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Uses of Skin Biopsy for Sensory and Autonomic Nerve Assessment

  • Nerve and Muscle (M Hirano and LH Weimer, Section Editors)
  • Published:
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Abstract

Skin biopsy is a valuable diagnostic tool for small-fiber-predominant neuropathy by the quantification of intraepidermal nerve fiber density (IENFD). It has the unique advantage of being a minimally invasive procedure with the potential for longitudinal evaluation of both sensory and autonomic fibers. Unmyelinated small fibers are not otherwise quantified objectively with such a level of sensitivity as has been reported with IENFD. Recent advances include an expansion of the skin punch biopsy technique to evaluate larger myelinated fibers and mechanoreceptors, and recent work has also focused on additional methods of quantifying dermal fibers and densely innervated autonomic structures. This review discusses current work using skin biopsy for the pathologic analysis of peripheral nerve fibers in neuropathy of various causes as well as its use in clinical trials.

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  1. Wang L, Hilliges M, Jernberg T, et al. Protein gene product 9.5-immunoreactive nerve fibres and cells in human skin. Cell Tissue Res. 1990;261:25–33.

    Article  PubMed  CAS  Google Scholar 

  2. Lauria G. Innervation of the human epidermis. A historical review. Ital J Neurol Sci. 1999;20:63–70.

    Article  PubMed  CAS  Google Scholar 

  3. Herrmann DN, Griffin JW, Hauer P, et al. Epidermal nerve fiber density and sural nerve morphometry in peripheral neuropathies. Neurology. 1999;53:1634–40.

    Article  PubMed  CAS  Google Scholar 

  4. Myers MI, Peltier AC, Li J. Evaluating dermal myelinated nerve fibers in skin biopsy. Muscle Nerve. 2012. doi:10.1002/mus.23510.

  5. Kennedy WR, Nolano M, Wendelschafer-Crabb G, et al. A skin blister method to study epidermal nerves in peripheral nerve disease. Muscle Nerve. 1999;22:360–71.

    Article  PubMed  CAS  Google Scholar 

  6. Herrmann DN, Boger JN, Jansen C, Alessi-Fox C. In vivo confocal microscopy of Meissner corpuscles as a measure of sensory neuropathy. Neurology. 2007;69:2121–7.

    Article  PubMed  Google Scholar 

  7. Almodovar JL, Ferguson M, McDermott MP, et al. In vivo confocal microscopy of Meissner corpuscles as a novel sensory measure in CMT1A. J Peripher Nerv Syst. 2011;16:169–74.

    Article  PubMed  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  9. Lauria G, Hsieh ST, Johansson O, 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;17:903–9.

    Article  PubMed  CAS  Google Scholar 

  10. Saporta MA, Katona I, Lewis RA, et al. Shortened internodal length of dermal myelinated nerve fibres in Charcot-Marie-Tooth disease type 1A. Brain. 2009;132:3263–73.

    Article  PubMed  Google Scholar 

  11. Ebenezer GJ, McArthur JC, Thomas D, et al. Denervation of skin in neuropathies: the sequence of axonal and Schwann cell changes in skin biopsies. Brain. 2007;130:2703–14.

    Article  PubMed  Google Scholar 

  12. Sommer C, Lauria G. Skin biopsy in the management of peripheral neuropathy. Lancet Neurol. 2007;6:632–42.

    Article  PubMed  Google Scholar 

  13. Smith AG, Howard JR, Kroll R, et al. The reliability of skin biopsy with measurement of intraepidermal nerve fiber density. J Neurol Sci. 2005;228:65–9.

    Article  PubMed  Google Scholar 

  14. Panoutsopoulou IG, Wendelschafer-Crabb G, Hodges JS, Kennedy WR. Skin blister and skin biopsy to quantify epidermal nerves: a comparative study. Neurology. 2009;72:1205–10.

    Article  PubMed  Google Scholar 

  15. Manganelli F, Iodice V, Provitera V, et al. Small-fiber involvement in spinobulbar muscular atrophy (Kennedy's disease). Muscle Nerve. 2007;36:816–20.

    Article  PubMed  Google Scholar 

  16. Nolano M, Provitera V, Crisci C, et al. Small fibers involvement in Friedreich's ataxia. Ann Neurol. 2001;50:17–25.

    Article  PubMed  CAS  Google Scholar 

  17. Kennedy WR, Wendelschafer-Crabb G, Polydefkis M, McArthur JC. Pathology and quantitation of cutaneous innervation. In: Dyck PJ, Thomas PK, editors. Peripheral meuropathy. Philadelphia: Elsevier; 2005. p. 869–95.

    Chapter  Google Scholar 

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

    Article  PubMed  Google Scholar 

  19. • Gibbons CH, Illigens BM, Wang N, Freeman R. Quantification of sudomotor innervation: a comparison of three methods. Muscle Nerve. 2010;42:112–19. This study compared unbiased stereologic techniques, a recently published novel sudomotor quantification method, and semiquantitative methods of ranking the degree of sweat gland innervation. The authors reported a fast and reliable automated method of quantification and caution against semiquantitative methods shown to have low reliability and little clinical correlation.

  20. • Nolano M, Provitera V, Caporaso G, et al. Quantification of pilomotor nerves: a new tool to evaluate autonomic involvement in diabetes. Neurology 2010;75:1089–97. Nolano et al. recently proposed a new method of quantification of pilomotor nerves by counting fibers from a single frame of a confocal z stack. They reported high interobserver and intraobserver reliability with the technique. They described a reduction in the autonomic innervation of the pilomotor nerves of diabetic patients, with the severest depletion of noradrenergic dopamine β-hydroxylase immunoreactive fibers.

  21. Casanova-Molla J, Morales M, Sola-Valls N, et al. Axonal fluorescence quantitation provides a new approach to assess cutaneous innervation. J Neurosci Methods. 2011;200:190–8.

    Article  PubMed  Google Scholar 

  22. Vega JA, Garcia-Suarez O, Montano JA, et al. The Meissner and Pacinian sensory corpuscles revisited new data from the last decade. Microsc Res Tech. 2009;72:299–309.

    Article  PubMed  Google Scholar 

  23. Nolano M, Provitera V, Crisci C, et al. Quantification of myelinated endings and mechanoreceptors in human digital skin. Ann Neurol. 2003;54:197–205.

    Article  PubMed  Google Scholar 

  24. Dyck PJ. Enumerating Meissner corpuscles: future gold standard of large fiber sensorimotor polyneuropathy? Neurology. 2007;69:2116–8.

    Article  PubMed  Google Scholar 

  25. Pare M, Albrecht PJ, Noto CJ, et al. Differential hypertrophy and atrophy among all types of cutaneous innervation in the glabrous skin of the monkey hand during aging and naturally occurring type 2 diabetes. J Comp Neurol. 2007;501:543–67.

    Article  PubMed  Google Scholar 

  26. Provitera V, Nolano M, Pappone N. di GC, et al.: Distal degeneration of sensory and autonomic cutaneous nerve fibres in systemic sclerosis. Ann Rheum Dis. 2005;64:1524–6.

    Article  PubMed  CAS  Google Scholar 

  27. •• Hutton EJ, Carty L, Laura M, et al. c-Jun expression in human neuropathies: a pilot study. J Peripher Nerv Syst. 2011;16:295–303. In an interesting recent study, glabrous skin biopsies and sural nerve biopsies were examined for an upregulation of c-Jun expression as a marker of Schwann cell plasticity. A clear sign of nuclear Schwann cell expression of c-Jun was seen in glabrous skin biopsies from patients with Charcot–Marie–Tooth disease type 1A, GBS, and CIDP, suggesting c-Jun as a marker of dedifferentiation and demyelination.

  28. Verma A. Epidemiology and clinical features of HIV-1 associated neuropathies. J Peripher Nerv Syst. 2001;6:8–13.

    Article  PubMed  CAS  Google Scholar 

  29. Polydefkis M, Yiannoutsos CT, Cohen BA, et al. Reduced intraepidermal nerve fiber density in HIV-associated sensory neuropathy. Neurology. 2002;58:115–9.

    Article  PubMed  CAS  Google Scholar 

  30. Simpson DM, Katzenstein D, Haidich B, et al. Plasma carnitine in HIV-associated neuropathy. AIDS. 2001;15:2207–8.

    Article  PubMed  CAS  Google Scholar 

  31. Simpson DM, Kitch D, Evans SR, et al. HIV neuropathy natural history cohort study: assessment measures and risk factors. Neurology. 2006;66:1679–87.

    Article  PubMed  CAS  Google Scholar 

  32. McArthur JC, Stocks EA, Hauer P, et al. Epidermal nerve fiber density: normative reference range and diagnostic efficiency. Arch Neurol. 1998;55:1513–20.

    Article  PubMed  CAS  Google Scholar 

  33. Lauria G, Bakkers M, Schmitz C, 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 

  34. Callaghan BC, Cheng HT, Stables CL, et al. Diabetic neuropathy: clinical manifestations and current treatments. Lancet Neurol. 2012;11:521–34.

    Article  PubMed  Google Scholar 

  35. Bursova S, Dubovy P, Vlckova-Moravcova E, et al. Expression of growth-associated protein 43 in the skin nerve fibers of patients with type 2 diabetes mellitus. J Neurol Sci. 2012;315:60–3.

    Article  PubMed  CAS  Google Scholar 

  36. Singleton JR, Smith AG. Therapy insight: neurological complications of prediabetes. Nat Clin Pract Neurol. 2006;2:276–82.

    Article  PubMed  Google Scholar 

  37. Malik RA, Tesfaye S, Newrick PG, et al. Sural nerve pathology in diabetic patients with minimal but progressive neuropathy. Diabetologia. 2005;48:578–85.

    Article  PubMed  CAS  Google Scholar 

  38. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group. N Engl J Med. 1993;329:977–86.

  39. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352:854–65.

  40. Burakgazi AZ, Messersmith W, Vaidya D, et al. Longitudinal assessment of oxaliplatin-induced neuropathy. Neurology. 2011;77:980–6.

    Article  PubMed  CAS  Google Scholar 

  41. Burakgazi AZ, Polydefkis M, Hoke A. Skin biopsy-proven flecainide-induced neuropathy. Muscle Nerve. 2012;45:144–6.

    Article  PubMed  Google Scholar 

  42. Tan IL, Polydefkis MJ, Ebenezer GJ, et al. Peripheral nerve toxic effects of nitrofurantoin. Arch Neurol. 2012;69:265–8.

    Article  PubMed  Google Scholar 

  43. Koskinen MJ, Kautio AL, Haanpaa ML, et al. Intraepidermal nerve fibre density in cancer patients receiving adjuvant chemotherapy. Anticancer Res. 2011;31:4413–6.

    PubMed  CAS  Google Scholar 

  44. Erasmus Medical Center: Skin biopsies in chemotherapy-induced neuropathy. 2011. http://clinicaltrials.gov/ct2/show/NCT00956033?term=skin+biopsy&rank=12. Accessed Sep 2012.

  45. •• 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. This study evaluated both unmyelinated epidermal fibers and myelinated dermal fibers in proximal thigh biopsies from a large cohort of patients with neuropathy of various causes, revealing abnormalities in both fiber populations. This study demonstrates the valuable potential to investigate both large-fiber and small-fiber innervation in skin biopsy.

  46. Myers MI, Li J, Artibee K, Peltier AC. Evaluation of dermal myelinated fibers in diabetic polyneuropathy. Paper presented at the American Academy of Neurology annual meeting. New Orleans; 21-28 April, 2012.

  47. • Lauria G, Cazzato D, Porretta-Serapiglia C, et al. Morphometry of dermal nerve fibers in human skin. Neurology 2011;77:242–9. The dermis is densely innervated by nerves typically arranged in large bundles that have proven difficult to quantify. Lauria et al. proposed a new method of quantifying dermal nerve fiber density by delineating a manageable portion of the dermis (200 μm below the basement membrane) and measuring the length of dermal nerves. Reported values demonstrated reliability and reproducibility, indicating that the method could potentially be used in clinical practice.

  48. England JD, Gronseth GS, Franklin G, et al. Practice parameter: the evaluation of distal symmetric polyneuropathy: the role of laboratory and genetic testing (an evidence-based review). Report of the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation. PM R 2009;1:5–13.

  49. Periquet MI, Novak V, Collins MP, et al. Painful sensory neuropathy: prospective evaluation using skin biopsy. Neurology. 1999;53:1641–7.

    Article  PubMed  CAS  Google Scholar 

  50. Freeman R, Chase KP, Risk MR. Quantitative sensory testing cannot differentiate simulated sensory loss from sensory neuropathy. Neurology. 2003;60:465–70.

    Article  PubMed  Google Scholar 

  51. Selim MM, Wendelschafer-Crabb G, Hodges JS, et al. Variation in quantitative sensory testing and epidermal nerve fiber density in repeated measurements. Pain. 2010;151:575–81.

    Article  PubMed  Google Scholar 

  52. Narayanaswamy H, Facer P, Misra VP, et al. A longitudinal study of sensory biomarkers of progression in patients with diabetic peripheral neuropathy using skin biopsies. J Clin Neurosci. 2012;19:1490–6.

    Article  PubMed  CAS  Google Scholar 

  53. Lee G, Xiang Z, Brannagan III TH, et al. Differential gene expression in chronic inflammatory demyelinating polyneuropathy (CIDP) skin biopsies. J Neurol Sci. 2010;290:115–22.

    Article  PubMed  CAS  Google Scholar 

  54. Lombardi R, Erne B, Lauria G, et al. IgM deposits on skin nerves in anti-myelin-associated glycoprotein neuropathy. Ann Neurol. 2005;57:180–7.

    Article  PubMed  CAS  Google Scholar 

  55. Pan CL, Tseng TJ, Lin YH, et al. Cutaneous innervation in Guillain-Barré syndrome: pathology and clinical correlations. Brain. 2003;126:386–97.

    Article  PubMed  Google Scholar 

  56. Ceuterick-deGroote GC, De JP, Timmerman V, et al. Infantile demyelinating neuropathy associated with a de novo point mutation on Ser72 in PMP22 and basal lamina onion bulbs in skin biopsy. Pathol Res Pract. 2001;197:193–8.

    Article  CAS  Google Scholar 

  57. Lee JE, Shun CT, Hsieh SC, Hsieh ST. Skin denervation in vasculitic neuropathy. Arch Neurol. 2005;62:1570–3.

    Article  PubMed  Google Scholar 

  58. Dib-Hajj SD, Cummins TR, Black JA, Waxman SG. Sodium channels in normal and pathological pain. Annu Rev Neurosci. 2010;33:325–47.

    Article  PubMed  CAS  Google Scholar 

  59. Dib-Hajj SD, Rush AM, Cummins TR, et al. Gain-of-function mutation in Nav1.7 in familial erythromelalgia induces bursting of sensory neurons. Brain. 2005;128:1847–54.

    Article  PubMed  CAS  Google Scholar 

  60. Dib-Hajj SD, Cummins TR, Black JA, Waxman SG. From genes to pain: Nav1.7 and human pain disorders. Trends Neurosci. 2007;30:555–63.

    Article  PubMed  CAS  Google Scholar 

  61. Cox JJ, Reimann F, Nicholas AK, et al. An SCN9A channelopathy causes congenital inability to experience pain. Nature. 2006;444:894–8.

    Article  PubMed  CAS  Google Scholar 

  62. Faber CG, Hoeijmakers JG, Ahn HS, et al. Gain of function Nav1.7 mutations in idiopathic small fiber neuropathy. Ann Neurol. 2012;71:26–39.

    Article  PubMed  CAS  Google Scholar 

  63. Han C, Hoeijmakers JG, Liu S, et al. Functional profiles of SCN9A variants in dorsal root ganglion neurons and superior cervical ganglion neurons correlate with autonomic symptoms in small fibre neuropathy. Brain. 2012;135:2613–28.

    Article  PubMed  Google Scholar 

  64. Han C, Hoeijmakers JG, Ahn HS, et al. Nav1.7-related small fiber neuropathy: impaired slow-inactivation and DRG neuron hyperexcitability. Neurology. 2012;78:1635–43.

    Article  PubMed  CAS  Google Scholar 

  65. Thakor DK, Lin A, Matsuka Y, et al. Increased peripheral nerve excitability and local NaV1.8 mRNA up-regulation in painful neuropathy. Mol Pain. 2009;5:14.

    Article  PubMed  Google Scholar 

  66. Craner MJ, Klein JP, Renganathan M, et al. Changes of sodium channel expression in experimental painful diabetic neuropathy. Ann Neurol. 2002;52:786–92.

    Article  PubMed  CAS  Google Scholar 

  67. Smith AG, Russell J, Feldman EL, et al. Lifestyle intervention for pre-diabetic neuropathy. Diabetes Care. 2006;29:1294–9.

    Article  PubMed  Google Scholar 

  68. Shikuma C, Gerschenson M, Ananworanich J, et al. Determinants of epidermal nerve fibre density in antiretroviral-naive HIV-infected individuals. HIV Med. 2012;13:602–8.

    Article  PubMed  Google Scholar 

  69. Valcour V, Yeh TM, Bartt R, et al. Acetyl-l-carnitine and nucleoside reverse transcriptase inhibitor-associated neuropathy in HIV infection. HIV Med. 2009;10:103–10.

    Article  PubMed  CAS  Google Scholar 

  70. Schiffmann R, Hauer P, Freeman B, et al. Enzyme replacement therapy and intraepidermal innervation density in Fabry disease. Muscle Nerve. 2006;34:53–6.

    Article  PubMed  CAS  Google Scholar 

  71. Polydefkis M, Hauer P, Sheth S, et al. The time course of epidermal nerve fibre regeneration: studies in normal controls and in people with diabetes, with and without neuropathy. Brain. 2004;127:1606–15.

    Article  PubMed  Google Scholar 

  72. • Ebenezer GJ, O'Donnell R, Hauer P, et al. Impaired neurovascular repair in subjects with diabetes following experimental intracutaneous axotomy. Brain 2011;134:1853–63. Mechanical axotomy and capsaicin were both used in this study to extensively characterize neurovascular repair. The results showed regenerative deficits in patients with diabetes (e.g., slowed Schwann cell migration and axonal regrowth). Blood vessel growth preceded other measures, suggesting a supportive role of blood vessels in axonal repair.

  73. •• Gibbons CH, Wang N, Freeman R. Capsaicin induces degeneration of cutaneous autonomic nerve fibers. Ann Neurol. 2010;68:888–98. This study reported both sensory and autonomic fiber degeneration following topical application of capsaicin. Sensory fibers were found to degenerate more quickly and regeneration proceeded much more slowly than for autonomic sudomotor, vasomotor, and pilomotor fibers. This is the first study focusing on autonomic fibers following denervation by capsaicin.

  74. Luo KR, Chao CC, Hsieh PC, et al. Effect of glycemic control on sudomotor denervation in type 2 diabetes. Diabetes Care. 2012;35:612–6.

    Article  PubMed  Google Scholar 

  75. Giannoccaro MP, Donadio V, Gomis PC, et al. Somatic and autonomic small fiber neuropathy induced by bortezomib therapy: an immunofluorescence study. Neurol Sci. 2011;32:361–3.

    Article  PubMed  Google Scholar 

  76. Wakabayashi K, Takahashi H, Ohama E, et al. Lewy bodies in the visceral autonomic nervous system in Parkinson's disease. Adv Neurol. 1993;60:609–12.

    PubMed  CAS  Google Scholar 

  77. Dabby R, Djaldetti R, Shahmurov M, et al. Skin biopsy for assessment of autonomic denervation in Parkinson's disease. J Neural Transm. 2006;113:1169–76.

    Article  PubMed  CAS  Google Scholar 

  78. Miki Y, Tomiyama M, Ueno T, et al. Clinical availability of skin biopsy in the diagnosis of Parkinson's disease. Neurosci Lett. 2010;469:357–9.

    Article  PubMed  CAS  Google Scholar 

  79. Nolano M, Provitera V, Estraneo A, et al. Sensory deficit in Parkinson's disease: evidence of a cutaneous denervation. Brain. 2008;131:1903–11.

    Article  PubMed  Google Scholar 

  80. Robertson D, Gilman S. Multiple system atrophy. In: Robertson D, Biaggioni I, Burnstock G, Low PA, Paton J, editors. Primer on the autonomic nervous system. New York: Elsevier; 2012. p. 453–7.

  81. Donadio V, Cortelli P, Elam M, et al. Autonomic innervation in multiple system atrophy and pure autonomic failure. J Neurol Neurosurg Psychiatry. 2010;81:1327–35.

    Article  PubMed  CAS  Google Scholar 

  82. Kaufmann H, Goldstein DS. Pure autonomic failure: a restricted Lewy body synucleinopathy or early Parkinson disease? Neurology. 2010;74:536–7.

    Article  PubMed  Google Scholar 

  83. Singer W, Spies JM, McArthur J, et al. Prospective evaluation of somatic and autonomic small fibers in selected autonomic neuropathies. Neurology. 2004;62:612–8.

    Article  PubMed  CAS  Google Scholar 

  84. Loseth S, Lindal S, Stalberg E, Mellgren SI. Intraepidermal nerve fibre density, quantitative sensory testing and nerve conduction studies in a patient material with symptoms and signs of sensory polyneuropathy. Eur J Neurol. 2006;13:105–11.

    Article  PubMed  CAS  Google Scholar 

  85. Kennedy WR, Wendelschafer-Crabb G, Johnson T. Quantitation of epidermal nerves in diabetic neuropathy. Neurology. 1996;47:1042–8.

    Article  PubMed  CAS  Google Scholar 

  86. Li J, Bai Y, Ghandour K, et al. Skin biopsies in myelin-related neuropathies: bringing molecular pathology to the bedside. Brain. 2005;128:1168–77.

    Article  PubMed  Google Scholar 

  87. Provitera V, Nolano M, Pagano A, et al. Myelinated nerve endings in human skin. Muscle Nerve. 2007;35:767–75.

    Article  PubMed  Google Scholar 

  88. Katona I, Wu X, Feely SM, et al. PMP22 expression in dermal nerve myelin from patients with CMT1A. Brain. 2009;132:1734–40.

    Article  PubMed  Google Scholar 

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Myers, M.I., Peltier, A.C. Uses of Skin Biopsy for Sensory and Autonomic Nerve Assessment. Curr Neurol Neurosci Rep 13, 323 (2013). https://doi.org/10.1007/s11910-012-0323-2

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