Trench Foot or Non-Freezing Cold Injury As a Painful Vaso-Neuropathy: Clinical and Skin Biopsy Assessments

Abstract

BackgroundTrench foot, or non-freezing cold injury (NFCI), results from cold exposure of sufficient severity and duration above freezing point, with consequent sensory and vascular abnormalities which may persist for years. Based on observations of Trench foot in World War II, the condition was described as a vaso-neuropathy. While some reports have documented nerve damage after extreme cold exposure, sensory nerve fibres and vasculature have not been assessed with recent techniques in NFCI.ObjectiveTo assess patients with chronic sensory symptoms following cold exposure, in order to diagnose any underlying small fibre neuropathy, and provide insight into mechanisms of the persistent pain and cold hypersensitivity.MethodsThirty soldiers with cold exposure and persistent sensory symptoms (>4 months) were assessed with quantitative sensory testing, nerve conduction studies, and skin biopsies. Immunohistochemistry was used to assess intraepidermal (IENF) and subepidermal (SENF) nerve fibres with a range of markers, including the pan-neuronal marker protein gene product 9.5 (PGP 9.5), regenerating fibres with growth-associated protein 43 (GAP43), and nociceptor fibres with transient receptor potential cation channel subfamily V member 1 (TRPV1), sensory neuron-specific receptor (SNSR), and calcitonin gene-related peptide (CGRP). von Willebrand factor (vWF), endothelial nitric oxide synthase (eNOS), and vascular endothelial growth factor (VEGF) were used for assessing blood vessels, and transient receptor potential cation channel, subfamily A member 1 (TRPA1) and P2X purinoceptor 7 (P2X7) for keratinocytes, which regulate nociceptors via release of nerve growth factor.ResultsClinical examination showed pinprick sensation was abnormal in the feet of 20 patients (67%), and between 67 and 83% had abnormalities of thermal thresholds to the different modalities. 7 patients (23%) showed reduced sensory action potential amplitude of plantar nerves. 27 patients (90%) had decreased calf skin PGP 9.5 IENF (p < 0.0001), the remaining 3 patients had decreased nerve markers in subepidermis or foot skin. There were marked increases of all vascular markers (for vWF in calf skin, p < 0.0001), and increased sensory or regenerating SENF (for calf skin, GAP43, p = 0.002). TRPA1 (p = 0.0012) and P2X7 (p < 0.0001) were increased in basal keratinocytes.ConclusionA range of skin biopsy markers and plantar nerve conduction studies are useful objective assessments for the diagnosis of peripheral neuropathy in NFCI. Our results suggest that an increase in blood vessels following tissue ischaemia/hypoxia could be associated with disproportionate and abnormal nerve fibres (irritable nociceptors), and may lead to NFCI as a “painful vaso-neuropathy.”

Nonfreezing Cold Injury in a Pediatric Hiker

“…2,3 While the exact underlying etiology of this condition is unknown, both vascular and neurological etiologies have been proposed, including sensory neuropathy related to reduction in intraepidermal nerve fiber density. 4,5 The literature on NFCI has been limited to predominantly military populations, though it has also been described in other individuals at risk for prolonged exposure to wet and cold environments including fishermen, homeless populations, alcoholics, and hikers. While other similar injuries such as frostbite have been described in children, there is currently no literature detailing NFCI in pediatric patients.…”

Increased Intraepidermal Nerve Fiber Degeneration and Impaired Regeneration Relate to Symptoms and Deficits in Parkinson's Disease

“…In the present study, we show a reduction in both IETNFL/length and IETNFL/area, indicating impaired IENF regeneration in patients with moderate PD. Anand et al have also used GAP-43 staining to show increased sensory or regenerating subepidermal nerve fibers in non-freezing cold injury (36).…”

Capsaicin 8% Patch Treatment in Non-Freezing Cold Injury: Evidence for Pain Relief and Nerve Regeneration

“…Nerve conduction and sympathetic skin response (SSR) studies were performed only at baseline to characterise the neuropathy, on a Medtronic Keypoint electromyogram system (Medtronic, Minneapolis, MN, USA) ( 3 ). Antidromic sensory action potentials for the sural and superficial peroneal nerves and orthodromic sensory action potentials for the medial and lateral plantar, median, and ulnar nerves on both sides were recorded.…”

“…An underlying small fibre neuropathy and neuro-vascular changes have been demonstrated recently in skin biopsies, which may account for the chronic pain and persistent cold hypersensitivity ( 3 ). Currently prescribed oral treatments for neuropathic pain generally have limited efficacy, with multiple side effects.…”