Denervation of skin in neuropathies: the sequence of axonal and Schwann cell changes in skin biopsies
1Departments of Neurology, 2Pathology, 3Epidemiology and 4Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21287-7609/7613, USA
Correspondence to: John W. Griffin, M.D., Professor, Departments of Neurology, Neuroscience, and Pathology, Johns Hopkins University School of Medicine, 600 N. Wolfe St, Meyer 6-113, Baltimore, MD 21287-7613, USA E-mail: jgriffi{at}jhmi.edu
We compared the pathological changes in cutaneous axons and Schwann cells of individuals with nerve transection to the changes in patients with chronic neuropathies. Following axotomy there was segmentation of axons in the epidermis and dermis on the first day, and loss of axons from the skin was virtually complete by Day 11. Epidermal and small superficial dermal axons were lost before larger caliber and deeper dermal axons. Within the first 50 days following nerve transection, the denervated Schwann cells in the dermis were easily identified by their markers p75 and S100, but by 8 months they had largely disappeared.
The chronic neuropathy patients had distally predominant fibre loss, with greater loss of epidermal and dermal fibres in the distal regions of the leg than proximal regions. Several patients had large axonal swellings, often alternating with axonal attenuation, even in regions with normal or nearly normal fibre densities. By electron microscopy the swellings contained accumulations of mitochondria and other particulate organelles as well as neurofilaments. These swellings are likely to represent predegenerative changes in sites of impaired axonal transport, and previous data indicate that the swellings presage fibre loss in the subsequent months.
Some of the severely denervated regions had remaining Schwann cells, as judged by immunocytochemistry and by electron microscopy, but others lacked Schwann cells. By analogy with animal experiments, these regions are likely to have had more prolonged denervation. The distribution of axonal loss, the axonal swellings and the changes in Schwann cells all have implications for the design of clinical trials of agents intended to protect cutaneous innervation and to promote regeneration of cutaneous axons in peripheral neuropathies.
Key Words: epidermis; dermis; unmyelinated axon; Schwann cell; skin biopsy
Abbreviations: IENF, intraepidermal nerve fibre; EM, electron microscopy; ATN, antiretroviral toxic neuropathy; SSN, silent sensory polyneuropathy; ISN, idiopathic sensory neuropathy; IR, immunoreactivity
Received March 20, 2007. Revised July 31, 2007. Accepted August 2, 2007.
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