Corneal Confocal Microscopy as a Non-Invasive Marker of Small Fiber Neuropathy and Systemic Complications in Type 2 Diabetes: A Cross-Sectional Study

Small fiber neuropathy (SFN) is an early and common manifestation of diabetic polyneuropathy in type 2 diabetes mellitus (T2DM), often presenting with pain, dysesthesia, and autonomic dysfunction. Conventional diagnostic methods primarily assess large nerve fibers and may miss early small fiber damage, while skin biopsy, though considered the reference standard, is invasive. Corneal confocal microscopy (CCM) offers a rapid, noninvasive alternative for visualizing and quantifying small nerve fiber pathology in vivo. This was a monocentric observational study including 80 adults with T2DM (18–75 years), conducted at Alexandrovska Hospital, Sofia. Peripheral neuropathy was evaluated using a modified Neuropathy Disability Score and CCM-derived corneal nerve fiber density (CNFD), length (CNFL), and branching density (CNBD). Autonomic and sudomotor function were assessed by cardiovascular reflex tests and Sudoscan. Additional measures included vibration perception threshold, carotid intima–media thickness, body composition analysis, and laboratory parameters. Autonomic neuropathy was present in 66.7% and peripheral neuropathy in 57.5% of participants. Affected patients were older and had higher BMI and longer diabetes duration; peripheral neuropathy was additionally associated with higher HbA1c. Corneal nerve parameters negatively correlated with diabetes duration, HbA1c, intima–media thickness, and vibration threshold. Patients with diabetic retinopathy showed significantly reduced CNFD and CNFL. ROC analysis demonstrated significant discriminative ability of the HRV index for identifying peripheral neuropathy and of CNFD for detecting sudomotor dysfunction. These findings support CCM as a valuable, noninvasive marker of small fiber damage, closely linked to metabolic control, vascular impairment, and both sensory and autonomic dysfunction in T2DM.