Visual Psychophysics in Diabetic Retinopathy

may reflect the neural activity of the whole visual pathway, but it is known that these tests are valuable clinical indicators of retinal function derangements induced by the metabolic changes secondary to diabetes mellitus. In fact, in diabetic patients, impaired vision in dim light and difficulties in recognizing the contour of objects in low-contrast conditions are common complaints even with good visual acuity and full visual fields [3]. Moreover, health-related quality of life can become affected in diabetics even prior to vision loss due to anxiety about the future and emotional reaction to diagnosis and treatment of retinopathy [4].

Visual acuity is still considered the gold standard in clinical practice of vision testing, but it does not entirely reflect functional vision. Functional vision describes the impact of sight on quality of life that represents the patient’s point of view [5, 6]. This approach is better quantified using available psychophysical tests (visual acuity, color vision, contrast sensitivity, macular recovery function, perimetry, and microperimetry).

VISUAL ACUITY

The quantification of visual acuity (VA) is the best known and most widely used test for assessing the integrity of the visual function in clinical settings. It represents the ability to discriminate, at high contrast (black symbols/letters on a white background), two separated stimuli. The Snellen chart is the most widely used tool for VA assessment, and it is routinely used in any clinical setting worldwide. The prototype of this chart was developed in 1862 by the Dutch ophthalmologist Hermann Snellen. He defined “standard vision” as the ability to recognize one of his optotypes at a visual angle of 1 min of arc. Later, the original chart was modified and became what is now known as a standard Snellen chart. This chart has well-documented limits owing to design flaws, such as inconsistent progression of letter size from one line to another, unequal legibility of letters used, unequal and unrelated spacing between letters and rows, and large gaps between acuity levels at the lower end of the chart [7–10]. Variability in background ambient illumination and contrast and poor reliability during test–retest evaluation make, in some cases, Snellen measurements clinically inadequate and prevent reliable evaluation of data obtained from different studies [11–13].

Therefore, new and standardized charts with logMAR (logarithm of the minimal angle of resolution) progression have been developed and introduced into clinical practice, based on design suggested by Bailey and Lovie in 1976, lately described in detail by Ferris et al., and adopted for the Early Treatment Diabetic Retinopathy Study (ETDRS chart) [14, 15]. The major advantages of this chart are regular geometric progression of the size and spacing of the letters, following a logarithmic scale with 0.1 log units steps, equal number of letters in each row, five Sloan optotypes, comparable legibility of the sans serif letters, high accuracy, and reliability for both high and low levels of VA [14–17]. Thus, the ETDRS chart has become the gold standard for measuring VA at least in clinical trials.

In diabetic patients, the full functional impact of macular edema (diabetic macular edema, DME) and the functional effects of its treatment on visual function are still poorly documented and understood [18]. Ang et al. found that VA was a poor predictor of presentation and type of DME and that its usefulness as a sole screening tool is limited [19]. On the contrary, Sakata et al. [20] reported a correlation of VA with macular

microcirculation characteristics (perifoveal capillary blood flow velocity and severity of perifoveal capillary occlusion) and central foveal retinal thickness in diabetics.

Since the ETDRS study demonstrated that focal macular laser photocoagulation prevents moderate vision loss in approximately 50% of cases, visual acuity has been considered the primary endpoint in all clinical trials evaluating both the natural history as well as the efficacy of any treatment strategy in clinically significant diabetic macular edema (CSME) [21–26]. But in clinical practice, DME is currently assessed not only with VA but also with optical coherence tomography (OCT), a retinal structure test. Therefore, the correlation between these two investigations, one functional and one structural, has been widely, even if not definitively, investigated. Recently, the Diabetic Retinopathy Clinical Research Network reported only modest correlation between VA and OCT-measured center point retinal thickness with a possible wide range of VA for a given degree of retinal edema. These authors also found modest correlation of changes in retinal thickening and VA after focal laser treatment for DME [27]. Browning et al. [28] found no correlation between the extension of DME by OCT and changes of VA after laser photocoagulation, during 12 months follow-up. These results suggest that OCT measurement alone may not be a good surrogate for VA as a primary outcome in studies of DME. Moreover, VA data needs to be integrated with more comprehensive visual function information.

COLOR VISION

As a predominantly macular function, color discrimination may be impaired by any degenerative process affecting the central retina [29]. In diabetes, the underlying mechanism of color dysfunction is uncertain and may relate to metabolic derangement in the neural retina other than to microvascular disease [30]. Several hypotheses have been proposed such as (a) osmotic distortion of the retina caused by the fluid shifts inside the retina, followed by distortion and dysfunction of the neural cells and (b) disorders of metabolisms of neural cells caused by direct diabetes damage or mediated by the alterations of the retinal microcirculation [31–35]. Dean et al. [36] suggested a major role of retinal hypoxia showing that color vision deficits in diabetics with retinopathy can be partially reversed by inhalation of pure oxygen. Different tests are available to assess color vision; unfortunately, most of them are negatively affected by lens opacities [37]. Moreover, approximately 10% of male population and 0.5% of female population show varying degree of congenital color deficiency. Therefore, studies evaluating color vision in diabetics should account for all these factors. One of the most widely known and reported test is the Farnsworth–Munsell 100-Hue Test (FM 100 Hue Test); this is also the most time-consuming diagnostic procedure [38].

Since the first report (in 1905) describing the association between abnormalities in color vision and diabetes mellitus, many researchers have reported the relationship between diabetic retinopathy and color vision dysfunction [39–43]. The first controlled study of color vision in diabetics was reported by Kinnear et al. [44] and Lakowski et al. [29] who showed in a large group of subjects that blue-yellow and blue-green color vision losses were found significantly more among diabetic patients with retinopathy than in normal controls. Other studies confirmed that the blue-yellow axis

(the short-wavelength-sensitive cone system) is more vulnerable to diabetes than the green and the red axes [45, 46]. But this conclusion is not unanimously accepted. Hue discrimination in diabetics without retinopathy or with only microaneurysms has been reported not to significantly differ from controls, whereas other studies concluded that diabetics show abnormal results in color vision tests and a tritanopic reduction in a chromatic-contrast threshold when compared with normal controls [47–50] (Table 1). Different studies showed deficits in blue-yellow color discrimination in both adults and adolescents with type 1 diabetes mellitus who had no evidence of retinopathy [41, 44, 51–60]. Hardy et al. [61] found in young patients with insulin-dependent diabetes mellitus (IDDM) that FM 100 Hue Test was more sensitive and specific in detecting dysfunction of the visual pathway than both flash and pattern electroretinogram, and proposed this test for the early visual dysfunction evaluation without success. In the ETDRS, the FM 100 Hue Test was performed in 2,701 patients and showed abnormal hue discrimination in approximately 50% of cases when compared with published data on normal subjects [62]. Macular edema severity, age, and the presence of new vessels were the factors most strongly associated with impaired color discrimination, especially the tritan-like defect [62].

Green et al. [63] examined the FM 100 Hue Test as a screening device for sightthreatening diabetic retinopathy and reported sensitivity of 73% and specificity of 66%, concluding that the test was not sensitive enough for screening of sight-threatening diabetic retinopathy. In a similar study, Bresnick et al. [41] reported sensitivity of 65% and specificity of 59%. Therefore, new color vision tests have been proposed and evaluated. The Mollon–Reffin “Minimalist” test showed sensitivity of 88.9% and specificity of 93.3% in detecting DME [64]. An automated tritan contrast threshold showed 94% sensitivity and 95% specificity in screening for sight-threatening diabetic retinopathy, mainly for DME before the onset of visual loss [65, 66]. Although more advanced stages of retinopathy and DME show greater effect on color vision, subtle specific spectral losses, especially related to blue-yellow discrimination, seem widespread in patients with diabetes, irrespective of the presence of retinopathy and duration of diabetes. Moreover, decreased hue discrimination is present after successful panretinal laser photocoagulation for proliferative DR [67]. These data are also confirmed by studies on contrast sensitivity, and they should be considered in the evaluation and counseling of patients with diabetic retinopathy.

CONTRAST SENSITIVITY

Perhaps the chief merit of the human contrast sensitivity function is that it provides considerably more information than visual acuity: The contrast sensitivity function is a description of the visual system’s sensitivity to course-scale detail and medium-scale detail as well to fine detail, while visual acuity quantifies sensitivity to fine detail only. For any given spatial frequency, contrast sensitivity is the reciprocal of contrast detection threshold. The contrast sensitivity function is a plot of the reciprocal of the contrast detection threshold for a grating vs. the spatial frequency of that grating. Contrast sensitivity (CS) function may be quantified using different laboratory and clinical tests [68]. CS determines the person’s contrast detection threshold, the lowest contrast at which

Table 1. Studies which have investigated color vision in patients with diabetic retinopathy

Table 1. (continued)

Principal

Pts patients; VA visual acuity; DR diabetic retinopathy; NPDR non proliferative diabetic retinopathy; bDR background diabetic retinopathy; PDR proliferative diabetic retinopathy; CV color vision; STDR sight-threatening diabetic retinopathy; NSTDR non sight-threatening diabetic retinopathy; CSME clinically significant diabetic macular edema

a certain pattern can be seen. An assumption which often underlies the clinical use of the CS function is that it predicts whether a patient is likely to have difficulty in seeing visual targets typical of everyday life. A contrast sensitivity assessment procedure consists of presenting the observer with a sine-wave grating target of a given spatial frequency (i.e., the number of sinusoidal luminance cycles per degree of visual angle). The contrast of the target grating is then varied while the observer’s contrast detection threshold is determined. Typically, contrast thresholds of this sort are collected using vertically oriented sine-wave gratings varying in spatial frequency from 0.5 (very wide) to 32 (very narrow) cycles per degree of visual angle.

Whereas standard visual acuity testing is a high-contrast test by definition and it measures only size, it does not provide full information about visual function in the everyday life activities. Contrast sensitivity measures the two major variables: size and contrast, offering a more realistic quantification of visual impairment. There are different types of chart tests to capture the different aspects of the CS function (charts with white and black bars of decreasing contrast, charts with letters). Among them, the Pelli– Robson chart is the most commonly used chart in clinical trials. It consists of letters of a single (large) size (low spatial frequency). The chart is arranged by triplets of letters and each triplet is 0.15 log units higher in contrast than the preceding triplet.

Both hue discrimination and contrast sensitivity may reflect (if the lens is clear) macular function, but their exact physiological relationship has not yet been fully explained. Some data suggest that the CS function more significantly correlates to DR grading than color vision and macular recovery function [69, 70]. Unfortunately, data about CS function in diabetics are still controversial. This difference in clinical results may be, at least methodologically, explained by the different methods used to quantify CS, as well as the lack of homogeneity in the examined groups (type of diabetes, age, criteria, and methods for DR evaluation). This fact points to the importance of developing a standardized test to accurately and reliably quantify contrast sensitivity function in both clinical practice and clinical trials. Diabetic patients with retinopathy and good visual acuity frequently show spatial resolution defects, which can be detected measuring CS function. The reductions in CS involve mainly the intermediate and medium-high spatial frequencies in relation to the severity of retinopathy and previous laser photocoagulation; nevertheless, some patients show losses at the medium-low spatial frequencies [71–74]. In DME, Arend et al. [75] found that loss of CS correlates with the enlargement of the foveal vascular zone. Midena et al. [76] studied the effect of both focal and grid laser photocoagulation on CS of patients with DME and found that CS function improved after treatment, but it never normalized. The same finding was reported by Talwar et al. [77] who found improved CS and stabilization of visual acuity after focal argon laser photocoagulation for CSME.

Farahvash et al. described the early improvement of CS at midfrequencies after macular laser photocoagulation. This benefit appeared only in patients with resolved CSME, suggesting that CS is probably a more sensitive parameter than visual acuity for early monitoring of CSME after laser photocoagulation [78]. The significant reduction in CS function documented in diabetics with retinopathy is not confirmed when a subject has no retinopathy: There is still not strong evidence of significant difference in CS between diabetics without retinopathy and normal controls. According to Arend et al., there