This 30-year old patient presented with tingling and burning sensation to their feet and ankles. Electrodiagnostic studies (NCS) showed no evidence of large fiber neuropathy.
What are the dark staining structures which extend upward into the epidermis?
A. Melanocytes
B. Nerve fibers
C. Blood vessels
D. Squamous cells
This medium magnification image of the stained skin biopsy shows the subepidermal nerve plexus (large arrow) and intraepidermal nerve fibers (small arrows) which penetrate the subepidermal basement membrane and extend into the epidermis.
Answer: Nerve fibers
The quantification of intraepidermal nerve fibers is useful in helping to establish the diagnosis of a “small fiber neuropathy”. These neuropathies can be debilitating and have a variety of causes.
Typically 3mm punch biopsies are taken from 10 cm above the lateral malleolus (and 10cm distal to the greater trochanter to enable evaluation of a proximal body site for comparison). The biopsies need to be fixed in Zamboni’s fixative (2% paraformaldehyde and picric acid) or PLP (periodate-lysine-paraformaldehyde) rather than formalin.
Thick frozen sections (50um) are stained with PGP9.5 as floating sections to highlight the small nerve fibers. After the sections are stained they are transferred to a glass slide for microscopic evaluation. It is interesting that a “relatively” non-invasive 3mm skin punch biopsy can give you information about the peripheral nervous system.
Reference(s) / additional reading:
Devigili G, Rinaldo S, Lombardi R, Cazzato D, Marchi M, Salvi E, Eleopra R, Lauria G. Diagnostic criteria for small fibre neuropathy in clinical practice and research. Brain. 2019 Dec 1;142(12):3728-3736. doi: 10.1093/brain/awz333. PMID: 31665231; PMCID: PMC6906595.
Lauria G, Hsieh ST, Johansson O, Kennedy WR, Leger JM, Mellgren SI, Nolano M, Merkies IS, Polydefkis M, Smith AG, Sommer C, Valls-Solé J; European Federation of Neurological Societies; Peripheral Nerve Society. European Federation of Neurological Societies/Peripheral Nerve Society Guideline on the use of skin biopsy in the diagnosis of small fiber neuropathy. Report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society. Eur J Neurol. 2010 Jul;17(7):903-12, e44-9. doi: 10.1111/j.1468-1331.2010.03023.x. PMID: 20642627.
Kennedy WR, Wendelschafer-Crabb G. The innervation of human epidermis. J Neurol Sci. 1993 Apr;115(2):184-90. doi: 10.1016/0022-510x(93)90223-l. PMID: 8482979.
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