SPECIAL CORNEA ISSUE

Revealing Dry Eye's Secrets

Research from the recent ARVO meeting offers more clues in the elusive dry eye disease mystery.

BY RENÉ LUTHE, SENIOR ASSOCIATE EDITOR

Anyone who studies dry eye would likely agree that "the simple things you see are all complicated" is more than just a line from an old classic rock song; it's also an apt description of why dry eye is such a chronic source of frustration to doctors and patients alike. What seems to be a fairly straightforward condition is actually laden with complexity.

But researchers continue to make strides in better understanding the anatomical processes and clinical presentations that make up this deceptively tricky disease. Following are a sample of some of the most insightful findings presented at this year's ARVO on the topic.

Treatment and Management

■ OCT to measure efficacy of blepharitis treatment. Researchers at the University of Michigan and Loyola University measured the change in tear meniscus area and tear volume with optical coherence tomography before and after treatment for posterior blepharitis to gauge the treatment's efficacy. Forty-four eyes with both posterior and anterior blepharitis used warm compresses b.i.d. with lid hygiene and topical azithromycin ophthalmic solution 1% (AzaSite, Inspire Pharmaceuticals) before bed. Images of the inferior tear meniscus were obtained with OCT prior to treatment and three to four weeks after treatment. Included in the study were 20 control eyes without blepharitis.

Following one month of treatment, the blepharitis eyes showed a significant increase in the area of inferior tear meniscus. Statistical analysis indicated a difference in the area prior to treatment compared to after.

There was no significant difference found in the area of the inferior tear meniscus for the control group when measured for the first set of images, nor for the second set two weeks later. And while statistical analysis indicated a significant difference when comparing the area of the inferior tear meniscus of the controls at week 1 to patients before treatment began, when comparing the controls at two weeks to the subjects after treatment ended, there was then no significant difference in that area.

Researchers concluded that the combination of warm compresses, lid hygiene and azithromycin was an effective treatment for combined posterior and anterior blepharitis. It had "a beneficial effect in evaporative dry eye with secondary increase in tear meniscus and hence tear volume."

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Pullos AN, John T. Effects of posterior blepharitis treatment on tear meniscus. Presented May 4, 2010.

■ Azithromycin to treat corneal inflammation. The potential anti-inflammatory effects of azithromycin on corneal inflammation was studied by re search ers at the Schepens Eye Research Institute. They induced murine corneal inflammation by thermal cautery, then treated corneas topically with either azithromycin ophthalmic solution 1%, prednisolone acetate 1% or "relevant vehicles," b.i.d. Corneas were harvested on days 1, 3 and 7 to characterize the inflammatory infiltrates and to quantitate and analyze relevant chemokines/cytokines and intercellular adhesion molecule (ICAM-1).

The azithromycin-treated group showed a 30% reduction in total infiltration of pan-leukocyte marker CD45+ at day 1, and a 39% reduction at day 7; this was similarly observed in the prednisolone-treated group. Researchers reported a 6% reduction in macrophages at later time time points in the study for the azithromycin-treated group, and a 16% reduction in the prednisolone-treated group. In addition, dendritic cells showed a 35% reduced infiltration at later time points in the azithromycin group, while the prednisolone groups showed a 40% reduction. ICAM-1 expression was "reduced by two-fold at day 7" for the azithromycin group, the researchers wrote.

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Sadrai Z, Hajrasouliha AR, Chauhan S, Saban D, Dana R. Anti-inflammatory activity of topical azithromycin ophthalmic solution 1% in the treatment of ocular inflammation. Presented May 4, 2010.

■ Hydroxypropyl cellulose ophthalmic inserts for dry eye syndrome. In an effort to ascertain the efficacy of hydroxypropyl cellulose ophthalmic inserts for moderate to severe dry eye syndrome, researchers enrolled 520 patients in a two-visit, open-label, multicenter registry. They measured tear film break-up time (TFBUT) and rated symptoms, activities of daily living (ADL) limitations and degree of ocular discomfort in various environments for the month before visit 1 and during treatment using the Ocular Surface Disease Index (OSDI) and ADL questionnaires. Subjects received the insert once daily, alone or with existing therapy.

In 418 patients who completed the study, analysis of variance showed significant differences in OSDI scores between severity groups. The most notable decrease in scores, 29.8%, occurred in the severe group; in the moderate group, scores fell by 18.9%. At visit 1, 65.3% of patients scored within the severe range, but after one month of therapy, 44% of the group scored as severe, shifting the distribution to the moderate, mild and normal groups. There was no significant difference in TFBUT between groups. However, in the severe group there was a significant increase in TFBUT for both eyes compared with baseline.

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Luchs J. Efficacy of hyroxypropyl cellulose ophthalmic inserts in dry eye syndrome at all levels of severity. Presented May 6, 2010.

■ Imaging device for tear film images. Researchers working on an imaging device intended to capture, archive, manipulate and store digital images of specular (interferometric) observations of the tear film presented their findings on the LipiView ocular surface inter ferometer (OSI). According to the researchers, the device allows the images to be visually and photographically monitored and numerically defined and documented as well, after it acquires the specularly reflected colors of the tear film. A spatially modulated light source allows for removal of unwanted background images and stray light. Statistical data are compared to a master look-up table (LUT) for lipid layer grading. The LUT has a spiral locus in RGB space. The processes output are expressed as interference color units, which correlate with lipid layer thickness (LLT), using a kinemetric distribution. A previous report on a prototype of the OSI in clinical practice showed that LLT measurements correlate strongly with patient symptoms of dry eye.

These researchers found that the processed instrument data "match well to the expected spiral of RGB values of the LUT, demonstrating an agreement with theory" — thus, the OSI is a viable tool for the evaluation of patient LLT.

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Grenon SM, Korb DR, Blackie CA, Weber W, Chinnock R. A unique ocular surface interferometer to measure and evaluate lipid layer thickness. Presented May 4, 2010

■ 0.1% sodium hyaluronate and corneal sensitivity. Spanish researchers investigated changes in corneal sensitivity evoked by the topical application of 0.1% sodium hyalur onate (NaH) in 10 volunteers. Changes in threshold, intensity and components of the sensation evoked by selective mechanical, chemical and thermal stimulation of the cornea induced by the drug have been studied previously in humans. Here, mechanical, chemical and cold stimuli were applied at the center of the cornea and sensitivity measured with the Belmonte gas ethesiometer. Intensity and perceived magnitude of several psychophysical attributes of the evoked sensation were scored at the end of each pulse, using separate 10 cm visual analogue scales (VAS); threshold for sensation parameters was taken as the stimulus intensity that evoked a score of <0.5. In a separate session, corneal sensitivity was again measured in both eyes, one without treatment and the other 30 minutes after topical solution of a drop of 0.1% NaH solution or of balanced saline solution.

All participants reported the sensation of ocular comfort during and at least 30 minutes after NaH instillation, and no changes in comfort after saline solution. For mechanical and chemical stimulation, the intensity of the evoked sensation was "modestly reduced" after NaH; significantly lower VAS values were given to the irritation sensation. The subjective intensity evoked by thermal cold stimuli remained unaltered after NaH, while the small irritative component of the sensation evoked by cold was very significantly reduced. For the saline treatment, no significant changes of sensitivity were obtained. Researchers concluded that because NaH reduced the irritative components of sensations evoked by certain mechanical, chemical and cold stimulation of the cornea without affecting subjects' ability to identify the intensity of the stimuli, NaH drops would be useful in managing of ocular dryness sensations without disturbing the protective role of corneal neural input.

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Acosta MC, Gallar J, Belmonte C. Mechanical, chemical and thermal sensitivity of the cornea after topical application of sodium hyaluronate eye drops. Presented May 3, 2010.

■ OCT to quantify efficacy of treatments. Optical coherence tomography can quantify the increase in lower tear meniscus after instillation of artificial tears in dry eye patients, according to researchers at Doheny Eye Institute at UCLA. They used Fourier-domain OCT to study the longitudinal effect of instillation of artificial tears on tear meniscus volume in four patients with significant dry eye. The lower tear meniscus of one eye in each subject was imaged by vertical scans centered on the inferior cornea and the lower eyelid with Fourier-domain OCT with a corneal adaptor. Two baseline measurements were taken for each subject prior to administration of artificial tears. Then five serial pairs of measurements were taken after the instillation of artificial tears at one minute, two minutes, five minutes, 10 minutes and 15 minutes.

Baseline tear measurements were 317 �m, 512.5 �m, 0.0695 mm2 for meniscus height, depth and area, respectively. At one minute after instillation of artificial tears, the measurements increased by 212%, 488% and 2212%. The time to depletion of half of the gains in tear meniscus were 2.75 minutes, 4.75 minutes and 2.0 minutes for height, depth and area, respectively. The time to depletion of 75% of the tear meniscus gains was 3.5 minutes, 5.5 minutes and 5.5 minutes. "Optical coherence tomography may serve as an invaluable tool in objectively quantifying the efficacy of dry eye treatments," the researchers concluded.

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Bujak MC, Huang D, Sadda SR, et al. Serial measurement of tear meniscus by Fourier-domain optical coherence tomography after instillation of artificial tears in patients with dry eyes. Presented May 4, 2010.

■ Biofilm formation on dry eye devices. Researchers at the University of North Carolina, Chapel Hill evaluated punctal plugs and intracanalicular devices for biofilm formation, and to characterize the micro-organisms that form such biofilms. Fifty-four patients underwent removal of punctal plugs and intracanalicular stents for routine clinical indications. The devices were submitted for microbiology culture before and after water-bath sonication to loosen adherent micro-organisms. The main outcomes measures in the prospective, observational study were clinical signs and symptoms of lacrimal infection, culture positivity, identification of isolated micro-organisms and enhanced recovery of micro-organisms from culture after sonication. Eighty-one punctal plugs and five monocanalicular stents were submitted for culture. Devices were in place an average of 76.5 ± 53.5 days. No patients had lacrimal infection.

Cultures were positive in 42% of samples, with 56% positive for oropharyngeal flora and 19% positive for skin flora. Gram-negative rods were isolated in 14% of samples, anaerobes and Stenotrophomonas maltophilia were each isolated in 11% of samples, and nocardia was isolated in 6%. These are rare but clinically significant pathogens, the researchers point out; water-bath sonication did not aid in the enhanced detection of biofilms.

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Esmaili N, McCall-Culbreath K, Gilligan P, Fowler C, Fowler A. Evaluation of biofilm on punctal plugs and intracanalicular devices. Presented May 4, 2010.

Diagnosis

■ Lid tension's effect on fluorescein staining. Japanese researchers studied the relationship between eyelid tension (LT) and the localization of fluorescein staining (FS) in dry eye patients. They measured LT in 130 eyes of dry eye patients and 58 control eyes with a specially designed blepahro-tensiometer. The maximum and average LT of the superior and inferior eyelids were determined as parameters of LT. FS of corneal and conjunctival epithelium was evaluated by clinical scores, by dividing the cornea into superior, middle and inferior regions, and the conjunctiva into superior, nasal/temporal, interpalpebral and inferior regions. Schirmer I test value and TFBUT were also examined.

The LT values of the superior maximum LT, superior average LT, inferior maximum LT and inferior average LT in the dry-eye group were 26.1±5.9, 20.2±5.7, 25.2±7.1, 19.6±6.6, while those in the control group were 21.5±6.8, 16.2±6.2, 21.0±7.8 and 16.4±6.8, respectively. Further, the LT values of the control group significantly decreased with age, while those of the dry eye group did not. FS scores for the inferior cornea and conjunctiva were well-correlated with the inferior maximum LT and average LT, respectively (P<0.005), and those for the superior conjunctiva were correlated with the superior maximum LT and average LT (P<0.005) as well. Researchers found no correlations between any of the LT values and FS scores for the superior and middle cornea or the interpalpebral conjunctiva.

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Noda E, Yamaguchi M, Shiraishi A, et al. The influence of eyelid tension on fluorescein staining in dry eye. Presented May 4, 2010.

■ Dry eye screening device. Investigating the reliability of an ocular surface-oriented thermography for dry eye screening, researchers measured ocular surface temperatures in 30 eyes of 30 dry eye patients and 30 normal eyes. Temperatures were obtained with an ocular surface-oriented, infrared radiation thermographic device (Tomey Corp.) in a noncontact manner. Temperatures were recorded at the center of the cornea and the nasal and temporal conjunctiva immediately after opening closed eyes, and again after 10 seconds of sustained eye opening. Correlations between changes in surface temperature and tear film break-up time (TFBUT), Schirmer I test values and corneal and conjunctival epithelial fluorescein staining scores were analyzed.

While no significant differences were found between surface temperatures of the two groups immediately after eye opening in any of the three regions, differences did emerge after 10 seconds of sustained eye opening. The temperature of the dry eye group was significantly decreased in all three areas compared with the control group. "The decrease in the center of the cornea was particularly noteworthy and was significantly correlated with TFBUT," the researchers note. When the change in temperature at the center of the cornea was applied as an index for dry eye screening, the sensitivity and specificity for the 10 seconds of sustained eye opening were 0.83 and 0.80, respectively.

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Yamaguchi M, Kamao T, Kawasaki S, et al. Ocular Surface thermographer: A new device for screening dry eye. Presented May 6, 2010.

■ Sjögren's risk factors. To determine if medical history, ocular exam characteristics and serologic test results of dry eye patients can be used to predict eventual diagnosis of Sjögren's, US and Turkish researchers studied 237 patients previously diagnosed with dry eye. Subjects underwent additional serologic work-up for Sjögren's. Gender, age, duration of symptoms and presence of other comorbid rheumatologic conditions did not differ significantly between the Sjögren's and non-Sjögren's groups.

Features significantly associated with an eventual Sjögren's diagnosis included presence of dry mouth, family history of SLE, Raynaud's, corneal staining and DM Type I. A positive biopsy also was strongly associated with the eventual diagnosis. "Primary Sjögren's is a common cause of dry eye and should be the focus of diagnostic evaluations," the researchers concluded.

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Swamy RN, Utine CA, Thorne JE, Baer A, Akpek EK. Clinical predictors of Sjogren's Syndrome diagnosis in a population of individuals with dry eye. Presented May 4, 2010

Dry Eye and Refractive Surgery

■ Goblet cells after refractive surgery. To determine if the population of goblet cells (GC) and filled goblet cells changes in the conjunctiva of patients who develop dry eye after refractive surgery, researchers studied 10 postop dry eye patients. Five had undergone LASIK and five had undergone PRK, with an average age of 28.4 years. Preand postoperative tear film status was evaluated by slitlamp biomicroscopy, Schirmer test, TFBUT and a dry eye questionnaire. Impression cytology samples were obtained from the superior and temporal conjunctivae pre- and at one week, one month and three months postop. ICS on membranes were stained to identify goblet cell bodies.

Researchers found the average number of GC per patient was significantly different between PRK and LASIK patients — 72.5 ±11.8 cells vs. 169.5 ±36 cells, respectively. The number of cells declined significantly at one week in both PRK and LASIK, to 47.3 ±17.9 cells and 63.8 ±17.9 cells, respectively. At three months, however, the number of cells had returned to preop levels. The percentage of total GC (filled plus unfilled) significantly decreased at one week in both PRK and LASIK when compared with their respective preoperative levels, but recovered at three months.

In patients who develop dry eye after refractive surgery, the investigators wrote, goblet cells are sensitive to stress and are easily lost. "The remaining goblet cells are predominantly filled goblet cells indicating that neural regulation of goblet cell secretion is disregulated but begins to recover at three months," investigators concluded.

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Shatos M, Ryan DS, Bower KS, et al. Refractive surgery alters the conjunctival goblet cell population in individuals who develop dry eye. Presented May 3, 2010.

■ Screening in refractive surgery candidates. Researchers at the University of South Carolina examined contact lens wear as a possible risk factor for dry eye in refractive surgery candidates. They quantified and compared ocular surface dryness associated with contact lens and non-contact lens wear patients in a retrospective review of 104 eyes. Ocular surface dryness was measured with both subjective and objective methods. Thirty-four patients were contact lens wearers and 18 were not. Among the contact-lens group, five patients had at least one eye with a Schirmer I test of less than 10, indicating aqueous tear deficiency. Question naire results for the contact-lens group showed that nine of the 34 patients had symptoms of ocular dryness. In the non-contact lens group, six of eight patients had at least one eye with Schirmer I test of less than 10; on the subjective questionnaire, one patient reported symptoms of ocular dryness.

The investigators concluded that ocular dryness was common in patients presenting for refractive surgery whether they wore contact lenses or not. According to the questionnaire, non-contact lens wearers were less likely to report symptoms of ocular dryness despite this group's being more likely to have an aqueous tear deficiency by more objective testing. Conversely, contact-lens wearers were less likely to have aqueous tear deficiencies, but were more likely to report symptoms of dryness. "An adequate aqueous tear production screening device should be considered prior to performing refractive surgery in all patients." OM

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Vahjen BP, Markowitz BB, McCamant E. Ocular surface dryness associated with contact lens wear in patients presenting for refractive surgery. Presented May 4, 2010.

A Soup-to-Nuts Rethinking of Meibomian Gland Dysfunction Although Meibomian gland dysfunction is highly correlated with dry eye, its mechanisms and remedies remain poorly understood. To help, an international committee of 50 experts devoted a year to reviewing the literature on the disease, with the aim of achieving consensus on the definition, classification, diagnosis and management of MGD. ARVO attendees were given a preview of the forthcoming report, to be published later this year in Investigative Ophthalmology & Visual Science. Presentations included, "Anatomy, physiology and pathophysiology of the Meibomian gland," "Epidemiology of, and associated risk factors for, Meibomian gland dysfunction," "Evaluation, diagnosis and grading of severity of Meibomian gland dysfunction" and several more. The full report is destined to be a landmark in improving the understanding of MGD.