Questionnaire score vs corneal fluorescein staining score and Schirmer 1 test score (in millimeters) (see Table 2).
Questionnaire score vs fluorescein clearance test (FCT) and FCT corrected by the Schirmer test (FCT Corrected) scores (see the "Patients and Methods" section and Table 2).
A, Log fluorescein clearance test (FCT) vs corneal fluorescein staining score for patients with aqueous tear deficiency (Spearman r = 0.54, P<.001). B, Log FCT corrected by the Schirmer test vs corneal fluorescein staining score for patients with aqueous tear deficiency (Spearman r = 0.54, P<.001).
Schirmer test (wetting in millimeters) vs corneal fluorescein staining score for patients with aqueous tear deficiency (Spearman r = −0.38, P = .01).
A, Log fluorescein clearance test (FCT) vs corneal fluorescein staining score for patients with meibomian gland disease (Spearman r = 0.47, P = .003). B, Log FCT corrected by the Schirmer test vs corneal fluorescein staining score for patients with meibomian gland disease (Spearman r = 0.58, P<.001).
Schirmer test (wetting in millimeters) vs fluorescein staining score for patients with meibomian gland disease (Spearman r = −0.06, P>.1).
Schirmer 1 test, fluorescein clearance test (FCT), FCT plus Schirmer vs corneal fluorescein staining score, and percentage of meibomian gland acinar dropout (MGAD) for all patients. The exact Spearman correlation coefficients (r) appear above the bars.
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Macri A, Pflugfelder S. Correlation of the Schirmer 1 and Fluorescein Clearance Tests With the Severity of Corneal Epithelial and Eyelid Disease. Arch Ophthalmol. 2000;118(12):1632–1638. doi:10.1001/archopht.118.12.1632
To evaluate the correlations of the fluorescein clearance test (FCT) and the Schirmer 1 test with the severity of corneal epithelial and eyelid disease in normal patients and patients with tear film disorders due to meibomian gland disease (MGD) and/or aqueous tear deficiency (ATD).
Nineteen normal control subjects, 16 patients with MGD associated with rosacea, 21 patients with noninflammatory atrophic MGD, and 43 patients with ATD were enrolled. There was a similar age and sex distribution in each group. Each patient completed a symptom severity questionnaire that consisted of 11 questions and then underwent a panel of diagnostic tests in the following order: assessment of corneal and conjunctiva sensation with the Cochet-Bonnet esthesiometer, FCT, assessment of corneal fluorescein staining, Schirmer 1 test (5 minutes without anesthesia), and biomicroscopic examination of the eyelid margins and meibomian glands. The FCT was performed with a fluorophotometer by measuring the fluorescein concentration in minimally stimulated tear samples collected from the inferior tear meniscus. By studying the best area under the receiver operating characteristic curves, we developed a formula that combined the FCT and Schirmer test results, which we termed the FCT corrected by Schirmer test.
The FCT showed stronger correlation with ocular irritation symptoms (r = 0.35, P <.001), corneal fluorescein staining (r = 0.54, P<.001), and meibomian gland and eyelid pathologic signs than the Schirmer 1 test. A correction factor that was based on the best area under the receiver operating characteristic curves, added to the FCT score, improved its correlation with ocular irritation symptoms, eyelid margin and meibomian gland pathologic signs, and ocular surface sensitivity scores.
Corneal epithelial disease is correlated with decreased aqueous tear production and delayed tear clearance, whereas eyelid and MGD are correlated with delayed tear clearance. The FCT corrected by Schirmer 1 test improves the correlations of the FCT with ocular irritation symptoms, corneal epithelial and eyelid pathologic signs, and corneal and conjunctival sensitivity for patients with MGD and ATD.
THE NATIONAL Eye Institute/Industry Workshop on dry eye proposed a classification scheme that stratified patients with dry eye into those with aqueous tear deficiency (ATD) due to lacrimal gland disease or dysfunction and those with evaporative tear loss.1 This represented an important step in standardizing the diagnosis and classification of dry eye. Although some patients visit their physicians with clearly defined dry eye conditions such as Sjögren syndrome ATD or meibomian gland disease (MGD), following therapy with isotretinoin, many patients who are seen have a combination of clinical problems contributing to their tear film deficiency (eg, ATD, MGD, incomplete blink, lid laxity, and conjunctivochalasis).
Regardless of the underlying cause, patients with tear film deficiencies complain of irritation symptoms and often show ocular surface epithelial disease, eyelid marginal disease, and MGD. The cause of these problems has not been established. Previous studies2,3 evaluating patients complaining of ocular irritation have reported that there is poor correlation between the severity of irritation symptoms and the Schirmer test (either the Schirmer 1 or the basic secretion test) and only moderate correlation with corneal or ocular surface dye staining. This may be in part because symptomatic patients with MGD often have normal or only minimally reduced aqueous tear production.2,4 This finding suggests that factors other than ATD play a role in the pathogenesis of dry eye. One of these other factors may be clearance of tears from the ocular surface. We recently observed that tear fluorescein clearance showed better correlation with ocular irritation symptoms than the Schirmer 1 test.2
The purpose of this study was to evaluate the correlations of the fluorescein clearance test (FCT) and the Schirmer test with the severity of corneal epithelial and eyelid disease in normal subjects and patients with tear film disorders due to MGD and/or ATD.
This research was conducted by medically qualified personnel in strict accordance with the guidelines of the University of Miami School of Medicine, Miami, Fla, institutional review board and the tenets of the Declaration of Helsinki.
The enrolled patients had no history of ocular surgery, contact lens use, punctal occlusion, or eyedrop use (other than nonpreserved artificial tears) for at least 1 month. Subjects did not instill any teardrops in their eyes on the day they were evaluated. Adult patients who had complaints of ocular irritation were evaluated by the 2 investigators (A.M. and S.C.P.) at the Ocular Surface Center (Bascom Palmer Eye Institute, University of Miami School of Medicine). Each subject was first asked to complete a symptom questionnaire that consisted of 11 questions describing the severity and the nature of their irritation symptoms (Table 1).
The patients then underwent a panel of diagnostic tests that were performed in the following order: corneal and conjunctiva sensation, FCT, corneal fluorescein staining, Schirmer 1 test, and biomicroscopic examination of the eyelid margins and meibomian glands. The patients were classified into 1 of 3 groups. The ATD group included patients who had a Schirmer 1 test result of 5 or lower in at least 1 eye and a questionnaire score of greater than 5. The MGD group included patients who had a Schirmer 1 test result of greater than 5 in both eyes and a symptom questionnaire score of greater than 5. These patients were classified as having rosacea-associated (inflammatory) MGD or noninflammatory meibomian gland atrophy. Diagnosis of rosacea was based on previously reported criteria and required the presence of at least 2 facial signs of rosacea (which include rhinophyma, teleangiectasia, persistent erythema, papules, pustules, and hypertrophic sebaceous glands in facial flush areas) and hyperemia of lid margins (brush marks) and/or conjunctival hyperemia.5 Atrophic MGD was defined as at least 30% atrophy of meibomian gland acini in the lower lid (determined by transillumination of the lower lid as described herein), no facial signs of rosacea, and mild or no hyperemia of the lid margins or conjunctiva.4 The normal group consisted of 19 healthy subjects of similar age and sex distribution. Subjects were considered normal if they had no history of ocular irritation (symptom score ≤5), no use of eyedrops, and a Schirmer 1 test result of more than 10 mm.
The FCT was performed with a fluorophotometer (CytoFluor II; PerSeptive Biosystems, Framingham, Mass) by measuring the fluorescein concentration in minimally stimulated tear samples collected from the inferior tear meniscus 15 minutes after instillation of 5 µL of 2% sodium fluorescein as previously reported.2
The ocular surface was examined with a biomicroscope and the ×10 objective under blue light illumination 2 minutes after fluorescein instillation into the tear film. The density of corneal fluorescein staining was assessed as previously described2 in each of 4 quadrants on the cornea (temporal, nasal, superior, and inferior) using a standardized 4-point scale (0 = none, 1 = mild, 2 = moderate, 3 = severe). The staining scores ranged from 0 to 12.
Without previously instilling anesthetic drops, Schirmer paper test strips (Alcon Laboratories Inc, Fort Worth, Tex) were placed over the lid margin at the junction of the lateral and middle thirds of the lower eyelid for 5 minutes. The length of strip wetting in millimeters was recorded.
Cornea and conjunctiva sensation were assessed using the Cochet-Bonnet esthesiometer.6,7 The stimulus from the Cochet-Bonnet instrument consists of a nylon filament that can vary in length from 0 to 6 cm. The procedure for measuring ocular surface sensitivity was as follows. Under visual control, the nylon filament of the Cochet-Bonnet instrument was approached smoothly and perpendicularly toward the center of the cornea. Contact was detected by the slightest bend of the nylon; sensitivity was taken as the length of the filament that gave a 50% positive response from a minimum of 4 stimulus applications. Subject reliability was tested by bringing the filament close to the cornea without actually touching. The same procedure was used to test conjunctival sensation, with the stimulus applied to the middle of the exposed temporal-bulbar conjunctiva.
The meibomian gland orifices were examined by slitlamp biomicroscopy for the presence of metaplasia (abnormal growth and keratinization of duct epithelium manifesting as white shaft protruding from the orifices). The inferior tarsus was transilluminated with a halogen Finhoff transilluminator (Welch Allyn Inc, Schenectady, NY), and the percentage of meibomian gland acinar dropout was measured as previously reported.4
The presence of irregularity of the lid margin and anterior migration of the Marx line was evaluated by slitlamp biomicroscopy. Anterior migration of the Marx line was determined using criteria described by Norn.8
For statistical evaluation, only the right eye was considered for each patient. Data distribution was analyzed. If data were normally distributed, then parametric statistical tests were used, otherwise nonparametric tests were used. The differences in age among the 3 groups (normal controls, patients with MGD, and patients with ATD) were studied by means of 1-way analysis of variance and the Bartlett test for equal variances. The difference in sex among the 3 groups was studied using the Kruskal-Wallis statistic.
Correlation coefficients were calculated between the FCT and Schirmer 1 test, corneal fluorescein staining score, anterior migration of the Marx line, percentage of meibomian gland acinar loss, presence of orifice metaplasia (0 = absent, 1 = present), and cornea and conjunctiva sensitivity scores. If data distribution was normal, then the Pearson correlation coefficient was used, otherwise the Spearman rank correlation coefficient was calculated. Furthermore, the correlation coefficients between symptom questionnaire score and FCT, Schirmer test, and corneal fluorescein staining scores were evaluated for each group of patients (MGD patients, ATD patients, and normal controls).
The following equation was used to correct the results of the FCT by the Schirmer test: FCT + (Schirmer Score × y) = FCT (Corrected) The coefficient y was calculated by looking for the best corresponding area under the receiver operating characteristic curves according to previously described methods.9
All statistical calculations were performed with GraphPad Prism 2.0 Software (GraphPad Software, Inc, San Diego, Calif).
No significant differences in age and sex were found among normal control subjects (mean + SD age, 59.4 + 15.4 years), patients with MGD (mean + SD age, 59.7 + 17.5 years), and patients with ATD (mean + SD age, 66.3 + 16.2 years); for age, a 1-way analysis of variance (P = .2) and Bartlett statistic (corrected) (P = .8) were used; for sex, the Kruskal-Wallis statistic was used (P = .7).
Sixteen of the patients with MGD had rosacea, and 21 had noninflammatory atrophic disease. There was no statistical difference in age (Mann-Whitney U test, P = .2) and sex (Mann-Whitney U test, P = .7) between these 2 groups. The 2 groups of patients with MGD were combined for statistical analysis.
The mean and SD values of diagnostic tests for the 3 studied groups are provided in Table 2, and the significant differences among them are noted.
The best value for y in the FCT corrected by the Schirmer test score was found to be 4. Thus, the formula that provided the best area under the receiver operating characteristic curves was as follows: FCT (Corrected) = FCT + (Schirmer Score × 4) The differences in FCT corrected among the 3 groups was found to be statistically significant (Kruskal-Wallis statistic = 30.2, P<.001), and also the differences in FCT corrected between the patients with MGD and ATD were statistically significant (Mann-Whitney U test = 474, P<.001) (Table 1).
Correlations among the symptom questionnaire score, the Schirmer 1 test score, the corneal fluorescein staining score, the FCT, and the corrected FCT are provided in Table 3 and in Figure 1 and Figure 2.
The results of correlation analyses among the Schirmer test, the FCT, the corrected FCT, eyelid and meibomian gland pathologic signs (anterior migration of the Marx line, meibomian gland orifice metaplasia, percentage of meibomian gland acinar dropout), and cornea and conjunctiva sensitivity scores are presented in Table 4.
Table 5 and Figure 3, Figure 4, Figure 5, Figure 6, and Figure 7 present the correlations among the corneal fluorescein staining scores, the Schirmer 1 test, the FCT, and the FCT corrected by Schirmer 1 test for patients with MGD, patients with ATD, and all subjects.
This study evaluated the correlations of the FCT and the Schirmer test with the severity of corneal epithelial and eyelid disease in normal subjects and patients with tear film disorders due to MGD and/or ATD. These studies were performed to gain a greater understanding regarding the factors that cause ocular surface disease. The results of these studies may improve the ability of clinicians to identify a tear film disorder as the cause of a patient's ocular surface disease.
In a previously reported study,2 we found that the FCT showed greater correlation with irritation symptoms than the Schirmer 1 test, whereas the Schirmer 1 test showed slightly better correlation with the severity of corneal fluorescein staining. In the present study performed on a different patient population, the FCT showed better correlation with both irritation symptoms and corneal fluorescein staining scores than the Schirmer 1 test. These findings indicate that clearance of tears from the ocular surface is a key factor in the pathogenesis of keratoconjunctivitis sicca. These correlations were further improved by adding a correction factor for the Schirmer test result to the FCT score. This suggests that the correlation of decreased aqueous tear production with ocular irritation and ocular surface disease is not solely due to its effect on reducing tear clearance. Indeed, secretory dysfunction of the lacrimal gland may promote ocular surface inflammation and decrease delivery of protective proteins and growth factors needed to maintain ocular surface homeostasis.10,11 We have reported that in patients with Sjögren syndrome as aqueous tear production decreases the levels of inflammatory cytokines in the conjunctival epithelium and tear fluid increase and that the concentration of epidermal growth factor in the tear fluid decreases.12
The corrected FCT is a relatively easy test for clinicians to perform. Unlike tear osmolarity, a diagnostic technique touted as a gold standard for diagnosis of dry eye,13 which requires expensive instrumentation, tear fluorescein clearance can be assessed in an inexpensive fashion by practitioners. Our group and others4,14,15 have reported the use of colorimetric techniques to evaluate tear clearance by collecting fluorescein-stained tear fluid on a Schirmer test strip. We have developed a 7-point visual scale to assess tear fluorescein clearance that shows very strong correlation with the results of the fluorometric technique used in the present study.16
It is well recognized that anesthesia of the ocular surface decreases aqueous tear production.17 The results of our study support recently proposed unified concepts for development of dry eye where perturbations on the ocular surface affect tear fluid secretion by the lacrimal glands by inhibiting afferent sensory to efferent cholinergic neural reflex loops.18,19 Both decreased aqueous tear production and delayed tear clearance are associated with decreased ocular surface sensation.4,7 Decreased ocular surface sensation could explain why patients with MGD were noted to have significantly reduced aqueous tear production compared with a control group of similar age and sex (Table 1). Patients with MGD and lipid tear deficiency have been noted to have increased tear film evaporation and a decreased tear volume.20 These factors alone could be responsible for the delayed tear clearance and the secondary changes to the eyelid and ocular surface that occur in MGD. Regardless of the mechanism by which tear clearance decreases in MGD, delayed tear clearance leads to decreased ocular surface sensation and decreased sensory stimulation of lacrimal gland tear secretion. This creates a viscous, self-perpetuating cycle on the ocular surface.
An intriguing finding of this study was that the FCT and to a greater degree the FCT corrected by the Schirmer test showed very strong correlation with the pathologic changes of the eyelid margin that develop in patients with MGD (Table 3). It is possible that the biochemical changes in the tear fluid that accompany delayed tear clearance, such as an increased concentration of the inflammatory cytokine interleukin 1 and increased activity of the matrix-degrading enzyme matrix metalloproteinase 9, could be responsible for these changes.21 These changes could also explain the increased prevalence of MGD in patients with severe ATD, a condition where tear clearance is markedly decreased.2,22
Future research may identify the mechanism(s) by which delayed tear clearance decreases ocular surface sensation and promotes corneal epithelial and eyelid disease. Our results indicate that the corrected FCT appears to be an even better tool to study these mechanisms than the FCT alone.
Accepted for publication April 13, 2000.
This study was supported in part by Public Health Service Research Grant EY11915, Department of Health and Human Services, National Eye Institute, Bethesda, Md, an unrestricted grant from Research to Prevent Blindness, and the Drs. David and Maureen Smith Ocular Surface and Tear Research Fund.
Reprints: Stephen C. Pflugfelder, MD, Cullen Eye Institute, 6565 Fannin St, NC 205, Houston, TX 77030 (e-mail: email@example.com).
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