Quantitative and qualitative normative dataset for intraepidermal nerve fibers using skin biopsy

Abstract

BackgroundSkin biopsy is the most relevant tool to diagnose small-fiber neuropathy. A well-documented normal dataset for intraepidermal nerve fiber in the distal leg is required to improve its diagnostic value.MethodsThree hundred healthy subjects were enrolled in the study, after clinical and biological screening to exclude neurological and systemic pathologies. A distal leg biopsy was taken and intraepidermal nerve fiber density after protein gene product-9.5 immunocytochemistry with brightfield microscopy was determined. Morphological variations of intraepidermal nerve fibers, previously described in small-fiber neuropathies, were analyzed. One hundred biopsies were also analyzed at the ultrastructural level.FindingsThe median number of fibers was lower in men compared to women and decreased with age. Using statistical modeling taking into account age and gender, we calculated the 5th percentile of intraepidermal nerve fiber density as follows: 7.6156–0.0769 x age (years) + 1.5506 x gender (woman = 1; man = 0). We observed a low frequency of large swellings or horizontal branchings but an increasing frequency of small swellings of intraepidermal nerve fibers and irregular distribution along the dermal-epidermal junction with age. Axonal diameter of unmyelinated fibers of the papillary dermis did not vary with age or gender. Ultrastructural analysis also showed that fiber endings in close apposition to Merkel cells should not be mistaken for small-fiber swellings.ConclusionsOur dataset allows accurate calculation of the normal density of intraepidermal nerve fibers for each year of age and provides original morphological observations that improve the diagnostic value of skin biopsy in the distal leg for small-fiber neuropathy.

Functional and histological improvements of small nerve neuropathy after high-concentration capsaicin patch application: A case study

“…10 IENF density was assessed with bright-field immunohistochemistry. In this patient, a reduced IEFN density was shown at distal leg 3.03 IENF/mm (lower fifth percentile normal IENF density for the age and gender, as defined by Collongues et al 6 , is 4.9 IENF/mm). Extensive explorations were made to find the origin, although none was found, and she was diagnosed with idiopathic small fiber neuropathy.…”

“…10 A more recent study published new intraepidermal nerve fiber (IEFN) density normative values for clinical use for each year of age and patients' sex. 6…”

Diagnosis and management of sensory polyneuropathy

“…201 It is a reproducible and reliable technique with a specificity greater than 90%, sensitivity approaching 80%, and favorable positive and negative predictive values 12202203204. Multiple large cohort studies have been conducted to establish normative values for IENFD at the distal leg because age, ethnicity, and sex are known to produce variations 202203205. A recent longitudinal case-control study showed that rates of IENFD decrease are similar at proximal and distal biopsy sites, regardless of cause, supporting a non-length dependent process 41.…”

Intraepidermal nerve fibre density as biomarker in Charcot–Marie–Tooth disease type 1A

“…In healthy subjects, IENFD is known to decrease with age, whereas women have higher IENFDs compared with men of the same age ( Collongues et al , 2018 ). In previous studies, IENFD has consistently been reported to be decreased in biopsies from the distal leg or the fingertips in CMT1A ( Nolano et al , 2015 ; Duchesne et al , 2018 ).…”