Epidermal Nerve Fiber Density: Normative Reference Range and Diagnostic Efficiency
Abstract
BACKGROUND: The sensitivity of neuron-specific antibodies permit the identification of the small unmyelinated nerve fibers within the skin. OBJECTIVES: To develop a reference range of epidermal nerve fiber density in humans, and to evaluate their diagnostic efficiency for sensory neuropathies. METHODS: Ninety-eight normal controls (age range, 13-82 years) were examined with both directed neurologic examinations and quantitative sensory testing. The diagnostic utility was examined in 20 patients with sensory neuropathies. Each subject had 2 punch biopsies performed at each site in the thigh and distal part of the leg (total of 392 biopsies). After formalin fixation, 50-microm-thick free-floating sections were stained with a polyclonal antibody to neuron-specific ubiquitin hydrolase, anti-protein gene product 9.5. We enumerated intraepidermal nerve fibers per millimeter to derive a "linear density." The linear density technique was validated against a stereological technique that used the fractionator to measure the total length of intraepidermal nerve fibers per 3-mm punch. RESULTS: The biopsy technique was well tolerated, with no notable complications. The linear density quantitation was rapid and had high intraobserver and interobserver reliability. We determined that the density of intraepidermal fibers in normal controls was 21.1+/-10.4 per millimeter (mean +/- SD) in the thigh (fifth percentile, 5.2 per millimeter), and was 13.8+/-6.7 per millimeter at the distal part of…
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The authors' normative values for IENFD are based merely on one standard deviation from the mean, and published studies reported similar or higher cut-off values.
“Our normative values for IENFD are already based merely on one standard deviation from the mean, considering that published studies addressing normative values for IENFD reported similar or even higher cut-off values.19,24,29”
From Pain and small fiber pathology in men with fibromyalgia syndrome (2024) · cites this paper as [29]
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- Authors
- McArthur, J. C., Stocks, E. A., Hauer, P., Cornblath, D. R., & Griffin, J. W.
- Affiliations
- Johns Hopkins University (US)
- Venue
- Archives of Neurology
- Publisher
- American Medical Association (AMA)
- Published
- 1998-12-01
- Volume
- 55
- Issue
- 12
- Pages
- 1513
- ISSN
- 0003-9942 (ISSN-L)
- OpenAlex
- W2024864390
- Cited by
- 560
- References
- 0
- Citations by year
- 2026: 13 · 2025: 10 · 2024: 13 · 2023: 15 · 2022: 18 · 2021: 16 · 2020: 25 · 2019: 29 · 2018: 24 · 2017: 22 · 2016: 16 · 2015: 25 · 2014: 28 · 2013: 29 · 2012: 17
- FWCI
- 3.82
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Archives of Neurology (publishedVersion, public-domain)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r01ns014784-18)
- National Institute of Neurological Disorders and Stroke (P01NS026643, NS 14784, NS 26643)
- National Center for Research Resources (M01RR000722, RR00722)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
- Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
- Health Sciences › Medicine › Neurology › Peripheral Neuropathies and Disorders
- Keywords
- epidermal nerve fiber density, intraepidermal nerve fibers, sensory neuropathy, quantitative sensory testing, reference values, diagnostic accuracy, proximal-distal gradient, skin biopsy, positive predictive value, negative predictive value, neuropathic pain
- MeSH terms
- Epidermal Cells, Adolescent, Adult, Aged, Aged, 80 and over, Antibodies, Axons, Biopsy, Cell Count, Epidermis, Female, Humans, Male, Middle Aged, Nerve Fibers, Peripheral Nervous System Diseases, Predictive Value of Tests, Reference Values
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