Patterns of cutaneous nerve fibre loss and regeneration in type 2 diabetes with painful and painless polyneuropathy

Abstract

Dermal nerve fibre regeneration is enhanced in DSPN, particularly in DSPN+p, and increases with advancing intraepidermal nerve fibre loss. These data suggest that, despite progressive epidermal fibre loss, dermal nerve repair is preserved, particularly in DSPN+p, but fails to adequately counteract epidermal neurodegenerative processes.

A pain in the skin. Regenerating nerve sprouts are distinctly associated with ongoing burning pain in patients with diabetes

“…However, a previous multicentre study showed that both methods, although on a different scale, are comparable in assessing epidermal innervation in patients with polyneuropathy (Nolano et al, 2015). Furthermore, previous studies (Cheng et al, 2013;B€ onhof et al, 2017) investigating GAP43 skin innervation in patients with diabetic polyneuropathy with immunofluorescence did not show a higher density of GAP43-stained intraepidermal nerve fibres than that we report in this study with the bright-field method.…”

“…Admittedly, GAP43‐stained regenerating nerve fibres are commonly found also in skin biopsy from normal humans (Cheng et al., ; Bönhof et al., ). For this reason, we used the GAP43/PGP9.5 ratio to estimate the association between regenerating nerve fibre density and pain.…”

“…Recent skin biopsy studies showed that patients with painful diabetic polyneuropathy have an increased dermal and intraepidermal density of regenerating nerve sprouts, as assessed with the GAP43 immunostaining (Cheng et al., ; Bönhof et al., ), than patients with painless diabetic polyneuropathy. However, no study has investigated how the most common types of pain, that is ongoing burning pain and dynamic mechanical allodynia, are associated with regenerating sprouts and whether a specific risk for ongoing burning pain or dynamic mechanical allodynia can be associated with the intraepidermal density of GAP43‐stained regenerating nerve sprouts.…”

Small Fibre Neuropathy in Parkinson’s Disease: Comparison of Skin Biopsies from the More Affected and Less Affected Sides

“…Extensive search for bilateral skin biopsies in healthy individuals using GAP43 immunolocalisation did not yield any results. We support our choice of using nerve regeneration marker GAP43 for comparing innervation in symmetric bilateral skin biopsies in PD on the basis of the recent study localising small nerve fibres using double immunofluorescence for both PGP9.5 and GAP43 in SFN and healthy controls [24]. Admittedly, following Lauria recommendations they used single biopsies, but they clearly demonstrated that the ratio of GAP43/PGP9.5 measurements in control group was 0.93 ± 0.13 in control group (similar age to our PD patients), demonstrating that in healthy skin, expression of both markers is very similar.…”

Increased Intraepidermal Nerve Fiber Degeneration and Impaired Regeneration Relate to Symptoms and Deficits in Parkinson's Disease

“…Growth-associated protein-43 (GAP-43) was first described in growing nerve cones and has been shown to play a crucial role in neuromodulation and axonal regeneration in both animal and human studies (18, 19). GAP-43 staining has been applied to show altered cutaneous nerve fiber regeneration in patients with painful diabetic neuropathy (20). We have recently immunostained with GAP-43 and quantified Intraepidermal Total Nerve Fiber Length (IETNFL) and demonstrated increased epidermal nerve regeneration in patients with sarcoid neuropathy after treatment with Cibinetide (21).…”