FormalPara Key Summary Points

Why carry out this study?

The cornea has the largest concentration of sensory and autonomic nerve fibers of any human tissue and prolonged irritation of the ocular surface may damage corneal nerves, resulting in reduced corneal sensitivity.

Frequent causes of loss of tear film homeostasis are dry eye disease and the use of topical eye medications, such as intraocular pressure-lowering eye drops, especially if used for a long time.

What was learned from the study?

The Brill esthesiometer is a portable and easy-to-use screening device to test for corneal sensitivity in all patients.

The Brill esthesiometer can detect damage to corneal sensitivity in dry eye disease and in patients taking glaucoma medication.

The Brill esthesiometer can detect corneal damage in patients taking glaucoma medications not otherwise represented through the ocular surface disease questionnaire, keratography, or corneal staining.

Introduction

The cornea is the human tissue with the highest density of sensory and autonomic nerve fibers [1, 2]. Different studies have demonstrated the existence of three different types of sensory receptors that detect mechanical, thermal, and chemical stimuli [3, 4]. Additionally, corneal nerves provide important trophic supply to the corneal epithelium and contribute to the maintenance of a healthy ocular surface [1, 2, 5]. Disruption of this balance, such as lacrimal instability and epithelial damage, can compromise the barrier function of the cornea and increase its vulnerability to adverse environmental conditions [6, 7].

Dry eye disease (DED) is one of the most frequent causes of inflammation, neurosensory abnormalities, and tear film instability [8]. Chronic use of topical treatments, as in the case of patients with glaucoma, is another significant cause of ocular surface disease [9, 10]. Certain medications, such as timolol and latanoprost, have demonstrated adverse effects, such as reduced tear production and keratitis [11, 12]. The preservatives contained in these eye drops also cause corneal irritation [13]. Prolonged erosion and irritation of the ocular surface may elevate the pain threshold, resulting in reduced corneal sensitivity [5, 14, 15] and long-term dysfunction of corneal innervation, a degenerative condition known as neurotrophic keratitis (NK) [16, 17].

NK is a challenging diagnosis even for ocular surface specialists. The misdiagnosis of NK as simple DED is common. Many patients using glaucoma drops experience insidious worsening of neurotrophic symptoms. By the time this damage is identified, the interventions available are often inadequate for restoring corneal nerve function [18]. There is clinical need for screening tools capable of identifying those patients at risk of corneal injury.

Although there is a relationship between stimulation of ocular surface nerve fibers and cornea sensitivity [19], there is often a lack of correlation between objective exam findings and subjective patient symptoms [20]. Various methodologies have been utilized to evaluate corneal nerves. Cochet–Bonnet is the most used esthesiometer in research and clinic [21, 22]. However, it has certain drawbacks, including the fact that it is invasive, the force delivered is non-linear, and the precise position and force of the stimuli are poorly replicated [23, 24]. Different prototypes of esthesiometers were developed to correct the shortcomings of Cochet–Bonnet. One of the best known is the Belmonte noncontact esthesiometer, which allows users to alter the flow, temperature, and CO2 concentration of the gas jet, and provide various stimuli for the ocular surface [25,26,27,28].

The purpose of the study was to analyze corneal sensitivity with a new noncontact and handheld esthesiometer (Brill Engines esthesiometer) [29, 30] in patients with DED signs and/or symptoms, as well as patients receiving intraocular pressure (IOP)-lowering therapy. This esthesiometer is a sensitive, non-invasive, portable, and easy-to-use device to test corneal sensitivity. We hypothesize that this test may allow the identification of patients whose corneal nerves are subclinically impaired, allowing the physician to implement early therapeutic decisions that minimize long-term irreversible corneal damage (e.g., surgical indications, use of preservative-free eye drops, review drug combinations).

Methods

Study Population

Patients in this cross-sectional study were evaluated at the Bascom Palmer Eye Institute. The DED group in the study were those with Ocular Surface Disease Index (OSDI) score ≥ 13 and/or signs of DED, corneal staining (CS) ≥ 2 and/or non-invasive breakup time (NIBUT) average < 10. The calculation of these metrics is discussed below. The glaucoma group included those who were diagnosed with glaucoma and were using topical ocular hypotensive medications at the time of recruitment. Finally, the control group comprised healthy, asymptomatic patients with no signs or symptoms of dry eye on clinical ophthalmic exam and did not use any type of eye drops except for sporadic use of artificial tears. Exclusion criteria for both groups included pregnancy and ages less than 21 or over 90 years. None of the patients had allergic disease, active infection, or had previous ocular surgery.

This study was approved by the Institutional Review Board of the University of Miami Miller School of Medicine (IRB# 20230376). The protocol conformed to the requirements of the US Health Insurance Portability and Accountability Act and the tenets of the Declaration of Helsinki. Patients in the study were evaluated at the Bascom Palmer Eye Institute and informed consent was obtained from all of them prior to clinical examination.

OSDI

Ocular symptoms were evaluated using the OSDI test [31]. It comprises 12 questions about the signs and symptoms of DED, how they affect vision, the restrictions they bring about, and environmental variables that may contribute to dry eye. Each question is given a score between 0 and 4. A score ≥ 13 was considered symptomatic.

Esthesiometry

The corneal sensitivity was measured by two trained certified ophthalmic technicians using a noncontact esthesiometer (Brill Engines, Spain) (Fig. 1). This device produces pulses of air at different intensities, with five levels and a pressure range of 2–10 mbar. Each pressure range is defined as the average estimated pressure over a 0.4-mm-diameter surface which is 4 mm distant from the outlet nozzle. To ensure that the assessment is performed at the correct distance, it has a camera and an electronic positioning system. The test was performed by placing the device on the slit lamp. Three measurements at each level were taken, in the lower quadrant of the cornea, starting at the lowest level (level 1, 2 mbar) and increasing it until the patient sensed the air puff. The lowest level that the patient could feel the air was recorded. In patients who denied any sensation, the value was recorded as 11 mbar, i.e., 1 mbar above the maximum value of the instrument.

Fig. 1
figure 1

Portable and non-invasive corneal esthesiometer (Brill Engines, Spain) for corneal sensitivity assessment through controlled air pulses as stimuli

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Keratography

The Oculus Keratograph 5M Topographer (Oculus Optikgeräte GmbH, Wetzlar, Germany) was used for the examination of the ocular surface. The following parameters were measured: tear meniscus height (TMH) measured in millimeters, average NIBUT measured in seconds, and bulbar redness (Jenvis grading scale). After application of topical fluorescein, CS was determined using the Oxford Scheme grading scale [32,33,34].

Statistical Analysis

Statistical analysis was performed using R 4.2.2 (R Core Team, Vienna, Austria). P values were generated using linear mixed models with random effects placed at the patient level to account for inter-eye correlations as previously completed [35]. Data were centered on mean age of the total population, and models adjusted for both age and gender. Outcome variables that were analyzed were esthesiometry value, NIBUT, TMH, redness, and CS. DED, glaucoma, and control groups were compared. Relationships between corneal sensitivity levels and the number of daily IOP-lowering drop applications and hypotensive medications in patients with glaucoma were also examined. An alpha level of 0.05 was used to evaluate statistical significance.

Results

Demographic Characteristics and Clinical Parameters

This study evaluated a total of 136 eyes from 75 subjects. A total of 57 eyes from 31 subjects were in the DED group, 46 eyes from 23 subjects were in the glaucoma group, and 33 eyes from 21 subjects were controls. Only the eyes that met the inclusion criteria were included in the study. Demographic data are provided in Table 1. There was a statistically significant difference in age between the three groups. Data on topical medication use are listed in Table 2. Ocular surface parameters measured are provided in Table 3. Overall, the DED group had the most severe signs of ocular surface damage, with 13 (41.9%) eyes having a CS ≥ 3.

Table 1 Demographic characteristics of the population
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Table 2 Ocular topical medication (per individual eye)
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Table 3 Coefficients from multivariable linear mixed effects model estimating various corneal parameters
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Comparison of Corneal Sensitivity Levels Between Controls, DED, and Glaucoma Groups

Given differences in demographics between groups could impact outcome variables, linear mixed models adjusting for age and sex were completed to compare corneal sensitivity levels among the study groups. With random effects placed at the patient level, data from both eyes of a patient could be utilized. Esthesiometry levels were significantly reduced in eyes receiving topical hypotensive medications, followed by the DED and control eyes (7.5 ± 3, 6 ± 3, and 3.2 ± 1 mbar, respectively) with significant differences observed between the glaucoma and DED eyes when compared to controls (P = 0.009 and P = 0.023, respectively, Fig. 2).

Fig. 2
figure 2

Ocular surface parameters in patients with dry eye disease (DED), glaucoma, and healthy controls. a Noncontact esthesiometry was significantly reduced in patients with DED and patients with glaucoma when compared with the controls. b Non-invasive tear breakup time (NIBUT) scores were significantly lower in the DED and glaucoma groups. c Tear meniscus height (TMH) was significantly lower in patients with glaucoma compared with the controls. d Ocular Surface Disease Index (OSDI) scores were significantly worse in the DED group. e The patients with DED showed a significant higher value of corneal staining (Oxford scale). f Conjunctival redness (Jenvis scale) scores were significantly higher in the DED group when compared with the healthy controls. Statistical significance was derived from linear mixed models adjusting for age and sex. Data are presented as boxplots. P values are displayed for significant comparisons

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Relationships Between Corneal Sensitivity Levels and Topical Hypotensive Medications

Relationships between the number of daily IOP-lowering drop applications and topical hypotensive medications with corneal sensitivity levels were examined. Corneal sensitivity levels in eyes that receive ≥ 3 administrations of IOP-lowering hypotensive eye drops daily were significantly lower compared to eyes receiving < 3 applications of hypotensive eye drops daily (P = 0.04) (Fig. 3). When evaluating the relationship between corneal sensitivity and the total number of IOP-lowering medications that an eye was receiving, there was a trend towards lower corneal sensitivity in those eyes on ≥ 3 IOP-lowering medications but no statistical significance (P = 0.059).

Fig. 3
figure 3

Ocular surface parameters in patients with glaucoma who apply ≥ 3 drops daily and patients with glaucoma who apply < 3 drops daily. a Noncontact esthesiometry was significantly reduced in patients who apply ≥ 3 drops daily when compared with patients who apply < 3 drops daily. b Noninvasive tear breakup time (NIBUT) scores were similar between patients applying ≥ 3 drops and < 3 drops. c Tear meniscus height (TMH) was similar between patients applying ≥ 3 drops and < 3 drops. d Ocular Surface Disease Index (OSDI) scores were similar between patients applying ≥ 3 drops and < 3 drops. e Patients applying ≥ 3 drops and < 3 drops showed similar values of corneal staining (Oxford scale). f Conjunctival redness (Jenvis scale) scores were similar between patients applying ≥ 3 drops and < 3 drops. Statistical significance was derived from linear mixed models adjusting for age and sex. Data shown as boxplots. P values are displayed for significant comparisons

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Comparison of Ocular Surface Parameters Between Controls, DED, and Glaucoma Groups

NIBUT was significantly reduced in DED and patients using IOP-lowering medications, with significant differences observed (P < 0.001 and P = 0.001, respectively; Table 3) versus the control patients. Redness and CS were significantly higher in the DED group (P = 0.04 and P = 0.001 respectively), but not in the glaucoma group (P = 0.35 and P = 0.09 respectively). TMH was significantly lower in glaucoma eyes compared to controls (P = 0.03). OSDI score was significantly higher in the DED group, but in not the glaucoma group, compared to controls (P < 0.001 and P = 0.13, respectively).

Discussion

Corneal sensitivity has been previously evaluated in several studies with other devices, like the Cochet–Bonnet esthesiometer [21, 22]. The first difference between the Brill device and Cochet–Bonnet is that the former uses an air puff instead of mechanical contact, so it may be stimulating different corneal nociceptors. For this reason, the results obtained with this esthesiometer cannot be compared with those obtained with Cochet–Bonnet or other mechanical esthesiometers. Other authors report the use of different noncontact esthesiometers [25,26,27]. However, these devices are difficult to use in daily practice. In contrast, Brill’s noncontact esthesiometer is portable, minimally invasive, and easy to use by physicians, optometrists, or ophthalmic technicians.

In this study, corneal sensitivity was reduced in both patients with DED and those using ocular hypotensive drops compared to healthy controls. This finding is consistent with prior studies in which esthesiometry was analyzed [5, 14, 15]. It is known that corneal damage caused by ocular surface diseases or topical medications may produce damage to the corneal nerve endings [2, 13, 19, 20]. Noncontact corneal esthesiometry may be an excellent diagnostic tool to determine when corneal sensitivity starts to decline. At this point, it may be appropriate to switch these patients to different medications or consider surgical intervention [36] to eliminate or reduce the number of glaucoma medications. This strategy may avoid causing an irreversible neurotrophic keratopathy [16, 17].

The ocular surface parameters measured with keratography were NIBUT, TMH, conjunctival redness, and CS. NIBUT was significantly lower in the DED and glaucoma group compared to controls, as shown in other previous studies [37, 38]. The TMH was significantly lower in the glaucoma group. The same result was obtained by other groups [37, 39]. Compared to healthy patients, conjunctival redness and CS were also higher in both patients with DED and patients with glaucoma but were statistically significant only in the DED group.

DED eyes had significantly higher OSDI test scores compared to controls. It is interesting how in these patients symptoms are greater than in healthy subjects despite having decreased corneal sensitivity. This has already been shown in some studies that have observed that there is no correlation between symptoms and signs in patients with ocular surface disease [39]. On the other hand, the OSDI score was lower in the glaucoma group than in the DED group. The reason could be greater damage of the corneal nerves in these patients, demonstrated by the fact that they are the group with the most reduced corneal sensitivity. This demonstrates the importance of screening these patients, since despite having reduced corneal sensitivity, they present fewer ocular symptoms than patients with DED.

This study also evaluated whether corneal sensitivity levels had a relationship with topical medications used in the glaucoma group. For the analysis we have utilized two different metrics, the number of drops applications daily and the number of different IOP-lowering medications. For example, a patient on timolol twice daily and latanoprost nightly would have 3 drop administrations daily but would only be on two medications. On one hand, the relationship between the number of daily drop instillations and corneal sensitivity showed a significant reduction in those who used ≥ 3 IOP-lowering drops per day. On the other hand, when examining the relationship between the number of medications used and corneal sensitivity, a tendency to lower sensitivity was observed in patients using ≥ 3 different medications, but it was not statistically significant. These differences in results may be because the use of a greater number of drops per day also involves a greater application of preservatives, which have been associated with corneal nerve damage in patients with glaucoma [13]. Nonetheless, a larger sample size with a diverse number of eyes on both preserved and non-preserved medications would be needed to provide further insight into any potential associations.

There are various limitations to this study. First, sensitivity testing is subjective because the patient determines whether they perceive the stimulus or not. The differences between esthesiometry levels are minimal and sometimes patients did not perceive the air puff, but when repeating the measurement with the same pressure they did feel it. For this reason, the measurement was repeated three times at each level. Second, patients in this study were not separated on the basis of the type or duration of the hypotensive eye drops they were using. In addition, given the novel nature of this study, sample size calculations could not be performed because of the lack of effect size information. While we still identified several significant associations, this study may have been underpowered to identify associations for which statistical significance was not observed in our analysis. Further studies will be required to expand our findings.

Conclusion

Despite its limitations, to our knowledge, this study is the first to evaluate corneal sensitivity in patients with DED and patients using glaucoma medications using Brill’s noncontact air esthesiometer. In clinical practice, this esthesiometer is a portable and easy-to-use screening device to evaluate corneal sensitivity in patients with DED and patients with glaucoma. Non-contact esthesiometry can aid in detection of changes to corneal sensitivity and enable early intervention for patients with glaucoma or DED, to prevent the onset of neurotrophic keratopathy.