Shirin Barez

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.

Disruption of the Retinal Parafoveal Capillary Network in Type 2 Diabetes before the Onset of Diabetic Retinopathy

PURPOSE To establish, using adaptive optics scanning laser ophthalmoscopy (AOSLO), that the retinal parafoveal capillary network is altered before the onset of diabetic retinopathy in adult patients with type 2 diabetes. METHODS AOSLO videos were acquired in the parafoveal region of one eye from control subjects and from patients with type 2 diabetes and no retinopathy. Detailed images of the parafoveal capillary network were generated with custom motion contrast enhancement algorithms. The combination of AOSLO images and videos enabled the simultaneous assessment of several features of the parafoveal capillary network. Arteriovenous (AV) channels were identified by finding the least tortuous capillary channels connecting terminal arterioles to postcapillary venules. Measures of capillary dropout and capillary hemodynamics were also quantified. RESULTS The average tortuosity of AV channels was 26% higher in patients with type 2 diabetes when compared with controls, even though there were no signs of diabetic retinopathy in any of the eyes that were assessed (P < 0.05). In addition, the metrics of capillary dropout showed small changes (between 3% and 7%), leukocyte speed 14% lower, and pulsatility 25% higher, but none of these differences was statistically significant. CONCLUSIONS It is often difficult to find consistent changes in the retinal microvasculature due to large intersubject variability. However, with a novel application of AOSLO imaging, it is possible to visualize parafoveal capillaries and identify AV channels noninvasively. AV channels are disrupted in type 2 diabetes, even before the onset of diabetic retinopathy.

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 ≤ 0.03) retinal thinning (10.3 &mgr;m) and significant venular dilation (16.2 &mgr;m). 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.

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.

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 models 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.

Associations between Local Retinal Thickness and Function in Early Diabetes

PURPOSE To investigate, using multifocal electroretinography (mfERG) and optical coherence tomography (OCT), potential spatial associations between local neuroretinal function and local retinal thickness in patients with diabetes. METHODS Forty-five patients without retinopathy (10 with Type 1 diabetes; 35 with Type 2 diabetes; 49.9 ± 10.9 years old) and 29 age-similar controls (47.0 ± 12.8 years old) were studied. N1-P1 amplitude (AMP) and P1 implicit time (IT) of mfERGs within the central approximately 20° diameter were compared to spatially corresponding full retinal thickness measurements acquired by Stratus OCT3. AMP and IT were converted to Z-scores and retinal thickness was converted to percentile values. Local abnormalities were defined as P ≤ 0.023. Subject group differences were examined using t-tests. Retinal thickness was compared to mfERGs to determine spatial associations. RESULTS Average retinal thicknesses were similar for all subject groups. The Type 1 group and controls had similar IT and AMP. The Type 2 group had reduced AMP and longer IT than the controls and the Type 1 group (P < 0.001). Local associations between retinal thickness and mfERGs were not significant within any subject group or individuals, even for abnormal locations (P ≥ 0.09). Abnormalities in most measures were greater in the patient groups than in the controls (P < 0.008) except retinal thinning in the Type 1 group. CONCLUSIONS Local neuroretinal function is not associated with full retinal thickness measured locally in patients with diabetes and no retinopathy, even in abnormal locations. Full retinal thickness measured locally by OCT is not a surrogate for mfERGs in early diabetes. Neuroretinal function in Type 2 diabetes is worse than in Type 1 diabetes and controls. Fewer subjects in the Type 1 group could be a potential limitation.

Interocular Symmetry of Abnormal Multifocal Electroretinograms in Adolescents with Diabetes and No Retinopathy

PURPOSE To investigate, in adolescents with type 1 diabetes and no retinopathy, the spatial correspondence between abnormal multifocal electroretinogram (mfERG) responses in the two eyes. METHODS mfERG and fundus photographs were measured in both eyes of 68 adolescents with type 1 diabetes and no retinopathy (13 to 19 years old; best corrected visual acuity ≥ 20/20), and 30 age-matched controls. The mfERG stimulus was comprised of 103 hexagons, and subtended 45°. mfERG implicit times (IT) and amplitudes (AMP) were derived. Fifteen patients for IT, and five for AMP with at least one eye defined as abnormal (six or more locations with abnormal Z-scores; P < 0.03) were analyzed. RESULTS Nasal retina had significantly more abnormal IT locations compared with temporal retina (P = 0.015), and the opposite was true with regard to abnormal AMP (P < 0.001). The proportion of abnormal responses in the superior retina was not significantly different from that in the inferior retina (P > 0.1 for IT and AMP). Interocular correspondence of locations with abnormal mfERG IT was significant for all 15 patients (P values <0.0001-0.012), and agreement between eyes was 68% to 94% (AC1 agreement coefficient: 0.48-0.94). Overall interocular correspondence was also significant (P < 0.0002), with 86% agreement (AC1 = 0.76). Overall interocular correspondence of locations with abnormal mfERG AMP was also significant (P < 0.0002). CONCLUSIONS Interocular spatial correspondence of abnormal mfERG responses exists in adolescents with type 1 diabetes and no retinopathy. This is most apparent for IT abnormalities. This correspondence could be used in clinical trials, and raises the possibility of initiating treatment in both eyes at early disease stages as new topical treatments emerge.

Neurophysiological Model of the Normal and Abnormal Human Pupil

A model of the pathways controlling the size of the human pupil is presented. Computer simulation of this model demonstrates the role played by each of the elements in the pupil pathways. Simulations of the effects of drugs and a few common abnormalities in the system also help to illustrate the workings of the internal processes. Computer models of this type can be used as teaching aids or as tools for testing of hypotheses regarding the system.

Association between local neuroretinal function and control of adolescent type 1 diabetes.

PURPOSE To evaluate associations between neuroretinal function measured with multifocal electroretinogram (mfERG) and disease variables in adolescents with type 1 diabetes and no retinopathy. METHODS Fundus photographs, blood glucose (BG) concentration, HbA1c, and monocular mfERG were performed on 115 adolescent patients (mean age ± SD; 15.7 ± 1.8 years) and 30 controls (18.0 ± 2.8 years). All subjects had best-corrected visual acuity ≥ 20/20. The 45° mfERG stimulus included 103 hexagons, reversing between dark and bright according to a pseudorandom m-sequence. Amplitudes (AMPs) and implicit times (ITs) were derived from local mfERG response waveforms, and Z-scores were calculated. Retinal maps of abnormality frequencies were generated. Differences between controls and patients were evaluated using t-tests. Associations between mfERG and age, duration, and diabetes control were examined using linear regression analysis. RESULTS Mean mfERG IT was significantly longer in the patients compared with that in the controls (P = 0.019), but AMP was not different (P > 0.05). In all, 26 eyes (23%) of the patients had abnormal IT and 3 eyes (3%) had abnormal AMP. IT abnormalities were essentially distributed randomly across the retina. There were too few AMP abnormalities to examine their retinal distribution. IT was positively correlated with HbA1c (P < 0.0002) but not correlated with diabetes duration, BG, or age. CONCLUSIONS Higher long-term blood glucose concentration is associated with degraded neuroretinal function in adolescents with type 1 diabetes and no retinopathy. Over 20% of these patients have abnormal neuroretinal function. It will be important to determine longitudinally whether the relationship between mfERG IT and diabetes control exists within individual adolescent patients.

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 females compared with the males. 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.