Dry eye is a highly prevalent condition1–6 that significantly affects quality of life2,7 and is additionally a major risk factor for a variety of corneal and ocular surface morbidities such as corneal infection,8,9 thinning,10,11 and contact lens intolerance.12 Disease definitions vary between studies, but studies that define dry eye based on symptoms report a prevalence ranging from 6.5 to 52.4%, with the majority reporting a prevalence of around 20%.3 The prevalence of disease increases with age, and women are more frequently affected.3 Dry eye not only results in decreased quality of life but also can affect visual function. In a recent natural history study of dry eye, blurred vision was reported as moderate to very severe in 58% of dry eye patients compared with only 10.5% in healthy controls.13 Although there are many reports of decreased visual quality of life and symptoms in dry eye patients compared with controls,2,7,12 there is little information surrounding which specific dry eye signs contribute to diminished visual function.
Previous studies have assessed corneal irregularity from superficial punctate keratitis and tear film instability in their relationship to visual function. Central superficial punctate keratitis in dry eye has been associated with significant deterioration of visual function and optical quality measured by functional visual acuity measurements (time-wise change in continuous visual acuity14) and contrast sensitivity.15–17 Ocular surface damage in the central cornea has also been associated with increased higher-order aberrations and increased corneal backward light scatter.18 In addition, tear film instability has been associated with an irregular optical surface affecting visual function. For example, temporal changes in higher-order aberrations are associated with the tear film interface in dry eye.19 However, additional studies are needed to understand the relationship between specific dry eye signs and the corresponding effects on visual function, which in turn will aid clinicians in designing appropriate treatment plans for dry eye patients.
Various methods have been used to subjectively assess visual function in dry eye disease including high- and low-contrast visual acuity, dynamic visual acuity,14 contrast sensitivity,20 and disability glare.15,20–22 Because standard high-contrast visual acuity is not sensitive enough to detect mild ocular disease in other conditions such as cataract and glaucoma and is known to be variable in dry eye disease, other measures of visual function are needed. Contrast sensitivity is a candidate because it is a sensitive indicator of visual function and ocular disease progression.23–27 However, although previous studies have shown that contrast sensitivity is a sensitive measure of the effects of dry eye on visual function,15,17 very few have assessed which particular clinical signs impact this measurement. To address this knowledge gap, we obtained data from the Dry Eye Assessment and Management study that has a large, well-characterized cohort with dry eye disease, including information on both the standardized assessment of logMAR visual acuity and contrast sensitivity. In addition, because Sjögren syndrome patients were included in the study, this subset allowed for an assessment of the effect of aqueous deficiency on both measures. Herein, we explore the association of dry eye signs and symptoms at baseline with best-corrected high-contrast logMAR visual acuity and contrast sensitivity.
The Dry Eye Assessment and Management study was a multicenter, randomized, double-masked clinical trial to evaluate the effectiveness and safety of supplementation with ω3 fatty acids in relieving the symptoms of moderate to severe dry eye disease.28 A total of 535 subjects across 27 sites in the United States were enrolled and followed up for 12 months in the primary trial. Eligible participants were randomized to receive either 3 g of fish-derived ω3 eicosapentaenoic and docosahexaenoic acids daily (n = 349) or a placebo containing 5 g of refined olive oil (n = 186). Candidates for the clinical trial were assessed at a screening visit and an eligibility confirmation visit, which together encompass the baseline data used in this secondary cross-sectional analysis. The study protocol was approved by the institutional review board associated with each center, carried out under an Investigational New Drug application for the Food and Drug Administration, conformed with the tenets of the Declaration of Helsinki, and registered on ClinicalTrials.gov (NCT02128763). All subjects provided written informed consent.
The trial was designed to include a broad spectrum of symptomatic patients with moderate or severe dry eye. Eligibility criteria included age ≥18 years, dry eye–related ocular symptoms for at least 6 months, use or desire to use artificial tears on average of two more times a day during the 2 weeks preceding the screening visit, and scores on the Ocular Surface Disease Index between 25 and 80, inclusive, at the screening visit and between 21 and 80, inclusive, at the eligibility confirmation visit. Scores on the 12-item Ocular Surface Disease Index range from 0 to 100, where 0 indicates no ocular discomfort.29 Three subscales of the Ocular Surface Disease Index (ocular symptoms, vision-related function, and environmental triggers) also provide scores between 0 and 100. In addition to the Ocular Surface Disease Index, participants completed the Medical Outcomes Study 36-Item Short Form Health Survey (scores range from 0 to 100, with higher scores indicating better health-related quality of life), although this was not part of the eligibility assessment. Patients needed to have at least one eye with at least two of the following four signs: conjunctival lissamine green staining score ≥1 on a scale of 0 to 6, corneal fluorescein staining score ≥4 on a scale of 0 to 15, tear film breakup time ≤7 seconds, and Schirmer test with anesthesia measurement ≥1 to ≤7 mm/5 min at each of the screening and eligibility visits. Patients with a history of Sjögren syndrome were included, as were patients with thyroid disease, rheumatoid arthritis, or inflammatory diseases if they were otherwise eligible. Medications for dry eye or regular use of systemic medications including those known to cause ocular dryness was allowed if the patient committed to using them for the next 12 months. However, those who wore contact lens 30 days before the screening visit were ineligible, as were those who had a history of laser-assisted in situ keratomileusis, ocular infection, recent ocular surgery, or contraindications to high-dose ω3 supplementation.
Visual Function Testing
Visual function testing was performed by a Dry Eye Assessment and Management clinician or technician who had completed a certification program. Visual acuity testing and contrast sensitivity testing were performed with correction after manifest refraction during the baseline visit. Monocular visual acuity testing was performed using the Early Treatment of Diabetic Retinopathy Study charts and technique at 3.2 m; different charts were used for the right and left eyes. A light meter was used to ensure that the light hitting the chart was 189 to 377 lux. The sum of the number of letters read correctly on each line was recorded. A letter score of 85 corresponds to an approximate Snellen equivalent of 20/20. Contrast sensitivity was measured with the Mars Letter Contrast Sensitivity Test following the instructions provided from the manufacturer. Briefly, the chart was illuminated uniformly such that a light meter measured 189 to 377 lux on the chart. Participants wore the refractive correction determined by refraction with an add of +2.00 diopters and an occluder or patch on the untested eye. The participants' viewing distance to the chart was 50 cm (20 inches). Different charts were used for the right and left eyes. Each letter read on the chart was marked as correct or incorrect until two consecutive letters were read incorrectly by the patient. The number of letters read on the Mars Contrast Sensitivity Chart was converted to a log contrast sensitivity value where one additional letter was associated with an increase of 0.04 units.
A Dry Eye Assessment and Management clinician who completed a certification program for clinical assessment and grading examined each eye and performed an external examination and biomicroscopy with a slit lamp. Tear film debris was graded for each eye as none, mild (present in the inferior tear meniscus), moderate (present in the inferior tear meniscus and in the tear film overlying the cornea), and severe (present in the inferior tear meniscus and in the tear film overlying the cornea or presence of mucus strands in the inferior fornix or on the bulbar conjunctiva). At separate time points, 2% fluorescein dye and 1% lissamine green dye were instilled by placing a small pool of dye into a sterile container using an Eppendorf micropipette and a tip to draw up 5 μL of dye and placing the volume into the inferior cul-de-sac. After instillation of fluorescein dye in the right eye, assessment of tear breakup time was followed sequentially by assessment of corneal fluorescein staining and meibomian gland evaluation, and after instillation of lissamine green, staining evaluation of the interpalpebral conjunctiva was conducted; the sequence of testing was repeated for the left eye. Intraocular pressure was measured for each eye, and Schirmer test was administered to each eye simultaneously.
Measurement of fluorescein tear breakup time began approximately 30 seconds after instillation of fluorescein dye. The clinician viewed the cornea through a slit lamp using broad-beam cobalt blue illumination and a yellow barrier filter. The clinician instructed the patient to blink and measured the time to the first discontinuity in the tear film with a stopwatch. The measurement was repeated two more times. The average of the three measurements of tear breakup time per eye was used for analysis. The central five meibomian glands of the lower lid were assessed after application of pressure to the lower eyelid below the lashes using the Meibomian Gland Evaluator (Johnson & Johnson [previously Tear Science], Jacksonville, FL). The number of plugged glands was counted, and secretions were graded as clear liquid oil, mild haze/cloudy liquid, paste (toothpaste consistency), or obstructed (no secretion, including capped orifices). Assessment of corneal staining under the same viewing conditions as those for tear breakup time began approximately 2 to 3 minutes after the fluorescein dye instillation. The staining of the central cornea and four surrounding sectors was each scored from 0 (no staining) to 3 (dense staining). The central cornea was defined as a circular area encompassing approximately one-fifth of the corneal surface with superior, nasal, inferior, and temporal quadrants extending from the central circular zone to the periphery of the cornea, each encompassing another one-fifth of the corneal surface. Grading of conjunctival staining began 1 to 2 minutes after instillation of lissamine green dye. The clinician viewed the temporal and nasal conjunctiva through a slit lamp using white light and graded punctate staining from 0 (no staining) to 3 in each area. The sum of the scores from all sectors per eye was used for corneal and conjunctival staining; in addition, only the central corneal staining score was assessed for association with visual acuity and contrast sensitivity. Approximately 5 minutes after instillation of a topical anesthetic, Schirmer test strips were hung onto the lower conjunctival sac in the temporal one-third of the eyelid. The patient was instructed to close both eyes. After 5 minutes, as measured by a stopwatch, the strips were removed, and the length of wetting of the strip was recorded in millimeters.
Participants were excluded from analysis if their visual acuity scores in at least one eye were worse than 0.44 logMAR (approximate Snellen equivalent of 20/50) or if there was a history of diabetic retinopathy in one or both eyes because ocular pathology other than dry eye would be more likely to be responsible for their decreased vision. We performed descriptive analyses using mean (standard deviation) for continuous measures and percentages for categorical measures. Baseline values for the Ocular Surface Disease Index were the average of the values from the screening and eligibility confirmation visits.
We used the generalized linear model to assess the association between visual acuity and contrast sensitivity with each of the dry eye symptom measurements (Ocular Surface Disease Index total score, vision-related subscale score of the Ocular Surface Disease Index, and Short Form-36 score). In these analyses, visual acuity or contrast sensitivity was modeled as an independent variable, and each dry eye symptom score was modeled as a dependent variable, to determine whether subjects with worse vision reported more symptoms. Because the dry eye symptom measure is person specific, the visual acuity or contrast sensitivity was based on the better eye of this specific measurement. To help with the clinical interpretation and to avoid the strong assumption of linear association, the continuous measures (when modeled as independent variables) were categorized into severity levels, and a linear trend P value was used to test the association.
We used the generalized linear models to evaluate the associations between each dry eye sign with visual acuity and with contrast sensitivity. In these models, each dry eye sign was modeled as an independent variable, and visual acuity or contrast sensitivity was modeled as the dependent variable, to determine whether eyes with more severe signs had worse visual acuity scores or contrast sensitivity. Because measures of dry eye signs, visual acuity, and contrast sensitivity are all eye specific, these analyses were performed at the eye level, and their intereye correlation was accounted for by using generalized estimating equations.
Because these associations may differ by the status of Sjögren syndrome, we tested the interaction of Sjögren syndrome status with each independent variable. When a statistically significant interaction was found, analyses stratified by Sjögren syndrome status were performed. Dry Eye Assessment and Management patients were classified as having Sjögren syndrome if an antibody profile met the 2012 American College of Rheumatology criteria and had a sum of the Dry Eye Assessment and Management corneal and conjunctival staining scores of ≥3.
All these statistical models included adjustment of pre-selected covariates (age, refractive error, and status of cataract). All statistical analyses were performed in SAS v9.4 (SAS Institute Inc., Cary, NC). To account for the multiple comparisons from analyzing the association of multiple factors with dry eye symptoms and from analyzing multiple dry eyes signs as predictors for visual acuity and contrast sensitivity, we calculated adjusted P value using the Hochberg procedure.30 Adjusted P values of <.05 were considered statistically significant.
Characteristics of Analysis Cohort
Among 535 Dry Eye Assessment and Management participants, 487 participants (974 eyes) were eligible for the analysis after excluding participants with visual acuity 20/50 or worse in at least one eye (n = 45 participants), without visual acuity (n = 1 participant), or with diabetic retinopathy (n = 2 participants; Fig. 1). Among these remaining 487 eligible subjects, 61 had no Sjögren syndrome tests or indeterminate Sjögren syndrome status, leaving 45 subjects who had Sjögren syndrome at baseline and 381 subjects without Sjögren syndrome.
The participant and ocular characteristics of the 487 participants are displayed in Table 1. The mean (standard deviation) age was 58 (13) years, 81% were female, 74% were white, 13% were black, and 13% were Hispanic. The mean (standard deviation) Ocular Surface Disease Index scores were 42 (16) for the total and 35 (19) for the vision-related subscale. The mean Medical Outcomes Study 36-Item Short Form Health Survey scores were 48 (9.7) for physical health and 52 (9.4) for mental health. The mean (standard deviation) scores of dry eye signs for the cohort are displayed in Table 1.
Association of Visual Acuity and Contrast Sensitivity with Dry Eye Symptoms
In adjusted analyses (adjusted for age, refractive error, and status of cataract), poorer visual acuity was significantly associated with worse mean Ocular Surface Disease Index vision-related subscale score (adjusted means, 39.4 for visual acuity 20/32 or worse and 32.4 for visual acuity 20/16 or better; adjusted linear trend, P = .02). However, visual acuity was not significantly associated with the mean Ocular Surface Disease Index total score or the mean Medical Outcomes Study 36-Item Short Form Health Survey scores (Table 2).
Contrast sensitivity was not significantly associated with mean Ocular Surface Disease Index scores and mean Medical Outcomes Study 36-Item Short Form Health Survey scores (Table 2). There were no significant interactions between Sjögren syndrome and visual acuity or contrast sensitivity on the association with dry eye symptoms (all, P ≥ .21).
Association between Dry Eye Signs and Visual Acuity
The results of the adjusted analysis (adjusted for age, refractive error, and status of cataract) for associations between dry eye signs and visual acuity are shown in Table 3. Measures of tear film disruption, including tear film debris and tear breakup time, were not associated with worse mean visual acuity. Counterintuitively, increased tear film debris was significantly associated with better visual acuity score (adjusted mean visual acuity scores, 83.5 letters for moderate tear film debris and 81.5 letters for none; linear trend adjusted, P = .02), and longer tear breakup time was significantly associated with worse visual acuity score (adjusted mean visual acuity scores, 79.7 letters for tear breakup time >5 seconds and 82.7 letters for tear breakup time ≤2 seconds; linear trend, P < .0001; Fig. 2). When the tear film debris and tear breakup time were considered together in a multivariate model that was adjusted for age, refractive error status, and cataract status, their association with visual acuity remained statistically significant for both tear film debris (P = .004) and tear breakup time (P = .0009; Table 4). Signs of meibomian gland dysfunction (plugged glands and cloudy secretions), conjunctival staining, and Schirmer test scores were not significantly associated with visual acuity (all linear trends, P > .64; Table 3).
There was a statistically significant interaction between the presence of Sjögren syndrome and tear film debris (adjusted, P = .02) for the association with visual acuity. In an analysis stratified by Sjögren syndrome status (Appendix Table A1, available at http://links.lww.com/OPX/A404), the mean visual acuity score significantly increased with severity of tear film debris (adjusted linear trend, P = .001) in non–Sjögren syndrome patients; however, in Sjögren syndrome patients, the mean visual acuity scores did not show an association with tear film severity (linear trend, P = .07).
Associations between Dry Eye Signs with Contrast Sensitivity
The adjusted analyses for associations of dry eye signs with contrast sensitivity are shown in Table 3. Severe meibomian gland plugging was significantly associated with worse mean log contrast sensitivity in both the unadjusted and adjusted analyses (adjusted mean log contrast sensitivity score, 1.48 for severe vs. 1.54 for none plugged; linear trend adjusted, P = .04). Similarly, the degree of abnormality in meibomian gland secretions was significantly associated with worse mean log contrast sensitivity (adjusted mean log contrast sensitivity scores, 1.49 for obstructed and 1.57 for clear; linear trend adjusted, P = .002). Longer tear breakup time was significantly associated with better mean log contrast sensitivity (adjusted log contrast sensitivity scores, 1.57 for tear breakup time >5 seconds and 1.51 for tear breakup time ≤2 seconds; linear trend adjusted, P = .02). When meibomian gland plugging and tear breakup time were considered together in a multivariate model that was adjusted for age, refractive error status, and cataract status, the significant association with contrast sensitivity remained for meibomian gland plugging (P = .01) and tear breakup time (P = .009; Table 4, Fig. 3). Tear film debris, conjunctival staining, corneal staining, and Schirmer test score were not significantly associated with contrast sensitivity (all linear trend adjusted, P ≥ .55, Table 4).
Dry eye has a deleterious effect on multiple aspects of visual function despite normal visual acuity being documented using standard testing techniques.31 Our data substantiate the finding that, even among patients with relatively good visual acuity (20/50 or better), worse visual acuity corresponded to worse scores on the Ocular Surface Disease Index vision-related symptoms subscale in dry eye patients. However, none of the dry eye signs we measured in the study deleteriously impacted visual acuity. Although subtle visual acuity changes could be documented based on differences in tear film debris and tear breakup time, the mean changes were small (approximately two letters) and not in the direction one would expect. Alternatively, we found that contrast sensitivity measurements were more sensitive to differences based on dry eye signs related to tear film stability (tear breakup time and meibomian gland dysfunction) than conventional visual acuity assessments.
We included evaluation of central corneal fluorescein staining on vision in the Dry Eye Assessment and Management participants, as this has been shown to decrease quality of life in other ocular surface disease patients and central corneal staining directly impacted functional, dynamic visual acuity in a small dry eye study of 22 patients.15,32 In addition, Huang and colleagues15 previously found that, in dry eye patients with punctate epithelial keratopathy, contrast sensitivity improved after instillation of artificial tears. However, we were not able to demonstrate an impact on high-contrast visual acuity or contrast sensitivity with increased central corneal staining in our dry eye cohort. The Dry Eye Assessment and Management cohort had relatively low corneal staining scores overall (mean staining score, 3.6 of 15; Table 1), and we used static measures of visual acuity and contrast sensitivity rather than dynamic, which may account for the differences in our findings compared with others.
Using low-contrast optotypes, the measurement of contrast sensitivity can detect subtle vision changes that may not be detected with standard visual acuity testing. In our study, we detected a ~0.07 difference in log contrast sensitivity in eyes with severe meibomian gland dysfunction or obstructed meibomian gland secretions compared with normal eyes and in eyes with short (≤2 seconds) tear breakup time compared with eyes with longer (>5 seconds) times. In other ocular diseases such as glaucoma and age-related macular degeneration, standard high-contrast visual acuity testing did not differentiate between milder ocular disease states when contrast sensitivity did.23–27 For example, in patients with different stages of glaucoma, mean log contrast sensitivity differed significantly between patients with early and moderate visual field defects (1.76 vs. 1.51, respectively).33 In another study, the mean log contrast sensitivity was 1.62 for healthy subjects aged 22 to 77 years, with significantly lower values in patients with glaucoma (1.56) or age-related macular degeneration (1.03).34 In addition, in a study evaluating visual function in recalcitrant neovascular age-related macular degeneration after switching anti–vascular endothelial growth factor treatments, mean log contrast sensitivity improved from 1.32 to 1.40 units, whereas visual acuity remained stable throughout.35
The findings of improved visual acuity with worse tear film debris and shorter breakup time were unexpected and counterintuitive. These patients may be compensating by blinking more to distribute the tear film and remove debris that could contribute to improved vision. Evaluating only the Sjögren syndrome group can provide us an indication of the impact of aqueous deficiency on these associations. When we scrutinized only the Sjögren syndrome group, we found no impact of any ocular signs on high-contrast visual acuity. That is, the previous associations and trends of tear film debris and tear breakup time on visual acuity as noted in the entire cohort were not present in the Sjögren syndrome group, suggesting that aqueous deficiency does not contribute to these relationships.
Limitations of our study and analyses include having patients with a limited range of symptoms because patients with mild or very severe symptoms as measured by the Ocular Surface Disease Index were excluded. Also, as in most research studies, visual function was measured as a patient read a chart in an examination room where blinking may differ from other everyday activities such as viewing a display screen or reading printed material.
In conclusion, our study found that poorer visual acuity rather than worse contrast sensitivity drives visual symptoms and complaints in dry eye. However, contrast sensitivity measurements are more sensitive to worse tear film stability measures (such as tear breakup time and Meibomian gland plugging) than standard visual acuity assessments. Future studies that examine how specific ocular signs affect various measures of visual function would be helpful in elucidating these relationships and could in turn guide therapies.
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