Chronic non-freezing cold injury results in neuropathic pain due to a sensory neuropathy

Abstract

Non-freezing cold injury develops after sustained exposure to cold temperatures, resulting in tissue cooling but not freezing. This can result in persistent sensory disturbance of the hands and feet including numbness, paraesthesia and chronic pain. Both vascular and neurological aetiologies of this pain have been suggested but remain unproven. We prospectively approached patients referred for clinical assessment of chronic pain following non-freezing cold injury between 12 February 2014 and 30 November 2016. Of 47 patients approached, 42 consented to undergo detailed neurological evaluations including: questionnaires to detail pain location and characteristics, structured neurological examination, quantitative sensory testing, nerve conduction studies and skin biopsy for intraepidermal nerve fibre assessment. Of the 42 study participants, all had experienced non-freezing cold injury while serving in the UK armed services and the majority were of African descent (76.2%) and male (95.2%). Many participants reported multiple exposures to cold. The median time between initial injury and referral was 3.72 years. Pain was principally localized to the hands and the feet, neuropathic in nature and in all study participants associated with cold hypersensitivity. Clinical examination and quantitative sensory testing were consistent with a sensory neuropathy. In all cases, large fibre nerve conduction studies were normal. The intraepidermal nerve fibre density was markedly reduced with 90.5% of participants having a count at or below the 0.05 centile of published normative controls. Using the Neuropathic Pain Special Interest Group of the International Association for the Study of Pain grading for neuropathic pain, 100% had probable and 95.2% definite neuropathic pain. Chronic non-freezing cold injury is a disabling neuropathic pain disorder due to a sensory neuropathy. Why some individuals develop an acute painful sensory neuropathy on sustained cold exposure is not yet known, but individuals of African descent appear vulnerable. Screening tools, such as the DN4 questionnaire, and treatment algorithms for neuropathic pain should now be used in the management of these patients.

Keywords: nerve conduction studies; neuropathic pain; peripheral nerve injury; sensory neuropathy; small fibre neuropathy.

Figure 1

Participant recruitment pathway. Flow diagram of the recruitment of study participants.

Figure 2

Pain was located in the distal extremities and had neuropathic qualities. (A) Composite heat map depicting the location of neuropathic pain (in red) and non-neuropathic pain (blue) reported by study participants. Study participants completed a body map highlighting the distribution of any pain experienced as part of the BPI questionnaire. (B) Histogram illustrating the frequency of different neuropathic pain characteristics from the DN4 questionnaire. The bars in purple (electric shock–burning) are pain descriptors. The bars in green (itching–tingling) are associated symptoms.

Figure 3

Small fibre pathology was demonstrated on skin biopsy. (A) Scatter plot and mean (95% CI) for IENFD assessment. The mean (95% CI) IENFD for NFCI participants was 3.9 fibres/mm (3.5–4.4). Blue circles represent values below the 0.05 quantile reference value for age/gender. Green circles represent values at or above the 0.05 quantile reference value. Red circles represent healthy African American study participants, whose IENFDs were all above the 0.05 quantile reference value for age and gender. (B) Bright field images of skin biopsies taken from the leg of (i) a healthy study participant; and (ii) participant with NFCI demonstrating PGP 9.5-immunoreactive fibres (arrow heads) crossing the basement membrane of the epidermis (dashed line). Scale bar = 40 μm. There is a clear reduction in intraepidermal nerve fibres in the participant with NFCI.

Figure 4

Worse neuropathy is associated with more recent injury and more severe pain. Sensory impairment was demonstrated on QST. Scatter plot and mean (95% CI) for QST parameters in the (A) hand and (B) foot. By comparing participant data to normative data from the DFNS a z-score can be generated, which indicates the number of standard deviations from the mean control population. Positive z-scores denote gain of function, whereas negative z-scores denote loss of function. There were significant reductions in the mean z-score in both the hand (for CDT, WDT, TSL, MDT and VDT) and foot (MDT and VDT). (C) Loss or gain of sensory function in the hand and foot. The y-axis shows the percentage of patients in each group with ‘gain’ of sensory function plotted upwards and ‘loss’ of sensory function plotted downwards i.e. z-scores that were greater or less than two standard deviations from the mean. CDT = cold detection threshold; CPT = cold pain threshold; DMA = dynamic mechanical allodynia; HPT = heat pain threshold; MDT = mechanical detection threshold; MPS = mechanical pain sensitivity; MPT = mechanical pain threshold; PHS = paradoxical heat sensation; PPT = pressure pain threshold; TSL = thermal sensory limen; VDT = vibration detection threshold; WDT = warm detection threshold; WUR = wind-up ratio.

Figure 5

Worse neuropathy is associated with more recent injury and more severe pain. Scatter plot of (A) time of injury to assessment, and (B) BPI pain severity, against sensory sum score showing that sensory deficits as a measure of neuropathy severity are negatively correlated (r = −0.45, P = 0.003) with the duration of time that had elapsed between injury and assessment (i.e. those participants in whom a longer period of time has elapsed have less severe deficits). More severe pain was positively correlated with sensory sum score (r = 0.42, P = 0.005), thus neuropathic pain is associated with a more extensive neuropathy as revealed on clinical examination. Spearman correlations.