual fields (VFs) were seen. Although many studies have described complications of ethambutol, continuing reduction in RNFL thickness 2 years after discontinuation has not been described elsewhere. PURPOSE: It is well known that ethambutol can cause optic nerve toxicity, visual impairment, and VF loss. Visual acuity can be regained after stopping the drug; however, the amount and time frame are variable. There are few data on long-term follow-up of these cases to direct clinicians how to proceed once VA has stabilized. Here we present a case with 2 years of follow-up for a patient with ethambutol toxicity, showing the condition change even after VA becomes normal. CASE REPORT: A 61-year-old man presented shortly after discontinuing ethambutol for Mycobacterium avium complex. Visual acuity values were 20/70 in the right eye and 20/125 in the left eye with cecocentral VF scotomas. Optical coherence tomography showed normal RNFL. Visual-evoked potentials were significantly reduced and delayed. Over the course of 2 years, the patient became asymptomatic as VA and VF returned to normal and visual-evoked potential improved. However, the optical coherence tomography RNFL was reduced from each visit to the next, and the electroretinogram showed decreased scotopic and photopic amplitudes. CONCLUSIONS: Signs of ethambutol toxicity may remain or worsen years after discontinuation, even in the absence of patient symptoms and with normal VA and VF.

Functional retinal outcomes in patients with prediabetes and type 2 diabetes.

PURPOSE: Type 2 diabetes (T2DM) is a leading cause of visual impairment. Its precursor, prediabetes (preDM), is growing in numbers every year. While it is well known that T2DM causes changes in retinal function early in the disease process, it is likely that some of these changes emerge during the preDM stage. This study evaluates retinal function measures in patients with preDM to determine if there are differences in colour vision, contrast sensitivity (CS), and multifocal electroretinogram (mfERG) measures present before T2DM is diagnosed. METHODS: The L'Anthony desaturated D-15 test, Mars Chart CS test, and mfERG were administered on the right eye of 43 participants; 15 controls (HbA1c ≤ 5.6%), 17 with preDM (HbA1c 5.7%-6.4%), and 11 with T2DM (either physician diagnosed or with untreated HbA1c ≥ 6.5%). HbA1c values were measured at the time of the other tests. Colour vision confusion scores (CVCS) were calculated from the D-15 using the method developed by Torok. Multivariate regression (which controlled for age differences) was used to evaluate the relationship of HbA1c and functional measures. Kruskal-Wallis tests were also used to evaluate differences between groups with post-hoc analysis. RESULTS: CVCSs were significantly different between the three groups (p = 0.009). There was an association between higher CVCS and higher HbA1c values across all groups as well as specifically within the preDM group when controlling for age (R2  = 0.29, p = 0.01 and R2  = 0.39, p = 0.02 respectively). Multivariate regression of all of the functional tests together and HbA1c found only colour vision remained significant, indicating that the functional examination metrics may provide redundant data, with similar changes in prediabetes where colour vision may be the strongest indicator early in the process. CONCLUSIONS: Patients with prediabetes have functional changes that can be measured in the retina before the diagnosis of diabetes, with the L'Anthony D-15 colour vision test providing the strongest association with glucose dysregulation in this population. This has important implications for follow up and screening for diabetes within optometric practices. Further studies are needed to follow these patients over time to see how and when these metrics change.

The corneal nerve density in the sub-basal plexus decreases with increasing myopia: a pilot study.

PURPOSE: Myopia can cause many changes in the health of the eye. As it becomes more prevalent worldwide, more patients seek correction in the form of glasses, contact lenses and refractive surgery. In this study we explore the impact that high myopia has on central corneal nerve density by comparing sub basal nerve plexus density measured by confocal microscopy in a variety of refractive errors. METHODS: Seventy healthy adult subjects between the ages of 21-50 years participated in this study. The study took place in two phases with no overlapping subjects (n = 30 phase 1 and n = 40 phase 2). In both phases an autorefraction, keratometry reading, corneal thickness measure and confocal corneal scan of the sub basal nerve plexus were performed for both eyes. There were 11 hyperopes (+0.50 to +3.50DS), six emmetropes (-0.25 to +0.50DS), 30 low myopes (-5.50 to -0.50DS), and 23 high myopes (-5.50DS and above). In the second phase of the study additional tests were performed including an axial length, additional corneal scans, and a questionnaire that asked about age of first refractive correction and contact lens wear. Corneal nerves were imaged over the central cornea with a Nidek CS4 confocal microscope (460 × 345 µm field). Nerves were evaluated using the NeuronJ program for density calculation. One eye was selected for inclusion based on image quality and higher refractive error (more myopic or hyperopic). RESULTS: As myopia increased, nerve density decreased (t1  = 3.86, p < 0.001). We also note a decrease in data scatter above -7 D. The relationship between axial length values and nerve density was also significant and the slope was not as robust as refractive error (t1  = 2.4, p < 0.04). As expected there was a significant difference between the four groups in axial length (F3  = 19.9, p < 0.001) and age of first refractive correction of the myopic groups (14.9 vs 11.5 years; t46  = 2.99 p < 0.01). There was no difference in keratometry readings or corneal thickness between the groups (F3  = 0.6, p = 0.66 and F3  = 1.2, p = 0.33 respectively). CONCLUSION: Corneal nerve density in the sub-basal plexus decreased with increasing myopia. This could have implications for corneal surgery and contact lens wear in this patient population.

Arteriole tortuosity associated with diabetic retinopathy and cholesterol.

PURPOSE: Earlier identification of diabetic eye disease is an important research effort. Retinopathy is widely acknowledged but retinal vessel changes are not evaluated as stringently. Here, we create a multivariate model for the association between retinal vessel tortuosity (RVT) and other health factors in patients with diabetes. METHODS: Three hundred eyes of 150 patients with diabetes were included. Three investigators independently reviewed telemedicine fundus photographs and scored the level of diabetic retinopathy (DR) and RVT. These scores were evaluated for agreement and averaged. Also collected were age, duration of diabetes, presence or absence of diabetic nephropathy or neuropathy, blood pressure, total cholesterol, and hemoglobin A1c. A regression model evaluating the association of tortuosity with other factors was created. RESULTS: There was very high agreement between the three graders for level of DR (κ = 0.84). Agreement between the three graders for RVT varied substantially: poor for venous tortuosity (κ = 0.23) and fair for arteriole tortuosity (κ = 0.44) and overall gut tortuosity (κ = 0.42). The overall gut tortuosity was the most reproducible for the graders with a correlation coefficient of 0.923. There were univariate associations between arteriole tortuosity and venous tortuosity, DR level, and cholesterol. The selected best multivariate model found arteriole tortuosity to be associated with DR and cholesterol levels. CONCLUSIONS: First, RVT, particularly for venules, is difficult to grade consistently; therefore, future studies examining tortuosity should focus on arterioles. Second, the model indicates that there is an association between vessel changes, DR, and systemic cholesterol levels. Although DR and RVT are readily available to assess concurrently on a photograph, the addition of cholesterol to this model indicates that patients with RVT may warrant further follow-up on health factors, such as cholesterol levels.

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.

Variations in Retinal Oxygen Saturation in a Diverse Healthy Population.

Purpose: Local retinal oxygen saturation is a research technique, which has the potential as a biomarker for diabetes. However, normative data has not been established. This study examined differences in oxygen saturation around the macula and characterizes the relationship between age, race, refractive error (RE), sex, blood pressure (BP), prediabetic status and oxygen saturation. Methods: Fifty-nine subjects aged 22-69 (38.8 ± 14.7 years) were included who were racially diverse and with equal gender distribution. None had eye disease. Oxygen saturation was taken with the Zilia Ocular in 4 locations around the macula 3.1 degrees from the fovea and they were also averaged. BP, RE, and HbA1c were noted. Regression analyses for oximetry and other factors were completed as were t-tests with multiple comparison corrections. Results: There were significant variations in oximetry measures by race, with higher pigmentation levels associated with lower oximetry values (p < 0.01). There was no relationship between oximetry and sex (p = 0.34), RE (p = 0.67), BP (systolic p = 0.61, diastolic p = 0.71) nor prediabetic status (p = 0.87). Oximetry was associated with age when controlling for race (P < 0.002). Nasal-temporal variations showed nasal oximetry to higher than temporal measures (P < 0.01). Conclusion: This study revealed race/pigmentation is an important influence on oximetry measures. Retinal location also caused variations, likely due to proximity to larger vessels nasally. No differences in sex, RE nor BP were observed to alter local oxygen saturation. However, age was correlated when considered with race. This study will inform our future work in different disease states and is an important first step in evaluating this technology.

This study evaluates a new research instrument (Zilia Ocular) which measures how much oxygen is in the very small blood vessels of the retina. Our group wanted to evaluate healthy people to find out if the measurements the instrument takes are different in different sexes, ages, races, glasses prescriptions and blood pressures. We also looked at if they were changed in people with prediabetes and if it is different in different locations on the retina. We found that the measures are different in different races and ages. The measures also change with location in the eye. The other factors did not change the measurements of oxygen saturation on this instrument. We need to know this information because we want to detect changes in the retina in diabetes in diverse patient groups; however, we need to know about normal variations to better understand and collect that data.

Evaluation of retinal structure and function in prediabetes.

Purpose: Alterations in retinal structure and function have been well documented in type 2 diabetes (T2DM). However, few studies have evaluated the eye in prediabetes (preDM), a precursor to T2DM. It is unknown which retinal deficits, if any, occur before T2DM diagnosis. This study evaluates retinal structure via optical coherence tomography (OCT) and retinal function via multifocal electroretinogram (mfERG) N1 and P1 in those with PreDM. The goal is to evaluate associations between structure and function across glucose dysfunction. Methods: 85 subjects (aged 28-69yrs) were tested with VERIS mfERG and Heidelberg Spectralis OCT. Demographic and health information was collected. Subjects were grouped by HbA1c: 33 controls (HbA1c <5.7%), 31 with preDM (HbA1c 5.7-6.4%), and 21 with T2DM (HbA1c >6.4% at the time of testing or diagnosed by physician) and mild or no retinopathy. mfERG N1 and P1 latency and amplitude were measured for the right eye in the foveal hexagon (central 2.4°). Average macular thickness was also measured over the central 3.3°. Groups were compared with ANOVA and corrected t-tests. Models of these associations with diabetes diagnosis (in groups above) were created with backward multivariate regression. Results: The T2DM group was exceptionally well-controlled with an HbA1c of 7.0% ± 0.68 but also had elevated systolic blood pressure compared to other groups (P<0.01). The age of the control group was younger (P<0.01), so other testing was age controlled. There was a borderline but statistically significant difference in P1 between the control group and both the preDM and T2DM groups after Bonferroni corrections (P<0.03). There was also a difference in N1 latency between the control and other groups (P<0.001). A multivariate model demonstrated a significant relationship between T2DM/PreDM diagnosis and delayed N1 latency, reduced foveal thickness, and age. Conclusions: Structure and function together can provide an associative model of preDM or T2DM changes for patients. Based on this multivariate model, N1 is strongly associated with preDM and T2DM. N1 findings and decreasing foveal thickness are additive and can together inform ocular health related to preDM. Future longitudinal studies are needed to understand changes in function and structure in preDM and T2DM.

Test-retest repeatability in macular retinal oximetry.

CLINICAL RELEVANCE: Evaluation of retinal macular oxygen saturation in healthy controls can aid in understanding the pathological changes seen in similar locations of those with vascular diseases like diabetes. BACKGROUND: The aim of this study was to determine the test-retest repeatability of localised retinal oximetry measurements in the macula on the Zilia Oximeter within healthy subjects of different races, 18-40 years old. Oxygen saturation was measured between three time points within the same locations of the right eye. METHODS: Twenty seven subjects were included (aged 26.3 ± 3.6 years). All were confirmed to have healthy retinas and at least 6/9 vision. Oximetry measurements were taken using the Zilia to acquire local oxygen saturation measurements (300 µm diameter) at four points 3.1 degrees from the fovea in the superior/temporal, superior/nasal, inferior/temporal, and inferior/nasal locations. Oximetry measurements were taken twice on the same day 20 minutes apart and then again 1-2 weeks later. Oximetry data was analysed with intraclass correlation between visits. To assess intrasubject repeatability, the Bland-Altman repeatability coefficient and coefficient of variation were calculated. RESULTS: Average Intraclass correlation for the three acquisition times of the right eye was 0.78. The averaged intrasubject repeatability coefficient for the three acquisition times was 8.4. The averaged coefficient of variation was 5.4%. CONCLUSION: The Zilia oximeter has good macular test-retest repeatability; however, multiple measurements may be needed to ensure accuracy.

Twenty-four hour diurnal variation in retinal oxygen saturation.

Retinal oxygen saturation is influenced by systemic and local vasculature, intraocular pressure (IOP), and individual cellular function. In numerous retinal pathologies, early changes take place at the level of the microvasculature, thereby affecting retinal oxygenation. The purpose of this study was to investigate diurnal variations in retinal oximetry measures and evaluate the relationship with other ocular and systemic physiological processes. Healthy adults (n = 18, mean age 27 ± 5.5 years) participated. Ocular and systemic measures were collected every four hours over 24 h and included retinal oximetry, IOP, optical coherence tomography (OCT), OCT-angiography (OCTA), biometry, blood pressure, and partial pressure of oxygen. Amplitude and acrophase for retinal oxygen saturation, axial length, retinal and choroidal thickness, OCTA parameters, and mean arterial and ocular perfusion pressure (MAP, MOPP) were determined were determined using cosine fits, and multiple regression analysis was performed to compare metrics. Retinal oxygenation saturation demonstrated a significant diurnal variation with an amplitude of 5.84 ± 3.86% and acrophase of 2.35 h. Other parameters that demonstrated significant diurnal variation included IOP, MOPP, axial length, choroidal thickness, superficial vessel density, heart rate, systolic blood pressure, and MAP. Diurnal variations in retinal oxygen saturation were in-phase with choroidal thickness, IOP, and density of the superficial vascular plexus and out-of-phase with axial length and MOPP. In conclusion, retinal oxygenation saturation undergoes diurnal variations over 24 h. These findings contribute to a better understanding of intrinsic and extrinsic factors influencing oxygenation of the area surrounding the fovea.

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.

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.

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.

Neurodegenerative differences in the retinas of male and female patients with type 2 diabetes.

PURPOSE: The purpose of our study is to determine whether neuroretinal function, measured by the multifocal electroretinogram, differs between males and females with type 2 diabetes and no retinopathy. METHODS: This study included 70 eyes from 70 adult subjects (14 control males, 22 control females, 16 males with type 2 diabetes, and 18 females with type 2 diabetes). A template-scaling technique was used to obtain first-order P1 implicit times and N1-P1 amplitudes from photopic multifocal electroretinograms within the central 45 degrees. RESULTS: The males with type 2 diabetes were significantly more abnormal than their female counterparts in two separate analyses of local neuroretinal function. First, the total number of retinal locations with an abnormally delayed implicit time (z score ≥ 2) was higher (P < 0.001) in the diabetic males (482 locations = 29.2%) compared to the diabetic females (298 locations = 16.1%). Second, in the response topographies that consisted of 103 means of local implicit times for each group, the diabetic males were significantly delayed (P < 0.025) at 23 corresponding positions (22.3%) compared to the diabetic females. At the same time, no corresponding stimulus locations were significantly delayed in the diabetic females compared to the diabetic males. CONCLUSIONS: Neuroretinal function is more abnormal in males than in females for adults with type 2 diabetes and no retinopathy. These results suggest that, relative to males, females may have some protection from, or resistance to, neurodegenerative changes that precede the development of background retinopathy in type 2 diabetes.

Multifocal electroretinograms predict onset of diabetic retinopathy in adult patients with diabetes.

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

Prediction, by retinal location, of the onset of diabetic edema in patients with nonproliferative diabetic retinopathy.

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

The influence of first near-spectacle reading correction on accommodation and its interaction with convergence.

PURPOSE: Accommodation and convergence can adapt to blur and disparity stimuli and to age-related changes in accommodative amplitude. Does this ability decline with age? The authors investigated short-term adaptation to first near-spectacle reading correction on the accommodative-stimulus response (ASR) function, accommodative amplitude (AA), AC/A, and CA/C ratios in a pre-presbyopic and an incipient presbyopic population and determined whether changes in these functions recovered after discontinuation of the use of near spectacles. METHODS: Thirty subjects with normal vision participated; their ages ranged from 21 to 30 years (n = 15) and 38 to 44 years (n = 15). Oculomotor functions were measured before and after single-vision reading spectacles were worn for near tasks over a 2-month period and then 2 months after the use of near spectacles was discontinued. RESULTS: The slope of the ASR function and the AC/A and CA/C ratios did not change significantly after near spectacles were worn. There was a hyperopic shift of the ASR function that significantly reduced the near point of accommodation (NPA) and lowered the far-point refraction. These changes were age invariant and did not recover after 2 months of discontinuation of near spectacle wear. CONCLUSIONS: These results imply that the NPA may be enhanced normally by tonic bias of accommodation that elevates the entire ASR function and produces myopic refraction bias. When this bias relaxes after reading spectacles are worn, there is a hyperopic shift of the refractive state and a reduction of the NPA, specified from optical infinity.

Menisci and fullness of the blink in dry eye.

PURPOSE: This study was to investigate the role of the upper meniscus in tear film formation and blinking. METHODS: One microliter of 2% fluorescein was instilled under the upper lid of 15 dry eye (DE) and 15 control subjects. Subjects were instructed to blink partially and hold the eye open as long as possible, and analysis of tear breakup dynamics was used to quantify the area of breakup. This procedure was repeated following a full blink. Meniscus height was measured from digital videos. RESULTS: Both menisci were significantly decreased in DE compared with controls (p < 0.02, t test). Tear breakup dynamics analysis showed that significantly greater areas of breakup occurred with full compared with incomplete blinks in DE (p < 0.003 Mann Whitney U test), but not in controls. CONCLUSIONS: A stable tear film can be deposited by the upper meniscus alone following a partial blink, without contribution from the lower meniscus. The increased tear stability of partial blinks in DE may be due to less stretching of the already fragile tear film compared with a full blink, which covers more surface area.

Multifocal pattern electroretinogram: cellular origins and clinical implications.

PURPOSES: The purposes of this article are to gain insight into the cellular origins of the multifocal pattern electroretinogram (mPERG) and evaluate its potential for clinical use. METHODS: mPERGs were recorded from four anesthetized monkeys before and after pharmacologic blockade of light-driven activity of inner-retinal neurons and from 55 normal human subjects (19-91 years) and six patients with glaucoma (43-77 years of age). Stimuli consisted of counterphase-modulated black and white triangles organized in 61-scaled hexagons with mean luminance 100 cd/m2 and 100% contrast. The stimulus array subtended 31 degrees vertically and 37 degrees horizontally at 48 cm. The amplifier cutoff frequencies were 3 and 100 Hz. Responses were grouped as quadrants and the first slice of the second-order kernel was analyzed. RESULTS: The mPERG responses of monkeys and humans were similar. In the monkey responses, there was an early positive potential (P1) around 25 ms and a later positive potential (P2) found selectively in the nasal field quadrants around 31 ms. These responses were seen around 22 and 36 ms in the human responses. After blockade of inner-retinal activity in monkeys, P1 amplitude was greatly reduced at all retinal locations and P2 was eliminated. P1 and P2 amplitudes were significantly reduced in the glaucomatous eyes relative to amplitudes of age-matched controls. Reductions in the amplitudes of P1 and P2 could easily discriminate between glaucomatous visual field quadrants with and without behavioral sensitivity losses. However, these alterations are likely to reflect diffuse losses. CONCLUSIONS: mPERG responses contain prominent contributions from inner-retinal neurons that can be reduced in glaucomatous eyes. These findings raise the possibility that the mPERG could be potentially useful in the objective estimation of neural damage in glaucoma. However, further refinement of recording techniques will be required if the mPERG is to be used to detect focal damage.