Corneal permeability changes in dry eye disease: an observational study

DED affects a significant number of people, with prevalence ranging from 7 % in the United States to 33 % in Taiwan and Japan, but DED is difficult to diagnose and no clear gold standard to evaluate DED exists [9, 10]. Clinicians often rely on multitude of tests, including symptoms or signs and a battery of diagnostic tests, including TBUT, fluorescein, and lissamine. We strove to determine if fluorophotometry could fill that void through correlation with other established tests and better classify DED according to severity.

Past studies by Kinoshita et al. and Yokoi have found that the fluorophotometer could evaluate ocular surface epithelium barrier function using a similar methodology to our study [5, 11‐13]. In one of their studies, they showed that in accordance with severity, fluorescein uptake in dry eye patients showed significant increase, and that with treatment with hyaluronan eye drops, there was significant barrier function improvement after 2 weeks [12, 13]. In our study, we evaluated not only fluorophotometry’s ability to differentiate between dry eye and normal eyes, but also the correlations of its results with different diagnostic techniques of dry eye. Among the multitude of tests available, we aimed to investigate whether fluorophotometry could outperform any diagnostic tests, combine 2–3 diagnostic tests, or become another test that measures an aspect of dry eye that is not yet captured by any of the diagnostic tests for DED.

Consistent with our previous study, this study showed that fluorophotometry could differentiate between DED and normal eyes up to 30 min post fluorescein dye instillation [8]. However, except for minor correlations with lissamine and aggregate scores at 10 and 15 min, fluorophotometry in our current study did not show any significant correlations with other DED diagnostic tests, such as OSDI, TBUT, fluorescein, and lissamine. These differences could arise because fluorophotometry encompasses a larger view of DED, taking into account the overall increased permeability of the cornea in ocular surface disease patients rather than focusing on one aspect of DED. For instance, TBUT takes into account tear production and evaporation, but fluorophotometry includes all factors that damage the corneal epithelium, and utilizes tear break up as only one component of many factors that contribute to DED.

Another possible function for fluorophotometry is to measure aspects of DED not captured by other diagnostic tests, which are somewhat imperfect themselves and thus contribute to the difficulty of objectively diagnosing DED. Dry eye patients have ocular surface disease that increase corneal permeability to fluorescein, but the amount of change as we measured it did not correlate with other tests. Fluorophotometry may include a component not yet detected with current diagnostic tests and thus could be done to rule out DED when DED is suspected, but other diagnostic tests are normal. Due to its unique position relative to other tests, adding fluorophotometry as one of its basic tests when evaluating DED may aid in diagnosing DED or in research settings studying DED. Continued research in this area could clarify this mismatch.

Fluorophotometry also did not correlate with clinical symptoms as measured by OSDI. Although there is some evidence showing OSDI can measure the severity of dry eye, the non-correlation was unsurprising since DED signs and symptoms are poorly correlated, compounded by variability between seasons, time of day, and findings among eye examinations, suggesting that symptoms may not truly reflect the whole dry eye state in patients [14, 15]. Though the cornea may be damaged, patients may still be asymptomatic. One possible explanation is that with damage to the ocular surface, the central cornea sensitivity decreases, making the patient less symptomatic [14, 16]. Similarly, the cornea may be healthy even as patients report multitude of symptoms. With fluorophotometry’s capability to differentiate dry eyes from normal eyes, one possibility could be to use fluorophotometry as one of DED screening tools to detect subclinical DED in seemingly healthy patients. Earlier detection could lead to earlier treatment, or possible prevention of progression to severe DED when it may be more difficult to intervene. Higher values of fluorophotometry in DED patients correlate with increased permeability of the cornea, so fluorophotometry could be used to measure progression of corneal damage and assess whether current treatments for DED are sufficient, adjusting as needed depending on the results [17].

This study is not without limitations. Sample size was limited, and this factor most likely contributed to the relatively high variability in fluorescein concentrations with the fluorophotometer. More eyes may reduce this variability, but the biggest likely cause of this variation is the lumping of all DED eyes into one dry eye group. Mild DED was not differentiated from severe DED, as there was no clear way to do so without a gold standard or correlations with other exams. The next step would be to explore whether fluorophotometry correlates with DED severity, especially if it may be a tool that can grade DED severity on a sliding scale. Furthermore, we cannot eliminate some of the intrinsic problems associated with fluorescein, especially at higher concentrations, and the Fluorotron Master flurophotometer itself. For instance, because the machine cannot clearly distinguish the tear film from the cornea, we utilized a similar washing method from previous studies to eliminate any excess fluorescein remaining in the tear film and to standardize the technique [8, 12, 18, 19]. Although the process was controlled as much as possible, some patients may have more or less fluorescein left on the tear film, possibly due to mechanical issues such as excessive tearing or blinking. Finally, although we aimed to capture most factors that contribute to DED, not all possible diagnostic tests were done to reduce burden on the patients. In future studies, comparing fluorophotometry to more diagnostic tests such as tear osmolarity may be beneficial.