Impact of Dry Eye on Visual Acuity and Contrast Sensitivity: Dry Eye Assessment and Management Study

Abstract

Significance.

Identification of the association of specific signs of dry eye disease with specific visual function deficits may allow for more targeted approaches to treatment.

Purpose.

To explore the association of dry eye signs and symptoms with visual acuity (VA) and contrast sensitivity in the Dry Eye Assessment and Management (DREAM) Study.

Methods.

Baseline data from participants in the DREAM study were used in this secondary cross-sectional analysis. Standardized procedures were used to obtain results on the Ocular Surface Disease Index (OSDI), high contrast LogMAR VA, contrast sensitivity, tear film debris, tear break up time (TBUT), corneal fluorescein staining, meibomian gland evaluation, conjunctival lissamine green staining, and Schirmer’s test scores. Generalized linear models that included age, refractive error status and cataract status were used to assess the association between VA and contrast sensitivity with OSDI score and each dry eye sign. The Hochberg procedure was used to account for multiple comparisons.

Results.

Among 487 participants (974 eyes), worse VA was associated with worse mean score on the OSDI vision subscale (39.4 for VA 20/32 or worse vs 32.4 for VA 20/16 or better, adjusted linear trend P = .02); scores were not associated with contrast sensitivity. Severe meibomian gland plugging and abnormal secretions were associated with worse mean log contrast sensitivity (1.48 for severe vs. 1.54 for not plugged, P = .04 and 1.49 for obstructed vs 1.57 for clear, P = .002, respectively). Longer TBUT was associated with better mean log contrast sensitivity (1.57 for TBUT >5 seconds and 1.51 for TBUT≤2 seconds, P <.0001).

Conclusions.

Worse visual acuity, rather than worse contrast sensitivity, drives vision-related symptoms in dry eye. Greater tear film instability was associated with worse contrast sensitivity.

Dry eye is a highly prevalent condition^1–6 that significantly affects quality of life,^2,7 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 upon symptoms report a prevalence ranging from 6.5 to 52.4% with the majority reporting a prevalence around 20%.³ The prevalence of disease increases with age, and females 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 normal controls.¹³ Although there are many reports of decreased visual quality of life and symptoms in dry eye patients compared to 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 Additionally, 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, while 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 (DREAM) Study that has a large, well-characterized cohort with dry eye disease, including information regarding both the standardized assessment of LogMAR visual acuity and contrast sensitivity. In addition, as Sjögren’s 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.

METHODS

The DREAM Study was a multicenter, randomized, double masked clinical trial to evaluate the effectiveness and safety of supplementation with omega-3 fatty acids in relieving the symptoms of moderate to severe dry eye disease.²⁸ 535 subjects across 27 sites centers in the United States were enrolled and followed for 12 months in the primary trial. Eligible participants were randomized to receive either 3 grams of fish-derived ω3 eicosapentaenoic and docosahexaenoic acids daily (N=349) or a placebo containing 5 grams 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.

Subjects

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 ≥2 times a day during the 2 weeks preceding the screening visit, and a score on the Ocular Surface Disease Index (OSDI) 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 OSDI range from 0 to 100, where 0 indicates no ocular discomfort.²⁹ Three subscales of the OSDI (ocular symptoms, vision-related function, and environmental triggers) also provide scores between 0 and 100. In addition to the OSDI, participants completed the Medical Outcomes Study 36-Item Short Form Health Survey (SF-36; 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 1 eye with at least 2 of the following 4 signs: conjunctival lissamine green staining score ≥1 on a scale of 0–6; corneal fluorescein staining score ≥4 on a scale of 0–15; tear film break up time ≤ 7 seconds; and Schirmer test with anesthesia measurement ≥1 to ≤ 7 mm/5min at each of the screening and eligibility visits. Patients with a history of Sjögren’s 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 were allowed if the patient committed to using them for the next 12 months. However, those who wore contact lens 30 days prior to the screening visit were ineligible, as were those who had a history of laser-assisted in situ keratomileusis (LASIK), ocular infection, recent ocular surgery, or contraindications to high-dose ω3 supplementation.

Visual Function Testing

Visual function testing was performed by a DREAM clinician or technician who had completed a certification program. Visual acuity 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 (ETDRS) Charts and technique at 3.2 meters; different charts were used for the right and left eye. A light meter was used to assure the light hitting the chart was 189–377 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 189–377 Lux on the chart. Participants wore the refractive correction determined by refraction with an add of +2.00 D, and an occluder or patch on the untested eye. The participants’ viewing distances to the chart was 50 cm (20 inches). Different charts were used for the right and left eye. Each letter read on the chart was marked as correct or incorrect until 2 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.

Clinical Examination

A DREAM 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 inferior tear meniscus), moderate (present in inferior tear meniscus and in tear film overlying cornea), and severe (present in inferior tear meniscus and in tear film overlying cornea or presence of mucus strands in inferior fornix or on bulbar conjunctiva). At separate timepoints, 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 tip to draw up 5 μL of dye, and placing the volume into the inferior cul de sac. Following instillation of fluorescein dye in the right eye, assessment of tear break-up time was followed sequentially by assessment of corneal fluorescein staining and meibomian gland evaluation, and following 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’s test was administered to each eye simultaneously.

Measurement of fluorescein tear break-up 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 stop watch. The measurement was repeated 2 more times. The average of the 3 measurements of tear break-up time per eye was used for analysis. The central 5 meibomian glands of the lower lid were assessed after application of pressure to the lower eyelid below the lashes with the Meibomian Gland Evaluator [Johnson & Johnson (previously Tear Science), Jacksonville, Florida]. The number of plugged glands was counted and secretions 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 for tear break-up time began approximately 2–3 minutes after the fluorescein dye instillation. The staining of central cornea and four surrounding sectors were each scored from 0 (no staining) to 3 (dense staining). The central cornea was defined as a circular area encompassing approximately 1/5 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 1/5^th of the corneal surface. Grading of conjunctival staining began 1–2 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’s 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 stop watch, the strips were removed and the length of wetting of the strip recorded in millimeters.

Statistical Analysis

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 OSDI 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 dry eye symptom measurements (OSDI total score, vision-related sub-scale score of the OSDI, 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 inter-eye correlation was accounted for by using generalized estimating equations.

As these associations may differ by the status of Sjögren’s syndrome, we tested the interaction of Sjögren’s syndrome status with each independent variable. When a statistically significant interaction was found, analyses stratified by Sjögren’s syndrome status were performed. DREAM patients were classified as Sjögren’s syndrome if an antibody profile that met 2012 American College of Rheumatology (ACR) criteria and with a sum of the DREAM corneal and conjunctival staining scores ≥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 <0.05 were considered statistically significant.

RESULTS

Characteristics of Analysis Cohort

Among 535 DREAM 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) (Figure 1). Among these remaining 487 eligible subjects, 61 had no Sjögren’s syndrome tests or indeterminate Sjögren’s syndrome status, leaving 45 subjects that had Sjögren’s syndrome at baseline and 381 subjects without Sjögren’s syndrome.

Figure 1.

Flow Chart of Participants for the Analysis Cohorts. Exclusions from the full study group because of different reasons are shown.

The participant and ocular characteristics of the 487 participants are displayed in Table 1. The mean (standard deviation [SD]) age was 58 (13) years, 81% female, 74% White, 13% Black, and 13% Hispanic. The mean (SD) OSDI score was 42 (16) for the total, and 35 (19) for the vision-related subscale. The mean SF-36 score was 48 (9.7) for physical health and 52 (9.4) for mental health. The mean (SD) score of dry eye signs for the cohort are displayed in Table 1.

Table 1.

Characteristics of study participants (n=487 patients, 974 eyes).

Participant Characteristics (n=487 patients)
Age, years, mean (SD)	57.5 (13.3)
Gender - no. (%)
Female	394 (80.9%)
Male	93 (19.1%)
Race - no. (%)
White	359 (73.7%)
Black	61 (12.5%)
Other	67 (13.8%)
Ethnicity
Hispanic or Latino	62 (12.7%)
Other	425 (87.3%)
OSDI score (0–100), Mean (SD)
Total	41.8 (15.5)
Vision-related function subscale	34.6 (19.0)
Short form −36 score (0–100), mean (SD)
Physical health	47.5 (9.7)
Mental health	52.4 (9.4)
Ocular Characteristics (n=974 eyes)
Conjunctival staining score (0–6), mean (SD)	3.0 (1.5)
Corneal staining score (0–15), mean (SD)	3.7 (2.9)
Tear break-up time, secs, mean (SD)	3.2 (1.8)
Schirmer test, mm, mean (SD)	9.8 (7.2)
Visual acuity
20/16 or better	239 (24.5%)
20/20	251 (25.8%)
20/25	282 (29.0%)
20/32	153 (15.7%)
20/40	49 (5.0%)
Mean (SD), in letters	82.5 (6.1)
Log Contrast Sensitivity Score
1.72– 1.92	300 (30.8%)
1.56– 1.68	207 (21.3%)
1.44– 1.52	237 (24.3%)
0.84– 1.40	230 (23.6%)
Mean (SD)	1.6 (0.2)
Refractive error
Myopia >6 to 11.5 D	40 (4.1%)
Myopia >3 to ≤6 D	88 (9.0%)
Myopia >0.5 to ≤3 D	277 (28.4%)
Emmetropia	325 (33.4%)
Hyperopia >0.5 to ≤1.5 D	124 (12.7%)
Hyperopia >1.5 to 5.5 D	120 (12.3%)
Mean (SD), diopter	−0.7 (2.7)
Cataract status
No cataract	612 (62.8%)
Pseudophakic/aphakic	154 (15.8%)
On-going cataract	208 (21.4%)

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 OSDI vision-related subscale score (adjusted mean: 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 OSDI total score or the mean SF-36 scores (Table 2).

Table 2.

Adjusted mean scores for the Ocular Surface Disease Index (OSDI) and Short Form-36 (SF-36) by visual acuity score and contrast sensitivity in the better eye.

	Patients	OSDI (total)	OSDI vision- related scale	SF-36 physical health scale	SF-36 mental health scale
	(N)	Mean (SE)*	Mean (SE)*	Mean (SE)*	Mean (SE)*
Visual acuity in better eye
20/16 or better	154	41.0 (1.57)	32.4 (1.92)	47.0 (0.98)	52.6 (0.92)
20/20	142	41.7 (1.54)	34.8 (1.89)	46.9 (0.96)	51.7 (0.91)
20/25	139	43.3 (1.54)	36.7 (1.88)	47.0 (0.96)	52.0 (0.91)
20/32 or worse	52	43.2 (2.37)	39.4 (2.91)	47.3 (1.48)	49.6 (1.40)
Linear trend P (adjusted P┼)		0.22 (0.44)	0.01 (0.02)	0.93 (0.93)	0.14 (0.14)
Contrast Sensitivity in better eye
1.72–1.92	187	42.5 (1.42)	34.2 (1.74)	46.9 (0.88)	52.7 (0.84)
1.56–1.68	105	40.3 (1.74)	32.9 (2.13)	47.7 (1.08)	51.8 (1.03)
1.44–1.52	120	43.2 (1.65)	38.5 (2.03)	46.4 (1.03)	51.1 (0.98)
0.84–1.40	77	42.1 (1.98)	35.4 (2.43)	47.2 (1.23)	51.1 (1.17)
Linear trend P (Adjusted P┼)		0.86 (0.86)	0.20 (0.20)	0.90 (0.93)	0.12 (0.14)

^*Adjusted by age (continuous), refractive error status (emmetropia, hyperopia >0.5 to ≤1.5 D, hyperopia >1.5 D, myopia >0.5 to ≤3 D, myopia >3 to ≤6 D, myopia >6 D), and cataract status.

^┼Adjust for 2 comparisons for each of outcome measure using Hochberg procedure.

Contrast sensitivity was not significantly associated with mean OSDI scores and mean SF-36 scores (Table 2). There was no significant interactions between Sjögren’s 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 break-up 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 score: 83.5 letters for moderate tear film debris and 81.5 letters for none, linear trend adjusted P =.02) and longer tear break-up time was significantly associated with worse visual acuity score (adjusted mean visual acuity score: 79.7 letters for tear break-up time >5 seconds and 82.7 letters for tear break-up time ≤2 seconds, linear trend P <.0001) (Figure 2). When the tear film debris and tear break-up 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 break-up time (P = .0009) (Table 4). Signs of meibomian gland dysfunction (plugged glands and cloudy secretions), conjunctival staining, and Schirmer’s test scores were not significantly associated with visual acuity (all linear trend P >.64, Table 3).

Table 3.

Adjusted mean scores (letters) for visual acuity and Log contrast sensitivity by eye-specific signs.

Dry eye signs	Eyes N	VA score (letters) Mean (SE)	Linear trend P (Adjusted P┼)	Log contrast sensitivity score Mean (SE)	Linear trend P (Adjusted P┼)
TBUT (seconds)			<0.0001 (<0.0001)		0.003 (0.02)
>5	114	79.7 (0.62)		1.57 (0.02)
>2 and ≤5	598	82.1 (0.38)		1.58 (0.01)
≤2	262	82.7 (0.49)		1.51 (0.02)
Schirmer test score			0.98 (0.98)		0.75 (0.96)
≤5	304	81.6 (0.45)		1.55 (0.02)
6–10	361	82.4 (0.44)		1.56 (0.02)
11–20	220	82.0 (0.51)		1.57 (0.02)
21–30	66	80.8 (0.77)		1.51 (0.03)
>30	23	82.5 (1.26)		1.52 (0.04)
Tear film debris			0.003 (0.02)		0.11 (0.55)
None	639	81.5 (0.38)		1.55 (0.01)
Mild	269	82.9 (0.49)		1.55 (0.02)
Moderate	66	83.5 (0.94)		1.64 (0.03)
Corneal staining score			0.70 (0.98)		0.96 (0.96)
0–1	266	81.4 (0.47)		1.54 (0.02)
2–3	210	82.5 (0.52)		1.58 (0.02)
4–5	278	82.5 (0.49)		1.57 (0.02)
6 or more	218	81.6 (0.55)		1.54 (0.02)
Central Corneal staining score			0.07 (0.42)		0.26 (0.78)
0	613	82.0 (0.36)		1.56 (0.01)
1	271	83.1 (0.47)		1.58 (0.02)
2	72	79.8 (0.80)		1.53 (0.03)
3	18	77.3 (1.34)		1.42 (0.06)
Conjunctival staining			0.82 (0.98)		0.15 (0.60)
0–1	136	81.3 (0.56)		1.56 (0.02)
2–3	511	82.5 (0.40)		1.57 (0.01)
4 or more	327	81.6 (0.45)		1.54 (0.01)
Meibomian gland			0.64 (0.98)		0.007 (0.04)
None plugged	144	82.1 (0.56)		1.54 (0.02)
Mild	295	82.3 (0.47)		1.59 (0.02)
Moderate	316	81.6 (0.45)		1.57 (0.02)
Severe	219	82.1 (0.56)		1.48 (0.02)
Secretions from Meibomian glands			0.94 (0.98)		0.0003 (0.002)
Clear	180	81.9 (0.53)		1.57 (0.02)
Mild Haze/cloudiness	387	82.2 (0.44)		1.58 (0.01)
Paste	182	81.9 (0.60)		1.56 (0.02)
Obstructed	225	82.0 (0.55)		1.49 (0.02)

^┼Adjusted for 8 comparisons of visual acuity scores and for 8 comparisons of contrast sensitivity scores using the Hochberg procedure.

Log contrast sensitivity score ranges from 0 (100 % contrast required to read letters) to 1.92 (1.2% contrast required to read letters). Score of 1.56 means 2.8% contrast is required to read letters.

VA is visual acuity, with score ranges from 0 to 100, score of 80 is equivalent to 20/25 and score of 85 is equivalent to 20/20.

^*Adjusted by age (continuous), refractive error status (emmetropia, hyperopia >0.5 to ≤1.5 D, hyperopia >1.5 D, myopia >0.5 to ≤3 D, myopia >3 to ≤6 D, myopia >6 D) and ocular status of cataract.

TBUT= tear breakup time

Figure 2.

Adjusted mean visual acuity score for signs of dry eye disease associated with visual acuity scores. Greater tear film debris (left) and longer tear breakup time (TBUT; right) were associated with better visual acuity. Letter score of 80 is Snellen 20/25.

Table 4.

Multivariable analysis for visual acuity and contrast sensitivity by signs of dry eye.

	All patients (N=974 eyes)_			Patients without Sjögren Syndrome (N=762 eyes)
Dry eye signs	Eyes (N)	Mean (SE)	Linear trend P	Eyes (N)	Mean (SE)	Linear trend P
	Visual acuity score (Letters)
Tear film debris			.004			.002
None	639	81.1 (0.40)		498	81.0 (0.43)
Mild	269	82.3 (0.53)		209	82.6 (0.61)
Moderate	66	83.0 (0.91)		55	83.3 (1.01)
TBUT (seconds)			.0009			.0002
>5	114	80.4 (0.67)		84	80.4 (0.73)
>2 and ≤5	598	82.7 (0.47)		478	82.7 (0.53)
≤2	262	83.3 (0.53)		200	83.9 (0.60)
	Log contrast sensitivity score
Meibomian gland			.01			.003
None plugged	144	1.54 (0.02)		109	1.57 (0.02)
Mild	295	1.58 (0.02)		241	1.59 (0.02)
Moderate	316	1.57 (0.02)		243	1.57 (0.02)
Severe	219	1.48 (0.02)		169	1.49 (0.03)
TBUT (seconds)			.009			0.10
>5	114	1.55 (0.02)		200	1.56 (0.03)
>2 and ≤5	598	1.56 (0.01)		478	1.57 (0.02)
≤2	262	1.51 (0.02)		84	1.53 (0.02)

^*The model includes age, refractive error status (emmetropia, hyperopia >0.5 to ≤1.5 D, hyperopia >1.5 D, myopia >0.5 to ≤ 3 D, myopia >3 to ≤6 D, myopia >6 D), and ocular status of cataract, tear film debris and TBUT as predictors. Bold numbers are significant. TBUT= tear breakup time

There was a statistically significant interaction between the presence of Sjögren’s syndrome and tear film debris (adjusted P = .02) for the association with visual acuity. In an analysis stratified by Sjögren’s syndrome status (see Appendix Table A1, available at [LWW insert link]), the mean visual acuity score significantly increased with severity of tear film debris (adjusted linear trend P = .001) in non-Sjögren’s syndrome patients, however, in Sjögren’s 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 analysis (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 score: 1.49 for obstructed and 1.57 for clear, linear trend adjusted P = .002). Longer tear break-up time was significantly associated with better mean log contrast sensitivity (adjusted log contrast sensitivity score: 1.57 for tear break-up time >5 seconds and 1.51 for tear break-up time ≤2 seconds, linear trend adjusted P = .02). When meibomian gland plugging and tear break-up 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 break-up time (P = .009) (Table 4, Figure 3). Tear film debris, conjunctival staining, corneal staining, and Schirmer’s test score were not significantly associated with contrast sensitivity (all linear trend adjusted P ≥ .55, Table 4).

Figure 3.

Adjusted mean log contrast sensitivity score for signs of dry eye disease associated with contrast sensitivity. Greater meibomian gland plugging (left) and shorter tear breakup time (TBUT; right) were associated with worse contrast sensitivity.

DISCUSSION

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 OSDI 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 break-up time, the mean changes were small (~ 2 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 break-up time and meibomian gland dysfunction) than conventional visual acuity assessments.

We included evaluation of central corneal fluorescein staining on vision in the DREAM 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 Additionally, Huang and colleagues previously found that in dry eye patients with punctate epithelial keratopathy, contrast sensitivity improved after instillation of artificial tears.¹⁵ 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 DREAM cohort had relatively low corneal staining scores overall (mean staining score 3.6 out 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 to 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 to normal eyes, and in eyes with short (<=2 seconds) tear break up time compared to 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).³⁴ In another study, the mean log contrast sensitivity was 1.62 for normal subjects aged 22 to 77 years, with significantly lower values in patients with glaucoma (1.56) or AMD (1.03).³⁵ Additionally, in a study evaluating visual function in recalcitrant neovascular age-related macular degeneration after switching anti-VEGF treatments, mean log contrast sensitivity improved from 1.32 to 1.40 units while visual acuity remained stable throughout.³⁶

The findings of improved visual acuity with worse tear film debris and shorter break up 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’s syndrome group can provide us an indication of the impact of aqueous deficiency on these associations. When we scrutinized only the Sjögren’s 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 break-up time on visual acuity as noted in the entire cohort were not present in the Sjögren’s 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 OSDI 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 break-up 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.

APPENDIX

Appendix Table A1:

Adjusted mean scores for visual acuity (letters) by tear film debris stratified by presence or absence of Sjögren Syndrome is available at [LWW insert link].

	Patients without Sjögren Syndrome (n=762)			Patients with Sjögren Syndrome (n=90)
Dry eye sign	Eyes (N)	VA score (letters) Mean (SE)	Linear trend P-value	Eyes (N)	VA score (letters) Mean (SE)	Linear trend P-value
Tear film debris			.001			.07
None	498	81.4 (0.42)		51	82.3 (1.42)
Mild	209	83.1 (0.56)		28	77.9 (1.21)
Moderate	55	83.9 (1.05)		11	81.0 (1.26)

^*Adjusted by age (continuous), refractive error status (emmetropia, hyperopia >0.5 to ≤1.5 D, hyperopia >1.5 D, myopia >0.5 to ≤ 3 D, myopia >3 to ≤6 D, myopia >6 D), and ocular status of cataract

The Dry Eye Assessment and Management (DREAM) Study Research Group

The members of the Dry Eye Assessment and Management (DREAM) Study Research Group who contributed to the research presented in this paper are listed below.

Certified Roles at Clinical Centers: Clinician (CL); Clinic Coordinator (CC), Data Entry Staff (DE) Principal Investigator (PI), Technician (T).

Milton M. Hom (Azusa, CA): Milton M. Hom, OD FAAO (PI); Melissa Quintana (CC/T); Angela Zermeno (CC/T).

Pendleton Eye Center (Oceanside, CA): Robert Pendleton, MD, PhD. (PI); Debra McCluskey (CC); Diana Amador (T); Ivette Corona (CC/T); Victor Wechter, MD (CL).

University of California School of Optometry, Berkeley (Berkeley, CA): Meng C. Lin, OD PhD FAAO (PI); Carly Childs (CC); Uyen Do (CC); Mariel Lerma (CC); Wing Li, OD (T); Zakia Young (CC); Tiffany Yuen, OD (CC/T).

Clayton Eye Center (Morrow, GA): Harvey Dubiner, MD (PI); Heather Ambrosia, OD (C); Mary Bowser (CC/T); Peter Chen, OD (CL); Helen Dubiner, PharmD, CCRC (CC/T); Cory Fuller (CC/T); Kristen New (DE); Tu Vy Nguyen (C); Ethen Seville (CC/T); Daniel Strait, OD (CL); Christopher Wang (CC/T); Stephen Williams (CC/T); Ron Weber, MD (CL).

University of Kansas (Prairie Village, KS) John Sutphin, MD (PI); Miranda Bishara, MD (CL); Anna Bryan (CC); Asher Ertel (CC/T); Kristie Green (T); Gloria Pantoja, Ashley Small (CC); Casey Williamson (T).

Clinical Eye Research of Boston (Boston, MA): Jack Greiner, MS OD DO, PhD (PI); EveMarie DiPronio (CC/T); Michael Lindsay (CC/T); Andrew McPherson (CC/T); Paula Oliver (CC/T); Rina Wu (T).

Mass Eye & Ear Infirmary (Boston, MA): Reza Dana, MD (PI); Tulio Abud (T): Lauren Adams (T); Marissa Arnofsky (T); Jillian Candlish, COA (T); Pranita Chilakamarri (DE); Joseph Ciolino, MD (CL); Naomi Crandall (T); Antonio Di Zazzo (T); Merle Fernandes (T); Mansab Jafri (T); Britta Johnson (T); Ahmed Kheirkhah (T); Sally Kiebdaj (CC/T); Andrew Mullins (CC/T); Milka Nova (T); Vannarut Satitpitakul (T); Chunyi Shao (T); Kunal Suri (T); Vijeeta Tadla (CC); Saboo Ujwala (T); Jia Yin MD, PhD (T); Man Yu (T).

Kellogg Eye Center, University of Michigan (Ann Arbor, MI): Roni Shtein, MD (PI); Christopher Hood, MD (CL); Munira Hussain, MS, COA, CCRP (CC/T); Erin Manno, COT (T); Laura Rozek, COT (T/DE).

Minnesota Eye Consultants (Bloomington, MN): David R. Hardten, MD FACS (PI); Kimberly Baker (T); Alex Belsaas (T); Erich Berg (CC/T); Alyson Blakstad, OD (CL); Ken DauSchmidt (T); Lindsey Fallenstein (CC/T); Ahmad M. Fahmy OD (CL); Mona M. Fahmy OD FAAO (CL); Ginny Georges (T); Deanna E. Harter (CL); Scott G. Hauswirth, OD (CL); Madalyn Johnson (T); Ella Meshalkin (T); Rylee Pelzer (CC/T); Joshua Tisdale (CC/T); JulieAnn C. Wick (CL).

Tauber Eye Center (Kansas City, MO): Joseph Tauber, MD, PHD (PI); Megan Hefter (CC/T).

Silverstein Eye Centers (Kansas City, MO): Steven Silverstein, MD (PI); Cindy Bentley (CC/T); Eddie Dominguez (CC/T); Kelsey Kleinsasser, OD (CL).

Icahn School of Medicine at Mt. Sinai, (New York, NY): Penny Asbell, MD, FACS, MBA (PI); Brendan Barry (CC/T); Eric Kuklinski (CC/T); Afsana Amir (CC/T); Neil Chen (CC/T); Marko Oydanich (CC/T); Viola Spahiu (CC/T); An Vo, MD (T); Matthew Weinstein, DO (T).

University of Rochester Flaum Eye Institute (Rochester, NY): Tara Vaz, OD (PI); Holly Hindman, MD (PI); Rachel Aleese (CC/T); Andrea Czubinski (CC/T); Gary Gagarinas, COMT CCRA (CC/T); Peter McDowell (CC); George O’Gara (DE); Kari Steinmetz (CC/T).

University of Pennsylvania Scheie Eye Institute (Philadelphia, PA): Vatinee Bunya, MD (PI); Michael Bezzerides (CC/T); Dominique Caggiano (CC/T); Sheri Drossner (T); Joan Dupont (CC); Marybeth Keiser (CC/T); Mina Massaro, MD (CL); Stephen Orlin, MD (CL); Ryan O’Sullivan (CC/T).

Southern College of Optometry (Memphis, TN): Michael Christensen, OD PhD (PI); Havilah Adkins (CC); Randy Brafford (CC/T); Cheryl Ervin (CL); Rachel Grant OD (CL); Christina Newman (CL).

Shettle Eye Research (Largo, FL): Lee Shettle, DO (PI); Debbie Shettle (CC).

Stephen Cohen, OD, PC (Scottsdale, AZ): Stephen Cohen, OD (PI); Diane Rodman (CC/T).

Case Western Reserve University (Cleveland, OH): Loretta Szczotka-Flynn, OD PhD (PI); Tracy Caster (T); Pankaj Gupta MD MS (CL); Sangeetha Raghupathy (CC/T); Rony Sayegh, MD (CL).

Mayo Clinic Arizona (Scottsdale, AZ): Joanne Shen, MD (PI); Nora Drutz, CCRC (CC); Lauren Joyner, COA (T); Mary Mathis, COA (T); Michaele Menghini, CCRP (CC); Charlene Robinson, CCRP (CC).

Wolston & Goldberg Eye Associates (Torrance, CA): Damien Goldberg, MD (PI); Lydia Jenkins (T); Brittney Rodriguez (CC/T); Jennifer Picone Jones (CC/T); Nicole Thompson (T), Barry Wolstan, MD (CL).

Northeast Ohio Eye Surgeons (Stow, OH): Marc Jones, MD (PI); April Lemaster (CC/T); Julie Ransom-Chaney (T); William Rudy, OD (CL).

Tufts Medical Center (Boston, MA): Pedram Hamrah, MD (PI); Mildred Commodore (CC); Christian Iyore (T); Lioubov Lazarev (T): Leah Mullen (T); Nicholas Pondelis (T); Carly Satsuma (CC).

University of Illinois at Chicago (Chicago, IL): Sandeep Jain, MD (PI); Peter Cowen (CC/T); Joelle Hallak (CC);Christine Mun (CC/T); Roxana Toh (CC).

The Eye Centers of Racine & Kenosha (Racine, WI): Inder Singh, MD (PI); Pamela Lightfield (CC/T); Eunice Lowery (T); Sarita Ornelas (T); R. Krishna Sanka, MD (CL); Beth Saunders (T).

Mulqueeny Eye Centers (St. Louis, MO): Sean P. Mulqueeny, OD (PI); Maggie Pohlmeier (CC/T).

Oculus Research at Garner Eyecare Center (Raleigh, NC): Carol Aune, OD (PI); Hoda Gabriel (CC); Kim Major Walker, RN MS (CC/T); Jennifer Newsome (CC/T).

Resource Centers

Chairman’s Office (Icahn School of Medicine at Mount Sinai, New York, NY): Penny Asbell, MD, FACS, MBA (Study Chair); Brendan Barry (Clinical Research Coordinator); Eric Kuklinski (Clinical Research Coordinator); Shir Levanon (Clinical Research Coordinator); Michael Farkouh, MD FRCPC, FACC, FAHA (Medical Safety Monitor); Seunghee Kim-Schulze, PhD (Consultant); Robert Chapkin, PhD, MSc. (Consultant); Giampaolo Greco, PhD (Consultant); Artemis Simopoulos, MD (Consultant); Ines Lashley (Administrative Assistant); Peter Dentone, MD (Clinical Research Coordinator); Neha Gadaria-Rathod, MD (Clinical Research Coordinator); Morgan Massingale, MS (Clinical Research Coordinator); Nataliya Antonova (Clinical Research Coordinator).

Coordinating Center (University of Pennsylvania Perelman School of Medicine, Philadelphia, PA): Maureen G. Maguire, PhD (PI); Mary Brightwell-Arnold, SCP (Systems Analyst) John Farrar, MD PhD (Consultant); Sandra Harkins (Staff Assistant); Jiayan Huang, MS (Biostatistician); Kathy McWilliams, CCRP (Protocol Monitor); Ellen Peskin, MA, CCRP (Director); Maxwell Pistilli, MS, MEd (Biostatistician); Susan Ryan (Financial Administrator); Hilary Smolen (Research Fellow); Claressa Whearry (Administrative Coordinator); Gui-Shuang Ying, PhD (Senior Biostatistician) Yinxi Yu (Biostatistician).

Biomarker Laboratory (Icahn School of Medicine at Mount Sinai, New York, NY): Yi Wei, PhD, DVM (co-Director, Biomarker Laboratory); Neeta Roy, PhD (co-Director, Biomarker Laboratory); Seth Epstein, MD (Former co-Director; Biomarker Laboratory); Penny A. Asbell, MD, FACS, MBA (Director and Study Chair).

Investigational Drug Service (University of Pennsylvania Perelman School of Medicine, Philadelphia, PA): Kenneth Rockwell, Jr., PharmD MS (Director).

Peroxisomal Diseases Laboratory at the Kennedy Krieger Institute, Johns Hopkins University Baltimore MD: Ann Moser (Co-Director/Consultant); Richard O. Jones, PhD (Co-Director/Consultant)

Meibomian Gland Reading Center (University of Pennsylvania Perelman School of Medicine, Philadelphia, PA): Ebenezer Daniel, MBBS, MPH, PhD, (PI); E. Revell Martin (Image Grader); Candace Parker Ostroff, (Image Grader); Eli Smith (Image Grader); Pooja Axay Kadakia (Student Researcher).

National Eye Institute, National Institutes of Health, Department of Health and Human Services: Maryann Redford, DDS, MPH (Program Officer).

Office of Dietary Supplements/National Institutes of Health, Department of Health and Human Services

Committees

Executive Committee: (Members from all terms of appointment): Penny Asbell, MD FACS, MBA (Chair); Brendan Barry, MS; Munira Hussain, MS, COA, CCRP; Jack Greiner, MS OD PhD; Milton Hom, OD, FAAO; Holly Hindman, MD, MPH; Eric Kuklinski, BA; Meng C. Lin OD, PhD. FAAO; Maureen G. Maguire, PhD; Kathy McWilliams, CCRP; Ellen Peskin, MA, CCRP; Maryann Redford, DDS, MPH; Roni Shtein, MD, MS; Steven Silverstein, MD; John Sutphin, MD.

Operations Committee: Penny Asbell, MD FACS, MBA (Chair); Brendan Barry, MS; Eric Kuklinski, BA; Maureen G. Maguire, PhD; Kathleen McWilliams, CCRP, Ellen Peskin, MA, CCRP; Maryann Redford, DDS, MPH.

Clinic Monitoring Committee: Ellen Peskin, MA, CCRP (Chair); Mary Brightwell-Arnold, SCP, Maureen G. Maguire, PhD; Kathleen McWilliams, CCRP.

Data and Safety Monitoring Committee: Stephen Wisniewski, PhD (Chair); Tom Brenna, PhD; William G. Christen Jr, SCD, OD, PhD; Jin-Feng Huang, PhD; Cynthia S. McCarthy, DHCE, MA; Susan T. Mayne, PhD; Mari Palta, PhD; Oliver D. Schein, MD, MPH, MBA.

Industry Contributors of Products and Services

Access Business Group, LLC (Ada, MI) Jennifer Chuang, PhD. CCRP; Maydee Marchan, M.Ch.E; Tian Hao, PhD; Christine Heisler; Charles Hu, PhD; Clint Throop, Vikas Moolchandani, PhD.

Compounded Solutions in Pharmacy (Monroe, CT)

Leiter’s (San Jose, CA)

Immco Diagnostics Inc. (Buffalo NY

OCULUS Inc. (Arlington, WA)

RPS Diagnostics, Inc. (Sarasota, FL)

TearLab Corporation (San Diego, CA)

TearScience Inc. (Morrisville, NC)