Peripheral Neuropathy Symptoms and Ocular Surface Lesions in Patients with Type 2 Diabetes Mellitus and Dry Eye: A Clinical Correlational Study

Abstract

Introduction: Reduced corneal sensation in individuals with type 2 diabetes mellitus (T2DM) leads to a dissociation between dry eye disease (DED) signs and symptoms, thereby affecting diagnostic accuracy. This study aimed to investigate the correlation between ocular surface signs and diabetic peripheral neuropathy (DPN) symptoms in patients with T2DM-associated DED.

Methods: The Michigan Neuropathy Screening Instrument Questionnaire (MNSIQ) was used to categorize patients with T2DM into MNSIQ-DPN and non-DPN groups. Ocular irritation symptoms were evaluated using the Ocular Surface Disease Index (OSDI) questionnaire. Ocular surface lesions were assessed via Cochet-Bonnet esthesiometry, corneal fluorescein staining (CFS), the Schirmer I tear test (SIT), tear meniscus height (TMH), noninvasive keratography break-up time (NIKf-BUT), and the meibomian gland loss (MGL) grade detected by OCULUS. Corneal nerve fiber parameters were evaluated using in vivo confocal microscopy (IVCM).

Results: A total of 116 patients with T2DM, comprising 76 non-DPN patients and 40 MNSIQ-DPN patients, along with 51 age-matched participants without diabetes, were enrolled. Although OSDI scores were equivalent between MNSIQ-DPN patients and non-DPN patients, MNSIQ-DPN patients presented significantly more severe CFS (p < 0.001), meibomian gland dysfunction (MGD) (p < 0.001), corneal nerve fiber loss (p < 0.001), sensory dysfunction (p = 0.02), and corneal microneuromas (p < 0.001). The MNSIQ score was significantly positively correlated with CFS (p < 0.001); MGD (p < 0.01); corneal nerve fiber loss, including corneal nerve fiber density and length and branch density, in the paracentral (all p < 0.001) and inferior-whorl areas (p < 0.01, p < 0.05 and p < 0.01, respectively); and corneal microneuromas, characterized by increased microneuroma numbers (p < 0.001) and areas (p < 0.001) in these regions.

Conclusion: MNSIQ scores were significantly and robustly correlated with the presence of corneal epithelial defects, MGD, and nerve fiber loss in patients with T2DM. These findings suggest that DPN is a critical factor in diabetic ocular surface complications, highlighting the importance of the MNSIQ for assessing these conditions.

Keywords: Diabetes; Diabetic peripheral neuropathy; Dry eye disease; In vivo confocal microscopy; Meibomian gland dysfunction; Microneuroma.

Fig. 1

Representative in vitro confocal microscopy (IVCM) images of A the five zones and their corresponding diameters and B comparative images of the four peripheral and whorl corneal zones from the right eye of a nondiabetic individual and a patient with type 2 diabetes mellitus (T2DM)

Fig. 2

A Representative slit-lamp images with fluorescein staining revealed varying degrees of corneal involvement: control group (corneal fluorescein staining [CFS] = 0), the nondiabetic nephropathy (DPN) group (CFS = 2), and the Michigan Neuropathy Screening Instrument Questionnaire (MNSIQ)-DPN group (CFS = 5). B Infrared imaging of the upper and lower eyelids was performed using the Keratograph 5M system. Meibomian gland loss (MGL) grades were scored as follows: 1 for participants without diabetes, 3 for the non-DPN group, and 6 for the MNSIQ-DPN group

Fig. 3

Boxplots illustrating corneal confocal microscopy parameters of nerve fibers from the paracentral (A–C) and inferior-whorl areas (D–F), as well as microneuromas from the paracentral (G and H) and inferior-whorl areas (I and J). Significant differences, determined using post hoc tests with Bonferroni correction, are indicated (*p < 0.05; **p < 0.01; ***p < 0.001). DPN diabetic peripheral neuropathy, MNSIQ Michigan Neuropathy Screening Instrument Questionnaire, CNFD corneal nerve fiber density, CNBD corneal nerve branch density, CNFL corneal nerve fiber length

Fig. 4

Corneal microneuroma formation in different groups. Representative in vitro confocal microscopy (IVCM) images of the superior cornea (first row) and the inferior-whorl cornea (second row). Images are representative images from participants without diabetes (A, D), participants with nondiabetic peripheral nephropathy (DPN) (B, E), and participants with Michigan Neuropathy Screening Instrument Questionnaire (MNSIQ)-DPN (C, F). In both the superior and inferior-whorl corneas, microneuromas were more evident in the MNSIQ-DPN group than in the non-DPN and control groups

Fig. 5

Heatmap of the correlation analysis of the Michigan Neuropathy Screening Instrument Questionnaire (MNSIQ) score, ocular surface parameters, corneal nerve fiber parameters, and number and area of corneal microneuromas in type 2 diabetes mellitus (T2DM) patients. Significant differences, determined using Spearman correlation analysis, are indicated (*p < 0.05; **p < 0.01; ***p < 0.001). DPN diabetic peripheral neuropathy, CNFD corneal nerve fiber density, CNBD corneal nerve branch density, CNFL corneal nerve fiber length, CNFW corneal nerve fiber width, MGL meibomian gland loss, OSDI Ocular Surface Disease Index, CFS corneal fluorescein staining, HbA1c glycated hemoglobin