A Meta-Analysis of Intraepidermal Nerve Fibre Density in Healthy and Neuropathic Subjects: A Proposed Guidance Model

Background: Skin spot biopsy is the gold standard for diagnosis of small fibre neuropathy. Here we systematically approached intraepidermal nerve fibre density (IENFD) with the aim of precisely estimating its value in healthy and neuropathic subjects. The present findings will serve as a guidance model for further use of IENFD, as an indicator of neuropathy predisposition. We also investigated how IENFD was influenced by age, gender, and neuropathy. Methods: We conducted a systematic search of PubMed, Web of Science, and ScienceDirect to identify clinical studies published during the last twenty years (1997-2017), which investigated IENFD in healthy and neuropathic adult population. Data were retrieved from longitudinal cohort studies including 5-188 healthy adult subjects and 6-40 neuropathic adult patients. We used meta-analysis techniques including multilevel meta-regression. Findings: In the healthy population, the estimated (95% CI) IENFD values (in fibres/mm) were 21.4 (19.9, 22.9) in the thigh, 17*7 (15.3, 20.1) in the forearm, 12*9 (11.8, 14.0) in the distal leg, 11*3 (6.1, 16.5) in the fingers, and 6*5 (4.4, 8.6) in the toes. The corresponding estimates in the neuropathic population were 17*2 (15.2, 19.2) in the thigh, 6*3 (2.3, 10.2) in the forearm, 5*1 (3.8, 6.4) in the distal leg, and 2*0 (0.0, 5.7) in the toes. In the healthy population, IENFD decreased with ageing, by 1*4 fibres/mm every 5 years (p