Validation of the Histamine‐ and Heat‐Induced Axon‐Reflex Flare Response in a Nonselected Population of People With Type 1 Diabetes

Introduction/Aims Diabetic peripheral neuropathy affects small nerve fibers early, but adequate evaluation has proven difficult. One method for functional assessment of small nerve fiber function is the axon‐reflex flare (ARF) response. This study aimed to 1) validate the histamine‐induced ARF response in a nonselected population with diabetes, 2) compare the response to that induced by local heating, and 3) compare both methods to an established method (quantitative sensory testing) in a nonselected population with diabetes. Methods Thirty‐four participants with type 1 diabetes were included. The participants underwent a neurological examination, quantitative sensory testing, sural nerve conduction, and histamine‐ and heat‐induced ARF response measurements by full‐field laser speckle perfusion imaging after epidermal application of histamine and after local heating by 44° Celsius thermode, respectively. Spearman's correlations were assessed. Logistic regression was used to generate receiver operating characteristic curves using the cold detection threshold of quantitative sensory testing as reference. Results The histamine‐induced ARF had an area under the curve (AUC) of 0.82, a sensitivity of 67%, and a specificity of 70%. The heat‐induced ARF had an AUC of 0.40, a sensitivity of 36%, and a specificity of 57%. No significant correlation between the histamine‐ and the heat‐induced ARF responses was found. Discussion The histamine‐induced ARF response is a valid marker for small fiber neuropathy even in nonselected populations with diabetes with good agreement with established markers and can thus be used for evaluation of C‐fiber function. The lack of correlation with the heat‐induced ARF may be due to insufficient heating.