Small Nerve Fiber Quantification in the Diagnosis of Diabetic Sensorimotor Polyneuropathy: Comparing Corneal Confocal Microscopy With Intraepidermal Nerve Fiber Density

Abstract

OBJECTIVEQuantitative 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 METHODSEighty-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.RESULTSManual 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).CONCLUSIONSThis 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.

New technologies for the assessment of neuropathies

“…As with skin biopsy, with which its agreement in a recent comparative study was good 172 , corneal confocal microscopy provided evidence of nerve fibre regeneration in patients with diabetes mellitus 173 and after pancreas transplantation 174,175 , suggesting a potential use as an outcome measure in clinical trials.…”

A fully automatic nerve segmentation and morphometric parameter quantification system for early diagnosis of diabetic neuropathy in corneal images

“…The images were saved in JPEG compressed format with a size of (384×384) pixels covering a 400 μm × 400 μm frame size at an optical magnification of 63X. The second database [14] consists of a total of 919 images where 445 images are from 84 control subjects and the remaining 350 images are from 63 diabetic patients without neuropathy, and 124 images are from 25 patients with neuropathy. The CCM images were captured using a Heidelberg Retina Tomograph equipped with Rostock Cornea Module (HRT-III).…”

“…Morphological alterations in the epithelium, stroma and endothelium provide insights into a variety of corneal diseases [3,4] and assessment of the effects of wearing contact lenses [1], LASIK or PRK [5], fungal keratitis [6], corneal transplantation [7] or conditions such as keratoconus [8,9]. CCM has also been used in the assessment of peripheral neuropathies [10,11,12,13,14,15,16,17,18,19]. The development of automated imaging algorithms for the processing of CCM images [20,21,22,23] is a necessary accompaniment to such work.…”

Distal Sensorimotor Neuropathy: Improvements in Diagnosis

“…Using CCM variables, studies have documented improvement in terms of nerve fiber repair with tight glycemic control [51], 6 months after pancreas transplantation [52], after simultaneous kidney-pancreas transplantation [53], and with insulin pump therapy [54]. The manual counting method is time-consuming and costly, but newer automated methods have been validated successfully, with reported area under the curve for identifying DSPN of 0.82 for the manual method and 0.80 for the automated algorithm [55][56][57].…”