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From the Departments of Neurology (Drs. McCarthy, Hsieh, Macko, Cornblath, Griffin, and McArthur, and A. Stocks and P. Hauer) and Neuroscience (Dr. Griffin), Johns Hopkins University School of Medicine, and the Department of Epidemiology (Dr. McArthur), School of Hygiene and Public Health, Johns Hopkins University, Baltimore, MD.
Presented in part at the 46th annual meeting of the American Academy of Neurology, Washington, DC, May 1994.
Supported by AI 35042, NS PO1-26643, NS PO1-22849, and 5M01 RR 00722, and by Genentech Inc.
Received December 13, 1994. Accepted in final form February 20, 1995.
Address correspondence and reprint requests to Dr. Justin McArthur, Johns Hopkins Hospital, Meyer 6-109, 600 N. Wolfe Street, Baltimore, MD 21287-7609.
Objective: To use punch skin biopsies to evaluate the loss of intra-epidermal nerve fibers in sensory neuropathies. Background: Previous assessments of epidermal nerve fibers have been constrained by relatively insensitive staining techniques and variability in quantification. Methods: Punch skin biopsies were performed on the heel and leg of HIV-seronegative controls, HIV-seropositive individuals without neuropathy, and patients with sensory neuropathies, including HIV-seronegative and HIV-positive individuals. After formalin fixation, 50-micro meter free-floating sections were stained with a monoclonal antibody to neuron-specific ubiquitin hydrolase, PGP9.5. The number of intraepidermal fibers/mm in at least three sections from each patient was counted by one observer blinded to site and clinical status. Results: Dermal and epidermal nerve fibers were readily identified and quantified. The immunostaining technique reliably demonstrated a dermal plexus of myelinated and unmyelinated fibers parallel to the surface of the skin. In the epidermis, unmyelinated fibers ascended vertically between the keratinocytes to reach the stratum corneum. The number of intra-epidermal fibers/mm in the distal leg (mean plus minus SEM) was 17.84 plus minus 3.03 in seven HIV-seronegative controls. Epidermal fiber number was significantly reduced (p equals 0.01) in five HIV-infected patients with sensory neuropathies associated with didanosine or zalcitabine therapy (1.07 plus minus 0.40) and in eight HIV-seronegative patients with sensory neuropathies (3.1 plus minus 3.1). Four of five neurologically normal HIV-seropositive subjects had reduced numbers of epidermal fibers, suggesting a subclinical neuropathy. Serial biopsies in one individual demonstrated the evolution of degenerating epidermal fibers after development of zalcitabine-induced sensory neuropathy. Conclusion: Skin biopsies stained with the sensitive panaxonal marker anti-PGP9.5 demonstrated significant reduction in intraepidermal fibers in sensory neuropathies. This simple and repeatable technique is a reliable method for quantitation of small cutaneous sensory fibers. In addition, skin biopsies may be useful in assessing the course and spatial distribution of involvement in peripheral nerve disease.
NEUROLOGY 1995;45: 1848-1855
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