Reduced intraepidermal nerve fiber density in patients with chronic ischemic pain in peripheral arterial disease

Abstract

Chronic ischemic pain in peripheral arterial disease (PAD) is a leading cause of pain in the lower extremities. A neuropathic component of chronic ischemic pain has been shown independent of coexisting diabetes. We aimed to identify a morphological correlate potentially associated with pain and sensory deficits in PAD. Forty patients with symptomatic PAD (Fontaine stages II-IV), 20 with intermittent claudication (CI), and 20 with critical limb ischemia (CLI) were enrolled; 12 volunteers served as healthy controls. All patients were examined using pain scales and questionnaires. All study participants underwent quantitative sensory testing (QST) at the distal calf and skin punch biopsy at the distal leg for determination of intraepidermal nerve fiber density (IENFD). Additionally, S100 beta serum levels were measured as a potential marker for ischemic nerve damage. Neuropathic pain questionnaires revealed slightly higher scores and more pronounced pain-induced disability in CLI patients compared to CI patients. QST showed elevated thermal and mechanical detection pain thresholds as well as dynamic mechanical allodynia, particularly in patients with advanced disease. IENFD was reduced in PAD compared to controls (P<0.05), more pronounced in the CLI subgroup (CLI: 1.3 ± 0.5 fibers/mm, CI: 2.9 ± 0.5 fibers/mm, controls: 5.3 ± 0.6 fibers/mm). In particular, increased mechanical and heat pain thresholds negatively correlated with lower IENFD. Mean S100 beta levels were in the normal range but were higher in advanced disease. Patients with chronic ischemic pain had a reduced IENFD associated with impaired sensory functions. These findings support the concept of a neuropathic component in ischemic pain.

Activation of cannabinoid receptor 2 attenuates mechanical allodynia and neuroinflammatory responses in a chronic post‐ischemic pain model of complex regional pain syndrome type I in rats

“…Loss of intraepidermal nerve fibers (IENFs) has been reported to play a critical role in the development of various neuropathic pain syndromes including chemotherapy-induced peripheral neuropathy (Boyette-Davis et al, 2011), diabetic and non-diabetic neuropathy (Pittenger et al, 2004), autoimmune diseases-associated neuropathy (Goransson et al, 2006), HIV-associated sensory neuropathy (Polydefkis et al, 2002) and ischemic pain (Grone et al, 2014). Immunohistochemical analysis of both upper and lower extremity skin biopsies from amputated CRPS patients revealed reduction of epidermal innervation supplied by c fibers and Ad fibers as compared to control skin (Albrecht et al, 2006).…”

Small‐fiber neuropathy: Expanding the clinical pain universe

“…IENFD has been reported to be reduced also in other painful conditions, such as Guillain‐Barré syndrome, meralgia paraesthestica, notalgia, Ehlers‐Danlos syndrome, and fibromyalgia and non‐painful disorders, such as Parkinson disease and related disorders, amyotrophic lateral sclerosis, critical illness, and peripheral arterial disease …”

“…amyotrophic lateral sclerosis, [44][45][46] critical illness, 47 and peripheral arterial disease. 48 New techniques to determine the IENFD with indirect immunofluorescence, 49 automated PGP9.5 immunofluorescence staining (laboratory developed test), 50 and 3D analysis 51 have been reported. One study investigated the global spatial sampling in order to determine the epidermal nerve fiber length density (ENFLD) taking into account its biologic complexity.…”

Human-like cutaneous neuropathologies associated with a porcine model of peripheral neuritis: A translational platform for neuropathic pain

“…To address the challenge of translating experimentally induced pain in animal models to successful human applications (Hill, 2000, Rice et al, 2008, Borsook et al, 2014, Hama and Takamatsu, 2016, Shidahara et al, 2016), we have developed a modified CCI peripheral neuritis trauma (PNT) model in pigs which, unlike rodents, have a close anatomical, physiological, and neurological similarity to humans (Rukwied et al, 2008, Schley et al, 2012, Swindle et al, 2012, Hirth et al, 2013, Castel et al, 2016). In particular, the structure and innervation of pig skin is especially more like that of humans (Rukwied et al, 2008, Dusch et al, 2009, Janczak et al, 2012, Schley et al, 2012, Di Giminiani et al, 2013, Hirth et al, 2013), providing a platform for comprehensive ChemoMorphometric Analysis (CMA) of skin biopsies which have been increasingly used to discover pathologies associated with a variety of painful peripheral neuropathies in humans (Holland et al, 1997, Kennedy and Wendelschafer-Crabb, 1999, Polydefkis et al, 2001, Obermann et al, 2008, Sommer, 2008, Vlckova-Moravcova et al, 2008, Lauria et al, 2009, Weis et al, 2011, Hoeijmakers et al, 2012, Boyette-Davis et al, 2013, Cheng et al, 2013, Uceyler et al, 2013, Grone et al, 2014, Doppler et al, 2015, Hoeijmakers et al, 2015, Divisova et al, 2016). As a large animal model, pigs also present as a more cost-effective and ethically acceptable alternative to non-human primate use for NP research.…”