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Pathology of Small Fiber Neuropathy: Skin Biopsy for the Analysis of Nociceptive Nerve Fibers

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Small Fiber Neuropathy and Related Syndromes: Pain and Neurodegeneration
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Abstract

Reduced skin innervation as shown by immunostaining in skin biopsies is a sensitive and specific indicator of small fiber neuropathy (SFN). Standard methods for staining and quantification have been established, and normative values are available. However, not every condition with reduced skin innervation is a SFN, and not all types of disorders with pathological small fiber function manifest with reduced skin innervation. Identification of nociceptor subpopulations in humans in the skin is only beginning to yield data. Detection of inflammatory cells and pathologic deposits are additional diagnostic benefits of skin biopsy.

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References

  1. McGlone F, Reilly D. The cutaneous sensory system. Neurosci Biobehav Rev. 2010;34:148–59.

    Article  PubMed  Google Scholar 

  2. Doppler K, Rittner HL, Deckart M, Sommer C. Reduced dermal nerve fiber diameter in skin biopsies of patients with fibromyalgia. Pain. 2015;156:2319–25.

    Article  CAS  PubMed  Google Scholar 

  3. Nolano M, Provitera V, Crisci C, Stancanelli A, Wendelschafer-Crabb G, Kennedy WR, et al. Quantification of myelinated endings and mechanoreceptors in human digital skin. Ann Neurol. 2003;54:197–205.

    Article  PubMed  Google Scholar 

  4. 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.

    Article  CAS  PubMed  Google Scholar 

  5. Kennedy WR, Wendelschafer-Crabb G. The innervation of human epidermis. J Neurol Sci. 1993;115:184–90.

    Article  CAS  PubMed  Google Scholar 

  6. 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;45:1848–55.

    Article  CAS  PubMed  Google Scholar 

  7. McArthur JC, Stocks EA, Hauer P, Cornblath DR, Griffin JW. Epidermal nerve fiber density: normative reference range and diagnostic efficiency. Arch Neurol. 1998;55:1513–20.

    Article  CAS  PubMed  Google Scholar 

  8. 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;12:747–58.

    Article  CAS  PubMed  Google Scholar 

  9. Lauria G, Borgna M, Morbin M, Lombardi R, Mazzoleni G, Sghirlanzoni A, et al. Tubule and neurofilament immunoreactivity in human hairy skin: markers for intraepidermal nerve fibers. Muscle Nerve. 2004;30:310–6.

    Article  PubMed  Google Scholar 

  10. Albrecht PJ, Hines S, Eisenberg E, Pud D, Finlay DR, Connolly MK, et al. Pathologic alterations of cutaneous innervation and vasculature in affected limbs from patients with complex regional pain syndrome. Pain. 2006;120:244–66.

    Article  PubMed  Google Scholar 

  11. Uno H, Parker F. Autonomic innervation of the skin in primary erythermalgia. Arch Dermatol. 1983;119:65–71.

    Article  CAS  PubMed  Google Scholar 

  12. Donadio V, Nolano M, Provitera V, Stancanelli A, Lullo F, Liguori R, et al. Skin sympathetic adrenergic innervation: an immunofluorescence confocal study. Ann Neurol. 2006;59:376–81.

    Article  PubMed  Google Scholar 

  13. 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;129:2119–31.

    Article  PubMed  Google Scholar 

  14. 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;14:6825–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Wilder-Smith EP, Chow A. Comparison of a simple method for quantitation of intraepidermal nerve fibres with a standard image analysis method using hypothenar skin. J Neurol. 2006;253:1011–5.

    Article  PubMed  Google Scholar 

  16. Chien HF, Tseng TJ, Lin WM, Yang CC, Chang YC, Chen RC, et al. Quantitative pathology of cutaneous nerve terminal degeneration in the human skin. Acta Neuropathol (Berl). 2001;102:455–61.

    CAS  Google Scholar 

  17. Kennedy WR, Wendelschafer-Crabb G, Polydefkis M, McArthur J. Pathology and quantitation of cutaneous nerves. In: Dyck PJ, Thomas PK, editors. Peripheral neuropathy. 4th ed. Philadelphia: Saunders; 2005. p. 869–96.

    Chapter  Google Scholar 

  18. 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;17:903–12, e44–9.

    Article  CAS  PubMed  Google Scholar 

  19. Ebenezer GJ, Hauer P, Gibbons C, McArthur JC, Polydefkis M. Assessment of epidermal nerve fibers: a new diagnostic and predictive tool for peripheral neuropathies. J Neuropathol Exp Neurol. 2007;66:1059–73.

    Article  PubMed  Google Scholar 

  20. Goransson LG, Mellgren SI, Lindal S, Omdal R. The effect of age and gender on epidermal nerve fiber density. Neurology. 2004;62:774–7.

    Article  CAS  PubMed  Google Scholar 

  21. Bakkers M, Merkies IS, Lauria G, Devigili G, Penza P, Lombardi R, et al. Intraepidermal nerve fiber density and its application in sarcoidosis. Neurology. 2009;73:1142–8.

    Article  CAS  PubMed  Google Scholar 

  22. Burns TM, Smith AG. “Measure twice, cut once”: improving diagnostic accuracy of skin biopsy. Neurology. 2012;79:2164–5.

    Article  PubMed  Google Scholar 

  23. Seger S, Stritt M, Doppler K, Frank S, Panaite A, Kuntzer T, et al. A semi-automated method to assess intraepidermal nerve fibre density in human skin biopsies. Histopathology. 2016;68:657–65.

    Article  PubMed  Google Scholar 

  24. Umapathi T, Tan WL, Tan NC, Chan YH. Determinants of epidermal nerve fiber density in normal individuals. Muscle Nerve. 2006;33:742–6.

    Article  CAS  PubMed  Google Scholar 

  25. Pan CL, Lin YH, Lin WM, Tai TY, Hsieh ST. Degeneration of nociceptive nerve terminals in human peripheral neuropathy. Neuroreport. 2001;12:787–92.

    Article  CAS  PubMed  Google Scholar 

  26. Nolano M, Biasiotta A, Lombardi R, Provitera V, Stancanelli A, Caporaso G, et al. Epidermal innervation morphometry by immunofluorescence and bright-field microscopy. J Peripher Nerv Syst. 2015;20:387–91.

    Article  CAS  PubMed  Google Scholar 

  27. 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;15:202–7.

    Article  PubMed  Google Scholar 

  28. Collongues N, Samama B, Schmidt-Mutter C, Chamard-Witkowski L, Debouverie M, Chanson JB, et al. Quantitative and qualitative normative dataset for intraepidermal nerve fibers using skin biopsy. PLoS One. 2018;13:e0191614.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Vlckova-Moravcova E, Bednarik J, Dusek L, Toyka KV, Sommer C. Diagnostic validity of epidermal nerve fiber densities in painful sensory neuropathies. Muscle Nerve. 2008;37:50–60.

    Article  PubMed  Google Scholar 

  30. Nebuchennykh M, Loseth S, Lindal S, Mellgren SI. The value of skin biopsy with recording of intraepidermal nerve fiber density and quantitative sensory testing in the assessment of small fiber involvement in patients with different causes of polyneuropathy. J Neurol. 2009;256:1067–75.

    Article  PubMed  Google Scholar 

  31. Engelstad JK, Taylor SW, Witt LV, Hoebing BJ, Herrmann DN, Dyck PJ, et al. Epidermal nerve fibers: confidence intervals and continuous measures with nerve conduction. Neurology. 2012;79:2187–93.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Donadio V, Incensi A, Giannoccaro MP, Cortelli P, Di Stasi V, Pizza F, et al. Peripheral autonomic neuropathy: diagnostic contribution of skin biopsy. J Neuropathol Exp Neurol. 2012;71:1000–8.

    Article  PubMed  Google Scholar 

  33. Kennedy WR, Wendelschafer-Crabb G. Utility of skin biopsy in diabetic neuropathy. Semin Neurol. 1996;16:163–71.

    Article  CAS  PubMed  Google Scholar 

  34. Holland NR, Crawford TO, Hauer P, Cornblath DR, Griffin JW, McArthur JC. Small-fiber sensory neuropathies: clinical course and neuropathology of idiopathic cases. Ann Neurol. 1998;44:47–59.

    Article  CAS  PubMed  Google Scholar 

  35. Holland NR, Stocks A, Hauer P, Cornblath DR, Griffin JW, McArthur JC. Intraepidermal nerve fiber density in patients with painful sensory neuropathy. Neurology. 1997;48:708–11.

    Article  CAS  PubMed  Google Scholar 

  36. Lauria G, Holland N, Hauer P, Cornblath DR, Griffin JW, McArthur JC. Epidermal innervation: changes with aging, topographic location, and in sensory neuropathy. J Neurol Sci. 1999;164:172–8.

    Article  CAS  PubMed  Google Scholar 

  37. Lauria G, Sghirlanzoni A, Lombardi R, Pareyson D. Epidermal nerve fiber density in sensory ganglionopathies: clinical and neurophysiologic correlations. Muscle Nerve. 2001;24:1034–9.

    Article  CAS  PubMed  Google Scholar 

  38. Herrmann DN, Griffin JW, Hauer P, Cornblath DR, McArthur JC. Epidermal nerve fiber density and sural nerve morphometry in peripheral neuropathies. Neurology. 1999;53:1634–40.

    Article  CAS  PubMed  Google Scholar 

  39. Periquet MI, Novak V, Collins MP, Nagaraja HN, Erdem S, Nash SM, et al. Painful sensory neuropathy: prospective evaluation using skin biopsy. Neurology. 1999;53:1641–7.

    Article  CAS  PubMed  Google Scholar 

  40. Scott LJ, Griffin JW, Luciano C, Barton NW, Banerjee T, Crawford T, et al. Quantitative analysis of epidermal innervation in Fabry disease. Neurology. 1999;52:1249–54.

    Article  CAS  PubMed  Google Scholar 

  41. Wakamoto H, Hirai A, Manabe K, Hayashi M. Idiopathic small-fiber sensory neuropathy in childhood: a diagnosis based on objective findings on punch skin biopsy specimens. J Pediatr. 1999;135:257–60.

    Article  CAS  PubMed  Google Scholar 

  42. Hsieh ST, Chiang HY, Lin WM. Pathology of nerve terminal degeneration in the skin. J Neuropathol Exp Neurol. 2000;59:297–307.

    Article  CAS  PubMed  Google Scholar 

  43. Polydefkis M, Allen RP, Hauer P, Earley CJ, Griffin JW, McArthur JC. Subclinical sensory neuropathy in late-onset restless legs syndrome. Neurology. 2000;55:1115–21.

    Article  CAS  PubMed  Google Scholar 

  44. Polydefkis M, Yiannoutsos CT, Cohen BA, Hollander H, Schifitto G, Clifford DB, et al. Reduced intraepidermal nerve fiber density in HIV-associated sensory neuropathy. Neurology. 2002;58:115–9.

    Article  CAS  PubMed  Google Scholar 

  45. Verze L, Viglietti-Panzica C, Plumari L, Calcagni M, Stella M, Schrama LH, et al. Cutaneous innervation in hereditary sensory and autonomic neuropathy type IV. Neurology. 2000;55:126–8.

    Article  CAS  PubMed  Google Scholar 

  46. Hoitsma E, Marziniak M, Faber CG, Reulen JP, Sommer C, De Baets M, et al. Small fibre neuropathy in sarcoidosis. Lancet. 2002;359:2085–6.

    Article  CAS  PubMed  Google Scholar 

  47. Boruchow SA, Gibbons CH. Utility of skin biopsy in management of small fiber neuropathy. Muscle Nerve. 2013;48:877–82.

    Article  PubMed  Google Scholar 

  48. 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;131:1912–25.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Abuzinadah AR, Kluding P, Wright D, D’Silva L, Ryals J, Hendry B, et al. Less is more in diabetic neuropathy diagnosis: comparison of quantitative sudomotor axon reflex and skin biopsy. J Clin Neuromuscul Dis. 2017;19:5–11.

    Article  PubMed  Google Scholar 

  50. Harrer JU, Uceyler N, Doppler K, Fischer TZ, Dib-Hajj SD, Waxman SG, et al. Neuropathic pain in two-generation twins carrying the sodium channel Nav1.7 functional variant R1150W. Pain. 2014;155:2199–203.

    Article  CAS  PubMed  Google Scholar 

  51. Üçeyler N, Ganendiran S, Kramer D, Sommer C. Characterization of pain in Fabry disease. Clin J Pain. 2014;30:915–20.

    Article  PubMed  Google Scholar 

  52. Üçeyler N, He L, Schönfeld D, Kahn AK, Reiners K, Hilz MJ, et al. Small fibers in Fabry disease: baseline and follow-up data under enzyme replacement therapy. J Peripher Nerv Syst. 2011;16:304–14.

    Article  PubMed  Google Scholar 

  53. Vlckova-Moravcova E, Bednarik J, Belobradkova J, Sommer C. Small-fibre involvement in diabetic patients with neuropathic foot pain. Diabet Med. 2008;25:692–9.

    Article  CAS  PubMed  Google Scholar 

  54. Sorensen L, Molyneaux L, Yue DK. The relationship among pain, sensory loss, and small nerve fibers in diabetes. Diabetes Care. 2006;29:883–7.

    Article  PubMed  Google Scholar 

  55. Günes HN, Bekircan-Kurt CE, Tan E, Erdem-Ozdamar S. The histopathological evaluation of small fiber neuropathy in patients with vitamin B12 deficiency. Acta Neurol Belg. 2018;118:405–10.

    Article  PubMed  Google Scholar 

  56. Üçeyler N, Vollert J, Broll B, Riediger N, Langjahr M, Saffer N, et al. Sensory profiles and skin innervation of patients with painful and painless neuropathies. Pain. 2018;159:1867–76.

    Google Scholar 

  57. Provitera V, Gibbons CH, Wendelschafer-Crabb G, Donadio V, Vitale DF, Loavenbruck A, et al. The role of skin biopsy in differentiating small-fiber neuropathy from ganglionopathy. Eur J Neurol. 2018;25:848–53.

    Article  CAS  PubMed  Google Scholar 

  58. Cazzato D, Lauria G. Small fibre neuropathy. Curr Opin Neurol. 2017;30:490–9.

    Article  CAS  PubMed  Google Scholar 

  59. Waxman SG, Merkies IS, Gerrits MM, Dib-Hajj SD, Lauria G, Cox JJ, et al. Sodium channel genes in pain-related disorders: phenotype-genotype associations and recommendations for clinical use. Lancet Neurol. 2014;13:1152–60.

    Article  CAS  PubMed  Google Scholar 

  60. Herrmann DN, O’Connor AB, Schwid SR, Da Y, Goodman AD, Rafferty J, et al. Broadening the spectrum of controls for skin biopsy in painful neuropathies. Muscle Nerve. 2010;42:436–8.

    Article  PubMed  Google Scholar 

  61. Ringkamp M, Raja SN, Campbell A, Meyer RA. Peripheral mechanisms of cutaneous nociception. In: McMahon SB, Koltzenburg M, Tracey I, Turk DC, editors. Wall and Melzack’s textbook of pain. Philadelphia: Elsevier; 2013. p. 1–30.

    Google Scholar 

  62. Taylor AM, Peleshok JC, Ribeiro-da-Silva A. Distribution of P2X(3)-immunoreactive fibers in hairy and glabrous skin of the rat. J Comp Neurol. 2009;514:555–66.

    Article  CAS  PubMed  Google Scholar 

  63. Nolano M, Provitera V, Caporaso G, Stancanelli A, Leandri M, Biasiotta A, et al. Cutaneous innervation of the human face as assessed by skin biopsy. J Anat. 2013;222:161–9.

    Article  PubMed  Google Scholar 

  64. Bechakra M, Schuttenhelm BN, Pederzani T, van Doorn PA, de Zeeuw CI, Jongen JLM. The reduction of intraepidermal P2X3 nerve fiber density correlates with behavioral hyperalgesia in a rat model of nerve injury-induced pain. J Comp Neurol. 2017;525:3757–68.

    Article  CAS  PubMed  Google Scholar 

  65. Schuttenhelm BN, Duraku LS, Dijkstra JF, Walbeehm ET, Holstege JC. Differential changes in the peptidergic and the non-peptidergic skin innervation in rat models for inflammation, dry skin itch, and dermatitis. J Invest Dermatol. 2015;135:2049–57.

    Article  PubMed  CAS  Google Scholar 

  66. McCoy ES, Taylor-Blake B, Street SE, Pribisko AL, Zheng J, Zylka MJ. Peptidergic CGRPalpha primary sensory neurons encode heat and itch and tonically suppress sensitivity to cold. Neuron. 2013;78:138–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Hsieh YL, Lin CL, Chiang H, Fu YS, Lue JH, Hsieh ST. Role of peptidergic nerve terminals in the skin: reversal of thermal sensation by calcitonin gene-related peptide in TRPV1-depleted neuropathy. PLoS One. 2012;7:e50805.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Dubin AE, Patapoutian A. Nociceptors: the sensors of the pain pathway. J Clin Invest. 2010;120:3760–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. da Silva Serra I, Husson Z, Bartlett JD, Smith ES. Characterization of cutaneous and articular sensory neurons. Mol Pain. 2016;12. https://doi.org/10.1177/1744806916636387.

    Article  CAS  Google Scholar 

  70. Wooten M, Weng HJ, Hartke TV, Borzan J, Klein AH, Turnquist B, et al. Three functionally distinct classes of C-fibre nociceptors in primates. Nat Commun. 2014;5:4122.

    Article  CAS  PubMed  Google Scholar 

  71. Lauria G, Morbin M, Lombardi R, Capobianco R, Camozzi F, Pareyson D, et al. Expression of capsaicin receptor immunoreactivity in human peripheral nervous system and in painful neuropathies. J Peripher Nerv Syst. 2006;11:262–71.

    Article  CAS  PubMed  Google Scholar 

  72. Axelsson HE, Minde JK, Sonesson A, Toolanen G, Hogestatt ED, Zygmunt PM. Transient receptor potential vanilloid 1, vanilloid 2 and melastatin 8 immunoreactive nerve fibers in human skin from individuals with and without Norrbottnian congenital insensitivity to pain. Neuroscience. 2009;162:1322–32.

    Article  CAS  PubMed  Google Scholar 

  73. Wilder-Smith EP, Ong WY, Guo Y, Chow AW. Epidermal transient receptor potential vanilloid 1 in idiopathic small nerve fibre disease, diabetic neuropathy and healthy human subjects. Histopathology. 2007;51:674–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Han SB, Kim H, Cho SH, Lee JD, Chung JH, Kim HS. Transient Receptor Potential Vanilloid-1 in Epidermal Keratinocytes May Contribute to Acute Pain in Herpes Zoster. Acta Derm Venereol. 2016;96:319–22.

    Article  CAS  PubMed  Google Scholar 

  75. Chao CC, Tseng MT, Lin YJ, Yang WS, Hsieh SC, Lin YH, et al. Pathophysiology of neuropathic pain in type 2 diabetes: skin denervation and contact heat-evoked potentials. Diabetes Care. 2010;33:2654–9.

    Article  PubMed  PubMed Central  Google Scholar 

  76. 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;129:977–85.

    Article  PubMed  Google Scholar 

  77. Casanova-Molla J, Morales M, Garrabou G, Sola-Valls N, Soriano A, Calvo M, et al. Mitochondrial loss indicates early axonal damage in small fiber neuropathies. J Peripher Nerv Syst. 2012;17:147–57.

    Article  CAS  PubMed  Google Scholar 

  78. Sommer C, Lindenlaub T, Zillikens D, Toyka KV, Naumann M. Selective loss of cholinergic sudomotor fibers causes anhidrosis in Ross syndrome. Ann Neurol. 2002;52:247–50.

    Article  PubMed  Google Scholar 

  79. Lauria G, Cazzato D, Porretta-Serapiglia C, Casanova-Molla J, Taiana M, Penza P, et al. Morphometry of dermal nerve fibers in human skin. Neurology. 2011;77:242–9.

    Article  CAS  PubMed  Google Scholar 

  80. Karlsson P, Porretta-Serapiglia C, Lombardi R, Jensen TS, Lauria G. Dermal innervation in healthy subjects and small fiber neuropathy patients: a stereological reappraisal. J Peripher Nerv Syst. 2013;18:48–53.

    Article  PubMed  Google Scholar 

  81. Doppler K, Frank F, Koschker AC, Reiners K, Sommer C. Nodes of Ranvier in skin biopsies of patients with diabetes mellitus. J Peripher Nerv Syst. 2017;22:182–90.

    Article  CAS  PubMed  Google Scholar 

  82. Doppler K, Werner C, Henneges C, Sommer C. Analysis of myelinated fibers in human skin biopsies of patients with neuropathies. J Neurol. 2012;259:1879–87.

    Article  PubMed  Google Scholar 

  83. Gibbons CH, Illigens BM, Wang N, Freeman R. Quantification of sweat gland innervation: a clinical-pathologic correlation. Neurology. 2009;72:1479–86.

    Article  PubMed  PubMed Central  Google Scholar 

  84. 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.

    Article  PubMed  Google Scholar 

  85. Kokotis P, Uceyler N, Werner C, Tsivgoulis G, Papanikola N, Katsanos AH, et al. Quantification of sweat gland innervation in patients with Fabry disease: a case-control study. J Neurol Sci. 2018;390:135–8.

    Article  PubMed  Google Scholar 

  86. Pare M, Smith AM, Rice FL. Distribution and terminal arborizations of cutaneous mechanoreceptors in the glabrous finger pads of the monkey. J Comp Neurol. 2002;445:347–59.

    Article  PubMed  Google Scholar 

  87. Rice FL, Albrecht PJ. Cutaneous mechanisms of tactile perception: morphological and chemical organization of the innervation to the skin. In: Basbaum A, Kaneko A, Shepherd GM, Westheimer G, editors. The senses. San Diego: Academic Press; 2008. p. 1–32.

    Google Scholar 

  88. Rice FL, Rasmusson DD. Innervation of the digit on the forepaw of the raccoon. J Comp Neurol. 2000;417:467–90.

    Article  CAS  PubMed  Google Scholar 

  89. Albrecht PJ, Hou Q, Argoff CE, Storey JR, Wymer JP, Rice FL. Excessive peptidergic sensory innervation of cutaneous arteriole-venule shunts (AVS) in the palmar glabrous skin of fibromyalgia patients: implications for widespread deep tissue pain and fatigue. Pain Med. 2013;14:895–915.

    Article  PubMed  Google Scholar 

  90. Üçeyler N, Devigili G, Toyka KV, Sommer C. Skin biopsy as an additional diagnostic tool in non-systemic vasculitic neuropathy. Acta Neuropathol. 2010;120:109–16.

    Article  PubMed  Google Scholar 

  91. Üçeyler N, Braunsdorf S, Kunze E, Riediger N, Scheytt S, Divisova S, et al. Cellular infiltrates in skin and sural nerve of patients with polyneuropathies. Muscle Nerve. 2017;55:884–93.

    Article  PubMed  CAS  Google Scholar 

  92. Casanova-Molla J, Morales M, Planas-Rigol E, Bosch A, Calvo M, Grau-Junyent JM, et al. Epidermal Langerhans cells in small fiber neuropathies. Pain. 2012;153:982–9.

    Article  PubMed  Google Scholar 

  93. Plante-Bordeneuve V. Transthyretin familial amyloid polyneuropathy: an update. J Neurol. 2018;265:976–83.

    Article  CAS  PubMed  Google Scholar 

  94. Adams D, Gonzalez-Duarte A, O’Riordan WD, Yang CC, Ueda M, Kristen AV, et al. Patisiran, an RNAi therapeutic, for hereditary transthyretin amyloidosis. N Engl J Med. 2018;379:11–21.

    Article  CAS  PubMed  Google Scholar 

  95. Benson MD, Waddington-Cruz M, Berk JL, Polydefkis M, Dyck PJ, Wang AK, et al. Inotersen treatment for patients with hereditary transthyretin amyloidosis. N Engl J Med. 2018;379:22–31.

    Article  CAS  PubMed  Google Scholar 

  96. Üçeyler N, Schröter N, Kafke W, Kramer D, Wanner C, Weidemann F, et al. Skin globotriaosylceramide 3 load is increased in men with advanced fabry disease. PLoS One. 2016;11:e0166484.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  97. Üçeyler N, Böttger J, Henkel L, Langjahr M, Mayer C, Nordbeck P, et al. Detection of blood Gb3 deposits as a new tool for diagnosis and therapy monitoring in patients with classic Fabry disease. J Intern Med. 2018;284:427–38.

    Article  PubMed  CAS  Google Scholar 

  98. Nolano M, Provitera V, Donadio V, Caporaso G, Stancanelli A, Califano F, et al. Cutaneous sensory and autonomic denervation in CADASIL. Neurology. 2016;86:1039–44.

    Article  PubMed  Google Scholar 

  99. Doppler K, Jentschke HM, Schulmeyer L, Vadasz D, Janzen A, Luster M, et al. Dermal phospho-alpha-synuclein deposits confirm REM sleep behaviour disorder as prodromal Parkinson’s disease. Acta Neuropathol. 2017;133:535–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Schrempf W, Katona I, Dogan I, Felbert VV, Wienecke M, Heller J, et al. Reduced intraepidermal nerve fiber density in patients with REM sleep behavior disorder. Parkinsonism Relat Disord. 2016;29:10–6.

    Article  PubMed  Google Scholar 

  101. Levine TD. Small fiber neuropathy: disease classification beyond pain and burning. J Cent Nerv Syst Dis. 2018;10:1179573518771703.

    Article  PubMed  PubMed Central  Google Scholar 

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Sommer, C. (2019). Pathology of Small Fiber Neuropathy: Skin Biopsy for the Analysis of Nociceptive Nerve Fibers. In: Hsieh, ST., Anand, P., Gibbons, C., Sommer, C. (eds) Small Fiber Neuropathy and Related Syndromes: Pain and Neurodegeneration. Springer, Singapore. https://doi.org/10.1007/978-981-13-3546-4_2

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