What techniques have been used to investigate NFCI?
Cold sensitivity
Sensitivity to cold can either be measured qualitatively using tools such as the cold intolerance symptom severity (CISS) questionnaire [1] or quantitatively using a cold sensitivity test (CST). In the CST, a cold hand or foot skin temperature (measured using thermography) in an ambient temperature of 30 °C and a slow rate of rewarming following a short cold exposure (2 minutes immersion in 15 °C water) are taken to indicate cold sensitivity. Individuals with chronic NFCI are generally more cold sensitive than control participants with similar previous cold exposure (without NFCI) or minimal previous cold exposure [2]. However, a wide range of responses are observed in an apparently “normal” uninjured population [3, 4], with individuals undertaking recreational activities such as windsurfing and open water swimming being cold sensitive in the absence of a NFCI [5, 6]. Whilst giving an indication of cold sensitivity, on its own, the CST is not able to diagnose NFCI [7].
Sensory neuropathy and neuropathic pain
Some patients who have sustained an NFCI can suffer from localised nerve damage (sensory neuropathy) which is sometimes associated with chronic neuropathic pain. Neuropathic pain is diagnosed using a widely accepted clinical algorithm which is used in the assessment of NFCI patients who report persisting sensory symptoms and pain [8]. Two tests are used to support this algorithm: quantitative sensory testing (QST) and skin biopsy for measurement of intraepidermal nerve fibre density (IENFD) [9].
Quantitative sensory testing (QST)
QST is used to characterise the somatosensory phenotype of individuals with neuropathic pain and has been used in a variety of patient populations (e.g. diabetics [10]). The standardised protocol for QST includes a number of measures of sensory function, although in practice in the diagnosis of NFCI-associated nerve damage (neuropathy) and associated neuropathic pain only warm detection threshold, cold detection threshold, thermal sensory limen, mechanical detection threshold, mechanical pain and stimulus/response function, vibration detection and pressure pain are routinely measured [11].
Individuals with chronic NFCI assessed at a neuropathic pain clinic were found to have impaired thermal (warm and cold), vibration and mechanical thresholds compared to normative values [12]. In another study, warm and mechanical thresholds were elevated in individuals with NFCI in their feet compared to matched controls [13]. The difference in results between these two studies can be attributed to the severity of NFCI and the comparator control group employed. Therefore, whilst QST is useful in identifying sensory function impairment, it is only used in the context of the above algorithm.
Intraepidermal nerve fibre density (IENFD)
IENFD testing identifies the number (density) of small nerve fibres in a skin biopsy sample which cross the basement membrane of the epidermis. Reduced IENFD have been found in skin biopsies taken from the calf in individuals with NFCI [12, 13] indicating small fibre neuropathy and were found to be negatively related to heat pain threshold [12]. A reduction in IENFD without any changes in thermal or mechanical detection thresholds has been reported in a single case study following severe cold exposure indicating there may be an effect of cold per se [14].
Blood screening
Sensory neuropathy can occur in other conditions and therefore it is important to rule these out using blood tests
Diabetes
HbA1c > 48 mmol/mol
Hepatitis B
HBsAg, anti-HBs and total anti-HBc levels [15]