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Normative Reference Range and Diagnostic Efficiency

Justin C. McArthur, MBBS, MPH; E. Adelaine Stocks, MS; Peter Hauer, BS; David R. Cornblath, MD; John W. Griffin, MD

Arch Neurol. 1998;55:1513-1520.

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-µm-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 the leg (fifth percentile, 3.8 per millimeter). Significantly higher intraepidermal fiber densities were seen in the youngest group (P=.004), and we observed no significant effect of race, sex, height, or weight. The density at the thigh was significantly correlated with that at the distal part of the leg (P=.01) and was consistently higher by about 60%, a reflection of the normal proximal-distal gradient. The results obtained with stereology and the linear density correlated significantly (P=.001), providing internal validation for the technique. Epidermal nerve fiber density was significantly reduced (P=.001) in patients with sensory neuropathies. With a cutoff derived from the fifth percentile of the normative range for the distal part of the leg, the technique had a positive predictive value of 75%, a negative predictive value of 90%, and a diagnostic efficiency of 88%.

Conclusions  We have established a reference range for intraepidermal nerve fiber density in normal humans by means of a simple quantitation method based on enumeration of individual intraepidermal nerve fibers on vertical sections of punch skin biopsy specimens stained with the sensitive panaxonal marker anti–protein gene product 9.5. The utility of the density measurement was confirmed for sensory neuropathy with a diagnostic efficiency of 88%. Skin biopsies may be useful to assess the spatial distribution of involvement in peripheral nerve disease and the response to neurotrophic and other restorative therapies.

From the Departments of Neurology (Drs McArthur, Cornblath, and Griffin, Ms Stocks, and Mr Hauer) and Neuroscience (Dr Griffin), The Johns Hopkins University School of Medicine, Baltimore, Md.

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