Pain Severity in Diabetic Neuropathy Correlates With Corneal Nerve Fiber Loss

Pain in a man’s palm on a white background. The concept of health.
Researchers sought to determine whether the severity of corneal nerve loss was associated with the severity of painful diabetic neuropathy.

Increasing severity of neuropathic pain was found to have a positive association with corneal nerve fiber loss among patients with painful diabetic neuropathy (PDN), according to study findings published in the European Journal of Neurology.

Patients (n=118) with diabetes and healthy control participants (n=38) underwent an assessment for clinical, neurological, and ophthalmic features. The study population was stratified by severity of neuropathic pain, and clinical differences were compared.

Control group participants, patients with no pain (n=43), mild pain (n=34), and moderate to severe pain (n=41) had a median age of 57, 68, 68, and 61 years; 18, 11, 12, and 21 were women; and glycated hemoglobin was 5.6%, 7.2%, 7.4%, and 8.1%, respectively.

Compared with control individuals, neuropathy disability was higher among all pain groups (all P <.0001). Between the pain cohorts, no significant difference in neuropathy disability was observed. A similar pattern was observed for vibration perception threshold (all P <.0001), sural sensory nerve conduction (all P <.0001), and sural nerve action potential (all P <.0001).

Cold perception threshold differed between control and patient cohorts (all P .004) and was different for patients with moderate to severe pain compared with no or mild pain (both P .009). A similar pattern was observed for warm perception threshold (all P .01).

Corneal sensitivity was significantly higher among the most severe pain cohort compared with all other groups (all P .02).

Control group participants differed significantly from all pain groups for corneal nerve fiber density (all P <.0001) and between patients with moderate to severe pain compared with no or mild pain (both P .01). A similar pattern was observed for corneal nerve fiber length (all P .004).

Corneal nerve branch density differed between controls and pain cohorts (all P <.0001) and between the most severe and least severe pain groups (P =.02).

The visual analogue scale correlated with corneal nerve fiber length (r, -0.4; P <.0001), fiber density (r, -0.3; P =.0002), and branch density (r, -0.3; P =.001), warm perception test (r, 0.3; P =.0004), and cold perception test (r, -0.35; P =.0001).

A diagnosis of PDN could be determined with a corneal nerve fiber density threshold of 23.69 no/mm2 (area under the receiving operator characteristic curve [AUC ROC], 0.78; sensitivity, 0.73; specificity, 0.72), corneal nerve branch density threshold of 51.04 no/mm2 (AUC ROC, 0.75; sensitivity, 0.66; specificity, 0.66), and corneal fiber length of 21.48 no/mm2 (AUC ROC, 0.74; sensitivity, 0.66; specificity, 0.65).

The study was limited by using the visual analog scale, which is a subjective tool and may have biased results.

The data indicated that PDN could be detected with ophthalmic examination and showed that PDN progression increases corneal nerve fiber loss.

“…[I]t is shown that [corneal confocal microscopy] has good diagnostic accuracy for PDN and detects progressively greater small nerve fiber loss in patients with increasing severity of PDN,” the study authors wrote. “[Corneal confocal microscopy] may have clinical utility as a rapid and objective test for the assessment of PDN.”


Kalteniece A, Ferdousi M, Azmi S, et al. Corneal nerve loss is related to the severity of painful diabetic Neuropathy. Eur J Neurol. 2022;29(1):286-294. doi:10.1111/ene.15129