Abstract
PURPOSE:
The purpose of the study was to evaluate the corneal sensitivity and its quadrature variability in patients with diabetic neuropathy (DN) diagnosed with electromyography and to compare these results with age- and sex-matched healthy individuals.
METHODS:
The left eyes of 32 patients who applied for refraction or fundus examination and had a diagnosis of DN by electromyography in their medical history were included in this study. Corneal sensitivity was evaluated using the Cochet–Bonnet esthesiometer (Luneau, Paris) in five zones: central, nasal, superior, temporal, and inferior. The measurements of the patients were compared with the measurements of 32 age- and sex-matched healthy volunteers. Furthermore, the measurements of five corneal zones were compared with each other, and the level of correlation was investigated in each group.
RESULTS:
The central corneal sensitivity values were measured as 4.12 ± 1.04 (mm) and 5.92 ± 0.14 (mm) (P < 0.001). While the sensitivity values at the superior, inferior, nasal, and temporal quadrants were detected as 5.85 ± 0.21, 5.85 ± 0.26, 5.94 ± 0.13, 5.93 ± 0.13, and 5.92 ± 0.14 (mm) in the control group, it was measured as 3.67 ± 0.66, 3.67 ± 0.62, 3.67 ± 0.62, and 3.89 ± 0.73 (mm) in the DN group, respectively. The corneal sensitivity values were all found to be significantly lower in the DN group (P < 0.001 for all parameters) at all quadrants as well as the central cornea. Furthermore, a moderate positive correlation between all five zones in the control group and a very strong positive correlation in the DN group were found in terms of the corneal quadrature sensitivity.
CONCLUSION:
The current study revealed a significant reduction in corneal sensitivity in patients with DN. In both the control group and DN group, all corneal zones showed positive correlations which show the consistency of the measurement in different quadratures. Evaluating corneal sensitivity with a Cochet–Bonnet esthesiometer might serve as a useful screening tool in detecting neuropathy development. By taking the necessary precautions, further damage can be prevented.
Keywords: Cochet–bonnet esthesiometer, corneal sensitivity, diabetic neuropathy
Introduction
Diabetes mellitus (DM) is a systemic, chronic disease characterized by chronic hyperglycemia, which can end up with serious complications, including neuropathy, retinopathy, or nephropathy.[1] Diabetic neuropathy (DN) is a serious complication of DM, which is characterized by sensory loss and pain that starts with affecting small unmyelinated C-fibers and progresses as involvement of large, myelinated nerve fibers.[2] It is estimated to affect 50% of the patients[3] and is also one of the leading causes of morbidity and mortality in DM patients.[3]
The cornea is the most densely innervated tissue of the human body, and corneal afferents consist of C-fibers, which are structurally equal to small fibers in the skin.[2] There are several studies investigating corneal sensitivity as a potential marker for detecting DN.[4,5]
The aim of this study was to evaluate if patients with DN diagnosed with electromyography have less corneal sensitivity when compared to age- and sex-matched healthy individuals. Furthermore, the current study involves the evaluation if different corneal quadratures show any consistency and correlation when measuring the corneal sensitivity with the Cochet–Bonnet esthesiometer in both the control group and DN group.
Methods
This study was approved by the Institutional Review Board of the Buca Seyfi Demirsoy Training and Research Hospital and adhered to the tenets of the Declaration of Helsinki. Each participant provided written informed consent. After Institutional Review Board approval, 32 patients who applied for refraction or fundus examination and had a diagnosis of DN by electromyography in their medical history were included in this study.
Patients with conditions that may cause changes in corneal sensitivity, such as trigeminal or facial nerve palsy, contact lens wear, herpetic keratitis, or pregnancy, and other concomitant systemic or ophthalmological diseases that may affect corneal esthesiometry results were excluded from this study. Patients using any kind of topical drug or patients with any ocular surgery or trauma history were excluded as well. Patients with any level of diabetic retinopathy or patients with diabetic retinopathy treatment history, including laser photocoagulation or intravitreal injections, and patients with cataract, glaucoma, and corneal opacity were also excluded.
Initially, corneal sensitivity was evaluated using the Cochet–Bonnet esthesiometer (Luneau, Paris). The device consists of a nylon filament that is 60 mm in length. When the sensitivity measurement was started, the filament was extended to 60 mm, and the tip of the filament was perpendicular to the corneal center. The response of the patient was observed and was considered positive if the patient blinked or responded subjectively. The filament was shortened by 5 mm each time, and the process was repeated until the response was positive. When the response was positive, the length of the filament in millimeters was recorded. Corneal sensitivity was evaluated in five zones: central, nasal, superior, temporal, and inferior. The process was repeated three times for each quadrature, and the average value was recorded. All measurements were made by the same ophthalmologist (P.K) who was masked to the DM status. Corneal sensation was expressed in terms of this filament length (in millimeters). Only left-eye values were evaluated for statistical purposes. All patients underwent a detailed ophthalmological examination, including slit-lamp-assisted anterior and posterior segment evaluation, intraocular pressure measurement with applanation tonometry, and best-corrected visual acuity determination with the Snellen chart.
The measurements of the patients were compared with the measurements of 32 age- and sex-matched healthy volunteers who visited the Buca Seyfi Demirsoy Training and Research Hospital’s Department of Ophthalmology for routine examinations. Furthermore, in both the DN group and control group, the results of the Cochet–Bonner esthesiometer were evaluated in terms of quadrature variability. All quadratures were investigated if they correlated with each other in both groups.
Statistical analysis
For statistical purposes, “IBM the Statistical Package for the Social Sciences version 25” (IBM, Chicago, USA) was used. The Kolmogorov–Smirnov tests were used to determine whether the data were normally distributed. Data were analyzed using the Student’s t-test for nonparametric values. Categorical variables were expressed as frequency and percentage, and numeric variables as mean and standard deviation. The Spearman correlation test was used to investigate the correlation between the quadrants of the cornea in both groups. P value under 0.05 was considered statistically significant.
Results
There were 18 (56%) males and 14 (44%) females in the DN group. There were 18 (56%) males and 14 (44%) females in the control group. The mean ages of the patients were 54.75 ± 9.65 years in the DN group and 54.65 ± 11.36 years in the control group (P = 0.971). In the DN group, the duration of the DM was 16.2 ± 8.7 years.
The central corneal sensitivity values were measured as 5.92 ± 0.14 (mm) and 4.12 ± 1.04 (mm) (P < 0.001) in the control group and DN group, respectively. While the sensitivity values at the superior, inferior, nasal, and temporal quadrants were detected as 5.85 ± 0.21, 5.85 ± 0.26, 5.94 ± 0.13, and 5.93 ± 0.13 5.92 ± 0.14 (mm), it was measured as 3.67 ± 0.66, 3.67 ± 0.62, 3.67 ± 0.62, and 3.89 ± 0.73 (mm), in the control group and DN group, respectively. The corneal sensitivity values were all found to be significantly lower in the DN group (P < 0.001 for all parameters) at all quadrants as well as the central cornea.
In the evaluation of corneal quadrature variability and the correlation between the quadratures when measuring corneal sensitivity with the Cochet–Bonnet esthesiometer, in the control group, a positive correlation was detected between the central zone and superior, inferior, nasal, and temporal quadrant measurements (r = 0.621, 0.508, 0.412, and 0.433, respectively, P < 0.001, 0.003, 0.019, and 0.013, respectively); the superior quadrant and inferior, nasal, and temporal quadrants (r = 0.784, 0.515, and 0.529, respectively, P < 0.001, 0.003, and 0.002, respectively); the inferior quadrant and nasal and temporal quadrants (r = 0.499 and 0.361, respectively, P = 0.004 and 0.042, respectively); and finally, the temporal and nasal quadrant (r = 0.695, P < 0.001).
Furthermore, a very strong positive correlation was detected in the DN group, between the central zone and superior, inferior, nasal, and temporal quadrant measurements (r = 0.747, 0.773, 0.800, and 0.817, respectively, P < 0.001, for all quadratures); the superior quadrant and inferior, nasal, and temporal quadrants (r = 0.955, 0.871, and 0.822, respectively, P < 0.001, for all quadrants); the inferior quadrant and nasal and temporal quadrants (r = 0.900 and 0.881, respectively, P < 0.001, for all quadratures); and finally, the temporal and nasal quadrant (r = 0.964, P < 0.001).
As conclusion, a moderate positive correlation between all five zones in the control group and a very strong positive correlation in the DN group were found in terms of the corneal quadrature sensitivity.
Discussion
DN is a complication of DM that affects 50% of all patients and often can be detected in later stages.[2,3] Diabetic corneal neuropathy, on the other hand, is caused by chronic hyperglycemia’s damage to the trigeminal nerve and results in a decrease in corneal innervation.[6] Corneal nerves play an important role in providing corneal protection by regulating tear production and eyelid closure, stimulating corneal collagen expression, and protecting epithelial cell function.[7] The importance of reduction in the amount of corneal nerve density and corneal sensitivity can be summarized as subsequently resulting in a deficiency in the corneal epithelial wound healing process and leading to persistent epithelial defects.[8] Patients with diabetic corneal neuropathy usually suffer from corneal hypoesthesia, ocular irritation, or pain. However, these symptoms may not correlate with the degree of clinical findings, and an important number of patients usually are asymptomatic due to corneal hypoesthesia, which shows the importance of detecting these patients early.[6]
It is well known that the main responsible factor in the development of DN is chronic hyperglycemia which stimulates several pathological mechanisms, including an increase in the production of reactive oxidative stress markers and accumulation of advanced glycosylation end products, sorbitol-aldose reductase pathway, and protein kinase C activation.[9,10] Increase in reactive oxidative stress can cause a mitochondrial injury, to which nerve fibers are known to be very prone.[9] There is also increasing evidence suggesting a role for inflammation in DN.[11] It is assumed that oxidative stress and related neuroinflammation may promote the pro-inflammatory cytokines and end up with nerve tissue damage in neuropathies.[8]
In previous studies, corneal sensitivity was investigated as a potential marker for DN.[12] In a study by Pritchard et al.,[13] it was reported that the corneal sensitivity threshold was detected higher in DN patients when compared to healthy individuals. Komolafe et al.[5] also reported a serious reduction in corneal sensitivity with the increase of peripheral neuropathy degree. A decrease in corneal sensitivity was also considered a component of the distal peripheral neuropathy in a study by Rosenberg et al.[14] In their study, they revealed that in patients with DN, a significant reduction in the number of long nerve fiber bundles was detected. An another study by Edwards et al.[15] showed that patients with DN had a significant reduction in the corneal subbasal nerve fiber length and nerve density when compared to healthy individuals. Researchers in different studies emphasized that corneal sensitivity loss and corneal neuropathy can be considered a manifestation of distal peripheral neuropathy in DM patients.[16] In addition, a corneal confocal microscopy device was used to show a significant loss in trigeminal sensory neurons’ ocular surface branches which might contribute to the corneal sensitivity reduction in DM patients. In that study, severe loss of subbasal nerve fiber bundles was detected,[17] which could be an explanation of the decline in corneal sensation in these patients. In a study by Bitirgen et al.,[18] an important finding was emphasized; they reported that 50% of DN patients had alterations in the corneal subbasal nerve plexus densities even before they developed clinical signs of peripheral neuropathy, which indicates that corneal nerve changes can be a valuable marker in following the progression of DN. All these studies support the theory that corneal sensitivity has already become a part of DN in DN patients.
Although there are several studies that evaluate the corneal sensitivity in DN, none of them provides any information about quadrative variability in the sensitivity. According to our knowledge, this is the first study about the evaluation of correlation and variability between different corneal quadrants for sensitivity in DN. It was demonstrated that while there is a moderate positive correlation between all five zones in the control group, a very strong positive correlation in the DN group in terms of the corneal zones’ sensitivity was present. This result shows the consistency of the measurements with the Cochet–Bonnet esthesiometer device and supports the theory of using the Cochet–Bonnet esthesiometer as a screening tool. It can be a rapid and safe tool for determining the corneal sensitivity loss regardless of the corneal zone, which can be an advantage for crowded clinics.
However, current study has some limitations. First, the sample size was small. Second, it was not possible to classify and compare patients with their DM severity or DN degree. Also the findings could not be compared with diabetic patients without DN. And lastly, the duration of neuropathy was not recorded because the population of DN patients in this current study were the ones that underwent electromyography and detected to have neuropathy.
Conclusion
it is well known that complications related to DM can only be prevented by early diagnosis.[19] Therefore, it would be beneficial to screen these patients with a cost-effective, minimally invasive, and widely available tool. Although the evaluation of corneal sensation in the examination performed in ophthalmology clinics does not constitute a routine step, it is an examination method applied in case of doubt. For this purpose, the Cochet-Bonnet esthesiometer is generally preferred. The results of this study support the idea of using the Cochet-Bonnet esthesiometer as a screening tool, a non-invasive and cost-effective method for screening the DN, although it is not part of the routine ophthalmologic examination. Also in literature, a study by Salami et al.[20] which evaluated the sensitivity and specificity of the Cochet-Bonnet esthesiometer in diabetic patients revealed that, the sensitivity and specificity of the device were found 100% and 58%, respectively. In another study the sensitivity and specificity were detected 72.2% and 57.4% respectively.[21] These results shows that the Cochet-Bonnet esthesiometer can be considered as a reliable tool in detecting corneal sensitivity in DM.
While using this device clinicians should keep in mind that various ocular surface pathologies including herpetic infections or contact lens usage can cause corneal hypoesthesia.[22]
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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