Pain-related changes in cutaneous innervation of patients suffering from bortezomib-induced, diabetic or chronic idiopathic axonal polyneuropathy

Malik Bechakra,Mariska D Nieuwenhoff,Joost Van Rosmalen,Geert Jan Groeneveld,Frank J.P.M Huygen,Chris I De Zeeuw,Pieter A Van Doorn,Joost L.M Jongen

doi:10.1016/j.brainres.2019.146621

Abstract

Consistent associations between the severity of neuropathic pain and cutaneous innervation have not been described. We collected demographic and clinical data, McGill Pain Questionnaires (MPQ) and skin biopsies processed for PGP9.5 and CGRP immunohistochemistry from patients with bortezomib-induced peripheral neuropathy (BiPN; n = 22), painful diabetic neuropathy (PDN; n = 16), chronic idiopathic axonal polyneuropathy (CIAP; n = 16) and 17 age-matched healthy volunteers. Duration of neuropathic symptoms was significantly shorter in patients with BiPN in comparison with PDN and CIAP patients. BiPN was characterized by a significant increase in epidermal axonal swellings and upper dermis nerve fiber densities (UDNFD) and a decrease in subepidermal nerve fiber densities (SENFD) of PGP9.5-positive fibers and of PGP9.5 containing structures that did not show CGRP labeling, presumably non-peptidergic fibers. In PDN and CIAP patients, intraepidermal nerve fiber densities (IENFD) and SENFD of PGP9.5-positive and of non-peptidergic fibers were decreased in comparison with healthy volunteers. Significant unadjusted associations between IENFD and SENFD of CGRP-positive, i.e. peptidergic, fibers and the MPQ sensory-discriminative, as well as between UDNFD of PGP9.5-positive fibers and the MPQ evaluative/affective component of neuropathic pain, were found in BiPN and CIAP patients. No significant associations were found in PDN patients. Cutaneous innervation changes in BiPN confirm characteristic features of early, whereas those in CIAP and PDN are in line with late forms of neuropathic pathology. Our results allude to a distinct role for non-peptidergic nociceptors in BiPN and CIAP patients. The lack of significant associations in PDN may be caused by mixed ischemic and purely neuropathic pain pathology.

Highlights

IntroductionNeuropathic pain is a frequent complication of peripheral neuropathies, such as bortezomib-induced peripheral neuropathy (BiPN; occurring in 25–80% of patients (Jongen et al, 2015; Rampen et al, 2013), painful diabetic neuropathy (PDN; in 16–40% of patients (Javed et al, 2015; Jongen et al, 2018) and chronic idiopathic axonal polyneuropathy (CIAP; in 42% of patients (Erdmann et al, 2010; Hanewinckel et al, 2016; Warendorf et al, 2017)
Median and range of duration of neuropathy symptoms until the moment of study entry was significantly shorter in bortezomib-induced peripheral neuropathy (BiPN) patients (2 [0.5–23] months) than in painful diabetic neuropathy (PDN) (36 [8–60] months) and in chronic idiopathic axonal polyneuropathy (CIAP) patients (60 [12–132]), while the difference between PDN and CIAP patients was not significantly different (p < 0.001, p < 0.001 and p = 0.831 respectively; Kruskal-Wallis test with post-hoc comparisons using Dunn’s test)
The specific epidermal innervation changes that we found in BiPN as opposed to the changes in PDN and CIAP (decreased intraepidermal nerve fiber densities (IENFD) of PGP9.5 and of (PGP9.5-CGRP) fibers) are consistent with previously described differential neuropathic changes inacute versus chronic neuropathies (Bennett et al, 2014; Ebenezer et al, 2007; Lauria et al, 2003)

Summary

Introduction

Neuropathic pain is a frequent complication of peripheral neuropathies, such as bortezomib-induced peripheral neuropathy (BiPN; occurring in 25–80% of patients (Jongen et al, 2015; Rampen et al, 2013), painful diabetic neuropathy (PDN; in 16–40% of patients (Javed et al, 2015; Jongen et al, 2018) and chronic idiopathic axonal polyneuropathy (CIAP; in 42% of patients (Erdmann et al, 2010; Hanewinckel et al, 2016; Warendorf et al, 2017). Apart from a recent study that showed a correlation between GAP43 intraepidermal nerve fiber density and the severity of burning pain in PDN patients (Galosi et al, 2018), no consistent associations between cutaneous innervation and the severity of neuropathic pain have been described (Kalliomaki et al, 2011; Lindenlaub and Sommer, 2002; Schley et al, 2012; Vlckova-Moravcova et al, 2008) This may be explained by mixed pathology, for example in painful diabetic neuropathy, or by the fact that selective degeneration of a subset of nociceptors, which may not be detected using the pan axonal marker PGP9.5, may drive hyperalgesia and eventually neuropathic pain. More recently it has been suggested that separate anatomical pathways exist for these respective components (Braz et al, 2005; Craig, 2003)

Objectives

Methods

Results

Discussion

Conclusion