Dry Eye Research in 2004: 32 Notable Human Studies

The 2004 picture

What the research shows

The 2004 literature broadened the field in two directions: a population cohort showed that new dry-eye reports are common over five years, and controlled trials tested specific therapies with more rigor. At the same time, measurement studies showed that symptoms, surface damage, tear tests, and vision quality are related imperfectly. The best-controlled trials answered focused questions about defined patients and treatments; smaller studies helped set the agenda for later work.

Treatments and supportive care

The strongest intervention evidence this year came from controlled drug trials. Smaller trials and clinical series explored lubricants, eyelid care, and tear drainage, but their results need proportionate weight.

1. Diquafosol in a large placebo-controlled trial

   A 24-week, double-masked trial randomized 527 people with dry eye to 1% or 2% diquafosol drops or vehicle. The 2% group had less corneal staining at the six-week primary assessment, and the separation continued during treatment. Some secondary symptom measures improved, but the prespecified foreign-body-sensation comparison was not significant at six weeks. The results support a surface-staining effect more clearly than broad symptom relief.

2. Loteprednol for dry eye with delayed tear clearance

   In a four-week, randomized, double-masked trial, 64 patients received loteprednol steroid drops or vehicle. A subgroup with at least moderate inflammation showed a benefit after two weeks, but the between-group difference was not statistically significant at week four. The study suggests that an inflammatory subgroup may respond; its small size and subgroup result limit a general claim about steroid treatment.

3. Oral pilocarpine for Sjögren-related eye dryness

   A placebo-controlled study at 11 centers followed 256 people with Sjögren syndrome for 12 weeks while oral pilocarpine was adjusted from 20 to 30 mg daily. Global dry-eye ratings and several eye symptoms improved at week 12 after the higher dose, whereas differences were small at week six. Sweating and other systemic effects were reported. The findings concern Sjögren-related dryness and the higher tolerated dose.

4. Cevimeline in Sjögren syndrome

   Sixty people with Sjögren syndrome were randomized to placebo or one of two oral cevimeline doses for four weeks. The 20-mg, three-times-daily group improved on reported symptoms, tear measures, and surface findings relative to placebo. The trial was short and small, and the result should not be assumed to apply to dry eye unrelated to Sjögren syndrome.

5. Trehalose compared with two lubricant ingredients

   A double-masked crossover trial assigned 36 patients with moderate to severe dry eye to trehalose and either hyaluronan or hydroxyethylcellulose drops, switching treatments after four weeks. Surface staining and tear breakup time favored trehalose in this small study. The short treatment periods and separate 18-person comparator groups limit how confidently the formulations can be ranked.

6. Carbomer gel in a noninferiority comparison

   A randomized, examiner-masked trial compared a fluid carbomer gel with a conventional carbomer gel in 169 people with dry eye. Symptoms fell by roughly one-third in each group by day 28, and the new formulation met the study's noninferiority criterion; staining and tear breakup results were similar. This established comparable short-term performance against an active gel, not superiority over no treatment.

7. Lid hygiene and preservative-free tears for meibomian gland dysfunction

   Thirty-seven people with meibomian gland dysfunction began heated saline lid care plus preservative-free artificial tears; 26 completed six weeks. Reported symptoms and tear breakup time improved, although masked grading of lid photographs did not. Without a comparison group, the study cannot separate the regimen's effect from natural variation or the effects of clinical attention.

8. A lipid emulsion and immediate tear-film changes

   Researchers compared a single emulsion drop with saline in five healthy volunteers and ten patients with aqueous-deficient dry eye. Imaging showed changes in how the tear-film lipid layer spread shortly after the emulsion was placed. This mechanistic observation offers a rationale for lipid-based drops but does not establish durable relief or an advantage during routine use.

9. Punctal plugs in severe Sjögren-related dryness

   A prospective series placed lower punctal plugs in 20 patients with severe sicca symptoms who had first responded to temporary plugs. Symptoms, tear stability, and several surface measures improved at three and nine months, but five participants with no baseline Schirmer wetting did not improve. Selection after a favorable trial and the absence of an untreated group limit the estimated benefit.

10. Surgical punctal closure for severe tear deficiency

    A clinical comparison followed 33 people with severe tear-deficient dry eye after either an older punctal-closure method or a revised procedure intended to reduce reopening. Surface damage improved more in the 21-person revised-method group over about eight months. Because this was a small nonrandomized comparison, differences in patients and care could also have contributed.

11. A serum-drop crossover trial found better comfort in refractory disease

    In a randomized crossover trial, 16 patients with severe ocular-surface disease completed three months each of their usual care and drops made from their own serum. Most had dry eye or Sjögren syndrome. Comfort scores and impression-cytology findings favored serum, while Schirmer and staining measures showed no clear difference. The sample was small, several entrants withdrew, and the diagnoses and usual treatments varied.

Who develops dry eye and how it changes

Population follow-up and clinical comparisons connected dry eye with age, other conditions, medication exposure, and refractive surgery. These designs identify associations more readily than causes.

12. Five-year incidence in the Beaver Dam population

    Among 2,414 Beaver Dam participants who had not reported dry eye at baseline, 322 reported it five years later, a 13.3% incidence. New reports rose with age and were associated with diabetes, allergies, and use of antihistamines or diuretics. Dry eye was based on history rather than a uniform clinical examination, and the medication associations do not prove that the drugs caused it.

13. Dry eye in thyroid-associated eye disease

    A comparison of 48 patients with active thyroid-associated eye disease and 26 controls found more surface staining, shorter tear breakup time, and lower tear secretion in the patient group. The investigators also detected thyroid-stimulating hormone receptor expression in healthy lacrimal tissue. Their proposal that autoantibodies impair the tear gland is biologically plausible but was not demonstrated by this cross-sectional comparison.

14. Ocular surface findings in premature ovarian failure

    Sixty-five women with premature ovarian failure and 36 age-matched controls underwent symptom questionnaires and surface and tear testing. The patient group reported more discomfort and had more surface staining, while Schirmer wetting and tear breakup time did not differ. This association supports studying hormonal effects on the ocular surface; it does not show that ovarian failure itself caused the findings.

15. LASIK flap hinge width and postoperative dryness

    Fifty-four people had a narrow nasal hinge in one LASIK eye and a wider hinge in the fellow eye. The wider-hinge eyes retained more corneal sensation at one and three months and generally had fewer early dry-eye findings; both groups improved over six months. Comparing fellow eyes reduces some patient differences, but the flap technique and postoperative setting limit application to current surgery.

16. Tear-film changes after LASEK

    A prospective series tracked 37 eyes of 21 patients for six months after LASEK. Corneal sensation, tear breakup time, and early staining worsened briefly, while symptom scores did not rise significantly and Schirmer results were stable. The small uncontrolled series suggests that several surface measures can change after surgery without matching symptom changes.

17. Preoperative tear function and vision soon after LASIK

    In 15 LASIK patients, investigators measured ordinary chart acuity and visual acuity during a ten-second period without blinking. Eyes classified as definitely dry before surgery showed a drop in the sustained-looking measure on the first postoperative day despite 20/20 or better chart acuity; it recovered by one week. The sample and follow-up were small, but the result illustrates a visual problem a standard chart can miss.

18. Antihistamines under a controlled drying challenge

    Eighteen adults with healthy eyes completed a randomized, double-masked comparison of four days of loratadine and cetirizine before exposure to a dry, visually demanding chamber. Both drugs were associated with more surface staining and shorter tear breakup time; loratadine produced more conjunctival staining. The artificial exposure and healthy sample make this a medication-effect experiment, not an estimate of dry-eye risk during ordinary use.

Symptoms, clinical tests, and visual quality

These studies asked whether familiar measurements reflect what patients feel or how well they see. The answer varied by test, population, and task.

19. Why dry-eye signs and symptoms can disagree

    In 75 patients previously diagnosed with dry eye, symptom interviews were compared with tear, staining, and meibomian gland tests. After accounting for age and artificial tear use, no clinical test reliably predicted frequent symptoms. This clinic sample does not make objective testing irrelevant, but it shows why symptom severity should not be inferred from a single office measurement.

20. Repeatability of common dry-eye tests

    A single examiner repeated a broad dry-eye assessment in 75 patients on two visits. Dryness and grittiness reports were moderately repeatable, whereas several staining and meibomian gland classifications were much less consistent. Averaging two tear breakup readings improved repeatability. The work warns against treating a small one-visit test change as a definite biological change.

21. OSDI and vision-related quality of life in Sjögren syndrome

    Forty-two patients with Sjögren syndrome completed the OSDI and a broader vision-function questionnaire alongside tear and surface tests. Questionnaire scores related to each other more strongly than to most objective findings. The study supports asking directly about daily function, although its small, predominantly female sample cannot settle which questionnaire works best in other dry-eye groups.

22. Corneal nerves seen with in vivo confocal microscopy

    Masked confocal imaging compared 21 people with dry eye, with or without Sjögren syndrome, against 21 healthy volunteers split by age. Dry-eye groups had altered superficial cells and nerve features, including more beadlike nerve formations. Age also related to nerve counts, so this small cross-sectional study points to nerve involvement without proving that dry eye caused the changes.

23. Optical aberrations in dry eyes

    Wavefront measurements from 20 dry eyes and 20 control eyes found substantially greater higher-order aberrations in the dry-eye group at two pupil sizes. An irregular tear film was the proposed explanation. The study connects tear-film quality with optical quality, although it was small and did not measure whether the aberration difference translated into a specific daily-life disability.

24. Corneal sensitivity and symptoms in Sjögren syndrome

    In 18 patients with Sjögren syndrome, greater corneal staining correlated with lower corneal sensitivity and, unexpectedly, fewer reported symptoms. This small correlational study suggests that reduced sensation can complicate symptom-based assessment in advanced disease. It cannot establish the direction of the relationship or predict the experience of every patient.

25. Artificial tears and short-term optical quality

    Investigators measured wavefront aberrations in 15 dry-eye patients before and after a single artificial tear dose. Aberrations fell immediately and the improvement remained measurable ten minutes later. This short experiment supports a tear-film contribution to blurred vision, but it does not show how long the effect lasts beyond the observation window or which formulations perform best.

26. Reliability of contact lens dry-eye classification

    A contact-lens dry-eye questionnaire was administered twice to 274 wearers. Its overall score showed moderate stability, and classification as having lens-related dry eye changed enough that the authors advised repeated measurement for epidemiologic work. The study addresses measurement reliability in contact lens wearers, not the diagnostic accuracy of the questionnaire for all forms of dry eye.

27. Serial corneal maps detected tear-film instability without dye

    A prospective case-control study took ten rapid corneal topography images in 27 dry-eye patients and 26 controls, then repeated measurements after punctal plugs in a subset of 14 patients. Surface regularity changed more in dry eyes and improved after plugging. The method showed promise for noninvasive measurement, but the small sample and uncontrolled treatment subset do not establish diagnostic performance in routine practice.

Ocular surface and tear biology

Human tissue and tear studies explored meibomian glands and mucins, while a healthy-volunteer study supplied context for interpreting tear stability measurements.

28. Physiologic patterns in blepharitis and dry eye

    Researchers tested tear volume, evaporation, and meibomian gland function in 513 people with and without ocular surface symptoms, then used cluster analysis to group them. Gland dropout and expressed lipid characteristics were important dividing features, yielding nine physiologic categories. Such a classification is exploratory: it describes patterns in this sample and needs external validation before guiding care.

29. MUC1-associated staining across dry-eye severity

    Impression cytology from 43 dry-eye patients and 24 volunteers examined a sugar marker associated with the surface mucin MUC1. Corneal and conjunctival staining patterns differed between groups and across severity, with weaker conjunctival labeling in severe dry eye. The observations suggest altered surface protection but do not establish that the marker change causes disease.

30. Lower tear sialic acid in dry-eye patients

    Tear samples from 45 dry-eye patients and 16 age-matched controls were analyzed for sialic acid, a component of tear glycoproteins. Concentrations were lower in the dry-eye group and related to several clinical measures. The study supports further work on tear mucins; sample collection by saline dilution and the observational design limit its immediate use as a diagnostic test.

31. Reference measurements in healthy Danish adults

    A stratified sample of 182 nonsmoking, nonallergic adults had tear breakup time, conjunctival surface damage, and eye irritation sensitivity measured. Tear stability decreased with age, while the three measures did not closely track one another. These are useful reference observations for interpreting ocular surface tests, but the healthy sample does not directly measure dry-eye prevalence or treatment response.

32. Meibomian secretion temperature and consistency

    Investigators compared ocular surface temperatures in 23 people with meibomian gland dysfunction and seven controls, and measured the melting point of expressed gland material. The secretions softened at a temperature above the measured lid and corneal surface temperatures, a possible reason thickened oil is hard to express. The groups differed greatly in age, and the study did not test a treatment.