Structure-Function Relationship Between Corneal Nerves and Conventional Small-Fiber Tests in Type 1 Diabetes

OBJECTIVE: In vivo corneal confocal microscopy (IVCCM) has been proposed as a noninvasive technique to assess small nerve fiber structural morphology. We investigated the structure-function relationship of small fibers in diabetic sensorimotor polyneuropathy (DSP). RESEARCH DESIGN AND METHODS: Ninety-six type 1 diabetic subjects with a spectrum of clinical DSP and 64 healthy volunteers underwent IVCCM examinations to determine corneal nerve structure, including corneal nerve fiber length (CNFL), fiber density (CNFD), branch density (CNBD), and fiber tortuosity (CNFT). Small nerve fiber function was assessed by cooling detection thresholds (CDTs), axon reflex–mediated neurogenic vasodilatation in response to cutaneous heating by laser Doppler imaging flare technique (LDI(FLARE)), and heart rate variability (HRV). Linear associations between structural and functional measures in type 1 diabetic subjects were determined using Spearman correlation coefficients and linear regression analysis. RESULTS: Of the type 1 diabetic subjects, with a mean age of 38.2 ± 15.5 years and a mean HbA(1c) of 7.9 ± 1.4%, 33 (34%) had DSP according to the consensus definition. Modest correlations were observed between CNFL, CNFD, and CNBD and all functional small-fiber tests (r(s) = 0.25 to 0.41; P ≤ 0.01 for all comparisons). For example, quantitatively every 1 mm/mm(2) lower CNFL was associated with a 0.61°C lower CDT, a 0.07 cm(2) lower LDI(FLARE) area, and a 1.78% lower HRV. No significant associations were observed for CNFT and the functional small-fiber measures. CONCLUSIONS: Small nerve fiber structural morphology assessed by IVCCM correlated well with functional measures of small nerve fiber injury. In particular, CNFL, CNFD, and CNBD demonstrated clear structure-function relationships.