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Abstract
Skin biopsy with investigation of small nerve fiber in human epidermis and dermis has been proven to be a useful method for demonstration of small fiber neuropathy. Quantification of intraepidermal nerve fiber density using anti-Protein Gene Product 9.5 (PGP 9.5) antibody is standardized method to diagnose the small fiber neuropathy. Skin biopsy method also makes it possible to differentiate the type of nerve fibers by using different antibodies. Quantification of dermal structures with different type of nerve fibers could be used to invest pathophysiologic mechanism of diseased state. (Korean J Clin Neurophysiol 2015;17:53-60)
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Fig. 1.
Nerve fibers of epidermis and superficial dermis. Epidermal nerve fibers (arrow) originate from the subepidermal neural plexus (arrow head) and travel vertically to the epidermal surface (anti-PGP 9.5 antibody for nerve fiber).
Fig. 2.
Dermal structures stained with anti-PGP 9.5 antibodies for nerve fibers (red) and anti-CD31 antibodies for blood vessels (green). (A,B) Deep dermal vessels are densely surrounded by innervating nerve fibers. (C) The nerve fibers innervating arrector pili muscle run parallel with muscle fibers. Intervening blood vessels were also showed. (D) Sweat gland and intervening capillaries. Sweat gland is innervated densely and complicatedly.
Fig. 3.
Samples of stained skin biopsy tissue. Epidermal C fiber and sub-epidermal neural plexus are located at the superficial dermis. Hair follicle travels from the deep dermis to the superficial dermis and arrector pili muscles are located near the hair follicle. Sweat glands are located in the deep dermis and innervated densely. (anti-PGP 9.5 antibodies for nerve fibers (green) and anti-CD31 antibodies for endothelia (red))
Fig. 4.
Example of images obtained by immunohistochemical staining. [A-C] A sweat gland. Endothelia of capillaries are stained with anti-CD31 antibody in green (A). Nerve fibers innervating sweat gland are stained with anti-PGP 9.5 antibody in red (B). Merged image (C). [D-F] A sweat gland and endothelia (anti-CD31 antibody, blue). Sympathetic cholinergic fibers are stained with anti-VIP antibody in green (D) and sympathetic adrenergic fibers are stained with anti-TH antibody in red (E). Merged image (F). [G-I] Cutaneous blood vessels. Endothelia are stained with anti-CD31 antibody in red and nerve fibers are stained with anti-PGP 9.5 antibody in green (G-I). [J-L] Arrector pili muscles are innervated with sympathetic adrenergic fibers (anti-TH antibody, J) and sympathetic cholinergic fibers (anti-VIP antibody, K). Merged image (L). (Originally adapted from Wang et al. 20136).
Fig. 5.
Dermal and epidermal nerve fibers stained with anti-PGP 9.5 antibodies. (A) Bright-field microscopy finding. Intraepidermal nerve fibers (arrow) cross from the sunepidermal neural plexus (arrow head) to the epidermis. (B) Confocal microscopy showing nerve fibers (in green) and blood vessels and basement membrane (in red).
Fig. 6.
Intraepidermal nerve fiber counting rule. Diagram of skin innervations: nerves (black), basement membrane (dark grey), dermis (medium grey), and epidermis (light grey). Nerve fibers which cross the basement membrane are only counted as one nerve fiber. Nerve fibers which branches after crossing the basement membrane or which resides only in the epidermis should be excluded when count the nerve fibers. The epidermal nerve fiber branches before crossing the basement membrane, it should be counted as two fibers (Originally adapted from Lauria et al., 20054).
Table 1.
Normal values of intraepidermal nerve fiber density at the ankle
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