Warner, Graham T. A.; (1997) Small fibre function tests in diabetic poly neuropathy. Doctoral thesis (M.D), UCL (University College London).

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Abstract

Most diabetic subjects remain asymptomatic with respect to polyneuropathy despite abnormal clinical and investigative findings. The exact frequency of neuropathy is therefore difficult to determine and no agreed minimal criteria for its diagnosis exist. This is important for screening for future treatments. To address these questions, sensory nerve function was tested in distal (foot and lateral calf) and proximal (volar forearm) areas of 28 IDDM subjects (mean age 39.82 years, mean duration 18.77 years) and 27 NIDDM subjects (mean age 56.04 years, mean duration 11.41 years) clinically mild and non- neuropathic diabetics, and compared with age-matched controls. Small nociceptor unmyelinated nerve (C-)fibres were assessed by measuring capsaicin-induced axon reflex vasodilatation, a skin 'flare' response, by laser Doppler fluxmetry. Using a Marstock stimulator thermal thresholds for warm sensation and heat-pain provided further information on unmyelinated small fibres, and cool sensation thin myelinated (A[delta]-)fibres. Large (A[beta]-)fibre tests included mechanical thresholds utilising Semmes-Weinstein monofilaments, vibration thresholds using biothesiometry and sural nerve sensory conduction velocity (SCV). Sympathetic small fibres were tested by measuring nicotine-induced axon reflex sweating with an evaporimeter. Results confirmed significant length-dependent small fibre dysfunction for thermal thresholds and axon reflex vasodilatation (feet and calves). This contrasted normal large fibre tests of vibration, only slight SCV delay and sparing of axon reflex sweating. Toe mechanical thresholds were raised in NIDDMs but normal in IDDMs. In conclusion, small sensory neurons are more susceptible to neuropathic processes in a length-dependent manner. This is further supported by relative frequencies of abnormality for each test in the feet: 'warm' 50[percent]/63[percent] (IDDMs/NIDDMs), 'cool' 50[percent]/48[percent], 'heat-pain' 30[percent]/30[percent], mechanical threshold 29[percent]/37[percent], vibration threshold 11.5[percent]/18.5[percent], SCV 9.5[percent]/18[percent], axon reflex sweating 0-27[percent] and axon reflex vasodilatation 0[percent]. These results have implications for the prevalence of polyneuropathy, the general order of neuronal failure and best means to screen individuals. Warm 2 sensitivity testing, an early abnormality in diabetic neuropathy, is simple, quick and non-invasive. Axon reflex flare varies widely in controls limiting its use in/for screening (individuals). Neuronal function declined with increasing age in controls for thermal and vibration thresholds. This was paralleled, but at an earlier age, in diabetics, in whom there was also an age effect for distal mechanical thresholds and flare. Diabetic lateral calf skin NGF levels (by ELISA) were significantly reduced in IDDM and NIDDM females, with a non-significant trend in IDDM males. Reduced target-organ (skin) NGF is explained by reduced production as a primary event or impaired axonal transport. Subjects with painful symptoms had lower NGF than those with none or "numbness" supporting the proposal that neurotrophins may influence diabetic polyneuropathy's pattern of presentation as part of a neurotrophic hypothesis. Higher NGF levels in females could explain their lower incidence of neuropathy. IDDMs' (males and females) axon reflex flare correlated with NGF concentration, confirming the relationship between NGF and substance P-containing nociceptor C-fibres.

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