Intraepidermal Nerve Fiber Density as an Indicator of Neuropathy Predisposition: A Systematic Review with Meta-Analysis.

: Skin spot biopsy is the gold standard for diagnosing small fiber neuropathy. A systematic approach to intraepidermal nerve fiber density (IENFD) was conducted to estimate its value precisely in healthy and neuropathic subjects, independent of the neuropathy disease. The findings will serve as a guidance model for IENFD as an indicator of neuropathy predisposition. It was also investigated how IENFD was influenced by age, gender, and neuropathy. : A systematic search of PubMed, Web of Science, and ScienceDirect was conducted to identify clinical studies from 1997 to 2022 concerning IENFD in healthy and neuropathic adult populations. Data were retrieved from longitudinal cohort studies, including 5-188 healthy and 6-40 neuropathic patients. Multilevel meta-regression was employed to assess associations between the anatomical region, mean patient age, and male/female ratio with IENFD. This method accounted for correlations between multiple outcomes from the same survey, offering a more nuanced analysis than standard meta-regression. : In the healthy population, the estimated (95% CI) IENFD values (fibers/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 a healthy population, IENFD decreased with aging by 1.35 fibers/mm every 5 years ( < 0.001). Gender dimorphism in IENFD existed, with females showing higher values in the distal leg (13.6-10.5) compared to males (9.3-7.2). : The systematic study and meta-analysis integrate evidence of IENFD in skin biopsies. This analysis reconciles findings from various methodologies and populations over two decades. Meta-regression techniques address variability due to biopsy site, fixation protocols, immunohistochemical markers, and demographics. To reduce future study heterogeneity, using the thigh is advisable as it shows the least variability. Additionally, standardizing the biopsy site internationally will ensure comparability. These findings urge further investigation into IENFD changes in neurodegenerative diseases and whether IENFD can be a reliable prognostic marker for neuropathy diagnosis.