Validation of the nerve axon reflex for the assessment of small nerve fibre dysfunction

Objective

To validate nerve–axon reflex‐related vasodilatation as an objective method to evaluate C‐nociceptive fibre function by comparing it with the standard diagnostic criteria.

Methods

Neuropathy was evaluated in 41 patients with diabetes (26 men and 15 women) without peripheral vascular disease by assessing the Neuropathy Symptom Score, the Neuropathy Disability Score (NDS), the vibration perception threshold (VPT), the heat detection threshold (HDT), nerve conduction parameters and standard cardiovascular tests. The neurovascular response to 1% acetylcholine (Ach) iontophoresis was measured at the forearm and at both feet by laser flowmetry. An age‐matched and sex‐matched control group of 10 healthy people was also included.

Results

Significant correlations were observed between the neurovascular response at the foot and HDT (r_s = −0.658; p<0.0001), NDS (r_s = −0.665; p<0.0001), VPT (r_s = −0.548; p = 0.0005), tibial nerve conduction velocity (r_s = 0.631; p = 0.0002), sural nerve amplitude (r_s = 0.581; p = 0.0002) and autonomic function tests. According to the NDS, in patients with diabetes who had mild, moderate or severe neuropathy, a significantly lower neurovascular response was seen at the foot than in patients without neuropathy and controls. A neurovascular response <50% was found to be highly sensitive (90%), with a good specificity (74%), in identifying patients with diabetic neuropathy.

Conclusion

Small‐fibre dysfunction can be diagnosed reliably with neurovascular response assessment. This response is already reduced in the early stages of peripheral neuropathy, supporting the hypothesis that small‐fibre impairment is an early event in the natural history of diabetic neuropathy.Diabetic neuropathy includes nerve fibres with both small and large diameter.¹ Small‐fibre neuropathy remains a diagnostic challenge because currently available techniques are not objective, have a high variability and are not routinely applied.^2,3 Consequently, the diagnosis of small‐fibre neuropathy can easily be missed.Assessment of nerve–axon reflex‐related vasodilatation, or neurovascular response, has been proposed as an objective method to quantify C‐nociceptive fibre function.⁴ Activation of peripheral C‐fibres by different noxious stimuli, or activation experimentally by acetylcholine (Ach), leads to the conduction of the impulse, both orthodromically to the spinal cord and antidromically to other branches of the same C‐fibres, which then release vasodilating neuropeptides. This vasodilative response is part of Lewis''s triple anti‐inflammatory response.⁵This neurovascular response is impaired in patients with diabetic neuropathy.⁶ Moreover, local anaesthesia markedly reduces the neurovascular response in controls and patients with diabetes without peripheral neuropathy, whereas in patients with diabetic peripheral neuropathy, the already low neurovascular response at the foot does not decrease further after the induction of local anaesthesia.⁷As all previous findings indicate that C‐fibre function is the main determinant of the neurovascular response, it is reasonable to hypothesise that the assessment of this response may be used as a surrogate measure of C‐fibre integrity. The aim of the present study was therefore to validate the neurovascular response for the assessment of small‐fibre function by comparing it with the currently used techniques.