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.

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.

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.

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.

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.

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.

Retinal neuropathy precedes vasculopathy in diabetes: a function-based opportunity for early treatment intervention?

Diabetes, now at epidemic levels, can have devastating effects on the eye and vision. Treatments of the ocular complications are currently focused on relatively advanced stages and are limited to the slowing down of the progressive sight-threatening retinal vasculopathy (diabetic retinopathy). Tiny signals from the neural retina have been shown to reveal early diabetic neuropathy prior to vascular retinopathy. These signals, in a clinical test format, are predictive, by precise retinal location, of impending vasculopathy in the retina within a year, including sight-threatening oedema. The discovery opens possibilities for the future development of treatments to prevent the onset of retinopathy and the more sight-threatening retinal oedema and changes patient management strategies.

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.

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.

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.

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.

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.