Purpose To analyse clinical signs and symptoms of ocular surface disease in patients with diabetes mellitus (DM), based on severity of diabetic peripheral neuropathy (DPN).
Methods This cross-sectional study included participants who were carefully phenotyped by a multidisciplinary team and categorised into groups based on severity of DPN. All study participants underwent ophthalmic evaluation and completed the Ocular Surface Disease Index (OSDI) and Visual Function Questionnaire (VFQ-25).
Results The 34 study participants were healthy controls (n=9), patients with DM and mild or no DPN (n=16) and patients with DM and severe DPN (n=9). Tear osmolarity was increased, and corneal nerve fibre length was decreased, with increasing severity of DPN. In addition, patients with DM were found to have decreased Schirmer's test values when compared with healthy controls. No statistically significant differences were found between groups in OSDI, tear breakup time or corneal sensitivity. No statistically significant correlations were noted between the OSDI or VFQ-25 scores and clinical signs of dry eyes.
Conclusion This study demonstrates some increased clinical signs of ocular surface disease but not an increase in subjective symptoms of dry eyes, with increasing severity of DPN. Furthermore, no significant correlation was found between OSDI scores and clinical signs of dry eye. A periodic evaluation of the ocular surface is important for patients with DM, in addition to retinopathy screening, as they may be asymptomatic but have severe dry eye disease, which can lead to further ocular surface complications such as corneal ulceration.
Trial registration number NCT01695629.
- Ocular surface
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According to the Centers for Disease Control (CDC), the prevalence of diabetes mellitus (DM) in the USA in 2010 was 25.8 million, or 8.3% of the population.1 It is well known that DM is a common cause, or risk factor, for ocular disease including retinopathy, cataract and glaucoma.2 There is also evidence of increased ocular surface disease in DM that includes dry eye disease (DED), recurrent corneal erosions, neurotrophic corneal ulceration and delayed epithelial healing.3–5
In addition to ocular manifestations of DM, there are also a plethora of well-known systemic abnormalities associated with DM, including vasculopathy and diabetic peripheral neuropathy (DPN). DPN is the most common complication of DM and is estimated to affect up to 50% of patients with DM.6 ,7 The risk of DPN has been found to increase with age and duration of diabetes.8
Previous studies have established a correlation between DED and diabetic retinopathy.9 However, a recent study did not find a significant correlation between DED and DPN, using the Michigan Neuropathy Screening Instrument (MNSI) to detect DPN.10 However, the MNSI, although a sensitive clinical instrument for detecting the presence of DPN, was not designed to evaluate DPN severity.
The goal of this study was to analyse clinical signs and symptoms of DED in patients with DM and different DPN severities, as defined using comprehensive, gold-standard evaluations11 performed by a multidisciplinary team.
This cross-sectional study included participants who were either healthy controls or had diabetes. This study was approved by the Institutional Review Board of the University of Michigan and is in compliance with the Declaration of Helsinki. All participants signed a written consent.
Main inclusion criteria were age ≥18 years and presence of diabetes as defined by the American Diabetes Association12 for the diabetic group. Exclusion criteria included the following: (1) any systemic neuropathy other than DPN; (2) history of any ocular surgery or corneal disease; (3) history of cancer; (4) history of stroke; (5) history of previous back surgery or spinal stenosis and (6) any neurodegenerative condition like multiple sclerosis.13
All participants were carefully phenotyped using nerve conduction and quantitative sensory testing (QST) by a multidisciplinary team to determine the presence and severity of DPN. Participants were classified as having mild DPN if they had the following: (1) small fibre dysfunction, as defined by abnormal QST and an abnormal neurological examination performed by a board-certified neurologist; (2) the presence of ≥1 abnormal attribute (of amplitude, latency, F-wave or nerve conduction velocity) in ≥2 separate nerves among the median, peroneal and sural nerves in nerve conduction studies (NCS).13
Participants were classified as having severe DPN if they had a combination of neuropathic symptoms and signs of distal sensorimotor polyneuropathy with ≥2 of the following: decreased/absent distal sensation (as diagnosed by a neurological examination from a board-certified neurologist and abnormal QST), unequivocally decreased or absent ankle reflexes, abnormalities in NCS as described above and the absence of a recordable sural nerve amplitude.13
Participants were healthy controls (group 1), patients with DM and mild or no DPN (group 2) and patients with DM and severe DPN (group 3). Gender, age, race, body mass index (BMI), haemoglobin A1c, type and duration of DM were recorded for all participants. All study participants completed the Ocular Surface Disease Index (OSDI; Allergan, Irvine, California, USA),14 a subjective 12-question survey for patients with DED that gives a score denoting severity of dry eye symptoms, and the National Eye Institute Visual Function Questionnaire (VFQ-25),15 which is designed to measure vision-targeted health status. The VFQ-25 measures the influence of visual disability and visual symptoms on generic health domains such as emotional well-being and social functioning, in addition to task-oriented domains related to daily visual functioning.
Participants also underwent clinical testing for tear osmolarity (Tearlab, San Diego, California, USA), tear breakup time (TBUT), corneal sensitivity (Cochet-Bonnet aesthesiometry), Schirmer's test (with anaesthesia) and ocular surface staining with fluorescein and lissamine green. Clinical evaluations were done on both eyes and the mean of the two eyes was used for analysis.
Corneal confocal microscopy (CCM) was performed to determine corneal nerve fibre length (CNFL). CCM was performed only on the right eye of study participants. All subjects underwent CCM imaging of the central corneal sub-basal nerve plexus using the Heidelberg Retina Tomograph-2 Rostock cornea module (Heidelberg Engineering, Heidelberg, Germany). After instilling one drop of topical proparacaine hydrochloride 0.5% into the right eye, the patient placed his or her head into the headrest of the confocal microscope. A small amount of Genteal eye gel (Novartis Pharmaceuticals, East Hanover, New Jersey, USA) was applied to the lens of the microscope, and a sterile plastic cap (Tomocap, Heidelberg Engineering, Heidelberg, Germany) was placed over the lens. The patient was instructed to look straight ahead as the plastic-covered lens contacted the patient's cornea. ‘Sequence’ mode was used to record consecutive 400×400 µm images of the sub-basal nerve layer at 8 frames/s.13
Analysis of the corneal nerve images began with selection of five representative, focused, non-overlapping images of the sub-basal nerve plexus from the central cornea of each participant. A masked grader used NeuronJ software (publicly available at http://www.imagescience.org/meijering/software/neuronj/) to calculate the sum length of all nerve fibres within each image. From this number, the CNFL was derived by dividing the sum length of the nerve fibres in each image by the area of the image (400×400 µm). The five CNFL measurements from each individual were averaged to determine the final CNFL per patient.13
Statistical analysis was performed using STATA Data Analysis and Statistical Software (Release11.StataCorpLP, College Station, Texas, USA). Analysis of variance was used to analyse differences between groups depending on severity of peripheral neuropathy and correlation testing was performed between areas of interest, using the Bonferroni correction for multiple comparisons. The χ2 test was used to analyse differences among the groups with regard to fluorescein and lissamine green staining, race, sex and type of DM. The t test was used to compare continuous variables including duration of diabetes between the two diabetic groups.
The 34 study participants were age-matched healthy controls (group 1, n=9), patients with DM and mild or no DPN (group 2, n=16) and patients with DM and severe DPN (group 3, n=9). Their characteristics (age, gender, race, BMI, haemoglobin A1c, type and duration of DM) are shown in table 1. As perhaps expected, patients with DM and more severe DPN were older and had a longer duration of DM.
Clinical evaluation of ocular surface parameters revealed statistically significant differences between groups with regard to tear osmolarity, Schirmer's test, CNFL (figure 1), and VFQ-25 score. Tear osmolarity was greater in patients with DM than controls, and increased with severity of DPN. Schirmer's test values were higher in controls than in patients with DM, but did not decrease with increasing severity of DPN. CNFLs were higher in controls than in patients with DM, and declined with increasing DPN severity (figure 2). The VFQ-25 score was greatest in controls, but did not decrease with increasing DPN severity.
No statistically significant differences were found between groups with the OSDI (figure 1), TBUT or corneal sensitivity. OSDI scores tended to be lower in controls than in the groups with DM, but decreased with severity of DPN. There was a correlation between decreased corneal sensitivity and increasing DPN severity. In addition, no significant differences were noted between the three groups when comparing fluorescein (positive staining noted in 22% in group 1, 31% in group 2 and 33% in group 3 patients, p=0.85) with lissamine green staining (positive staining noted in 11% in group 1, 40% in group 2 and 33% in group 3 patients, p=0.32). No statistically significant correlations were noted between the OSDI or VFQ-25 score and the following clinical signs of dry eyes: tear osmolarity, TBUT and Schirmer's test. Likewise, no significant correlations were present between CNFL and the clinical signs of DED or corneal sensation.
Patients with diabetes are known to have an increased prevalence of ocular surface disease and DED.16 Previous studies have shown that DM has been associated with decreased TBUT, Schirmer's test values, sub-basal nerve densities and corneal sensitivity and increased tear osmolarity, fluorescein and lissamine green staining.3–5 ,16–19 Several other studies have also analysed structural and metabolic corneal abnormalities that contribute to ocular surface disease in patients with DM.10 ,20
The goal of this study was to analyse clinical signs and symptoms of ocular surface disease in patients with DM, based on severity of DPN. Our results confirmed the majority of the associations noted above with additional analysis using DPN severity.
Patients in this study with DM had decreased Schirmer's test results, but test values were comparably decreased in patients with DM regardless of level of DPN. There is a known decrease in exocrine function in DM, and it is possible that DM affects tear function early in the disease but is not necessarily progressive.21 Previous authors10 have hypothesised that decreased Schirmer's test values in patients with DM are a result of either an autonomic neuropathy of the lacrimal gland or damage to the microvasculature feeding the lacrimal gland, both of which could occur early in the course of DM.
Patients with DM also had increased tear osmolarity when compared with healthy controls, and osmolarity increased with severity of DPN. Tear hyperosmolarity in DM occurs because of reduced aqueous secretion, increased tear evaporation and increased levels of glucose and protein in the tear film.22 ,23 Tear osmolarity is an objective measurement useful in the evaluation of dry eyes, and the diagnostic accuracy of tear osmolarity in normal versus dry eye diagnosis is greater than corneal sensitivity measurements, Schirmer's test, TBUT and fluorescein staining.10 ,24
In addition, CNFL was found to decrease with increasing severity of DPN. A recent study also found that CNFLs differed significantly between healthy controls and patients with DM, and progressively worsened with increasing neuropathy severity.25
Our study did not show a statistically significant difference in TBUT or ocular surface staining between DPN groups. TBUT is a rough estimate for the determination of tear film stability and has been shown to have large interindividual and intraindividual deviations even when performed in a standardised procedure.26 Not surprisingly, there are conflicting data in the literature regarding TBUT in patients with DM compared with controls, with some studies finding no difference26 and others finding decreased TBUT.27 Our results demonstrated a non-statistically significant increase in fluorescein and lissamine green staining in the DM groups compared with controls. This lack of statistical significance is likely due to our small sample size, as larger studies have shown a significant increase in ocular surface staining in patients with DM compared with controls.28
Even though there were some increased clinical findings of DED with increasing severity of DPN, dry eye symptoms, as measured by OSDI, were not significantly different based on severity of DPN. OSDI scores were higher in patients with DM versus healthy controls but were actually found to decrease with increasing DPN severity. This suggests that patients with increasing severity of DPN may have some pathology, like hypoesthesia of the cornea, which prevents them from being severely symptomatic even in the presence of advanced clinical findings. Our study demonstrated a non-statistically significant correlation between decreasing corneal sensitivity, as measured by Cochet-Bonnet, and increasing severity of DPN (r=−0.022, p=0.23). This may help explain the lack of subjective dry eye symptoms in patients with severe DPN. Patients with DM and no or mild DPN likely had higher OSDI scores than controls because of a decrease in tear production, as evidenced by decreased Schirmer's test values, in the setting of still intact corneal sensation. Previous studies18 have found statistical significance when comparing corneal sensitivities of patients with DM and patient without DM. Our small sample size likely precluded us from obtaining a similar statistical significance, but a correlation was noted. The OSDI has been shown to be a good measure of subjective symptoms in patients with dry eyes in the general population, but this may not hold true specifically for patients with DM and DPN. On a similar note, previous studies have also noted that patients with diabetic retinopathy seldom complain of dry eye symptoms despite clinical manifestations.17 ,29
The VFQ-25, in contrast to the OSDI, assesses a more comprehensive visual quality of life. Previous studies have shown a decrease in the VFQ-25 score in patients with dry eyes,16 and our study adds to that by demonstrating a significant decrease in VFQ-25 scores with increasing severity of DPN. Given the lack of correlation between dry eye symptoms and clinical signs in patients with DM, we suspect that VFQ-25 scores may be decreased in patients with severe DPN because of the association of DPN with other systemic and ocular complications of DM that decrease vision-related quality of life.
This study has several strengths. First, DPN was evaluated and quantified with a method that used nerve conduction velocity as part of a multidisciplinary evaluation. Unlike our study that finds increased clinical signs of dry eyes with increasing severity of DPN, a recent study in 2013 did not find a significant correlation between DED and DPN.10 However, this study used the MNSI for diagnosis of DPN, which the authors pointed out is not as accurate as methods such as nerve conduction velocities. Second, measurements of CNFL in our study were done in a masked fashion by the same person in all of the study participants, which minimises potential bias in image assessment. Our study had several limitations, including the relatively small number of subjects which likely limited our ability to find greater statistical significance. We were also unable to avoid some potential confounding factors, including differences in age, sex, BMI and duration of DM.
In conclusion, this study demonstrates increased clinical signs of ocular surface disease, but not an increase in subjective symptoms of dry eyes, with increasing severity of DPN. Furthermore, no significant correlation was found between OSDI scores and clinical signs of dry eye. It is well known that routine screening for diabetic retinopathy is beneficial for patients with DM. The results of this study suggest that a periodic evaluation of the ocular surface is also important for patients with DM, as they may be asymptomatic but have severe DED, which can lead to further ocular surface complications such as corneal ulceration.
Portions of this analysis were presented as a poster at the Association for Research in Vision and Ophthalmology Annual Meeting in Orlando, Florida, USA, in 2014.
Contributors All authors contributed significantly to the study and manuscript: study planning and study visits: MH, RP-B and RMS; data collection and data analysis: DLD, MH and RMS and manuscript writing and editing: DLD, MH, RP-B and RMS.
Funding This work was supported by Michigan Diabetes Research Center funded by NIH P60DK020572 from the National Institute of Diabetes and Digestive and Kidney Diseases (RMS) and 1R01 HL102334 (RPB).The sponsor or funding organisation had no role in the design or conduct of this research.
Competing interests None declared.
Ethics approval University of Michigan IRBMED.
Provenance and peer review Not commissioned; externally peer reviewed.
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