Small nerve fiber quantification in the diagnosis of diabetic sensorimotor polyneuropathy: comparing corneal confocal microscopy with intraepidermal nerve fiber density

Abstract

Objective: Quantitative assessment of small fiber damage is key to the early diagnosis and assessment of progression or regression of diabetic sensorimotor polyneuropathy (DSPN). Intraepidermal nerve fiber density (IENFD) is the current gold standard, but corneal confocal microscopy (CCM), an in vivo ophthalmic imaging modality, has the potential to be a noninvasive and objective image biomarker for identifying small fiber damage. The purpose of this study was to determine the diagnostic performance of CCM and IENFD by using the current guidelines as the reference standard.

Research design and methods: Eighty-nine subjects (26 control subjects and 63 patients with type 1 diabetes), with and without DSPN, underwent a detailed assessment of neuropathy, including CCM and skin biopsy.

Results: Manual and automated corneal nerve fiber density (CNFD) (P < 0.0001), branch density (CNBD) (P < 0.0001) and length (CNFL) (P < 0.0001), and IENFD (P < 0.001) were significantly reduced in patients with diabetes with DSPN compared with control subjects. The area under the receiver operating characteristic curve for identifying DSPN was 0.82 for manual CNFD, 0.80 for automated CNFD, and 0.66 for IENFD, which did not differ significantly (P = 0.14).

Conclusions: This study shows comparable diagnostic efficiency between CCM and IENFD, providing further support for the clinical utility of CCM as a surrogate end point for DSPN.

Figure 1

A: Original CCM image. B: Manually quantified CCM image. C: Automatically quantified CCM image. The red lines represent main nerve fibers, blue lines are branches, and green spots indicate branch points on the main nerve trunks. CCM images of the subbasal nerve plexus from a control subject (D), a DSPN(−) patient with type 1 diabetes (E), and a DSPN(+) patient with type 1 diabetes (F) show the reduction in corneal nerves in the DSPN(+) patient. The red arrows indicate main nerve fibers (to calculate CNFD), and yellow arrows indicate branch fibers (to calculate CNBD). Box plots of IENFD (G), manual CNFD values (H), automated CNFD (I), and automated CNFL (J) values in controls and in DSPN(−) and DSPN(+) patients with type 1 diabetes based on the TC. K: ROC curves for manual CNFD (MCNFD), automated CNFD (ACNFD), and IENFD to discriminate DSPN(+) and DSPN(−) patients with diabetes. G–J: Red lines represent median, the box borders 25th and 75th percentile. Whiskers represent the range of the data (without outliers). Red plus symbols represent outliers.

Figure 2

Skin biopsy specimens immunostained for neuronal marker PGP 9.5 from a healthy subject (A), a DSPN(−) patient with type 1 diabetes (B), and a DSPN(+) patient with type 1 diabetes (C). Note the depletion of IENFD (red arrows) and reduction of subepidermal nerve plexus (blue arrows) in B and C, with both features more severe in the DSPN(+) patient (C). Original magnification ×200, scale bar = 100 µm.