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Dry Eye in a Japanese Elderly Population
TEAR FILM & OCULAR SURFACE DRY EYE IN A JAPANESE ELDERLY POPULATION. Murat Dogru,1 Yukiko Yagi,1 Masao Tomita,2 Takashi Kon,2 Megumi Saeki,3 Eiki Goto,3 Yukihiro Matsumoto,1 Kazuo Tsubota.3 Tokyo Dental College, Tokyo, Japan;1 Japan Preventive Medicine Society,2 Keio University School of Medicine, Tokyo, Japan.3 Purpose. To assess the prevalence of dry eye disease and aggravating factors of dry eyes in a Japanese elderly population. Methods. Two hundred and twenty six eyes of 113 pensioners (50 males, 63 females; mean age:67.5 years) aged above 50 years were recruited in this study. The subjects underwent tear film break up time examinations, Schirmer test-1, and fluorescein staining of the ocular surface, assessing the staining patterns in detail with the area-density grading. Dry eye symptomatology was assessed with a symptom questionnaire. Extent of meibomian gland disease and conjunctivochalasis were also evaluated as risk factors for dry eye. Japanese Dry Eye Diagnostic Criteria were employed in this study. Results. Ocular tiredness, irritation, dryness and foreign body sensation were the most frequent complaints. 73.5% of the eyes had definite dry eyes. 35% of the eyes had a Schirmer test reading less than 5 mm. The mean BUT score was 4.6r2.6 seconds. 45% of the eyes had a fluorescein staining pattern above the A1D1 grade. Meibomian gland disease and conjunctivochalasis were found as major risk factors aggravating the dry eye disease. Conclusion. Qualitative and quantitative disorders of the tear film are far more common than recognized in the eldery people, meibomian gland disease and conjunctivochalasis being the most common risk factors aggravating the tear film disorder and dry eye status. ACTIVATED MACROPHAGES CONTRIBUTE TO CORNEA GRAFT FAILURE BY TARGETING CORNEAL ENDOTHELIAL CELLS. Jacqueline M. Doherty and J. Wayne Streilein.1 Schepens Eye Research Institute, Harvard Medical School, Boston, MA. Purpose. To investigate the mechanism, by which inflammatory cells and their products, known to contribute to cornea graft failure, directly damage corneal endothelial cells (CE). Methods. For every experiment described, confluent immortalized mouse corneal endothelial cells were used and were routinely treated for 24 hrs. Both the MTT and LIVE/DEAD assays were used to assess cell viability. Studies were designed: 1). Determine the effect of inflammatory mediators alone on CE viability. CE were incubated with or without lipopolysaccaride (LPS), interleukin-1 alpha (IL-1D), tumor necrosis factor (TNF-D), interferon gamma (IFN-J), or LPS/IFN-J in combination; 2). Examine whether inflammatory cells or their supernatants alter CE function. Resting or LPS/IFNJ-activated macrophages (RAW 264.7) (MI) were added to CE cultures; 3). Determine the specificity of the response. CE were exposed to exogenous nitric oxide donors, NOR-3 and NOR-4, and inhibitors of nitric oxide production (i.e. L-NMMA and 1400W); and 4). Elucidate the mechanism by which this response occurs. CE were tested for caspase-3 activation using western blot analysis. In selected experiments, nitric oxide (NO) levels were measured in supernatants using the Griess reagent. Results. CE viability was preserved in the presence of non-activated MI, but was markedly reduced following exposure to LPS/IFNJ-activated, nitric oxide-producing MI or their supernatants. The addition of the bacterial byproduct LPS, or the inflammatory mediators IL-1D, TNF-D, IFN-J, or LPS/IFN-J combined had no effect on CE viability. By contrast, exposure of CE to exogenously generated NO resulted in loss of viability. Moreover, inhibitors of nitric oxide production, only partially prevented loss of CE viability caused by activated MI. Finally, the activation of caspase-3 (i.e. apoptosis) was observed specifically when CE were exposed to activated MI, not resting MI, and/or their secreted products. Conclusions. Corneal endothelial cells are vulnerable to damage by activated macrophages, due to their production of NO. When CE encounter NO, caspase-3 activation is initiated, which in turn results in cell death. We propose that it is the NO produced by activated MI that may be responsible in part for the loss of corneal endothelial cell viability under conditions of inflammation-which may eventually lead to corneal graft failure. Support: NIH/NEI EY10765. 1 Deceased: March 15, 2004.
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CAN TEARS BE REPLACED BY AQUEOUS HUMOR IN VERY DRY EYES? Claes Dohlman, MD, PhD, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA Purpose. While attempting to regulate the intraocular pressure in eyes with a Keratoprosthesis, shunts have been developed to divert the aqueous to distant epithelial cavities where resistant fibrosis is unlikely to form. One of these sites has been the lower lid fornix. There the aqueous is made to flow continuously. While the purpose of this arrangement has been to reduce the pressure, the effect of wetting the eye has been observed. Methods. Dr. Ahmed (New World Medical, Inc) has been asked to make shunts where the valve is totally enclosed and a distal tube added. The valve housing is sutured to the sclera in the standard way and the distal tube is drawn through the conjunctiva to lodge at the bottom of the fornix. Low dose of topical antibiotics have been given postoperatively. Seven such cases have been followed from 3 to 14 months. Subjective responses and Schirmer values have been registered. Results. No endophthalmitis has occurred – the valve shunt is truly unidirectional. One patient could feel the tube initially, otherwise it was not noticed. In one patient the valve became plugged but aspiration relieved the blockage. Two patients noticed epiphora during the night. The Schirmer values ended up at 15-25mm/5 minutes, in one case from 1 mm. preoperatively. Conclusions. On a short-term basis it seems that diverting aqueous to the lower lid fornix will not necessarily result in intraocular infection. The shunt tube is well tolerated. The arrangement definitely wets the eye and it may hold some promise to relieve extreme ocular surface dryness where the risks of shunt implantation can be justified. IMPROVEMENT IN SUBJECT’S WORST SYMPTOM ASSOCIATED WITH TREATMENT OF 2.0% DIQUAFOSOL TETRASODIUM IN TWO STUDIES OF DRY EYE DISEASE. Todd A. Durham, Lisa M. LaVange, Donald J. Kellerman, Amy E. Schaberg. Inspire Pharmaceuticals, Durham, NC, USA. Purpose. Data from two studies of dry eye disease are presented to demonstrate greater improvement in worst symptom for subjects treated with 2.0% diquafosol tetrasodium compared to those treated with placebo. Methods. In a 6-week, Phase 2, randomized, multicenter, double-masked study, 53, 26, and 22 dry eye subjects treated with placebo, 1.0% diquafosol tetrasodium, or 2.0% diquafosol tetrasodium were analyzed for efficacy. In a 24-week, Phase 3, randomized, multicenter, double-masked study, 171, 173, and 175 dry eye subjects treated with these doses were analyzed for efficacy. Subjects recorded scores for dry eye symptoms in daily diaries. In the 6week study, the symptoms were itching, burning, foreign body sensation, photophobia, and blink to clear blur. In the 24-week study, the symptoms were itching, burning, foreign body sensation, and photophobia. In both studies, the most severe symptom was identified for each subject as the symptom with the highest average score during a single-masked, one-week, placebo run-in prior to initiation of double-masked study drug. The daily worst symptom score was averaged by week. Treatment differences across the treatment period were assessed for the 2.0% dose group compared to the placebo group using a repeated measures analysis. Differences at individual time points were assessed using ANCOVA with adjustments for site and baseline. Results. Among subjects in both studies treated with placebo, 1.0% or 2.0% diquafosol tetrasodium, photophobia and foreign body sensation were the most predominant worst symptoms. In both studies, the mean worst symptom score was lower at most time points among subjects treated with 2.0% diquafosol tetrasodium than for subjects treated with placebo. In the 6-week study the difference in means was significant at Week 2. In the 24-week study the difference in means was significant at Weeks 4 and 11. Conclusions. Results from two studies suggest that treatment with 2.0% diquafosol tetrasodium may provide relief for dry eye subjects’ most severe symptoms.
THE OCULAR SURFACE / JANUARY, 2005, VOL. 3, NO. 1 / SUPPLEMENT
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CAN TEARS BE REPLACED BY AQUEOUS HUMOR IN VERY DRY EYES? Claes Dohlman, MD, PhD, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA Purpose. While attempting to regulate the intraocular pressure in eyes with a Keratoprosthesis, shunts have been developed to divert the aqueous to distant epithelial cavities where resistant fibrosis is unlikely to form. One of these sites has been the lower lid fornix. There the aqueous is made to flow continuously. While the purpose of this arrangement has been to reduce the pressure, the effect of wetting the eye has been observed. Methods. Dr. Ahmed (New World Medical, Inc) has been asked to make shunts where the valve is totally enclosed and a distal tube added. The valve housing is sutured to the sclera in the standard way and the distal tube is drawn through the conjunctiva to lodge at the bottom of the fornix. Low dose of topical antibiotics have been given postoperatively. Seven such cases have been followed from 3 to 14 months. Subjective responses and Schirmer values have been registered. Results. No endophthalmitis has occurred – the valve shunt is truly unidirectional. One patient could feel the tube initially, otherwise it was not noticed. In one patient the valve became plugged but aspiration relieved the blockage. Two patients noticed epiphora during the night. The Schirmer values ended up at 15-25mm/5 minutes, in one case from 1 mm. preoperatively. Conclusions. On a short-term basis it seems that diverting aqueous to the lower lid fornix will not necessarily result in intraocular infection. The shunt tube is well tolerated. The arrangement definitely wets the eye and it may hold some promise to relieve extreme ocular surface dryness where the risks of shunt implantation can be justified. IMPROVEMENT IN SUBJECT’S WORST SYMPTOM ASSOCIATED WITH TREATMENT OF 2.0% DIQUAFOSOL TETRASODIUM IN TWO STUDIES OF DRY EYE DISEASE. Todd A. Durham, Lisa M. LaVange, Donald J. Kellerman, Amy E. Schaberg. Inspire Pharmaceuticals, Durham, NC, USA. Purpose. Data from two studies of dry eye disease are presented to demonstrate greater improvement in worst symptom for subjects treated with 2.0% diquafosol tetrasodium compared to those treated with placebo. Methods. In a 6-week, Phase 2, randomized, multicenter, double-masked study, 53, 26, and 22 dry eye subjects treated with placebo, 1.0% diquafosol tetrasodium, or 2.0% diquafosol tetrasodium were analyzed for efficacy. In a 24-week, Phase 3, randomized, multicenter, double-masked study, 171, 173, and 175 dry eye subjects treated with these doses were analyzed for efficacy. Subjects recorded scores for dry eye symptoms in daily diaries. In the 6week study, the symptoms were itching, burning, foreign body sensation, photophobia, and blink to clear blur. In the 24-week study, the symptoms were itching, burning, foreign body sensation, and photophobia. In both studies, the most severe symptom was identified for each subject as the symptom with the highest average score during a single-masked, one-week, placebo run-in prior to initiation of double-masked study drug. The daily worst symptom score was averaged by week. Treatment differences across the treatment period were assessed for the 2.0% dose group compared to the placebo group using a repeated measures analysis. Differences at individual time points were assessed using ANCOVA with adjustments for site and baseline. Results. Among subjects in both studies treated with placebo, 1.0% or 2.0% diquafosol tetrasodium, photophobia and foreign body sensation were the most predominant worst symptoms. In both studies, the mean worst symptom score was lower at most time points among subjects treated with 2.0% diquafosol tetrasodium than for subjects treated with placebo. In the 6-week study the difference in means was significant at Week 2. In the 24-week study the difference in means was significant at Weeks 4 and 11. Conclusions. Results from two studies suggest that treatment with 2.0% diquafosol tetrasodium may provide relief for dry eye subjects’ most severe symptoms.
THE OCULAR SURFACE / JANUARY, 2005, VOL. 3, NO. 1 / SUPPLEMENT