Journal List > Korean J Clin Neurophysiol > v.17(2) > 1084160

Sohn: Skin Biopsy: Emerging Method for Small Nerve Fiber Evaluation

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)

REFERENCES

1.Wang L., Hilliges M., Jernberg T., Wiegleb-Edstrom D., Johansson O. Protein gene product 9.5-immunoreactive nerve fibres and cells in human skin. Cell tissue Res. 1990. 261:25–33.
crossref
2.Kennedy WR., Wendelschafer-Crabb G. The innervation of human epidermis. J Neurol Sci. 1993. 115:184–190.
crossref
3.McCarthy BG., Hsieh ST., Stocks A., Hauer P., Macko C., Cornblath DR, et al. Cutaneous innervation in sensory neuropathies: Evaluation by skin biopsy. Neurology. 1995. 45:1848–1855.
crossref
4.Lauria G., Cornblath DR., Johansson O., McArthur JC., Mellgren SI., Nolano M, et al. Efns guidelines on the use of skin biopsy in the diagnosis of peripheral neuropathy. Eur J Neurol. 2005. 12:747–758.
crossref
5.Lauria G., Hsieh ST., Johansson O., Kennedy WR., Leger JM., Mellgren SI, et al. 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. 17:903–912. e944-909.
6.Wang N., Gibbons CH. Skin biopsies in the assessment of the autonomic nervous system. Handb Clin Neurol. 2013. 117:371–378.
crossref
7.Braverman IM. The cutaneous microcirculation. J Investig Dermatol Symp Proc. 2000. 5:3–9.
crossref
8.Mellgren SI., Nolano M., Sommer C. The cutaneous nerve biopsy: Technical aspects, indications, and contribution. Handb Clinical Neurol. 2013. 115:171–188.
9.Wang N., Gibbons CH., Freeman R. Novel immunohistochemical techniques using discrete signal amplification systems for human cutaneous peripheral nerve fiber imaging. J Histochem Cytochem. 2011. 59:382–390.
crossref
10.Pittenger GL., Ray M., Burcus NI., McNulty P., Basta B., Vinik AI. Intraepidermal nerve fibers are indicators of small-fiber neuropathy in both diabetic and nondiabetic patients. Diabetes care. 2004. 27:1974–1979.
crossref
11.Chai J., Herrmann DN., Stanton M., Barbano RL., Logigian EL. Painful small-fiber neuropathy in sjogren syndrome. Neurology. 2005. 65:925–927.
crossref
12.Kennedy WR., Wendelschafer-Crabb G. Utility of skin biopsy in diabetic neuropathy. Semin Neurol. 1996. 16:163–171.
crossref
13.Di Leo R., Nolano M., Boman H., Pierangeli G., Provitera V., Knappskog PM, et al. Central and peripheral autonomic failure in cold-induced sweating syndrome type 1. Neurology. 2010. 75:1567–1569.
crossref
14.Donadio V., Nolano M., Elam M., Montagna P., Provitera V., Bugiardini E, et al. Anhidrosis in multiple system atrophy: A preganglionic sudomotor dysfunction? Mov Disord. 2008. 23:885–888.
crossref
15.Lauria G., Bakkers M., Schmitz C., Lombardi R., Penza P., Devigili G, et al. Intraepidermal nerve fiber density at the distal leg: A worldwide normative reference study. J Peripher Nerv Syst. 2010. 15:202–207.
crossref
16.Devigili G., Tugnoli V., Penza P., Camozzi F., Lombardi R., Melli G, et al. The diagnostic criteria for small fibre neuropathy: From symptoms to neuropathology. Brain. 2008. 131:1912–1925.
crossref
17.Nebuchennykh M., Loseth S., Jorde R., Mellgren SI. Idiopathic polyneuropathy and impaired glucose metabolism in a norwegian patient series. Eur J Neurol. 2008. 15:810–816.
crossref
18.Nolano M., Provitera V., Donadio V., Stancanelli A., Saltalamacchia A., Caporaso G, et al. Ross syndrome: A lesson from a monozygotic twin pair. Neurology. 2013. 80:417–418.
crossref
19.Nolano M., Provitera V., Perretti A., Stancanelli A., Saltalamacchia AM., Donadio V, et al. Ross syndrome: A rare or a misknown disorder of thermoregulation? A skin innervation study on 12 subjects. Brain. 2006. 129:2119–2131.
crossref
20.Smith AG., Ramachandran P., Tripp S., Singleton JR. Epidermal nerve innervation in impaired glucose tolerance and diabetes- associated neuropathy. Neurology. 2001. 57:1701–1704.
21.Sumner CJ., Sheth S., Griffin JW., Cornblath DR., Polydefkis M. The spectrum of neuropathy in diabetes and impaired glucose tolerance. Neurology. 2003. 60:108–111.
crossref
22.Chao CC., Hsieh ST., Shun CT., Hsieh SC. Skin denervation and cutaneous vasculitis in eosinophilia-associated neuropathy. Arch Neurol. 2007. 64:959–965.
crossref
23.Tseng MT., Hsieh SC., Shun CT., Lee KL., Pan CL., Lin WM, et al. Skin denervation and cutaneous vasculitis in systemic lupus erythematosus. Brain. 2006. 129:977–985.
crossref
24.Nolano M., Manganelli F., Provitera V., Pisciotta C., Stancanelli A., Caporaso G, et al. Small nerve fiber involvement in cmt1a. Neurology. 2015. 84:407–414.
crossref
25.Sghirlanzoni A., Pareyson D., Lauria G. Sensory neuron diseases. Lancet Neurol. 2005. 4:349–361.
crossref
26.Kennedy WR., Wendelschafer-Crabb G., Brelje TC. Innervation and vasculature of human sweat glands: An immunohistochemistry-laser scanning confocal fluorescence microscopy study. J Neurosci. 1994. 14:6825–6833.
crossref
27.Dabby R., Djaldetti R., Shahmurov M., Treves TA., Gabai B., Melamed E, et al. Skin biopsy for assessment of autonomic denervation in parkinson's disease. J Neural transm (Vienna). 2006. 113:1169–1176.
crossref
28.Dabby R., Vaknine H., Gilad R., Djaldetti R., Sadeh M. Evaluation of cutaneous autonomic innervation in idiopathic sensory small-fiber neuropathy. J Peripher Nerv Syst. 2007. 12:98–101.
crossref
29.Gibbons CH., Illigens BM., Wang N., Freeman R. Quantification of sudomotor innervation: A comparison of three methods. Muscle Nerve. 2010. 42:112–119.
crossref
30.Gibbons CH., Illigens BM., Wang N., Freeman R. Quantification of sweat gland innervation: A clinical-pathologic correlation. Neurology. 2009. 72:1479–1486.
crossref
31.Tesfaye S., Boulton AJ., Dyck PJ., Freeman R., Horowitz M., Kempler P, et al. Diabetic neuropathies: Update on definitions, diagnostic criteria, estimation of severity, and treatments. Diabetes care. 2010. 33:2285–2293.
crossref
32.Nolano M., Provitera V., Caporaso G., Stancanelli A., Vitale DF., Santoro L. Quantification of pilomotor nerves: A new tool to evaluate autonomic involvement in diabetes. Neurology. 2010. 75:1089–1097.
crossref
33.Sohn E., Gibbons CH., Wang N., Freeman R. Quantitative analysis of human cutaneous vasomotor innervation. Auton Neurosci Basic Clin. 2015. 192:114.
crossref
34.Beach TG., White CL., Hamilton RL., Duda JE., Iwatsubo T., Dickson DW, et al. Evaluation of alpha-synuclein immunohistochemical methods used by invited experts. Acta neuropathol. 2008. 116:277–288.
35.Shannon KM., Keshavarzian A., Mutlu E., Dodiya HB., Daian D., Jaglin JA, et al. Alpha-synuclein in colonic submucosa in early untreated parkinson's disease. Mov Disord. 2012. 27:709–715.
crossref
36.Pouclet H., Lebouvier T., Coron E., des Varannes SB., Rouaud T., Roy M, et al. A comparison between rectal and colonic biopsies to detect lewy pathology in parkinson's disease. Neurobiol Dis. 2012. 45:305–309.
crossref
37.Orimo S., Uchihara T., Nakamura A., Mori F., Kakita A., Wakabayashi K, et al. Axonal alpha-synuclein aggregates herald centripetal degeneration of cardiac sympathetic nerve in parkinson's disease. Brain. 2008. 131:642–650.
38.Nolano M., Provitera V., Estraneo A., Selim MM., Caporaso G., Stancanelli A, et al. Sensory deficit in parkinson's disease: Evidence of a cutaneous denervation. Brain. 2008. 131:1903–1911.
crossref
39.Wang N., Gibbons CH., Lafo J., Freeman R. Alpha-synuclein in cutaneous autonomic nerves. Neurology. 2013. 81:1604–1610.
40.Schneider SA., Boettner M., Alexoudi A., Zorenkov D., Deuschl G., Wedel T. Can we use peripheral tissue biopsies to diagnose parkinson's disease? A review of the literature. Eur J Neurol. 2015.
crossref
41.Shin RK., Galetta SL., Ting TY., Armstrong K., Bird SJ. Ross syndrome plus: Beyond horner, holmes-adie, and harlequin. Neurology. 2000. 55:1841–1846.
crossref

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).
kjcn-17-53f1.tif
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.
kjcn-17-53f2.tif
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))
kjcn-17-53f3.tif
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).
kjcn-17-53f4.tif
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).
kjcn-17-53f5.tif
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).
kjcn-17-53f6.tif
Table 1.
Normal values of intraepidermal nerve fiber density at the ankle
Age Females (n = 97) Males (n = 91)
Age (years) 0.05 Quantile values per age span Median values per age span 0.05 Quantile values per age span Median values per age span
20-29 6.7 11.2 5.4 9.0
30-39 6.1 10.7 4.7 8.4
40-49 5.2 9.9 4.0 7.8
50-59 4.1 8.7 3.2 7.1
60-69 3.3 7.9 2.4 6.3
≥70 2.7 7.2 2.0 5.9
TOOLS
Similar articles