Dry Eye Research in 2000: 31 Notable Human Studies

The 2000 picture

What the research shows

Research published in 2000 sharpened how clinicians describe dry-eye burden and added controlled evidence for cyclosporine in selected patients. Smaller studies of surgery, tear-film mechanisms, and environmental exposure raised questions that later research would pursue.

Treatments tested in patients

The strongest treatment evidence came from randomized cyclosporine trials. Smaller comparisons explored lubricants and care for specific severe forms of dry eye, while pilot work tested other approaches.

1. Two large trials supported topical cyclosporine for selected dry eye signs

   Two six-month, double-masked randomized trials enrolled 877 people with moderate to severe dry eye and compared twice-daily 0.05% or 0.1% cyclosporine emulsion with its vehicle. Both doses improved corneal staining and categorized Schirmer tear measurements more than vehicle; the 0.05% dose also performed better on selected subjective measures. The benefits differed across outcomes, and the higher dose showed no clear advantage.

2. An earlier cyclosporine trial found no clear dose-response pattern

   A multicenter, double-masked trial randomized 162 patients to four cyclosporine strengths or vehicle for 12 weeks, then observed them for four more weeks. In a 90-patient moderate-to-severe subgroup, active treatment improved several staining and symptom measures, but no dose was consistently best and the vehicle also performed well. The small groups for each dose and subgroup-based findings limit conclusions about an optimal concentration.

3. A cyclosporine biopsy substudy found less conjunctival immune activation

   Researchers compared conjunctival biopsies taken before and after six months of cyclosporine or vehicle in 32 participants from a dry eye treatment trial. The 0.05% cyclosporine group had fewer cells expressing two lymphocyte activation markers than the vehicle group, while changes in several overall lymphocyte counts were not statistically clear. This small substudy measured tissue markers rather than a separate clinical benefit and shares patients with a larger trial.

4. Hypotonic hyaluronic acid drops outperformed another tear substitute on some measures

   Investigators randomized 135 patients with keratoconjunctivitis sicca to preservative-free hypotonic 0.4% hyaluronic acid or hydroxypropyl methylcellulose with dextran drops, used six times daily. Both groups improved, but tear osmolarity, tear-ferning patterns, and some ocular-surface measures favored hyaluronic acid during follow-up of up to 90 days. The comparison was between two active lubricants, and the study does not establish longer-term benefit.

5. Diclofenac sped symptom relief in Sjögren-related filamentary keratitis

   An open-label randomized study assigned 32 people with secondary Sjögren syndrome and filamentary keratitis to diclofenac or 5% sodium chloride drops for 28 days. Corneal filaments disappeared in both groups, while symptoms improved faster with diclofenac. The short trial addressed a specific dry eye complication and cannot establish broad or long-term treatment value.

6. Retinoic acid improved tear tests without clear symptom benefit

   A randomized, open-label pilot compared a 0.01% retinoic acid emulsion with placebo in 22 patients with dry eye. Tear production and breakup time improved with retinoic acid, but dryness, light sensitivity, and foreign-body sensation did not improve more than with placebo. The small unmasked study leaves clinical benefit uncertain.

7. Steroid pretreatment before punctal occlusion looked promising in severe Sjögren dry eye

   In a prospective comparison of 30 patients with severe Sjögren-related dry eye, one group received preservative-free steroid drops before punctal occlusion and the other had occlusion immediately. More patients in the pretreatment group had no reported symptoms at one week and two months, and corneal staining also improved. The groups were small and not described as randomized, so the added value of steroid pretreatment remains uncertain.

8. Eyelid botulinum toxin slowed tear drainage in a small pilot

   Researchers injected botulinum toxin near the tear-drainage area in 19 people with dry eye and 13 volunteers without it, then measured drainage and asked about comfort. Drainage fell, and 13 of the 19 patients reported better comfort across two injection patterns. Without a sham-treated comparison or long follow-up, this pilot cannot establish durable treatment benefit.

Symptoms, vision, and tear-film disruption

Prospective refractive-surgery studies tracked short-term changes in tears, while surveys and small experiments examined the everyday and optical effects of tear-film instability.

9. Dry eye symptoms were common in the first month after LASIK

   A prospective study followed 58 patients undergoing myopic LASIK, measuring symptoms and tear function before surgery and through one month afterward. Symptoms rose sharply soon after surgery, and basal tear secretion remained below its preoperative level at one month; lower preoperative Schirmer values predicted later symptoms. Follow-up was short and there was no nonsurgical comparison group.

10. LASIK produced larger tear changes than PRK in a small comparison

    Investigators prospectively compared 36 eyes after photorefractive keratectomy with 39 eyes after LASIK for myopia, testing tear secretion, breakup time, and osmolarity through six months. Both procedures changed the tear film, but reduced secretion and increased osmolarity were greater after LASIK. The groups were small and not randomized to surgery, so patient differences may explain part of the contrast.

11. Contact lens wearers reported worse dryness later in the day

    A questionnaire given to 83 contact lens wearers at one Toronto practice found dryness to be their most frequent eye complaint, with symptoms generally worse in the evening than in the morning. Fluctuating vision was also common, although most respondents said symptoms did not stop their usual activities or lens wear. This single-practice survey did not compare wearers with people who did not use lenses.

12. Tear breakup impaired measured visual quality

    Researchers measured retinal image contrast, contrast sensitivity, and tear-film changes in three human eyes during extended periods without blinking, both with and without a soft contact lens. Optical and visual quality fell as the tear film broke up, offering a plausible explanation for fluctuating vision. The experiment involved only three eyes and did not test treatment or measure outcomes in diagnosed dry eye patients.

13. Removing the tear layer briefly disrupted the corneal surface

    In six healthy volunteers, investigators removed a small area of the precorneal tear layer and measured corneal shape, staining, thickness, and contrast sensitivity over four hours. Surface irregularity and several visual or barrier measures worsened briefly, then moved toward baseline. This controlled physiology experiment did not reproduce chronic dry eye disease and was too small to quantify clinical risk.

14. Contact lens discomfort coincided with tear and surface changes

    Researchers compared tear-film tests and ocular-surface cytology in symptomatic wearers of frequent-replacement and conventional daily-wear soft lenses. Both groups showed tear instability and evidence of low-grade surface inflammation, with some findings more pronounced in the frequent-replacement group. Lens type was not randomly assigned, and the study cannot show that replacement schedules caused the differences.

How dry eye was measured

Researchers tested symptom questionnaires, tear clearance and meniscus measurements, and ocular-surface markers. Two additional studies documented what clinicians actually used in practice at the time.

15. The OSDI questionnaire distinguished dry eye severity

    The Ocular Surface Disease Index was evaluated in 109 patients with dry eye and 30 controls alongside other questionnaires and clinical tests. Its symptom, visual-function, and environmental-trigger items showed good reliability and separated physician-rated severity groups. This validation supports symptom measurement, but a questionnaire alone is not a complete diagnostic test.

16. A tear-meniscus measurement was lower in dry eyes

    Using a new noninvasive reflective meniscometer, researchers measured the lower tear meniscus in 45 normal eyes and 32 dry eyes. Average meniscus curvature radius was lower in dry eyes and related to corneal staining and tear-film lipid appearance. The selected samples were modest, and the study did not establish a stand-alone diagnostic cutoff.

17. A visual dye scale tracked tear clearance in selected patient groups

    A case-control study compared a simple visual fluorescein-clearance scale with laboratory fluorometry in 32 healthy people and 93 patients with meibomian gland disease or aqueous tear deficiency. The visual score tracked the laboratory measure and separated aqueous-deficient patients particularly well, with weaker sensitivity for gland disease. Accuracy was assessed in preselected groups, so performance in routine mixed-symptom clinics remains uncertain.

18. Temperature and evaporation measurements separated a very small dry eye sample

    Researchers compared tear evaporation, temperature variation, osmolarity, stability, and lipid layers in nine patients with dry eye and 13 healthy controls. Dry-eye eyes showed greater evaporation and temperature variation, higher osmolarity, and poorer tear stability. The small cross-sectional study identified physiologic differences but did not validate a clinical diagnostic threshold or show which change came first.

19. Conjunctival cells showed more inflammatory markers in dry eye

    Before treatment in a multicenter trial, investigators collected conjunctival samples from 243 patients with moderate to severe dry eye and compared interpretable samples from 169 of them with 50 normal controls. HLA-DR and CD40-related markers were higher in the dry eye group, with some markers higher still in Sjögren syndrome. The study was cross-sectional at baseline and could not determine whether inflammation caused or followed tear-film disease.

20. Rosacea and dry eye shared inflammatory surface changes

    A prospective comparative series examined conjunctival cell samples from 13 people with ocular rosacea, 13 with dry eye, and 12 healthy controls. Both patient groups had more HLA-DR and ICAM-1 expression and fewer goblet cells than controls. The groups were small, and these shared findings do not make the markers specific tests for dry eye.

21. Dry eye specialists disagreed on a single best test

    Sixty-eight optometrists and ophthalmologists who worked on tear-film disorders answered a survey about their preferred dry eye tests. History or a symptom questionnaire was the most common first choice, followed by fluorescein breakup time; no one method won a majority. The study records expert preferences in 2000, not which tests most accurately diagnose disease.

22. Chart review found symptoms were recorded more often than tear tests

    Investigators reviewed 467 charts of patients already diagnosed with dry eye to see which assessments clinicians documented. Symptom assessment appeared in 82.8% of charts, fluorescein staining in 55.5%, breakup time in 40.7%, and Schirmer testing in 8.5%. This retrospective practice audit describes documentation and test use, not test accuracy or the best diagnostic strategy.

Who reported dry eye and what was associated with it

Population and clinic samples linked dry eye or tear changes with age, hormones, diabetes, medication, and flight conditions. Most of these associations were observational and cannot show cause and effect.

23. Beaver Dam estimated dry eye prevalence in older adults

    At the second Beaver Dam Eye Study examination, 3,722 adults ages 48 to 91 reported their dry eye history. Overall prevalence was 14.4%, increasing with age and higher in women; smoking, arthritis, thyroid disease, and diabetes were among the associated factors. Dry eye was determined by history rather than a uniform clinical examination, and the cross-sectional associations cannot identify causes.

24. A clinic study found several distinct dry eye patterns

    A diagnostic protocol applied to 1,584 people presenting to optometry practices classified 10.8% as having dry eye. Tear-lipid abnormalities were the most common subtype, and dry eye was more frequent among patients age 40 or older than among younger patients. The clinic sample and the study's era-specific subtype rules limit how well these figures describe the general population.

25. Androgen suppression was associated with meibomian gland changes

    Researchers compared men receiving antiandrogen drugs for prostate conditions with age-matched controls, examining symptoms, tear stability, gland secretions, and surface staining. Treated men showed poorer meibomian secretion quality, altered gland lipids, shorter tear breakup, and more ocular-surface changes. The comparison was small and nonrandomized, so medication exposure and other patient differences cannot be fully separated.

26. Diabetes with retinopathy was linked to reduced reflex tearing

    Investigators compared 86 insulin-dependent patients with diabetic retinopathy with 84 age- and sex-matched people without diabetes. The diabetes group had Schirmer readings about 37% lower and more conjunctival cell changes, while basal tear flow and breakup time were similar. The study selected patients with established retinopathy and was cross-sectional, so it cannot attribute the differences to diabetes alone.

27. Dry eye test abnormalities increased with retinopathy severity

    A study of 72 people with diabetic retinopathy combined symptoms and several tear and ocular-surface tests into a sicca severity score. Scores were worse in severe or proliferative retinopathy than in milder disease, supporting an association between eye complications of diabetes. Prior retinal laser treatment and the cross-sectional design make cause and effect uncertain.

28. Pilots reported much more dryness during flight

    Questionnaires sent to 4,000 Australian commercial pilots drew 1,246 replies, mostly from men. Of respondents, 72.3% reported dry eye symptoms during flights, compared with 5.4% who reported them independent of flying; more flight hours and large jets were associated with in-flight symptoms. The low response rate and self-reported symptoms limit prevalence estimates and do not establish a clinical dry eye diagnosis.

29. Long-term glaucoma drops coincided with poorer tear tests

    Researchers compared 77 patients using long-term topical glaucoma medications with 30 controls, measuring tear production, breakup time, and conjunctival cell changes. Treated groups had worse tear-test and impression-cytology findings. Because people were not assigned to treatment, glaucoma, drug choice, preservatives, or other differences may explain part of the association.

30. Randomized glaucoma-drop comparison found different tear effects

    Forty glaucoma patients were randomized to timolol or unoprostone drops twice daily for 24 weeks. Tear production and clearance measures fell in the timolol group but not the unoprostone group, while corneal integrity was largely unchanged in both. The trial was small and measured tear physiology rather than whether patients developed symptomatic dry eye.

31. A small menopause survey suggested an uncertain hormone link

    Investigators surveyed 79 postmenopausal women and used an anesthetized Schirmer test to compare those using hormone therapy with nonusers. Users reported fewer eye complaints, and longer use was associated with more measured tearing. Treatment was not assigned at random, so this small study cannot show that hormone therapy prevents or treats dry eye.