The Utility of Corneal Confocal Microscopy in the Detection and Follow-up of Small Fibre Neuropathy in Diabetes and Sexual Dysfunction

Abstract

Diabetic peripheral neuropathy (DPN) is associated with significant morbidity due to resultant painful neuropathy, foot ulceration and lower limb amputation. Subjects with DPN are also at high risk of other vascular complications including erectile dysfunction (ED), diabetic retinopathy, nephropathy and premature cardiovascular disease. Although DPN involves both small and large nerve fibres, early damage occurs primarily to the small fibres. Previous studies have shown that corneal confocal microscopy (CCM) can quantify small nerve fibre neuropathy (SFN) in a reproducible manner. We evaluated the role of SFN in the symptoms of ED in men with type 2 diabetes (T2DM). We showed that ED was associated with SFN rather than autonomic or large fibre neuropathy. In addition, CCM in patients with ED was comparable to IENFD, the current gold standard for assessment of small nerve fibre damage thus showing its reliability in assessing for SFN in patients with ED. We also compared the prospective utility of CCM to the current ‘gold-standards’ for small (intraepidermal nerve fibre density [IENFD]) and large (nerve conduction studies [NCS]) nerve fibre assessments over a mean follow-up period of 6.5 years. Additionally, we undertook detailed neuropathy assessments, including clinical neuropathy measures and tests for autonomic nerve function. The changes in CCM were directly associated with changes in IENFD and autonomic nerve function but not NCS, showing a reliability in detecting SFN longitudinally. The deterioration in CCM was more pronounced than in IENFD which may suggest an increased sensitivity in detecting early deterioration nerve fibres using this method. The reduction in CCM parameters corresponded to progressive increases in albuminuria and reductions in estimated glomerular filtration rate, showing an association with alternate measures of microvascular disease. Finally, in a further study, this thesis examined the association of different measures of neuropathy, especially CCM, with sexual function and ED to understand if SFN or low testosterone levels had a greater effect on sexual function in men with both Type 1 and Type 2 diabetes. Corneal nerve loss was associated with the severity of ED with a significant association between CCM measurements and both erectile function scores and frequency of early morning erections. Importantly, testosterone and free testosterone levels were not associated with any measures of sexual function, suggesting that SFN rather than low testosterone levels may be the major driver of sexual dysfunction in men with diabetes. Current measures of SFN suffer multiple drawbacks. QST is highly subjective and has limited reproducibility, skin biopsy (IENFD) is invasive and NCS fail to identify small nerve fibre damage. CCM bridges this gap by virtue of being non-invasive, rapid, reproducible and reliable and as shown in this study it has advantage in assessing progression of DPN.

Date of Award	31 Dec 2021
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Rachelle Donn (Supervisor), Rayaz Malik (Supervisor) & Handrean Soran (Supervisor)