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To evaluate the effect of pupillary dilation on electronic-ETDRS visual acuity (EVA) in diabetic subjects and to assess post-dilation EVA as a surrogate for pre-dilation visual acuity (VA).
DRCR.net-protocol refraction and EVA were measured pre- and post-dilation in diabetic subjects by independent, masked examiners.
In 129 eyes of 66 subjects, median [25th, 75th percentiles] pre-dilation EVA score was 69 [54, 86] (Snellen-equivalent 20/40-1 [20/80-1, 20/20+1]). Pre-dilation VA was ≥20/20, 20/25-20/40, 20/50-20/80, and <20/80 in 29%, 19%, 26%, and 26% of eyes, respectively. Median EVA change post-dilation was -3 letters [-7, 0]. EVA change was ≥15 letters (≥ 3 ETDRS lines) in 9% of eyes and ≥10 letters (≥ 2 ETDRS lines) in 19% of eyes. Extent of change (range +12 to -25 letters) was associated with baseline VA. No relationship was identified between EVA change and gender, race, lens status, refractive error, DR severity, or primary cause of vision loss.
In an optimized clinical trial setting, there is a decline in best-corrected EVA after dilation in diabetic subjects. The large range and magnitude of VA change preclude using post-dilation EVA as a surrogate for undilated VA.
Accurate determination of visual acuity (VA) and the ability to precisely follow changes in VA over time are key outcome measures in most clinical trials and in daily eye care practice. In ophthalmic clinical trials, these measures are frequently used as primary endpoints, underscoring the importance of establishing reliable VA measurement while at the same time permitting efficient patient evaluation and throughput.
The methods for measuring VA in clinical trials have been extensively evaluated. Currently, the most common approach is based on the detailed and rigorous refraction and VA protocols of the Early Treatment Diabetic Retinopathy Study (ETDRS),1, 2 widely considered the gold standard for assessing VA in the ophthalmic clinical research setting. These protocols include specific requirements for refraction and VA lanes, acuity chart type, lighting and chart height, and careful, protocol-defined algorithms for performing refraction and VA measurement.
Recently, an electronic version of the VA measurement protocol called Electronic-ETDRS VA (EVA) has been evaluated and validated.3, 4 The reliability of VA measurements made with EVA compares favorably with the standard ETDRS VA protocol and has the benefits of being easier, requiring less space and reducing examiner bias. EVA testing has been accepted for use as a primary clinical trial endpoint by the United States Food and Drug Agency and has become the standard VA assessment tool for large clinical trials groups such as the Diabetic Retinopathy Clinical Research Network (DRCR.net) and other multi-center clinical trial groups.
Both ETDRS and EVA VA testing are typically performed prior to pupillary dilation. In many instances, however, the ability to obtain a post-dilation VA that accurately reflects pre-dilation VA would result in significant savings in time, efficiency and convenience for both patients and clinicians. These benefits arise from the increased flexibility of VA testing permitting optimal use of ophthalmic resources and patient flow. In addition, identification of patients for many clinical research studies requires evaluation of the retina after pupil dilation and before any informed consent or formal clinical study refraction and VA measurement is performed. Accurate post-dilation assessments of VA would allow immediate post-dilation recruitment of patients for many clinical research studies that otherwise demand re-evaluation of potentially eligible subjects in the undilated state. As such, post-dilation VA measurement would represent a valuable alternative to pre-dilation VA testing. We therefore evaluated the effect of dilation on EVA measurements and whether post-dilation EVA scores are a reliable reflection of pre-dilation EVA scores in patients with diabetes and a wide range of pre-dilation vision.
Patients with diabetes mellitus who were 18 years of age and older were recruited from the clinic population of the Beetham Eye Institute of the Joslin Diabetes Center, a tertiary eye care center specializing in diabetic eye disease. Written informed consent and authorization for medical information disclosure in accordance with HIPAA was obtained from all patients prior to study participation. The study design was approved by the DRCR.net Executive Committee and the Joslin institutional review board and was in accordance with the Declaration of Helsinki.
Demographic data including date of birth, gender, ethnicity, education level, and ocular medications were obtained at the time of a single study visit by experienced study-certified examiners. Eyes were stratified by pre-dilation EVA score into 4 groups as follows: EVA ≥85 (≥20/20), EVA from 70-84 (<20/20 to 20/40), EVA from 55-69 (<20/40 to 20/80) and EVA ≤54 (<20/80).
Pupil size for each subject was manually measured using a standard millimeter pupil gauge prior to refraction in a room illuminated to match protocol lighting conditions for EVA testing. DRCR.net protocol refraction was performed on each eye; details are available at www.drcr.net. EVA was then recorded first for the right eye and then for the left eye according to the DRCR.net EVA protocol.
The EVA testing method has been previously described3 and differs from the use of a standard ETDRS chart in that it utilizes a high-resolution monitor linked to a personal computer to present letters of standardized luminance (85-105 candelas/meter2) and contrast (98%). EVA letter size is within approximately 2% of the letter size at each logMAR level on the ETDRS chart. EVA testing is performed at 3 m rather than the standard 4 m used with standard ETDRS charts. Letters are presented individually with crowding lines and a letter score rather than a Snellen line acuity is generated. As with the ETDRS acuity score, the EVA letter score can be used to calculate a corresponding Snellen acuity in that an EVA score of 85 letters is equivalent to 20/20 VA and each 5 letter decrease in EVA score corresponds to a 1 line drop in VA.
Subjects then underwent a specified pre-dilation slit-lamp biomicroscope anterior segment eye exam which included assessment of corneal clarity (clear, peripheral opacity/stain, central opacity/stain), and lens status (phakic/pseudophakic). All study results were recorded on standardized forms.
The pupils were then dilated by instillation of 2.5% phenylephrine and 1% tropicamide eye drops attempting to attain a dilated pupil size of at least 5mm. After at least 20 minutes, pupil size was re-measured in a room illuminated to match protocol lighting conditions for EVA testing. Post-dilation refraction and EVA measurement were then performed by an independent examiner who was masked to the findings of the pre-dilation examiner. The post-dilation refraction was obtained according to DRCR.net protocol, using the pre-dilation refraction as the starting refraction. Visual acuity was measured first for the right eye and then for the left eye according to the DRCR.net EVA protocol.4 Subjects then underwent a post-dilation anterior segment assessment of corneal clarity (clear, peripheral opacity/stain, central opacity/stain) and extent of cataract based on the AREDS lens opacity grading scale (cataract absent, pseudophakic, or cataract < or ≥ AREDS Standard 2). Type of cataract was also recorded (nuclear sclerosis, cortical spoking, posterior subcapsular). Collection of post-dilated fundus examination information included diabetic retinopathy (DR) severity level and primary cause of visual loss.
SAS software version 9.1 (Cary, North Carolina, USA) was used for all statistical analyses. Statistical comparisons of pre- vs. post-dilation and change in EVA score after dilation among subgroups were performed using non-parametric analysis based on ranks (Van der Waerden scores). Repeated measures regression models were used to account for two eyes from the same subject. Due to multiple comparisons, p-values above 0.01 were not considered statistically significant.
This study evaluated 131 eyes of 66 study participants with diabetes (mean age 59 years). One subject had a phthisical eye that was not examined. Two eyes did not have complete examinations and were excluded from analysis. Baseline characteristics of the 66 subjects and 129 analyzed eyes are presented in Table 1.
The median pre-dilation EVA letter score was 69 (20/40-1), ranging from 95 to 0 letters (20/12.5 to <20/800). Pre-dilation EVA had a Snellen VA equivalent of 20/20 or better in 38 (29%) eyes, 20/25 to 20/40 in 24 eyes (19%), 20/50 to 20/80 in 34 eyes (26%), and worse than 20/80 in 33 eyes (26%) (Table 1). Thirty-six eyes (28%) had no significant ocular pathology other than refractive error. Primary cause of vision loss in the other eyes was diabetic macular edema in 35 (27%), cataract in 34 (26%), non-diabetic pathology in 16 (12%), vitreous hemorrhage in 4 (3%), and current or previous retinal detachment in 4 (3%).
Overall, the median change in EVA score from pre-dilation to post-dilation was a loss of 3 letters [lower and upper quartiles of -7 and 0 letters loss, range +12 to -25] (Table 2, p<0.001). EVA post-dilation tended to be reduced, reflecting a general drop in VA regardless of pre-dilated EVA (Figure 1, r = −0.18, 95% CI: −0.35, −0.05). The median [lower, upper quartiles] absolute change in EVA after dilation was 4 [2, 8] letters. EVA declined significantly in all VA subgroups (Table 2, p<0.001, p=0.007, p<0.001, and p=0.01, respectively). A large range in post-dilation EVA change was observed in all four VA groups, being +3 to -15, +3 to -25, +12 to -22, and +8 to -25 letters in the 20/20 or better, 20/25 to 20/40, 20/50 to 20/80, and the worse than 20/80 groups, respectively.
The distribution of post-dilation EVA score changes was associated with the baseline EVA score. As shown in Figure 2, worse baseline EVA was associated more frequently with post-dilation EVA change of 5 or more letters (change of 1 or more ETDRS lines), and less frequently with EVA change of less than 5 letters (change of less than 1 ETDRS line). After dilation, a 5 or more letter change was observed in 18%, 50%, 53% and 67% of eyes with baseline EVA of 20/20 or better, 20/25 to 20/40, 20/50 to 20/80, and worse than 20/80, respectively. In eyes with 20/20 or better baseline acuity, 3% experienced a change in acuity of 15 or more letters (3 or more ETDRS lines) after dilation.
After adjustment for baseline visual acuity, there was a tendency for older subjects to experience more EVA decline with dilation, although the associated p value of 0.05 did not achieve the threshold of statistical significance given the multiple comparisons performed (Table 3). Median losses were 2, 3 and 5 letters for persons age <50, 50-<70 and ≥70 years, respectively (Table 3). With increasing age, the median absolute change in EVA increased from 2 to 7 letters. In subjects less than age 50 years, 23% had post-dilation EVA change of 5 or more letters; however, at age 70 or older, 61% were changed by 5 or more letters.
As shown in Table 3, there was a tendency for post-dilation corneal opacity/staining (e.g., staining induced by applanation tonometry or corneal desiccation) and smaller pre-dilation pupil size to be associated with greater EVA decline after dilation. The study participant's gender, race, pre-dilation corneal clarity, lens status, and DR severity level did not substantially affect EVA change (Table 3). We also could not detect a relationship between EVA change and the subject's education level, phakic refractive error, extent of cataract (either nuclear sclerotic, cortical spoking, or posterior subcapsular), primary cause of vision loss, or examiner (data not shown).
Refractive error did not change substantially from pre to post-dilation in subjects overall or in the subset of study participants who were phakic. The median pre-dilation manifest refraction spherical equivalent was -0.125 diopters (D) (-1.250 D, +0.875 D, N = 129) in all subjects and -0.125 D (-1.188 D, +1.063 D, N = 96) in phakic subjects. The median post-dilation manifest spherical equivalent was -0.250 D (-1.125 D, +0.625 D) and -0.125 D (-1.063 D, +1.063 D) in these two groups, respectively. The median absolute change in manifest spherical equivalent from pre to post dilation was 0.250 D (0.125 D, 0.500 D) in all subjects and 0.250 D (0.125 D, 0.375 D) in phakic subjects. In general there was also minimal astigmatic change induced by dilation. The median post-dilation change in cylinder in both phakic and pseudophakic eyes was 0 diopters (Q1, Q3: 0 D, 0.25 D for both phakic and pseudophakic eyes). Change in spherical equivalent refractive error from pre to post-dilation appeared unrelated to change in EVA from pre to post-dilation or to baseline VA, age, pre-dilation pupil size or DR severity level.
This study demonstrates that in an optimized clinical trial setting using experienced examiners, there is a general decline in best-corrected VA in patients with diabetes as measured by EVA after pupil dilation. The magnitude of change varies greatly between patients and can be surprisingly large. In this study, results were not significantly influenced by which examiner performed EVA testing first or second. Regardless, it is unlikely that different pre- and post-dilation EVA examiners would have contributed substantially to EVA variability, since the EVA testing protocol is standardized and automated, and thus the examiner does not determine the stopping point or how many letters to administer at each level. In addition, the EVA testing protocol is specifically structured to minimize examiner influence by requiring subject response to letters that are near or below threshold acuity, and by presenting single letters to preclude the risk of patient errors due to reading speed.
Although the median change in dilated EVA score was a loss of 3 letters, the effect ranged from a gain of 12 letters to a loss of 25 letters. Overall, after dilation 9% and 19% of eyes experienced a ≥15 letter or ≥10 letter EVA decline, respectively. These percentages are substantially higher than those seen in test-retest reliability studies of EVA in subjects with undilated pupils: only 0.4% and 2% of subjects experience an absolute change of ≥ 15 letters and ≥ 10 letters, respectively when EVA is repeated with pupils left undilated in a non-diabetic population comparable in age, gender mix, and ethnic makeup.3 This suggests that the wide range of post-dilation EVA change demonstrated in this study is due to dilation rather than test-retest error.
The effect of dilation on EVA scores was partially dependent on baseline EVA. In eyes with EVA of 20/20 or better pre-dilation, 3% experienced a 15 or more letter change after dilation. In contrast, a 15 or more letter change was observed in nearly 15% of eyes with EVA of 20/50 to 20/80 at baseline. Dilation-induced changes of 10 or more letters were observed in 8% and 26% of eyes in these groups, respectively.
This study was not designed to directly address the causes of acuity differences between pre and post-dilation VA. There are several potential reasons for these differences including post-dilation changes in retinal illuminance, greater exposure to optical irregularities in the cornea or lens, and/or changes in the ocular surface due to corneal drying or tonometry. It is also possible that VA in different individuals is affected by more than one of these considerations at the same time. The results from this study suggest that changes in refractive error post-dilation did not contribute significantly to VA change.
The ability to use post-dilated VA as a surrogate for best-corrected VA in diabetic patients would be advantageous for both patients and clinicians for several reasons, including efficiencies in time, convenience and clinical trial recruitment. The results of the present study, however, do not support post-dilated EVA as an accurate surrogate for an individual's undilated VA. Given the wide range of EVA change after dilation (up to 25 letters in this study), post-dilation EVA testing cannot reliably substitute as a surrogate for an individual's undilated VA. It is unknown at this time whether baseline to endpoint visual acuity change in clinical trials would be similar if post-dilation VA was used at both baseline and follow-up throughout a trial as compared with only undilated vision evaluation throughout the trial.
Under selected circumstances, evaluation of post-dilation EVA might be considered, due to its general correlation with pre-dilation EVA. Post-dilation EVA might be of some use in estimating overall pre-dilation EVA in large cohorts, especially those with good baseline VA. Patients with EVA equal to or better than 20/20, and equal to or better than 20/40, had EVA changes post-dilation ranging from +3 to -15 and +3 to -25 letters, respectively. Thus, one might conclude that in these groups, a post-dilation EVA was unlikely to have been worse by a line or more pre-dilation, but could have been substantially better. Given this conclusion, post-dilation EVA testing might be useful in a situation such as initial screening for patients to meet a study enrollment criterion of EVA not worse than 20/20 or 20/40. If post-dilation EVA assessment is used in such a case, it may be appropriate for clinicians to avoid corneal staining related to tonometry measurements or corneal drying from infrequent blinking after anesthetic drops since the extent of EVA change after dilation appears related to post-dilation corneal clarity.
Given the previously reported high correlation between VA measured by EVA and ETDRS chart protocols, we would expect a similar degree of VA spread and worsening post-dilation if this study had been performed in a our patient population using standard ETDRS charts. It is also possible that similar results would arise in other, nondiabetic populations since previous studies with nondiabetic patient cohorts have also found visual worsening after dilation5-7. Previous studies of post-dilation VA have generally focused on the effects of dilation on functional performance of specific tasks such as driving. These studies suggest that dilation not only impairs accommodation due to cycloplegia, but may also alter aspects of functional vision including acuity, and both contrast and glare sensitivity.5-7 A study of 105 consecutive patients assessed using ETDRS and Snellen charts found a similar mean reduction of 4.8 letters read from the ETDRS chart following dilation and an association with baseline VA.7 We are not aware of any prior studies evaluating the effects of pupil dilation on vision measured by EVA nor studies specifically in the diabetic population.
In summary, this study demonstrates that in an optimized clinical trial setting using experienced examiners, it is common for best-corrected visual acuity to change substantially after pupillary dilation in patients with diabetes. Dilation generally reduced visual acuity and changes of up to 25 letters (5 lines) were observed. Given the wide range and large magnitude of VA change after dilation, post-dilation EVA testing cannot reliably substitute as a surrogate for undilated VA.
Supported through a cooperative agreement from the National Eye Institute and the National Institute of Diabetes and Digestive and Kidney Diseases EY14231, EY14269, EY14229.
A current list of the Diabetic Retinopathy Clinical Research Network is available at www.drcr.net
There are no financial conflicts of interest.
An address for reprints will not be provided.