Rapid Corneal Nerve Fiber Loss Is a Potential Biomarker for Diabetic Polyneuropathy

Among patients with diabetes, abnormally rapid corneal nerve fiber loss may indicate increased risk for the development and progression of diabetic distal symmetric polyneuropathy, according to study results published in Diabetes Care.

In vivo corneal confocal microscopy measurement of corneal nerve fiber length can aid in assessment of small nerve fibers and may help to identify early stages of diabetic distal symmetric polyneuropathy, as previous studies have shown that a single measure of corneal nerve fiber length is a potential biomarker for polyneuropathy risk and disease status.

The goals of this secondary post hoc analysis of a prospective observational study were to explore the annual change in corneal nerve fiber length in individuals without diabetes to determine a threshold for rapid loss of corneal nerve fiber length and to apply this reference threshold to patients with diabetes to determine the prevalence of and identify clinical variables associated with abnormal change in corneal nerve fiber length.

The study cohort included 590 patients with diabetes, 399 with type 1 diabetes (T1D) and 191 with type 2 diabetes (T2D), and 204 control individuals without diabetes. All underwent examination of the sub-basal nerve plexus of the cornea using the Heidelberg Tomograph Rostock Cornea Module III. Cases of distal symmetric polyneuropathy were defined by neuropathic signs or symptoms and corroborated the presence of electrophysiologic abnormality.

Among the control individuals without diabetes (mean age, 37.9 years; 50% women), baseline corneal nerve fiber length was 16.5±4.0 mm/mm² with an annual slope of 0.64% (90% CI, -5.9 to 5.0). Among patients with T1D (mean age, 40.1 years; 49% women), baseline corneal nerve fiber length was 13.8±4.2 mm/mm² with an annual slope of -0.82% (90% CI, -14.0 to 9.9). Among those with T2D (mean age, 60.4 years; 54% women), baseline corneal nerve fiber length was 13.8±4.3 mm/mm² with an annual slope of -0.25% (90% CI, -14.1 to 14.3).

The reference distribution for annual percent change in corneal nerve fiber length in the individuals without diabetes had a fifth percentile threshold value of -5.9%, indicating that a loss of ≥6% represented abnormal change (ie, rapid corneal nerve fiber loss).

The combined number of patients with T1D and T2D who had rapid loss of corneal nerve fiber was 101, equaling a prevalence of 17.1%. The prevalence was similar in patients with T1D (64 patients; 16.0%) and T2D (37 patients, 19.4%; P =.31).

Distal symmetric polyneuropathy was evident in 47 patients (47%) with T1D and in 144 patients (30%) with T2D.

There was a higher incidence of rapid corneal nerve fiber loss in the diabetes groups compared with control patients without diabetes (P <.001), and it was more prevalent in those with distal symmetric polyneuropathy at baseline (24.6%) compared with those with new-onset (19%) or no polyneuropathy (12.2%; P =.0018 for trend). Furthermore, patients with rapid corneal nerve fiber loss were more likely to have lower baseline cooling detection threshold (P <.001) and slower peroneal conduction velocity (P =.013).

Regarding changes in clinical variables from baseline to follow-up, there was a significant association between a 1%/y loss of corneal nerve fiber length and an increase in distal symmetric polyneuropathy signs (P ­=.012) and symptoms (P =.022), loss of other corneal nerve morphology corneal nerve fiber density (P <.001), and corneal nerve branch density (P <.001), as well as measures of large fiber function. In addition, there was a greater change in peroneal conduction velocity (-1.1 m/s) in rapid corneal nerve fiber loss cases compared with those without (-0.6 m/s; P =.001).

The researchers acknowledged several limitations of the study, including the limited sample size of the reference group and possible selection bias.

“These findings support the use of [in vivo corneal confocal microscopy of corneal nerve fiber length] as a simple, objective, and noninvasive test for assessing and monitoring [distal symmetric polyneuropathy]. The reference distribution presented herein can be used to help guide the design and inclusion criteria for clinical trials of [distal symmetric polyneuropathy] modifying agents,” concluded the researchers.

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Reference

Lewis EJH, Lovblom LE, Ferdousi M, et al. Rapid corneal nerve fiber loss: a marker of diabetic neuropathy onset and progression [published online March 5, 2020]. Diabetes Care. doi: 10.2337/dc19-0951