Progression of Early Retinal Dysfunction in Diabetes
We explored signs of retinal dysfunction over time in diabetic subjects before or early in the course of retinopathy. Patients with no, mild, or moderate retinopathy were consecutively recruited and underwent standard automated perimetry, visual acuity measurement, and fundus photography. These examinations and measurements of HbA1c and blood pressure were repeated for up to 5 years from baseline. Visual field improvement/deterioration in diabetic subjects was evaluated using significance limits for change. Progression or regression of retinopathy was defined as a two-step change on the Early Treatment Diabetic Retinopathy Study final severity scale. Seventy-four subjects completed at least 3 years of follow-up, and 22% showed visual field worsening, defined as repeated significant deterioration at ≥10% of the test points, whereas only 1% showed field improvement. Worsening occurred in subjects both with and without vascular lesions. The degree of retinopathy was stable throughout the observation period in 68 of 74 eyes, improved in 4, and worsened in 2. Visual field deterioration was not correlated with a change in retinopathy. By using perimetry with an analysis tailored for monitoring diabetic subjects, we were able to demonstrate progression of retinal dysfunction over time, which may represent early signs of retinal neurodegeneration.
Diabetic retinopathy has classically been considered to be a microvascular complication caused by elevated blood glucose levels and metabolic pathways triggered by hyperglycemia. Vascular lesions have been characterized in detail, and guidelines for treatment based on various grading scales have been developed to help preserve visual acuity. However, the retina is not primarily a vascular tissue; rather, it is a neuronal tissue with a vascular supply in which the retinal neurons, glia, and retinal vasculature are interconnected to form a functional neurovascular unit with intricate molecular interactions. Hyperglycemia likely affects not only the vasculature per se but also the neuroretina, resulting in dysfunctions other than impairment and loss of visual acuity.
There is increasing evidence of early retinal neurodegeneration in diabetes, which may even precede the vascular changes. Neuronal degeneration patterns have been observed in various animal models of diabetes, and early retinal dysfunction has been demonstrated. Postmortem studies in humans have revealed neuronal degeneration and apoptosis in retinas, mainly in the ganglion cell layer. Furthermore, use of the modern technique of spectral domain optical coherence tomography for retinal imaging has shown thinning of the retinal nerve fiber and photoreceptor layers in diabetic subjects in vivo before any visible vascular lesions could be detected. In addition, thinning of the ganglion cell layer and inner plexiform layers has been reported in patients with mild diabetic retinopathy.
The most commonly used methods for detecting retinal dysfunction in humans are psychophysical (e.g., perimetry) or electrophysiological (e.g., electroretinogram [ERG]). Several of those techniques have been applied to evaluate retinal dysfunction in diabetic subjects, but so far, very few long-term longitudinal studies have been performed to establish the usefulness of those methods.
The most widely used test of retinal dysfunction is standard automated perimetry (SAP), which has rendered results indicating a reduction of retinal sensitivity in diabetic subjects without retinopathy as well as in those with mild/moderate or moderate/severe retinopathy. Moreover, reduction of retinal sensitivity revealed by SAP was found to correlate with stepwise increases in the severity of retinopathy. That SAP can be used to predict the development of diabetic retinopathy has also been suggested.
Microperimetry is another perimetric method in which a small area of the central field is tested using white stimuli but on a darker background than in SAP. This test was recently reported to show reduced sensitivity in subjects who did or did not have various types of retinopathy. A drawback of microperimetry is that the short dynamic range of the stimulus presented results in truncation of threshold sensitivities, and hence, normal or nearly normal function cannot be accurately measured.
Frequency doubling technology and short wavelength automated perimetry (SWAP) are two examples of selective perimetry, the latter designed to expose blue stimuli on an intense yellow background. The stimuli used in these methods aim at testing specific subpopulations of retinal ganglion cells, which increases the sensitivity of the tests. Reduced SWAP sensitivity has been reported in diabetic subjects without retinopathy as well as in individuals with mild, moderate, or more severe diabetic retinopathy. SWAP is not optimal for analysis of longitudinal data. Compared with SAP, SWAP entails considerably larger test–retest variability, making it difficult to detect subtle changes, and SWAP is also much more sensitive to cataract development. Perimetry using frequency doubling technology stimuli has reported reduced retinal sensitivity in diabetic subjects without as well as with retinopathy, but so far this has only been noted in a limited number of cross-sectional studies.
The ERG is an electrophysiological test that can provide objective and quantitative information on retinal dysfunction in diabetic subjects. There is evidence that ERG abnormalities can be detected very early in the course of retinopathy and that special techniques can be used to demonstrate local responses. To our knowledge, changes in ERG responses over time have only been investigated in insulin-dependent diabetic patients and have yielded contradictory results, but it has been reported that a delayed ERG response can predict the onset of diabetic retinopathy. Those results could indicate that diabetes may affect the retinal neurons ahead of the retinal vascular network.
The purpose of our study was to demonstrate the usefulness of SAP for detecting early retinal dysfunction over time in patients with type 1 and type 2 diabetes. In our interim report published after 18 months of follow-up of subjects with and without mild/moderate diabetic retinopathy, we described how our previously defined limits of significant change for SAP in diabetes provided promising results regarding the monitoring of perimetric change. Here, we confirm those findings in an extended longitudinal study with an average follow-up time of 4 years.
Abstract and Introduction
Abstract
We explored signs of retinal dysfunction over time in diabetic subjects before or early in the course of retinopathy. Patients with no, mild, or moderate retinopathy were consecutively recruited and underwent standard automated perimetry, visual acuity measurement, and fundus photography. These examinations and measurements of HbA1c and blood pressure were repeated for up to 5 years from baseline. Visual field improvement/deterioration in diabetic subjects was evaluated using significance limits for change. Progression or regression of retinopathy was defined as a two-step change on the Early Treatment Diabetic Retinopathy Study final severity scale. Seventy-four subjects completed at least 3 years of follow-up, and 22% showed visual field worsening, defined as repeated significant deterioration at ≥10% of the test points, whereas only 1% showed field improvement. Worsening occurred in subjects both with and without vascular lesions. The degree of retinopathy was stable throughout the observation period in 68 of 74 eyes, improved in 4, and worsened in 2. Visual field deterioration was not correlated with a change in retinopathy. By using perimetry with an analysis tailored for monitoring diabetic subjects, we were able to demonstrate progression of retinal dysfunction over time, which may represent early signs of retinal neurodegeneration.
Introduction
Diabetic retinopathy has classically been considered to be a microvascular complication caused by elevated blood glucose levels and metabolic pathways triggered by hyperglycemia. Vascular lesions have been characterized in detail, and guidelines for treatment based on various grading scales have been developed to help preserve visual acuity. However, the retina is not primarily a vascular tissue; rather, it is a neuronal tissue with a vascular supply in which the retinal neurons, glia, and retinal vasculature are interconnected to form a functional neurovascular unit with intricate molecular interactions. Hyperglycemia likely affects not only the vasculature per se but also the neuroretina, resulting in dysfunctions other than impairment and loss of visual acuity.
There is increasing evidence of early retinal neurodegeneration in diabetes, which may even precede the vascular changes. Neuronal degeneration patterns have been observed in various animal models of diabetes, and early retinal dysfunction has been demonstrated. Postmortem studies in humans have revealed neuronal degeneration and apoptosis in retinas, mainly in the ganglion cell layer. Furthermore, use of the modern technique of spectral domain optical coherence tomography for retinal imaging has shown thinning of the retinal nerve fiber and photoreceptor layers in diabetic subjects in vivo before any visible vascular lesions could be detected. In addition, thinning of the ganglion cell layer and inner plexiform layers has been reported in patients with mild diabetic retinopathy.
The most commonly used methods for detecting retinal dysfunction in humans are psychophysical (e.g., perimetry) or electrophysiological (e.g., electroretinogram [ERG]). Several of those techniques have been applied to evaluate retinal dysfunction in diabetic subjects, but so far, very few long-term longitudinal studies have been performed to establish the usefulness of those methods.
The most widely used test of retinal dysfunction is standard automated perimetry (SAP), which has rendered results indicating a reduction of retinal sensitivity in diabetic subjects without retinopathy as well as in those with mild/moderate or moderate/severe retinopathy. Moreover, reduction of retinal sensitivity revealed by SAP was found to correlate with stepwise increases in the severity of retinopathy. That SAP can be used to predict the development of diabetic retinopathy has also been suggested.
Microperimetry is another perimetric method in which a small area of the central field is tested using white stimuli but on a darker background than in SAP. This test was recently reported to show reduced sensitivity in subjects who did or did not have various types of retinopathy. A drawback of microperimetry is that the short dynamic range of the stimulus presented results in truncation of threshold sensitivities, and hence, normal or nearly normal function cannot be accurately measured.
Frequency doubling technology and short wavelength automated perimetry (SWAP) are two examples of selective perimetry, the latter designed to expose blue stimuli on an intense yellow background. The stimuli used in these methods aim at testing specific subpopulations of retinal ganglion cells, which increases the sensitivity of the tests. Reduced SWAP sensitivity has been reported in diabetic subjects without retinopathy as well as in individuals with mild, moderate, or more severe diabetic retinopathy. SWAP is not optimal for analysis of longitudinal data. Compared with SAP, SWAP entails considerably larger test–retest variability, making it difficult to detect subtle changes, and SWAP is also much more sensitive to cataract development. Perimetry using frequency doubling technology stimuli has reported reduced retinal sensitivity in diabetic subjects without as well as with retinopathy, but so far this has only been noted in a limited number of cross-sectional studies.
The ERG is an electrophysiological test that can provide objective and quantitative information on retinal dysfunction in diabetic subjects. There is evidence that ERG abnormalities can be detected very early in the course of retinopathy and that special techniques can be used to demonstrate local responses. To our knowledge, changes in ERG responses over time have only been investigated in insulin-dependent diabetic patients and have yielded contradictory results, but it has been reported that a delayed ERG response can predict the onset of diabetic retinopathy. Those results could indicate that diabetes may affect the retinal neurons ahead of the retinal vascular network.
The purpose of our study was to demonstrate the usefulness of SAP for detecting early retinal dysfunction over time in patients with type 1 and type 2 diabetes. In our interim report published after 18 months of follow-up of subjects with and without mild/moderate diabetic retinopathy, we described how our previously defined limits of significant change for SAP in diabetes provided promising results regarding the monitoring of perimetric change. Here, we confirm those findings in an extended longitudinal study with an average follow-up time of 4 years.
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