Corneal Confocal Microscopy and Skin Biopsy to Differentiate Painful From Painless Diabetic Neuropathy: A Systematic Review With Multiple Meta‐Analyses

Background: Painful diabetic neuropathy affects ~20%–40% of individuals with diabetes, driven by peripheral small nerve fiber damage and modulated by spinal cord and brain mechanisms. Corneal nerve imaging using corneal confocal microscopy (CCM) and skin biopsy to quantify intraepidermal nerve fiber density (IENFD) are objective measures of small nerve fiber damage. Objectives: CCM and IENFD were assessed for their ability to distinguish painful from painless diabetic neuropathy. Methods: Following PROSPERO-registered protocol and PRISMA guidelines, PubMed, Embase, and Web of Science were searched for studies on corneal nerve fiber density (CNFD), corneal nerve branch density (CNBD), corneal nerve fiber length (CNFL), and IENFD in patients with painful and painless diabetic neuropathy. Standardized mean difference (SMD) with 95% confidence intervals (CI) was pooled using random-effects meta-analyses. Results: Seven studies (n = 683) showed lower CNFD (SMD −0.50, 95% CI −0.96 to −0.03, p = 0.03) and CNFL (SMD −0.32, 95% CI −0.59 to −0.05, p = 0.02) in painful compared to painless DPN, with no difference in CNBD. Ten studies (n = 664) demonstrated lower IENFD in painful compared to painless DPN (SMD −0.31, 95% CI −0.59 to −0.02, p = 0.03, I2 69%). In three studies assessing both CCM and IENFD (n = 161), CNFD (p < 0.0001), CNBD (p = 0.01), CNFL (p = 0.0001), and IENFD (p = 0.008) were significantly lower in painful compared to painless DPN. Conclusion: Both CCM and skin biopsy demonstrate small nerve fiber loss in painful compared to painless DPN, supporting their value in identifying alterations in small nerve fiber structure in painful DPN.