Levy, David Michael; (1993) Small-fibre studies in diabetic neuropathy. Doctoral thesis (M.D), UCL (University College London).

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Abstract

Distal small fibre studies in diabetes have been hindered by methodological problems. Psychophysical thermal thresholds have high variability and may not measure pure small fibre function, and most methods for measuring sympathetic function are complex and not quantitative. Three simple techniques for quantitating sympathetically-mediated sweating have been developed: computerised counts of pilocarpine-activated sweatspots, dynamic sweat responses to acetylcholine, and measurement of the sympathetic skin response, in order (a) to establish the frequency of sweating dysfunction; (b) to address the question of the length dependence of diabetic neuropathy; and (c) to compare sweat function with other peripheral nerve measurements. 14–20% of randomly-selected diabetic patients had diminished sweat-gland activation after cholinergic stimulation and abnormal sympathetic skin responses, many of whom had other evidence of neuropathy. Other neurological tests were as frequently abnormal, and had similar intraindividual coefficients of variation, though thermal thresholds were more frequently abnormal (30%). Approximately 5% had increased sweatspot density and acetylcholine-evoked sweat secretion, suggesting denervation supersensitivity. Some of these patients also had autonomic and somatic nerve dysfunction. Dynamic infrared pupillometry confirmed that proximal small-fibre function is less frequently abnormal than distal small-fibre measurements. The function and structure of neuropeptide-immunoreactive cutaneous sensory and autonomic nerves were investigated in two studies. Neuropathic patients showed supersensitivity to intradermal methacholine, and these responses were decreased by the addition of substance P (SP) and vasoactive intestinal polypeptide (VIP). The effect was more marked with VIP in non-neuropathic, compared with normal and neuropathic subjects. This result may be due to upgrading of sweat gland VIP receptors. Quantitative immunohistochemistry of lower limb skin biopsies confirmed depletion of epidermal nerves immunoreactive for PGP 9.5 and the neuropeptide calcitonin gene-related peptide (CGRP) in neuropathic patients. Non-statistically significant depletion was found in specimens from non-neuropathic patients. Some diabetic subjects had higher dermal and sweat gland immunoreactivity than expected. Nerve proliferation may therefore occur in diabetes, and may contribute to the structural basis for the enhanced functional sweat gland responses.

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