The diagnosis of small fiber neuropathy (SFN) is currently based on the presence of positive sensory symptoms and abnormal findings in thermal threshold testing (TTT). Decreased density of intraepidermal innervation (or its structural abnormities) seems to be a morphological correlate of small fiber dysfunction. Therefore, the assessment of intraepidermal nerve fibers (IENFs) density in skin punch biopsies as a new method for SFN diagnosis is introduced in this study. The aim of this work was to adopt a method of skin biopsy, to establish the reference values of IENFs density, and to correlate the skin biopsy results with TTT findings in a group of SFN patients. Methods: Skin punch biopsies were obtained from the distal calf of 17 healthy individuals and 76 SFN patients. IENFs were stained with antibodies to panneuronal marker PGP 9.5. The correlation between the skin biopsy findings and TTT results was calculated. Mean IENFs density was significatly higher in healthy volunteers if compared with SFN patients. Intraepidemal nerve fibers counts per millimeter of epidermis were 11.54 ± 2.87 (mean ± SD) and 5.98 ± 3.81, respectively (p< 0.0001). The reference value for IENFs density was calculated from the healthy volunteers findings and set at a value of 6.69 fibers per millimeter of epidermis (95. percentile). Using this normal limit, decreased intraepidermal nerve fibers density was found in 69% SFN patients. Skin biopsies reflect the structural changes of small sensory fibers and prove to be useful in the algorithm of SFN diagnosis, based on subjective sensitive symptoms and abnormal TTT findings at present. With respect to lower sensitivity (compared to TTT) and invasiveness of this method, the application of skin biopsy as a screening method is not convenient. Higher sensitivity of TTT (probably caused by the ability of TTT to reflect abnormal small fiber neuropathy function before the development of structural changes) together with its noninvasive character predetermine this method for the small fiber neuropathy screening.

        Key words: small fiber neuropathy, skin biopsy, thermal threshold testing, intraepidermal nerve fibers, protein gene product 9.5