Pathophysiology of neuropathic pain in type 2 diabetes: skin denervation and contact heat-evoked potentials

Abstract

Objective: Neuropathic pain due to small-fiber sensory neuropathy in type 2 diabetes can be diagnosed by skin biopsy with quantification of intra-epidermal nerve fiber (IENF) density. There is, however, a lack of noninvasive physiological assessment. Contact heat-evoked potential (CHEP) is a newly developed approach to record cerebral responses of Aδ fiber-mediated thermonociceptive stimuli. We investigated the diagnostic role of CHEP.

Research design and methods: From 2006 to 2009, there were 32 type 2 diabetic patients (20 males and 12 females, aged 51.63 ± 10.93 years) with skin denervation and neuropathic pain. CHEPs were recorded with heat stimulations at the distal leg, where skin biopsy was performed.

Results: CHEP amplitude was reduced in patients compared with age- and sex-matched control subjects (14.8 ± 15.6 vs. 33.7 ± 10.1 μV, P < 0.001). Abnormal CHEP patterns (reduced amplitude or prolonged latency) were noted in 81.3% of these patients. The CHEP amplitude was the most significant parameter correlated with IENF density (P = 0.003) and pain perception to contact heat stimuli (P = 0.019) on multiple linear regression models. An excitability index was derived by calculating the ratio of the CHEP amplitude over the IENF density. This excitability index was higher in diabetic patients than in control subjects (P = 0.023), indicating enhanced brain activities in neuropathic pain. Among different neuropathic pain symptoms, the subgroup with evoked pain had higher CHEP amplitudes than the subgroup without evoked pain (P = 0.011).

Conclusions: CHEP offers a noninvasive approach to evaluate the degeneration of thermonociceptive nerves in diabetic neuropathy by providing physiological correlates of skin denervation and neuropathic pain.

Figure 1

CHEP and skin innervation in type 2 diabetic neuropathy. Skin biopsies were stained with anti-protein gene product 9.5 (PGP 9.5) antiserum, and IENF densities were quantified. Skin innervation and CHEP in a representative patient with type 2 diabetic neuropathy (A and C) compared with an age- and sex-matched subject (B and D) are illustrated. A: Skin biopsy from a 60-year-old female patient shows marked depletion of cutaneous nerve terminals in the epidermis (epi) with an IENF density of 0.9 fibers/mm. Only loose and fragmented subepidermal nerve bundles (sn) are recognizable in the dermis (derm). B: Skin biopsy from a 58-year-old healthy woman shows varicose PGP 9.5(+) IENFs (arrows) in the epidermis with an IENF density of 7.9 fibers/mm. C and D: Averaged tracing of the CHEP (C) from the patient in A shows attenuation of N- and P-waves and relatively prolonged N-wave latency comparing with the well-defined complex of N- and P-waves (D) from the control subject in B. (For A and B, bar = 25 μm; for C and D, time base = 250 ms and sensitivity = 50 μV.)