Skin innervation at different depths correlates with small fibre function but not with pain in neuropathic pain patients

Abstract

Background: Neuropathy can lead not only to impaired function but also to sensory sensitization. We aimed to link reduced skin nerve fibre density in different levels to layer-specific functional impairment in neuropathic pain patients and tried to identify pain-specific functional and structural markers. Methods: In 12 healthy controls and 36 patients with neuropathic pain, we assessed clinical characteristics, thermal thresholds (quantitative sensory testing) and electrically induced pain and axon reflex erythema. At the most painful sites and at intra-individual control sites, skin biopsies were taken and innervation densities in the different skin layers were assessed. Moreover, neuronal calcitonin gene-related peptide staining was quantified. Results: Perception of warm, cold and heat pain and nerve fibre density were reduced in the painful areas compared with the control sites and with healthy controls. Warm and cold detection thresholds correlated best with epidermal innervation density, whereas heat and cold pain thresholds and axon reflex flare correlated best with dermal innervation density. Clinical pain ratings correlated only with epidermal nerve fibre density (r = 0.38, p < 0.05) and better preserved cold detection thresholds (r = 0.39, p < 0.05), but not with other assessed functional and structural parameters. Conclusions: Thermal thresholds, axon reflex measurements and assessment of skin innervation density are valuable tools to characterize and quantify peripheral neuropathy and link neuronal function to different layers of the skin. The severity of small fibre neuropathy, however, did not correspond to clinical pain intensity and a specific parameter or pattern that would predict pain intensity in peripheral neuropathy could not be identified.

Association between pain, central sensitization and anxiety in postherpetic neuralgia

“…Contralateral findings might be explained by a subclinical involvement of the contralateral DRG by the varicella zoster infection because skin biopsies revealed epidermal fibre loss also at the contralateral side (Oaklander et al, 1998). Supporting our results, very recent investigations also failed to show an association between nerve fibre function or epidermal nerve fibre density and pain in focal neuropathic pain and in polyneuropathy (Schley et al, 2012;Truini et al, 2014). A reduced flare vasodilation in PHN has also been reported previously (Baron and Saguer, 1993).…”

Treating small fiber neuropathy by topical application of a small molecule modulator of ligand-induced GFRα/RET receptor signaling

“…However, the absence of a simple linear association between IENF density and thermal sensitivity has been noted previously (23,42). This phenomenon may reflect the specificity of sensory neuron subpopulations for heat sensation and growth factors (43) and/or a step function between IENF loss and behavioral response to noxious thermal stimuli (44).…”

Assessment of Chronic Pain: Domains, Methods, and Mechanisms

“…For example, epidermal nerve fiber density (ENFD), which typically requires taking a punch biopsy of the skin, is a standard technique for diagnosing peripheral small fiber neuropathy; however, recent evidence shows ENFD to be unrelated to neuropathic pain. 40, 72, 85 However, ENFD did correlate with clinical pain in patients with HIV-associated polyneuropathy. 97 Also, a substantially greater proportion of FM patients than controls showed decreased ENFD findings consistent with small fiber polyneuropathy.…”