Corneal Confocal Microscopy as a Quantitative Imaging Biomarker of Diabetic Peripheral Neuropathy: A Review

Abstract

Distal symmetric polyneuropathy (DPN), particularly chronic sensorimotor DPN, represents one of the most frequent complications of diabetes, affecting 50% of diabetic patients and causing an enormous financial burden. Whilst diagnostic methods exist to detect and monitor this condition, they have significant limitations, mainly due to their high subjectivity, invasiveness, and non-repeatability. Corneal confocal microscopy (CCM) is an in vivo, non-invasive, and reproducible diagnostic technique for the study of all corneal layers including the sub-basal nerve plexus, which represents part of the peripheral nervous system. We reviewed the current literature on the use of CCM as an instrument in the assessment of diabetic patients, particularly focusing on its role in the study of sub-basal nerve plexus alterations as a marker of DPN. CCM has been demonstrated to be a valid in vivo tool to detect early sub-basal nerve plexus damage in adult and pediatric diabetic patients, correlating with the severity of DPN. Despite its great potential, CCM has still limited application in daily clinical practice, and more efforts still need to be made to allow the dissemination of this technique among doctors taking care of diabetic patients.

Ophthalmological involvement in wild‐type transthyretin amyloidosis: A multimodal imaging study

“…A reduction in sub‐basal nerve fiber length (CNFL) and an increase in stromal nerve tortuosity were found in all amyloidosis patients compared with control group. CNFL has already been shown to be the most reproducible and strong parameter for the detection of abnormalities of small fiber morphology in diabetes, also associated with different measures of neuropathy severity 31 . Moreover, Rousseau et al 31 proposed CNFL as a sensitive marker of denervation in ATTRv, correlating with the severity of both sensorimotor and autonomic neuropathies, as well as with walking status and lower limbs intraepidermal nerve fiber density (IENFD).…”

“…CNFL has already been shown to be the most reproducible and strong parameter for the detection of abnormalities of small fiber morphology in diabetes, also associated with different measures of neuropathy severity 31 . Moreover, Rousseau et al 31 proposed CNFL as a sensitive marker of denervation in ATTRv, correlating with the severity of both sensorimotor and autonomic neuropathies, as well as with walking status and lower limbs intraepidermal nerve fiber density (IENFD). The results of our study not only confirm the relevance of CNFL in ATTRv but also reveal its importance in ATTRwt.…”

“…Even if this has been suggested as a sign of suffering nerves, the study of the stromal nerves with CCM has been less extensively reported than the sub-basal nerve plexus and the meaning of their alterations should be cautiously interpreted. 13,31,32 OCTA allowed the identification of a diffuse reduction of all vascular parameters compared to controls both at the macula plexi and in the peripapillary plexus, particularly in ATTRwt and ATTRv eyes, but without significant difference among groups. Signs of angiopathy have been described in ATTRv patients using invasive imaging modalities.…”

Measuring pain and nociception: Through the glasses of a computational scientist. Transdisciplinary overview of methods

“…Compared to skin biopsies, CCM has the advantage that it is non-invasive. Similar to the measure of the number of intraepidermal nerve fibers (IENFD) this method is useful to assess morphological changes of nociceptors such as small fiber neuropathy or diabetic neuropathy (Cosmo et al, 2022) and changes in nociceptors in other degenerative diseases such as Parkinson's disease (Kass-Iliyya et al, 2015). Nevertheless, the relation of these measures to pain perception is not clear, similar to nerve fiber morphology in skin biopsies.…”

“…Similarly to intraepidermal nerve fiber density or corneal nerve fiber structure, nerve ultrasound is useful in assessing damage of so called "thin nerve fibers" including nociceptors. It is currently used to detect morphological changes in neuropathies (Cosmo et al, 2022) and nerve entrapment syndromes such as carpal tunnel syndrome (Lin et al, 2022). However, neither a direct link to evoked pain nor to ongoing pain has been shown so far.…”