- Email: [email protected]
Screening for Dry Eye With Newly Developed Ocular Surface Thermographer
Screening for Dry Eye With Newly Developed Ocular Surface Thermographer TOMOYUKI KAMAO, MASAHIKO YAMAGUCHI, SHIRO KAWASAKI, SHIRO MIZOUE, ATSUSHI SHIRAISHI, AND YUICHI OHASHI ● PURPOSE:
To evaluate the newly developed Ocular Surface Thermographer (TOMEY Corporation) for dry eye screening. ● DESIGN: Prospective, controlled study. ● METHODS: We studied 30 eyes of 30 patients diagnosed with dry eye (mean age ⴞ standard deviation, 52.9 ⴞ 17.1 years) and 30 eyes of 30 normal subjects (42.7 ⴞ 17.0 years). The ocular surface temperature was measured immediately after eye opening and every second during 10 seconds of eye opening. The reliability of the measurements was determined by calculating intraclass correlation coefficients. Then, the correlations between the change in the ocular surface temperature and tear film break-up time, Schirmer I test values, and fluorescein staining scores were determined. ● RESULTS: The measurements of the ocular surface temperature had a high degree of reliability. Immediately after eye opening, the temperature in the dry eye did not differ significantly from that in normal eyes in any of the 3 regions tested. The decrease in the ocular surface temperature in dry eyes was significantly greater than that in normal eyes (P < .001) at 10 seconds after eye opening. The decrease in the temperature of the cornea was correlated significantly with the tear film break-up time (r ⴝ ⴚ0.572; P < .001). When the changes in ocular surface temperature of the cornea were used as an index for dry eye, the sensitivity was 0.83 and the specificity was 0.80 after 10 seconds. ● CONCLUSIONS: Measurements of the ocular surface temperature obtained with our newly developed Ocular Surface Thermographer after 10 seconds of eye opening may provide a simple, noninvasive screening test for dry eyes. (Am J Ophthalmol 2011;151:782–791. © 2011 by Elsevier Inc. All rights reserved.)
Accepted for publication Oct 20, 2010. From the Department of Ophthalmology, Medicine of Sensory Function, Ehime University Graduate School of Medicine, Toon, Japan (T.K., M.Y., S.K., S.M., Y.O.); the Department of Ophthalmology, Ehime Prefectural Central Hospital, Matsuyama, Japan (M.Y.); and the Department of Ophthalmology and Regenerative Medicine, Ehime University Graduate School of Medicine, Toon, Japan (A.S.). Inquiries to Masahiko Yamaguchi, Department of Ophthalmology, Medicine of Sensory Function, Ehime University Graduate School of Medicine, Toon, Japan; e-mail: [email protected]
782
©
2011 BY
D
RY EYE IS A MULTIFACTORIAL DISEASE OF THE
tears and ocular surface that results in symptoms of discomfort, visual disturbances, and tear film instability and that has the potential to damage the ocular surface.1 The diagnosis of dry eye is based on the results of a comprehensive evaluation of the key findings: decrease in tear secretion, instability of the tear film, and corneal or conjunctival epithelial cell disorder identified by vital staining. However, the discomfort of patients during the Schirmer test and tear film break-up time (TBUT) test, and the toxicity of rose bengal staining are factors that need to be considered when these diagnostic tests are used. Therefore, a screening test for dry eyes that is objective, noninvasive, and rapid is needed. Thermography is a noninvasive method for measuring the surface temperature of an object. Thermography was applied to the eye first in 1968 by Mapstone.2 In 1995, Morgan and associates used thermography to measure ocular surface temperature in patients with dry eyes.3 They reported that the surface temperature was significantly higher in dry eyes than in normal eyes and that the temperature at the center of the cornea of dry eyes became lower than that in normal eyes after sustained eye opening. Subsequently, several groups reported on the difference between the surface temperatures of normal eyes and dry eyes,4 – 6 and this led to the suggestion that thermography might be used for diagnosing dry eye. However, attempts to use the existing medical thermographic devices to screen for dry eye had many problems. For example, to measure the ocular surface temperature with the existing devices, the tests had to be carried out in a specialized room with tightly controlled temperature and humidity. In addition, considerable skill was necessary to make the measurements under special conditions such as those necessary for serial radiography. Finally, a large amount of time was required for data analysis after the test. We have developed a thermographic instrument specialized to measure surface temperature which is based on the design of the TOMEY autorefractor/keratometer (TOMEY Corp, Nagoya, Japan). In addition to measuring the surface temperature, our device also incorporates data analyzing features. Thus, the purpose of this study was to determine whether our newly developed thermographer can provide reliable values of surface temperature and whether it can be used to screen for dry eye. To accomplish these goals, we
ELSEVIER INC. ALL
RIGHTS RESERVED.
0002-9394/$36.00 doi:10.1016/j.ajo.2010.10.033
FIGURE 1. Photograph of the Ocular Surface Thermographer (TOMEY Corporation, Nagoya, Japan). Infrared and visible light cameras are mounted in the optical head of a modified RC 5000 autorefractor/keratometer manufactured by the TOMEY Corporation. The head can be moved with a joystick. When the examiner touches the center of the device’s touch panel screen, the instrument automatically recognizes the pupil and aligns the center of the screen with the center of the pupil. The head of the Ocular Surface Thermographer also moves automatically to maintain the measurement apparatus at a fixed distance from the eye. Results can be analyzed quickly and easily using the computer shown next to the device.
measured the surface temperature in 30 patients who were diagnosed with dry eye by conventional examinations and compared their findings with those obtained from 30 individuals with no signs of dry eye.
METHODS ● DEVELOPMENT AND SPECIFICATIONS OF OCULAR SURFACE THERMOGRAPHER: The newly developed Oc-
ular Surface Thermographer (TOMEY Corp) is shown in Figure 1. The instrument is equipped with an infrared camera module (HX0830M1; NEC, Tokyo, Japan) and a color charged coupled device board camera (PKD-101; Pacific CO, Tokyo, Japan). Light can be directed into either an infrared camera or a visible light camera. The direction of the light is changed by a rotating mirror, and both infrared and visible light images can be recorded coaxially (Figure 2). The two mirrors are positioned with their optical axes displaced by 90 degrees, and the position of one mirror is fixed while the other mirror is rotated 45 degrees every 0.25 seconds to direct light alternately into the infrared camera (Figure 2, Right) or into the visible light camera (Figure 2, Left). The cameras and the controllers are mounted within a modified version of the optical head of an autorefractor/keratometer (RC-5000; TOMEY Corp). The infrared radiation detector module is sensitive to infrared radiation between 8 and 12 m. The infrared camera has a Germanium lens with a 90-mm working distance and can record images at a resolution of VOL. 151, NO. 5
320 ⫻ 240 pixels with a pixel size of 23.5 ⫻ 23.5 m and spatial resolution of 70 m at 0.1 C. The maximum recording rate is 6 frames/second. Color images are obtained with a 1/4-inch charged coupled device video camera that can record images at a resolution of 640 ⫻ 480 pixels, pixel size of 5.6 ⫻ 5.6 m, and a detection range of 0.5 lux at 1/30 frames/second. To correct for background radiation entering the infrared camera, a black body plate is inserted automatically to cover the sensor immediately before beginning the measurements. To correct for changes in the temperature of the interior of the instrument during the measurements, a sensor was embedded in the camera and a program was installed in the instrument to correct for changes in the internal temperature. An autoalignment function is incorporated in the instrument to ensure that the instrument and object are maintained in a fixed location relative to each other. With this autoalignment function, the position of the cameras with respect to the object to be measured can be held constant, which allows measurements of the ocular surface temperature to be performed at the same position. There is virtually no human error involved in operating the Ocular Surface Thermographer. This feature is identical to that of the RC-5000 Autorefractor/Keratometer, which recognizes the pupil and aligns the pupil in the center of the screen when the examiner touches the center of the touch panel. The head of the Ocular Surface Thermographer also moves along the z-axis automatically to maintain the instrument at a fixed distance from the eye. The images recorded by the Ocular Surface Thermographer are immediately fed to a Dell-compatible microcomputer to be stored and manipulated automatically by appropriate software. Monochromatic thermal images (65 536 grayscale increments) are recorded and analyzed with a computer program and are displayed on a monitor in up to 24-bit color. It required only 10 seconds to display the results of a measurement that has been analyzed. ● SUBJECTS:
Thirty eyes of 30 patients with dry eye who were recruited from the outpatients of the Department of Ophthalmology, Ehime University Graduate School of Medicine (7 men and 23 women; mean age ⫾ standard deviation, 52.9 ⫾ 17.1 years; range, 20 to 74 years), were examined. Thirty eyes of 30 normal subjects who were healthy volunteers (12 men and 18 women; mean age, 42.7 ⫾ 17.0 years; range, 20 to 81 years) served as controls. Individuals who had a history of atopy; allergic diseases; Stevens-Johnson syndrome; or chemical, thermal, or radiation injury were excluded. Subjects also were excluded if they had any other ocular or systemic disorders or had undergone any ocular surgery or contact lens use that would create an ocular surface problem or dry eye.
● DIAGNOSTIC CRITERIA:
The diagnosis of dry eye was based on the diagnostic criteria of the Japanese Dry Eye Research Group.1 Subjects who fulfilled the following 3
OCULAR SURFACE THERMOGRAPHER
FOR
DRY EYE SCREENING
783
FIGURE 2. Changes in the rotating mirror system in the Ocular Surface Thermographer (TOMEY Corporation, Nagoya, Japan) allow the examiner to view (Left) the visible light images or (Right) the thermal light images. By changing the optical axis by rotating a mirror, the light can be directed alternately into the 2 cameras, and infrared and visible images can be recorded coaxially. The 2 mirrors are positioned with their optical axes displaced 90 degrees. The position of one mirror is fixed, whereas the other mirror is rotated 45 degrees every 0.25 seconds to direct light alternately into the infrared and visible light cameras. CCD ⴝ charged coupled device.
temporal conjunctiva with a possible total score between 0 and 9 points, with a score of more than 3 points considered to be abnormal.1 The normal subjects had clear corneas and conjunctiva on slit-lamp biomicroscopy and displayed no signs or symptoms of dry eye or other ocular diseases. ● MEASUREMENT OF OCULAR SURFACE TEMPERATURE:
Ocular surface temperature was measured using the new Ocular Surface Thermographer in a standard clinical room at a relatively constant temperature (26.5 ⫾ 1.5 C), humidity (42.5 ⫾ 2.5%), and brightness (300 lux). The subject’s head was placed in a standard ophthalmic chin and head rest, and the subject was instructed to look straight ahead. The measurements were performed under the conditions described by Mori and associates: the subject blinked normally, then closed both eyes for 5 seconds, and then kept the eyes open for more than 10 seconds.4 Ocular surface temperature was measured immediately after the eye was opened, and then every second during the 10 seconds of continuous eye opening. The temperature was measured in 3 regions: the central cornea, the nasal conjunctiva, and the temporal conjunctiva (Figure 3). The center of the cornea was defined as a circular area 4 mm in diameter at the center of the cornea. To determine the nasal and temporal conjunctival regions, a horizontal line was drawn through the center of the cornea extending to both canthi. Then, the intersection of the line and the nasal and temporal corneal limbus were designated as points A and B, respectively. The nasal conjunctiva was defined as a circular region 2 mm in diameter, with its center at the midpoint of the line connecting the inner canthus with point A. Likewise, the temporal conjunctiva was defined as a circular region 2 mm in diameter with its center at the midpoint of the line
FIGURE 3. Three regions where the ocular surface temperatures are measured. The central cornea is the circular region in the center of the cornea 4 mm in diameter. Points A and B are the points of intersection between a horizontal line passing through the center of the cornea and the nasal and temporal corneal limbus, respectively. The nasal conjunctiva is a circular region 2 mm in diameter with its center at the midpoint of the line connecting point A to the inner canthus. The temporal conjunctiva is a circular region 2 mm in diameter with its center at the midpoint of the line connecting point B to the lateral canthus. Temperature measurements were recorded and averaged over each region.
criteria were diagnosed as having dry eye: subjective symptoms related to dry eye elicited during the examination or medical interview, Schirmer I test results of less than 5 mm or TBUT in fewer than 5 seconds, and positive staining of the cornea and conjunctiva by fluorescein, rose bengal, or lissamine green, as described below. The fluorescein, rose bengal, and lissamine green staining were graded from 0 to 3 at the cornea, nasal conjunctiva, and 784
AMERICAN JOURNAL
OF
OPHTHALMOLOGY
MAY
2011
FIGURE 4. Monitor screen showing the results of the measurements for a normal subject. The infrared and visible light images are displayed in the upper left-hand portion of the screen. The bottom of the screen shows infrared images obtained every second over a 10-second period after the beginning of the measurements. On the upper right side of the screen, a graph is displayed showing the changes in temperature over a 10-second period at the surface of the white circular region and the value of the net change in the temperature in these areas. In a normal eye, there is virtually no change in the color of the images and the temperature remains constant over the 10-second period.
connecting the lateral canthus with point B. The surface temperature was recorded over each region, and an average value for each region was calculated. Additionally, we recorded the body temperature immediately after we measured the ocular surface temperature.
TABLE 1. Intraclass Correlation Coefficients for Ocular Surface Temperatures in 3 Regions Measured by a Single Examiner in 10 Subjects Immediately after Eye Opening
● RELIABILITY OF OCULAR SURFACE THERMOGRAPHER MEASUREMENTS UNDER VARIOUS CONDITIONS: One
ophthalmic technician (M.M.) was instructed on the operation protocol for the Ocular Surface Thermographer. After the examiner became proficient with the device, she was instructed to perform the measurements masked to the type of patient. We first determined the reliability of the measurements of the Ocular Surface Thermographer and the effect of various conditions on the reliability of the measurements. Ten healthy volunteers were asked to blink naturally for at least 10 seconds and then to close their eyes. Then, the ocular surface temperature was measured immediately after the eye was opened. Next, subjects were asked to close their eyes for 5 seconds, and ocular surface temperature was measured immediately after the eye was opened. In the third trial, the subjects were instructed to keep their eyes closed for 10 seconds before opening. In all 3 trials, the measurements were repeated 5 times for each VOL. 151, NO. 5
Normal blinkinga After closing the eyes for 5 secb After closing the eyes for 10 secc
Central Cornea
Nasal Conjunctiva
Temporal Conjunctiva
0.900
0.860
0.948
0.947
0.931
0.960
0.958
0.926
0.967
a Measurements after eye opening after a 10-second period of natural blinking. b Measurements after eye opening after a 5-second period of eye closure. c Measurements after eye opening after a 10-second period of eye closure.
volunteer, with at least a 5-minute interval between each measurement. Discrepancies between the 5 measurements obtained at the center of the cornea, nasal conjunctiva, and temporal conjunctiva were examined in each of the 10
OCULAR SURFACE THERMOGRAPHER
FOR
DRY EYE SCREENING
785
TABLE 2. Mean Surface Temperatures at the Center of the Cornea and at the Nasal and Temporal Conjunctiva in Normal Subjects and Dry Eye Patients at 0 and 10 Seconds after Eye Opening Mean Surface Temperature (C; Mean ⫾ SD) Central Cornea
Nasal Conjunctiva
Temporal Conjunctiva
Normal (n ⫽ 30)
0 sec
34.58 ⫾ 0.75
35.09 ⫾ 0.72
34.79 ⫾ 0.75
Dry eye (n ⫽ 30)
0 sec
34.45 ⫾ 0.86
34.96 ⫾ 0.73
34.75 ⫾ 0.82
Normal (n ⫽ 30)
10 sec
34.51 ⫾ 0.79
35.08 ⫾ 0.74
34.82 ⫾ 0.75
Dry eye (n ⫽ 30)
10 sec
34.13 ⫾ 0.87
34.78 ⫾ 0.71
34.58 ⫾ 0.75
SD ⫽ standard deviation. a P ⬍ .05, unpaired t test. b P ⬍ .05, Tukey-Kramer test. c P ⬍ .01, Tukey-Kramer test.
FIGURE 5. Monitor screen showing the results from a dry eye patient. In the 11 thermographic images at the bottom of the screen, the center of the cornea gradually changes from warm colors to cool colors, signifying a drop in temperature. The graph shows that surface temperature has decreased by 0.68 C over the 10-second period.
subjects, and the reliability of the measurements was determined statistically.
ered reliable when the intraclass correlation coefficient was more than 0.7. The temperature measured immediately and 10 seconds after eye opening and the change in temperature observed over a 10-second period of sustained eye opening are presented as the means ⫾ standard deviations. Unpaired t tests were used to examine differences between ocular surface temperatures in patients with dry eye and those found in
● STATISTICAL ANALYSES:
The reliability of ocular surface temperature measurements obtained by the Ocular Surface Thermographer was determined by calculating the intraclass correlation coefficients. Measurements were consid-
786
AMERICAN JOURNAL
OF
OPHTHALMOLOGY
MAY
2011
FIGURE 6. Graphs showing the change in the temperature during the 10-second period immediately after eye opening at (Top left) the center of the cornea, (Top right) the nasal conjunctiva, and (Bottom left) the temporal conjunctiva in (open circles) normal subjects and (solid squares) patients with dry eye. Error bars ⴝ standard deviation. Values in boxes represent the net change in temperature over the 10-second period in normal subjects and dry eye patients. A comparison of mean values was performed using unpaired t tests, *P < .001. The mean values for the changes in temperature were significantly lower in the patients with dry eye than in the normal subjects beginning 2 seconds after eye opening. The decrease in temperature was greater in the center of the cornea.
normal subjects. Multiple comparisons for temperature values found at the 3 regions of the ocular surface were made with the Tukey-Kramer test. A P value less than .05 was considered significant. The Spearman rank correlation test was performed to determine the correlations between the change in temperature at the center of the cornea and the results of other tear function examinations, including the Schirmer I test, TBUT, and the fluorescein staining score. The receiver operating characteristic curve technique was used to evaluate the sensitivity and specificity of the Ocular Surface Thermographer measurements of change in temperature each second after eye opening as a diagnostic index for dry eye.
TABLE 3. Correlations between Magnitude of Change in Temperature at 3 Regions (Center of Cornea, Nasal Conjunctiva, and Temporal Conjunctiva) and Results of Different Dry Eye Tests
TBUT Schirmer I CCES
Surface Thermographer measurements is shown in Figure 4. The infrared and visible light images obtained when the eye was first opened are displayed in the upper left area of the screen. This feature enables easy identification of areas of interest during the data analyses, because placing the cursor on the infrared image automatically will display the corresponding portion of the visible light image. The infrared VOL. 151, NO. 5
Nasal Conjunctiva
Temporal Conjunctiva
⫺0.57a 0.128 ⫺0.213
⫺0.177 0.079 0.09
⫺0.203 –0.073 0.193
CCES ⫽ corneal conjunctival epithelial staining; TBUT ⫽ tear film break-up time. a A significant negative correlation was found between the degree of decrease in temperature at the center of the cornea and tear film break-up time (r ⫽ – 0.572; P ⬍ .001).
RESULTS ● DISPLAY OF MEASUREMENTS ON OCULAR SURFACE THERMOGRAPHER MONITOR: A display of the Ocular
Central Cornea
images obtained every second over a 10-second period are displayed at the bottom of the screen. The images are color coded so that changes in temperature can be seen as changes in the color of the images. In the upper right area of the screen, a graph plotting the changes in the temperature over the 10-second period at the surface of the white circular region and the value of net change in the temperature in that area are shown.
OCULAR SURFACE THERMOGRAPHER
FOR
DRY EYE SCREENING
787
FIGURE 7. Receiver operating characteristic (ROC) curve showing the sensitivity and specificity of the Ocular Surface Thermographer measurements of the change in temperature at the center of the cornea (Left) 10 seconds and (Right) 5 seconds after the eye opening as an index for the diagnosis of dry eye. AUC ⴝ area under the ROC curve.
● REPRODUCIBILITY OF MEASUREMENTS: The intraclass correlation coefficients for the temperatures are shown in Table 1. When the measurements were made immediately after eye opening after a 10-second period of natural blinking, the intraclass correlation coefficients were 0.900, 0.860, and 0.948 for the center of the cornea, nasal conjunctiva, and temporal conjunctiva, respectively. The intraclass correlation coefficients for the measurements performed immediately after eye opening after a 5-second period of eye closure were 0.947, 0.931, and 0.960, and the coefficients for measurements carried out after a 10-second period of eye closure were 0.958, 0.926, and 0.967 for the 3 regions, respectively. All values were more than 0.7. Even when the subjects were allowed to blink naturally before the measurements, it was possible to obtain reliable measurements of the ocular surface temperature. However, the measurements obtained after subjects closed their eyes for 5 seconds had the highest degree of reliability.
ature was found at the nasal conjunctiva, followed by the temporal conjunctiva, and the lowest temperature was found at the center of the cornea. ● CHANGES IN OCULAR SURFACE TEMPERATURE DURING SUSTAINED EYE OPENING: No change was found in
the temperature of the center of the cornea in normal eyes during the 10-second period of sustained eye opening (Figure 4). In contrast, in the dry eye group, the center of the cornea gradually became bluer, signifying a drop in temperature (Figure 5). In addition, the graph of the changes in the temperature over the 10-second period clearly showed a decrease in temperature, and the display indicated that the average temperature had decreased by 0.68 C over the 10-second period. Next, we compared the ocular surface temperatures measured in the normal and dry eye groups at the 3 selected areas during the 10-second period of sustained eye opening (Table 2). No significant difference was found between the normal and dry eye groups with respect to the surface temperatures of the nasal or temporal conjunctiva. However, the temperature of the center of the cornea was significantly lower in the dry eye group than in the normal group (P ⬍ .05). The 2 groups also were compared with respect to the decrease in temperature each second over the 10-second period at each of the 3 regions (Figure 6). In the normal group, surface temperature did not change significantly over the 10-second period, whereas in the dry eye group, the temperature at all 3 regions decreased shortly after eye opening. A significant decrease was found between the normal group and the dry eye group beginning 2 seconds after eye opening (P ⬍ .001). The decrease in temperature was especially prominent at the center of the cornea in the dry eye group over the 10-second period.
● OCULAR SURFACE TEMPERATURE IMMEDIATELY AFTER EYE OPENING: The average ocular surface tempera-
tures measured immediately after eye opening at the center of the cornea, nasal conjunctiva, and temporal conjunctiva in the normal and dry eye groups are shown in Table 2. There was no significant difference in the body temperature and at any of the 3 regions between the 2 groups. In both the normal and dry eye groups, a significant difference was found between the initial temperature at the center of the cornea and that of the nasal conjunctiva (P ⬍ .05). No significant difference was found between the temperature of the temporal conjunctiva and either the center of the cornea or the nasal conjunctiva. In both groups, the highest temper788
AMERICAN JOURNAL
OF
OPHTHALMOLOGY
MAY
2011
In both groups, a significant difference was noted between the temperatures over the 10-second period at the center of the cornea and the nasal conjunctiva, but no significant difference was found between the temporal conjunctiva and either the center of the cornea or the nasal conjunctiva. ● CORRELATIONS BETWEEN MAGNITUDE OF CHANGE IN TEMPERATURE AT CENTER OF CORNEA AND RESULTS OF DIFFERENT DRY EYE TESTS: The correlations
between the decrease in temperature at each of the 3 regions over 10 seconds of sustained eye opening and the results of dry eye diagnostic tests, namely the Schirmer I test, TBUT, and corneal conjunctival epithelial staining, were determined. In the dry eye group, a significant negative correlation was found between the degree of decrease in temperature at the center of the cornea and TBUT (r ⫽ ⫺0.572; P ⬍ .001). The correlation coefficients relating the degree of decrease in temperature at the center of the cornea to the Schirmer I test scores and the corneal conjunctival epithelial staining score were r ⫽ 0.128 (P ⫽ .502) and r ⫽ ⫺0.213 (P ⫽ .258), respectively. The correlation coefficients between the decrease in temperature at the nasal conjunctiva and TBUT, Schirmer I test scores, and corneal conjunctival epithelial staining scores were r ⫽ ⫺0.177 (P ⫽ .350), r ⫽ 0.079 (P ⫽ .679), and r ⫽ 0.09 (P ⫽ .635), respectively. Correlation coefficients between the decrease in temperature at the temporal conjunctiva and the same 3 parameters were r ⫽ ⫺0.203 (P ⫽ .280), r ⫽ ⫺0.073 (P ⫽ .700), and r ⫽ 0.193 (P ⫽ .306), respectively. None of these correlations was significant (Table 3).
receiver operating characteristic curve was 0.80, and when the cutoff value for the Ocular Surface Thermographer test was set at 0.11 C, the sensitivity and specificity of the Ocular Surface Thermographer measurements were 0.80 and 0.73, respectively. These values indicate that measurements obtained over 5 seconds of sustained opening provide acceptable sensitivity and specificity for detecting dry eye (Figure 7, Right). ● DIFFERENCES IN OCULAR SURFACE THERMOGRAPHER VALUES FOR AGE AND GENDER: We examined
whether these results were affected by the differences in the age or gender distribution between the dry eye group and normal group. Differences in age were compared with the use of unpaired t tests, and frequencies of gender were compared with the use of the Fisher exact test between the normal and dry eye groups. There was a statistically significant difference in the age, but not in gender, between the two groups. Next, age was adjusted because Horven showed a negative correlation between the ocular surface temperature and age, and the two groups were also compared with respect to the decrease in temperature after 5 and 10 seconds of sustained eye opening at each of the 3 regions with the use of an analysis of covariance.7 Ultimately, a significant decrease also was found between the normal group and the dry eye group after 5 and 10 seconds of sustained eye opening. Thus, age and gender did not affect the results in this study.
DISCUSSION WE HAVE PRESENTED OCULAR SURFACE TEMPERATURE
● SENSITIVITY AND SPECIFICITY OF OCULAR SURFACE THERMOGRAPHER VALUES FOR SCREENING OF DRY EYE: To determine whether the Ocular Surface Thermog-
rapher values at the center of the cornea after 10 seconds of sustained eye opening could be used for the screening of dry eye, cutoff values were varied and the sensitivity and specificity were determined. The cutoff value for screening of dry eye was designated as the value at which sensitivity (1⫺specificity) found using the receiver operating characteristic curve reached a maximum. The area under the receiver operating characteristic curve calculated by the receiver operating characteristic technique was 0.86, indicating acceptable sensitivity and specificity of values for change in temperature after 10 seconds of sustained eye opening as an index for dry eye screening (Figure 7, Left). When the cutoff value for the Ocular Surface Thermographer test was set at 0.13 C, the sensitivity and specificity of the Ocular Surface Thermographer values were 0.83 and 0.80, respectively. We also tested whether the decrease in temperature at the center of the cornea could be used to diagnose dry eye when the period of sustained eye opening was reduced to 5 seconds. Under these conditions, the area under the VOL. 151, NO. 5
findings obtained with a newly developed thermographer, the Ocular Surface Thermographer. Several features of Ocular Surface Thermographer made it possible to obtain these reliable results with consistency. First, the Ocular Surface Thermographer is able to perform measurements in the same manner as a standard autorefractor/keratometer with an autoalignment function, enabling data to be collected quickly, objectively, and noninvasively. In addition, because the Ocular Surface Thermographer displays visible light and thermal images simultaneously, regions of the thermal image can be identified easily and accurately. Moreover, the Ocular Surface Thermographer collects data every second and allows large amounts of data to be stored, analyzed, and displayed by connecting the device to a computer. These features allowed us to perform a detailed longitudinal investigation of changes in the ocular surface temperature in dry eyes. The highly reliable results obtained with the Ocular Surface Thermographer may clarify discrepancies in ocular surface temperature measurements from previous studies that used thermographic devices specialized for the skin. The first matter investigated was whether surface temperature changed in eyes with dry eye. Morgan and associates and Craig and
OCULAR SURFACE THERMOGRAPHER
FOR
DRY EYE SCREENING
789
associates reported that the temperature of the cornea decreases with sustained eye opening.3,6 They concluded that the instability of the tear film in dry eyes worsens the tear fluid evaporation, and the resulting heat of vaporization results in a decrease in ocular surface temperature. Our Ocular Surface Thermographer measurements clearly showed that the temperature at the center of the cornea decreased with sustained eye opening in patients with dry eyes. Furthermore, a significant negative correlation was found between the temperature change at the center of the cornea and the TBUT scores. This indicated that eyes with a shorter TBUT are more likely to have a decrease in the ocular surface temperature. Thus, thermographic measurements of ocular surface temperature during periods of sustained eye opening may reflect the tear film stability. The results of Mori and associates are contradictory to ours.4 They measured the corneal surface temperature using an existing medical thermographer after both natural blinking and sustained eye opening and calculated the changes in temperature/second, the k values, which is the rate of decline in corneal temperature after eye opening, in normal and dry eyes. Because the k values were larger in the normal eyes than in the dry eyes during natural blinking, Mori and associates concluded that the surface temperature was less likely to decrease in dry eye patients than in normal subjects. They also found no difference between the 2 groups when measurements were carried out during sustained eye opening. The reason for these discrepancies from our findings is unclear, but it may be related to the sensitivity in the thermographic instruments used and the degree of the dry eye in their dry eye patients. In fact, severe dry eye patients such as those with the StevensJohnson syndrome were excluded in our study, and such severe dry eye may have different properties compared with idiopathic dry eye. Further investigations will be necessary to resolve these differences. The second matter to be considered was whether the ocular surface temperature is higher in dry eye. Several studies have reported that the temperature is higher in dry eyes than in normal eyes immediately after the eye is opened,3,8 whereas others have shown no difference between the 2 groups.4,5 At first glance, these reports seem to be contradictory; however, this discrepancy may have been caused by differences in experimental design. For example, Purslow and Wolffohn reported that when measurements were carried out after natural blinking, the corneal surface temperature immediately after eye opening was higher in cases where the tear film was unstable.8 Morgan and associates also reported that after subjects closed their eyes for 3 seconds, the combined average surface temperature of the cornea and conjunctiva was higher in the dry eye group than in the normal group.3 In contrast, 3 other studies4,5,9
reported no significant difference in the corneal surface temperature of the normal and dry eye groups immediately after eye opening. In these studies, Mori and associates instructed their subjects to close their eyes for 5 seconds, and the surface temperature was measured immediately after the eyes were opened.4 Niimi and associates and Fujishima and associates used a 10-second period of eye closing. The differences between these results may be caused by the fact that the ocular surface temperature was altered to different degrees by the warmth of the palpebral conjunctiva. Our results showed that measurements were more consistent when performed after closing the eyes for 5 or 10 seconds. In addition, no significant difference was found between the corneal surface temperature of the normal and dry eye groups when subjects closed their eyes for 5 seconds. It has been inferred that ocular surface temperature is higher in dry eye patients because they blink at a higher frequency.10 Therefore, our study focused on measurements conducted after subjects closed their eyes for 5 seconds. The third factor to consider was whether the surface temperature of the conjunctiva is different at different regions of the ocular surface. Our results showed that the surface temperature of the nasal and temporal conjunctiva immediately after eye opening also agreed with those of earlier reports.11–13 In both the normal and dry eye groups, the temperature of the nasal conjunctiva tended to be higher than that of the temporal conjunctiva. Although the reason for this remains questionable, the temperature of the nasal conjunctiva may be higher than that of the temporal conjunctiva because of the influence of greater blood flow and vascularization in the nasal conjunctiva. There are more large vessels, including the dorsal nasal artery and the angular artery, on the nasal side of the eye, and the medial rectus muscle has 2 anterior ciliary arteries, whereas the lateral rectus muscle has only 1 artery. During sustained eye opening, the temperature of the conjunctival surface was found to decrease to a greater degree in the dry eye group than in the normal group, but conjunctival surface temperature did not decrease as much as corneal surface temperature. One possible explanation for this is that the conjunctiva is vascularized and also is insulated by the ciliary body and the choroid, which have high blood flow rates. In summary, we have shown that during sustained eye opening, a significant decrease in corneal surface temperature occurred in dry eyes. Although a significant correlation was found between the temperature change and the TBUT scores, the decrease in temperature was significantly greater in dry eyes than in normal eyes. The noninvasive measurement with the Ocular Surface Thermographer could be a simple and quick tool for screening of dry eye.
THE AUTHORS INDICATE NO FINANCIAL SUPPORT OR FINANCIAL CONFLICTS OF INTEREST. INVOLVED IN DESIGN AND conduct of study (T.K., M.Y.); Data collection (T.K., M.Y., S.K., S.M., A.S.); Analysis and interpretation of the data (T.K., M.Y.); Literature search (T.K., M.Y., S.K.); and Writing (T.K., M.Y.), critical revision (A.S., Y.O.), and approval (M.Y.) of the manuscript. The study was approved by
790
AMERICAN JOURNAL
OF
OPHTHALMOLOGY
MAY
2011
Institutional Review Board of Ehime University (no. 0701006) and University Hospital Medical Information Network Clinical Trials Registry (no. UMIN000004256). Informed consent for examination was obtained from all subjects, and the procedures used conformed to the tenets of the Declaration of Helsinki. The authors thank Miki Matsumoto for data collection, Hisashi Kataoka for technical support with the Ocular Surface Thermographer, and Duco Hamasaki for his critical discussion and final manuscript revision.
REFERENCES 1. The Dry Eye Society of Japan. Definition and diagnosis of dry eye 2006 [in Japanese]. Atarashii Ganka 2007;24(2):181– 184. 2. Mapstone R. Measurement of corneal temperature. Exp Eye Res 1968;7(2):237–243. 3. Morgan PB, Tullo AB, Efron N. Infrared thermography of the tear film in dry eye. Eye (Lond) 1995;9(5):615– 618. 4. Mori A, Oguchi Y, Okusawa Y, Ono M, Fujishima H, Tsubota K. Use of high-speed, high-resolution thermography to evaluate the tear film layer. Am J Ophthalmol 1997; 124(6):729 –735. 5. Niimi K, Esaki J. Distribution and changes of ocular surface temperature [in Japanese]. Rinsho Ganka 2001;55(4):521– 525. 6. Craig JP, Singh I, Tomlinson A, Morgan PB, Efron N. The role of tear physiology in ocular surface temperature. Eye (Lond) 2000;14(4):635– 641.
VOL. 151, NO. 5
7. Horven I. Corneal temperature in normal subjects and arterial occlusive disease. Acta Ophthalmol (Copenh) 1975; 53(6):863– 874. 8. Purslow C, Wolffohn JS. The relation between physical properties of the anterior eye and ocular surface temperature. Optom Vis Sci 2007;84(3):197–201. 9. Fujishima H, Toda I, Yamada M, Sato N, Tsubota K. Corneal temperature in patients with dry eye evaluated by infrared radiation thermometry. Br J Ophthalmol 1996;80(1):29 –32. 10. Nakamori K, Odawara M, Nakajima T, Mizutani T, Tsubota K. Blinking is controlled primarily by ocular surface conditions. Am J Ophthalmol 1997;124(1):24 –30. 11. Mapstone R. Determinants of corneal temperature. Br J Ophthalmol 1968;52(10):729 –741. 12. Alio J, Padron M. Normal variations in the thermographic pattern of the orbito-ocular region. Diag Imaging 1982; 51(2):93–98. 13. Fielder AR, Winder AF, Sheraidah GA, Cooke ED. Problems with corneal arcus. Trans Ophthalmol Soc UK 1981; 101(1):22–26.
OCULAR SURFACE THERMOGRAPHER
FOR
DRY EYE SCREENING
791
Biosketch Tomoyuki Kamao, MD, is a medical doctor of the Department of Ophthalmology at the Minamimatsuyama Hospital, Japan. He completed his ophthalmology residency at Kobe University Graduate School of Medicine and Hyogo Prefectural Kobe Children’s Hospital. He received his PhD from Ehime University Graduate School of Medicine in 2009. He currently specializes in dry eye.
VOL. 151, NO. 5
OCULAR SURFACE THERMOGRAPHER
FOR
DRY EYE SCREENING
791.e1
To evaluate the newly developed Ocular Surface Thermographer (TOMEY Corporation) for dry eye screening. ● DESIGN: Prospective, controlled study. ● METHODS: We studied 30 eyes of 30 patients diagnosed with dry eye (mean age ⴞ standard deviation, 52.9 ⴞ 17.1 years) and 30 eyes of 30 normal subjects (42.7 ⴞ 17.0 years). The ocular surface temperature was measured immediately after eye opening and every second during 10 seconds of eye opening. The reliability of the measurements was determined by calculating intraclass correlation coefficients. Then, the correlations between the change in the ocular surface temperature and tear film break-up time, Schirmer I test values, and fluorescein staining scores were determined. ● RESULTS: The measurements of the ocular surface temperature had a high degree of reliability. Immediately after eye opening, the temperature in the dry eye did not differ significantly from that in normal eyes in any of the 3 regions tested. The decrease in the ocular surface temperature in dry eyes was significantly greater than that in normal eyes (P < .001) at 10 seconds after eye opening. The decrease in the temperature of the cornea was correlated significantly with the tear film break-up time (r ⴝ ⴚ0.572; P < .001). When the changes in ocular surface temperature of the cornea were used as an index for dry eye, the sensitivity was 0.83 and the specificity was 0.80 after 10 seconds. ● CONCLUSIONS: Measurements of the ocular surface temperature obtained with our newly developed Ocular Surface Thermographer after 10 seconds of eye opening may provide a simple, noninvasive screening test for dry eyes. (Am J Ophthalmol 2011;151:782–791. © 2011 by Elsevier Inc. All rights reserved.)
Accepted for publication Oct 20, 2010. From the Department of Ophthalmology, Medicine of Sensory Function, Ehime University Graduate School of Medicine, Toon, Japan (T.K., M.Y., S.K., S.M., Y.O.); the Department of Ophthalmology, Ehime Prefectural Central Hospital, Matsuyama, Japan (M.Y.); and the Department of Ophthalmology and Regenerative Medicine, Ehime University Graduate School of Medicine, Toon, Japan (A.S.). Inquiries to Masahiko Yamaguchi, Department of Ophthalmology, Medicine of Sensory Function, Ehime University Graduate School of Medicine, Toon, Japan; e-mail: [email protected]
782
©
2011 BY
D
RY EYE IS A MULTIFACTORIAL DISEASE OF THE
tears and ocular surface that results in symptoms of discomfort, visual disturbances, and tear film instability and that has the potential to damage the ocular surface.1 The diagnosis of dry eye is based on the results of a comprehensive evaluation of the key findings: decrease in tear secretion, instability of the tear film, and corneal or conjunctival epithelial cell disorder identified by vital staining. However, the discomfort of patients during the Schirmer test and tear film break-up time (TBUT) test, and the toxicity of rose bengal staining are factors that need to be considered when these diagnostic tests are used. Therefore, a screening test for dry eyes that is objective, noninvasive, and rapid is needed. Thermography is a noninvasive method for measuring the surface temperature of an object. Thermography was applied to the eye first in 1968 by Mapstone.2 In 1995, Morgan and associates used thermography to measure ocular surface temperature in patients with dry eyes.3 They reported that the surface temperature was significantly higher in dry eyes than in normal eyes and that the temperature at the center of the cornea of dry eyes became lower than that in normal eyes after sustained eye opening. Subsequently, several groups reported on the difference between the surface temperatures of normal eyes and dry eyes,4 – 6 and this led to the suggestion that thermography might be used for diagnosing dry eye. However, attempts to use the existing medical thermographic devices to screen for dry eye had many problems. For example, to measure the ocular surface temperature with the existing devices, the tests had to be carried out in a specialized room with tightly controlled temperature and humidity. In addition, considerable skill was necessary to make the measurements under special conditions such as those necessary for serial radiography. Finally, a large amount of time was required for data analysis after the test. We have developed a thermographic instrument specialized to measure surface temperature which is based on the design of the TOMEY autorefractor/keratometer (TOMEY Corp, Nagoya, Japan). In addition to measuring the surface temperature, our device also incorporates data analyzing features. Thus, the purpose of this study was to determine whether our newly developed thermographer can provide reliable values of surface temperature and whether it can be used to screen for dry eye. To accomplish these goals, we
ELSEVIER INC. ALL
RIGHTS RESERVED.
0002-9394/$36.00 doi:10.1016/j.ajo.2010.10.033
FIGURE 1. Photograph of the Ocular Surface Thermographer (TOMEY Corporation, Nagoya, Japan). Infrared and visible light cameras are mounted in the optical head of a modified RC 5000 autorefractor/keratometer manufactured by the TOMEY Corporation. The head can be moved with a joystick. When the examiner touches the center of the device’s touch panel screen, the instrument automatically recognizes the pupil and aligns the center of the screen with the center of the pupil. The head of the Ocular Surface Thermographer also moves automatically to maintain the measurement apparatus at a fixed distance from the eye. Results can be analyzed quickly and easily using the computer shown next to the device.
measured the surface temperature in 30 patients who were diagnosed with dry eye by conventional examinations and compared their findings with those obtained from 30 individuals with no signs of dry eye.
METHODS ● DEVELOPMENT AND SPECIFICATIONS OF OCULAR SURFACE THERMOGRAPHER: The newly developed Oc-
ular Surface Thermographer (TOMEY Corp) is shown in Figure 1. The instrument is equipped with an infrared camera module (HX0830M1; NEC, Tokyo, Japan) and a color charged coupled device board camera (PKD-101; Pacific CO, Tokyo, Japan). Light can be directed into either an infrared camera or a visible light camera. The direction of the light is changed by a rotating mirror, and both infrared and visible light images can be recorded coaxially (Figure 2). The two mirrors are positioned with their optical axes displaced by 90 degrees, and the position of one mirror is fixed while the other mirror is rotated 45 degrees every 0.25 seconds to direct light alternately into the infrared camera (Figure 2, Right) or into the visible light camera (Figure 2, Left). The cameras and the controllers are mounted within a modified version of the optical head of an autorefractor/keratometer (RC-5000; TOMEY Corp). The infrared radiation detector module is sensitive to infrared radiation between 8 and 12 m. The infrared camera has a Germanium lens with a 90-mm working distance and can record images at a resolution of VOL. 151, NO. 5
320 ⫻ 240 pixels with a pixel size of 23.5 ⫻ 23.5 m and spatial resolution of 70 m at 0.1 C. The maximum recording rate is 6 frames/second. Color images are obtained with a 1/4-inch charged coupled device video camera that can record images at a resolution of 640 ⫻ 480 pixels, pixel size of 5.6 ⫻ 5.6 m, and a detection range of 0.5 lux at 1/30 frames/second. To correct for background radiation entering the infrared camera, a black body plate is inserted automatically to cover the sensor immediately before beginning the measurements. To correct for changes in the temperature of the interior of the instrument during the measurements, a sensor was embedded in the camera and a program was installed in the instrument to correct for changes in the internal temperature. An autoalignment function is incorporated in the instrument to ensure that the instrument and object are maintained in a fixed location relative to each other. With this autoalignment function, the position of the cameras with respect to the object to be measured can be held constant, which allows measurements of the ocular surface temperature to be performed at the same position. There is virtually no human error involved in operating the Ocular Surface Thermographer. This feature is identical to that of the RC-5000 Autorefractor/Keratometer, which recognizes the pupil and aligns the pupil in the center of the screen when the examiner touches the center of the touch panel. The head of the Ocular Surface Thermographer also moves along the z-axis automatically to maintain the instrument at a fixed distance from the eye. The images recorded by the Ocular Surface Thermographer are immediately fed to a Dell-compatible microcomputer to be stored and manipulated automatically by appropriate software. Monochromatic thermal images (65 536 grayscale increments) are recorded and analyzed with a computer program and are displayed on a monitor in up to 24-bit color. It required only 10 seconds to display the results of a measurement that has been analyzed. ● SUBJECTS:
Thirty eyes of 30 patients with dry eye who were recruited from the outpatients of the Department of Ophthalmology, Ehime University Graduate School of Medicine (7 men and 23 women; mean age ⫾ standard deviation, 52.9 ⫾ 17.1 years; range, 20 to 74 years), were examined. Thirty eyes of 30 normal subjects who were healthy volunteers (12 men and 18 women; mean age, 42.7 ⫾ 17.0 years; range, 20 to 81 years) served as controls. Individuals who had a history of atopy; allergic diseases; Stevens-Johnson syndrome; or chemical, thermal, or radiation injury were excluded. Subjects also were excluded if they had any other ocular or systemic disorders or had undergone any ocular surgery or contact lens use that would create an ocular surface problem or dry eye.
● DIAGNOSTIC CRITERIA:
The diagnosis of dry eye was based on the diagnostic criteria of the Japanese Dry Eye Research Group.1 Subjects who fulfilled the following 3
OCULAR SURFACE THERMOGRAPHER
FOR
DRY EYE SCREENING
783
FIGURE 2. Changes in the rotating mirror system in the Ocular Surface Thermographer (TOMEY Corporation, Nagoya, Japan) allow the examiner to view (Left) the visible light images or (Right) the thermal light images. By changing the optical axis by rotating a mirror, the light can be directed alternately into the 2 cameras, and infrared and visible images can be recorded coaxially. The 2 mirrors are positioned with their optical axes displaced 90 degrees. The position of one mirror is fixed, whereas the other mirror is rotated 45 degrees every 0.25 seconds to direct light alternately into the infrared and visible light cameras. CCD ⴝ charged coupled device.
temporal conjunctiva with a possible total score between 0 and 9 points, with a score of more than 3 points considered to be abnormal.1 The normal subjects had clear corneas and conjunctiva on slit-lamp biomicroscopy and displayed no signs or symptoms of dry eye or other ocular diseases. ● MEASUREMENT OF OCULAR SURFACE TEMPERATURE:
Ocular surface temperature was measured using the new Ocular Surface Thermographer in a standard clinical room at a relatively constant temperature (26.5 ⫾ 1.5 C), humidity (42.5 ⫾ 2.5%), and brightness (300 lux). The subject’s head was placed in a standard ophthalmic chin and head rest, and the subject was instructed to look straight ahead. The measurements were performed under the conditions described by Mori and associates: the subject blinked normally, then closed both eyes for 5 seconds, and then kept the eyes open for more than 10 seconds.4 Ocular surface temperature was measured immediately after the eye was opened, and then every second during the 10 seconds of continuous eye opening. The temperature was measured in 3 regions: the central cornea, the nasal conjunctiva, and the temporal conjunctiva (Figure 3). The center of the cornea was defined as a circular area 4 mm in diameter at the center of the cornea. To determine the nasal and temporal conjunctival regions, a horizontal line was drawn through the center of the cornea extending to both canthi. Then, the intersection of the line and the nasal and temporal corneal limbus were designated as points A and B, respectively. The nasal conjunctiva was defined as a circular region 2 mm in diameter, with its center at the midpoint of the line connecting the inner canthus with point A. Likewise, the temporal conjunctiva was defined as a circular region 2 mm in diameter with its center at the midpoint of the line
FIGURE 3. Three regions where the ocular surface temperatures are measured. The central cornea is the circular region in the center of the cornea 4 mm in diameter. Points A and B are the points of intersection between a horizontal line passing through the center of the cornea and the nasal and temporal corneal limbus, respectively. The nasal conjunctiva is a circular region 2 mm in diameter with its center at the midpoint of the line connecting point A to the inner canthus. The temporal conjunctiva is a circular region 2 mm in diameter with its center at the midpoint of the line connecting point B to the lateral canthus. Temperature measurements were recorded and averaged over each region.
criteria were diagnosed as having dry eye: subjective symptoms related to dry eye elicited during the examination or medical interview, Schirmer I test results of less than 5 mm or TBUT in fewer than 5 seconds, and positive staining of the cornea and conjunctiva by fluorescein, rose bengal, or lissamine green, as described below. The fluorescein, rose bengal, and lissamine green staining were graded from 0 to 3 at the cornea, nasal conjunctiva, and 784
AMERICAN JOURNAL
OF
OPHTHALMOLOGY
MAY
2011
FIGURE 4. Monitor screen showing the results of the measurements for a normal subject. The infrared and visible light images are displayed in the upper left-hand portion of the screen. The bottom of the screen shows infrared images obtained every second over a 10-second period after the beginning of the measurements. On the upper right side of the screen, a graph is displayed showing the changes in temperature over a 10-second period at the surface of the white circular region and the value of the net change in the temperature in these areas. In a normal eye, there is virtually no change in the color of the images and the temperature remains constant over the 10-second period.
connecting the lateral canthus with point B. The surface temperature was recorded over each region, and an average value for each region was calculated. Additionally, we recorded the body temperature immediately after we measured the ocular surface temperature.
TABLE 1. Intraclass Correlation Coefficients for Ocular Surface Temperatures in 3 Regions Measured by a Single Examiner in 10 Subjects Immediately after Eye Opening
● RELIABILITY OF OCULAR SURFACE THERMOGRAPHER MEASUREMENTS UNDER VARIOUS CONDITIONS: One
ophthalmic technician (M.M.) was instructed on the operation protocol for the Ocular Surface Thermographer. After the examiner became proficient with the device, she was instructed to perform the measurements masked to the type of patient. We first determined the reliability of the measurements of the Ocular Surface Thermographer and the effect of various conditions on the reliability of the measurements. Ten healthy volunteers were asked to blink naturally for at least 10 seconds and then to close their eyes. Then, the ocular surface temperature was measured immediately after the eye was opened. Next, subjects were asked to close their eyes for 5 seconds, and ocular surface temperature was measured immediately after the eye was opened. In the third trial, the subjects were instructed to keep their eyes closed for 10 seconds before opening. In all 3 trials, the measurements were repeated 5 times for each VOL. 151, NO. 5
Normal blinkinga After closing the eyes for 5 secb After closing the eyes for 10 secc
Central Cornea
Nasal Conjunctiva
Temporal Conjunctiva
0.900
0.860
0.948
0.947
0.931
0.960
0.958
0.926
0.967
a Measurements after eye opening after a 10-second period of natural blinking. b Measurements after eye opening after a 5-second period of eye closure. c Measurements after eye opening after a 10-second period of eye closure.
volunteer, with at least a 5-minute interval between each measurement. Discrepancies between the 5 measurements obtained at the center of the cornea, nasal conjunctiva, and temporal conjunctiva were examined in each of the 10
OCULAR SURFACE THERMOGRAPHER
FOR
DRY EYE SCREENING
785
TABLE 2. Mean Surface Temperatures at the Center of the Cornea and at the Nasal and Temporal Conjunctiva in Normal Subjects and Dry Eye Patients at 0 and 10 Seconds after Eye Opening Mean Surface Temperature (C; Mean ⫾ SD) Central Cornea
Nasal Conjunctiva
Temporal Conjunctiva
Normal (n ⫽ 30)
0 sec
34.58 ⫾ 0.75
35.09 ⫾ 0.72
34.79 ⫾ 0.75
Dry eye (n ⫽ 30)
0 sec
34.45 ⫾ 0.86
34.96 ⫾ 0.73
34.75 ⫾ 0.82
Normal (n ⫽ 30)
10 sec
34.51 ⫾ 0.79
35.08 ⫾ 0.74
34.82 ⫾ 0.75
Dry eye (n ⫽ 30)
10 sec
34.13 ⫾ 0.87
34.78 ⫾ 0.71
34.58 ⫾ 0.75
SD ⫽ standard deviation. a P ⬍ .05, unpaired t test. b P ⬍ .05, Tukey-Kramer test. c P ⬍ .01, Tukey-Kramer test.
FIGURE 5. Monitor screen showing the results from a dry eye patient. In the 11 thermographic images at the bottom of the screen, the center of the cornea gradually changes from warm colors to cool colors, signifying a drop in temperature. The graph shows that surface temperature has decreased by 0.68 C over the 10-second period.
subjects, and the reliability of the measurements was determined statistically.
ered reliable when the intraclass correlation coefficient was more than 0.7. The temperature measured immediately and 10 seconds after eye opening and the change in temperature observed over a 10-second period of sustained eye opening are presented as the means ⫾ standard deviations. Unpaired t tests were used to examine differences between ocular surface temperatures in patients with dry eye and those found in
● STATISTICAL ANALYSES:
The reliability of ocular surface temperature measurements obtained by the Ocular Surface Thermographer was determined by calculating the intraclass correlation coefficients. Measurements were consid-
786
AMERICAN JOURNAL
OF
OPHTHALMOLOGY
MAY
2011
FIGURE 6. Graphs showing the change in the temperature during the 10-second period immediately after eye opening at (Top left) the center of the cornea, (Top right) the nasal conjunctiva, and (Bottom left) the temporal conjunctiva in (open circles) normal subjects and (solid squares) patients with dry eye. Error bars ⴝ standard deviation. Values in boxes represent the net change in temperature over the 10-second period in normal subjects and dry eye patients. A comparison of mean values was performed using unpaired t tests, *P < .001. The mean values for the changes in temperature were significantly lower in the patients with dry eye than in the normal subjects beginning 2 seconds after eye opening. The decrease in temperature was greater in the center of the cornea.
normal subjects. Multiple comparisons for temperature values found at the 3 regions of the ocular surface were made with the Tukey-Kramer test. A P value less than .05 was considered significant. The Spearman rank correlation test was performed to determine the correlations between the change in temperature at the center of the cornea and the results of other tear function examinations, including the Schirmer I test, TBUT, and the fluorescein staining score. The receiver operating characteristic curve technique was used to evaluate the sensitivity and specificity of the Ocular Surface Thermographer measurements of change in temperature each second after eye opening as a diagnostic index for dry eye.
TABLE 3. Correlations between Magnitude of Change in Temperature at 3 Regions (Center of Cornea, Nasal Conjunctiva, and Temporal Conjunctiva) and Results of Different Dry Eye Tests
TBUT Schirmer I CCES
Surface Thermographer measurements is shown in Figure 4. The infrared and visible light images obtained when the eye was first opened are displayed in the upper left area of the screen. This feature enables easy identification of areas of interest during the data analyses, because placing the cursor on the infrared image automatically will display the corresponding portion of the visible light image. The infrared VOL. 151, NO. 5
Nasal Conjunctiva
Temporal Conjunctiva
⫺0.57a 0.128 ⫺0.213
⫺0.177 0.079 0.09
⫺0.203 –0.073 0.193
CCES ⫽ corneal conjunctival epithelial staining; TBUT ⫽ tear film break-up time. a A significant negative correlation was found between the degree of decrease in temperature at the center of the cornea and tear film break-up time (r ⫽ – 0.572; P ⬍ .001).
RESULTS ● DISPLAY OF MEASUREMENTS ON OCULAR SURFACE THERMOGRAPHER MONITOR: A display of the Ocular
Central Cornea
images obtained every second over a 10-second period are displayed at the bottom of the screen. The images are color coded so that changes in temperature can be seen as changes in the color of the images. In the upper right area of the screen, a graph plotting the changes in the temperature over the 10-second period at the surface of the white circular region and the value of net change in the temperature in that area are shown.
OCULAR SURFACE THERMOGRAPHER
FOR
DRY EYE SCREENING
787
FIGURE 7. Receiver operating characteristic (ROC) curve showing the sensitivity and specificity of the Ocular Surface Thermographer measurements of the change in temperature at the center of the cornea (Left) 10 seconds and (Right) 5 seconds after the eye opening as an index for the diagnosis of dry eye. AUC ⴝ area under the ROC curve.
● REPRODUCIBILITY OF MEASUREMENTS: The intraclass correlation coefficients for the temperatures are shown in Table 1. When the measurements were made immediately after eye opening after a 10-second period of natural blinking, the intraclass correlation coefficients were 0.900, 0.860, and 0.948 for the center of the cornea, nasal conjunctiva, and temporal conjunctiva, respectively. The intraclass correlation coefficients for the measurements performed immediately after eye opening after a 5-second period of eye closure were 0.947, 0.931, and 0.960, and the coefficients for measurements carried out after a 10-second period of eye closure were 0.958, 0.926, and 0.967 for the 3 regions, respectively. All values were more than 0.7. Even when the subjects were allowed to blink naturally before the measurements, it was possible to obtain reliable measurements of the ocular surface temperature. However, the measurements obtained after subjects closed their eyes for 5 seconds had the highest degree of reliability.
ature was found at the nasal conjunctiva, followed by the temporal conjunctiva, and the lowest temperature was found at the center of the cornea. ● CHANGES IN OCULAR SURFACE TEMPERATURE DURING SUSTAINED EYE OPENING: No change was found in
the temperature of the center of the cornea in normal eyes during the 10-second period of sustained eye opening (Figure 4). In contrast, in the dry eye group, the center of the cornea gradually became bluer, signifying a drop in temperature (Figure 5). In addition, the graph of the changes in the temperature over the 10-second period clearly showed a decrease in temperature, and the display indicated that the average temperature had decreased by 0.68 C over the 10-second period. Next, we compared the ocular surface temperatures measured in the normal and dry eye groups at the 3 selected areas during the 10-second period of sustained eye opening (Table 2). No significant difference was found between the normal and dry eye groups with respect to the surface temperatures of the nasal or temporal conjunctiva. However, the temperature of the center of the cornea was significantly lower in the dry eye group than in the normal group (P ⬍ .05). The 2 groups also were compared with respect to the decrease in temperature each second over the 10-second period at each of the 3 regions (Figure 6). In the normal group, surface temperature did not change significantly over the 10-second period, whereas in the dry eye group, the temperature at all 3 regions decreased shortly after eye opening. A significant decrease was found between the normal group and the dry eye group beginning 2 seconds after eye opening (P ⬍ .001). The decrease in temperature was especially prominent at the center of the cornea in the dry eye group over the 10-second period.
● OCULAR SURFACE TEMPERATURE IMMEDIATELY AFTER EYE OPENING: The average ocular surface tempera-
tures measured immediately after eye opening at the center of the cornea, nasal conjunctiva, and temporal conjunctiva in the normal and dry eye groups are shown in Table 2. There was no significant difference in the body temperature and at any of the 3 regions between the 2 groups. In both the normal and dry eye groups, a significant difference was found between the initial temperature at the center of the cornea and that of the nasal conjunctiva (P ⬍ .05). No significant difference was found between the temperature of the temporal conjunctiva and either the center of the cornea or the nasal conjunctiva. In both groups, the highest temper788
AMERICAN JOURNAL
OF
OPHTHALMOLOGY
MAY
2011
In both groups, a significant difference was noted between the temperatures over the 10-second period at the center of the cornea and the nasal conjunctiva, but no significant difference was found between the temporal conjunctiva and either the center of the cornea or the nasal conjunctiva. ● CORRELATIONS BETWEEN MAGNITUDE OF CHANGE IN TEMPERATURE AT CENTER OF CORNEA AND RESULTS OF DIFFERENT DRY EYE TESTS: The correlations
between the decrease in temperature at each of the 3 regions over 10 seconds of sustained eye opening and the results of dry eye diagnostic tests, namely the Schirmer I test, TBUT, and corneal conjunctival epithelial staining, were determined. In the dry eye group, a significant negative correlation was found between the degree of decrease in temperature at the center of the cornea and TBUT (r ⫽ ⫺0.572; P ⬍ .001). The correlation coefficients relating the degree of decrease in temperature at the center of the cornea to the Schirmer I test scores and the corneal conjunctival epithelial staining score were r ⫽ 0.128 (P ⫽ .502) and r ⫽ ⫺0.213 (P ⫽ .258), respectively. The correlation coefficients between the decrease in temperature at the nasal conjunctiva and TBUT, Schirmer I test scores, and corneal conjunctival epithelial staining scores were r ⫽ ⫺0.177 (P ⫽ .350), r ⫽ 0.079 (P ⫽ .679), and r ⫽ 0.09 (P ⫽ .635), respectively. Correlation coefficients between the decrease in temperature at the temporal conjunctiva and the same 3 parameters were r ⫽ ⫺0.203 (P ⫽ .280), r ⫽ ⫺0.073 (P ⫽ .700), and r ⫽ 0.193 (P ⫽ .306), respectively. None of these correlations was significant (Table 3).
receiver operating characteristic curve was 0.80, and when the cutoff value for the Ocular Surface Thermographer test was set at 0.11 C, the sensitivity and specificity of the Ocular Surface Thermographer measurements were 0.80 and 0.73, respectively. These values indicate that measurements obtained over 5 seconds of sustained opening provide acceptable sensitivity and specificity for detecting dry eye (Figure 7, Right). ● DIFFERENCES IN OCULAR SURFACE THERMOGRAPHER VALUES FOR AGE AND GENDER: We examined
whether these results were affected by the differences in the age or gender distribution between the dry eye group and normal group. Differences in age were compared with the use of unpaired t tests, and frequencies of gender were compared with the use of the Fisher exact test between the normal and dry eye groups. There was a statistically significant difference in the age, but not in gender, between the two groups. Next, age was adjusted because Horven showed a negative correlation between the ocular surface temperature and age, and the two groups were also compared with respect to the decrease in temperature after 5 and 10 seconds of sustained eye opening at each of the 3 regions with the use of an analysis of covariance.7 Ultimately, a significant decrease also was found between the normal group and the dry eye group after 5 and 10 seconds of sustained eye opening. Thus, age and gender did not affect the results in this study.
DISCUSSION WE HAVE PRESENTED OCULAR SURFACE TEMPERATURE
● SENSITIVITY AND SPECIFICITY OF OCULAR SURFACE THERMOGRAPHER VALUES FOR SCREENING OF DRY EYE: To determine whether the Ocular Surface Thermog-
rapher values at the center of the cornea after 10 seconds of sustained eye opening could be used for the screening of dry eye, cutoff values were varied and the sensitivity and specificity were determined. The cutoff value for screening of dry eye was designated as the value at which sensitivity (1⫺specificity) found using the receiver operating characteristic curve reached a maximum. The area under the receiver operating characteristic curve calculated by the receiver operating characteristic technique was 0.86, indicating acceptable sensitivity and specificity of values for change in temperature after 10 seconds of sustained eye opening as an index for dry eye screening (Figure 7, Left). When the cutoff value for the Ocular Surface Thermographer test was set at 0.13 C, the sensitivity and specificity of the Ocular Surface Thermographer values were 0.83 and 0.80, respectively. We also tested whether the decrease in temperature at the center of the cornea could be used to diagnose dry eye when the period of sustained eye opening was reduced to 5 seconds. Under these conditions, the area under the VOL. 151, NO. 5
findings obtained with a newly developed thermographer, the Ocular Surface Thermographer. Several features of Ocular Surface Thermographer made it possible to obtain these reliable results with consistency. First, the Ocular Surface Thermographer is able to perform measurements in the same manner as a standard autorefractor/keratometer with an autoalignment function, enabling data to be collected quickly, objectively, and noninvasively. In addition, because the Ocular Surface Thermographer displays visible light and thermal images simultaneously, regions of the thermal image can be identified easily and accurately. Moreover, the Ocular Surface Thermographer collects data every second and allows large amounts of data to be stored, analyzed, and displayed by connecting the device to a computer. These features allowed us to perform a detailed longitudinal investigation of changes in the ocular surface temperature in dry eyes. The highly reliable results obtained with the Ocular Surface Thermographer may clarify discrepancies in ocular surface temperature measurements from previous studies that used thermographic devices specialized for the skin. The first matter investigated was whether surface temperature changed in eyes with dry eye. Morgan and associates and Craig and
OCULAR SURFACE THERMOGRAPHER
FOR
DRY EYE SCREENING
789
associates reported that the temperature of the cornea decreases with sustained eye opening.3,6 They concluded that the instability of the tear film in dry eyes worsens the tear fluid evaporation, and the resulting heat of vaporization results in a decrease in ocular surface temperature. Our Ocular Surface Thermographer measurements clearly showed that the temperature at the center of the cornea decreased with sustained eye opening in patients with dry eyes. Furthermore, a significant negative correlation was found between the temperature change at the center of the cornea and the TBUT scores. This indicated that eyes with a shorter TBUT are more likely to have a decrease in the ocular surface temperature. Thus, thermographic measurements of ocular surface temperature during periods of sustained eye opening may reflect the tear film stability. The results of Mori and associates are contradictory to ours.4 They measured the corneal surface temperature using an existing medical thermographer after both natural blinking and sustained eye opening and calculated the changes in temperature/second, the k values, which is the rate of decline in corneal temperature after eye opening, in normal and dry eyes. Because the k values were larger in the normal eyes than in the dry eyes during natural blinking, Mori and associates concluded that the surface temperature was less likely to decrease in dry eye patients than in normal subjects. They also found no difference between the 2 groups when measurements were carried out during sustained eye opening. The reason for these discrepancies from our findings is unclear, but it may be related to the sensitivity in the thermographic instruments used and the degree of the dry eye in their dry eye patients. In fact, severe dry eye patients such as those with the StevensJohnson syndrome were excluded in our study, and such severe dry eye may have different properties compared with idiopathic dry eye. Further investigations will be necessary to resolve these differences. The second matter to be considered was whether the ocular surface temperature is higher in dry eye. Several studies have reported that the temperature is higher in dry eyes than in normal eyes immediately after the eye is opened,3,8 whereas others have shown no difference between the 2 groups.4,5 At first glance, these reports seem to be contradictory; however, this discrepancy may have been caused by differences in experimental design. For example, Purslow and Wolffohn reported that when measurements were carried out after natural blinking, the corneal surface temperature immediately after eye opening was higher in cases where the tear film was unstable.8 Morgan and associates also reported that after subjects closed their eyes for 3 seconds, the combined average surface temperature of the cornea and conjunctiva was higher in the dry eye group than in the normal group.3 In contrast, 3 other studies4,5,9
reported no significant difference in the corneal surface temperature of the normal and dry eye groups immediately after eye opening. In these studies, Mori and associates instructed their subjects to close their eyes for 5 seconds, and the surface temperature was measured immediately after the eyes were opened.4 Niimi and associates and Fujishima and associates used a 10-second period of eye closing. The differences between these results may be caused by the fact that the ocular surface temperature was altered to different degrees by the warmth of the palpebral conjunctiva. Our results showed that measurements were more consistent when performed after closing the eyes for 5 or 10 seconds. In addition, no significant difference was found between the corneal surface temperature of the normal and dry eye groups when subjects closed their eyes for 5 seconds. It has been inferred that ocular surface temperature is higher in dry eye patients because they blink at a higher frequency.10 Therefore, our study focused on measurements conducted after subjects closed their eyes for 5 seconds. The third factor to consider was whether the surface temperature of the conjunctiva is different at different regions of the ocular surface. Our results showed that the surface temperature of the nasal and temporal conjunctiva immediately after eye opening also agreed with those of earlier reports.11–13 In both the normal and dry eye groups, the temperature of the nasal conjunctiva tended to be higher than that of the temporal conjunctiva. Although the reason for this remains questionable, the temperature of the nasal conjunctiva may be higher than that of the temporal conjunctiva because of the influence of greater blood flow and vascularization in the nasal conjunctiva. There are more large vessels, including the dorsal nasal artery and the angular artery, on the nasal side of the eye, and the medial rectus muscle has 2 anterior ciliary arteries, whereas the lateral rectus muscle has only 1 artery. During sustained eye opening, the temperature of the conjunctival surface was found to decrease to a greater degree in the dry eye group than in the normal group, but conjunctival surface temperature did not decrease as much as corneal surface temperature. One possible explanation for this is that the conjunctiva is vascularized and also is insulated by the ciliary body and the choroid, which have high blood flow rates. In summary, we have shown that during sustained eye opening, a significant decrease in corneal surface temperature occurred in dry eyes. Although a significant correlation was found between the temperature change and the TBUT scores, the decrease in temperature was significantly greater in dry eyes than in normal eyes. The noninvasive measurement with the Ocular Surface Thermographer could be a simple and quick tool for screening of dry eye.
THE AUTHORS INDICATE NO FINANCIAL SUPPORT OR FINANCIAL CONFLICTS OF INTEREST. INVOLVED IN DESIGN AND conduct of study (T.K., M.Y.); Data collection (T.K., M.Y., S.K., S.M., A.S.); Analysis and interpretation of the data (T.K., M.Y.); Literature search (T.K., M.Y., S.K.); and Writing (T.K., M.Y.), critical revision (A.S., Y.O.), and approval (M.Y.) of the manuscript. The study was approved by
790
AMERICAN JOURNAL
OF
OPHTHALMOLOGY
MAY
2011
Institutional Review Board of Ehime University (no. 0701006) and University Hospital Medical Information Network Clinical Trials Registry (no. UMIN000004256). Informed consent for examination was obtained from all subjects, and the procedures used conformed to the tenets of the Declaration of Helsinki. The authors thank Miki Matsumoto for data collection, Hisashi Kataoka for technical support with the Ocular Surface Thermographer, and Duco Hamasaki for his critical discussion and final manuscript revision.
REFERENCES 1. The Dry Eye Society of Japan. Definition and diagnosis of dry eye 2006 [in Japanese]. Atarashii Ganka 2007;24(2):181– 184. 2. Mapstone R. Measurement of corneal temperature. Exp Eye Res 1968;7(2):237–243. 3. Morgan PB, Tullo AB, Efron N. Infrared thermography of the tear film in dry eye. Eye (Lond) 1995;9(5):615– 618. 4. Mori A, Oguchi Y, Okusawa Y, Ono M, Fujishima H, Tsubota K. Use of high-speed, high-resolution thermography to evaluate the tear film layer. Am J Ophthalmol 1997; 124(6):729 –735. 5. Niimi K, Esaki J. Distribution and changes of ocular surface temperature [in Japanese]. Rinsho Ganka 2001;55(4):521– 525. 6. Craig JP, Singh I, Tomlinson A, Morgan PB, Efron N. The role of tear physiology in ocular surface temperature. Eye (Lond) 2000;14(4):635– 641.
VOL. 151, NO. 5
7. Horven I. Corneal temperature in normal subjects and arterial occlusive disease. Acta Ophthalmol (Copenh) 1975; 53(6):863– 874. 8. Purslow C, Wolffohn JS. The relation between physical properties of the anterior eye and ocular surface temperature. Optom Vis Sci 2007;84(3):197–201. 9. Fujishima H, Toda I, Yamada M, Sato N, Tsubota K. Corneal temperature in patients with dry eye evaluated by infrared radiation thermometry. Br J Ophthalmol 1996;80(1):29 –32. 10. Nakamori K, Odawara M, Nakajima T, Mizutani T, Tsubota K. Blinking is controlled primarily by ocular surface conditions. Am J Ophthalmol 1997;124(1):24 –30. 11. Mapstone R. Determinants of corneal temperature. Br J Ophthalmol 1968;52(10):729 –741. 12. Alio J, Padron M. Normal variations in the thermographic pattern of the orbito-ocular region. Diag Imaging 1982; 51(2):93–98. 13. Fielder AR, Winder AF, Sheraidah GA, Cooke ED. Problems with corneal arcus. Trans Ophthalmol Soc UK 1981; 101(1):22–26.
OCULAR SURFACE THERMOGRAPHER
FOR
DRY EYE SCREENING
791
Biosketch Tomoyuki Kamao, MD, is a medical doctor of the Department of Ophthalmology at the Minamimatsuyama Hospital, Japan. He completed his ophthalmology residency at Kobe University Graduate School of Medicine and Hyogo Prefectural Kobe Children’s Hospital. He received his PhD from Ehime University Graduate School of Medicine in 2009. He currently specializes in dry eye.
VOL. 151, NO. 5
OCULAR SURFACE THERMOGRAPHER
FOR
DRY EYE SCREENING
791.e1