Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Small-fibre neuropathies—advances in diagnosis, pathophysiology and management

Abstract

Small-fibre neuropathy (SFN), a disorder of thinly myelinated Aδ-fibres and unmyelinated C-fibres, is clinically characterized by neuropathic pain symptoms and autonomic complaints. Diagnosis of SFN is challenging as the clinical picture can be difficult to interpret and results from nerve conduction studies are often normal. In cases of suspected SFN, measurement of intraepidermal nerve fibre density and/or analysis of quantitative sensory testing can enable diagnosis. New diagnostic techniques (including measurement of nerve fibre density using corneal confocal microscopy, and nociceptive evoked potentials) may contribute to the diagnostic work-up. SFN can be associated with systemic diseases such as immune-mediated disorders, but remains idiopathic in a substantial proportion of patients. Gain-of-function variants in the Nav1.7 sodium channel have recently been found in nearly 30% of patients with idiopathic SFN, but the mechanisms of axonal degeneration in the disorder remain under investigation. Identification of the systemic diseases underlying SFN will enable development of drugs that target affected pathways to improve the management of neuropathic pain and autonomic dysfunction. In this Review, we discuss recent advances in the diagnosis and pathophysiology of SFN, highlighting how improved understanding of these aspects of the disorder will contribute to better patient management.

Key Points

  • Small-fibre neuropathy (SFN) is a disorder of thinly myelinated Aδ-fibres and unmyelinated C-fibres

  • SFN is diagnosed on the basis of presence of typical SFN-related symptoms, normal nerve conduction studies, reduced intraepidermal nerve fibre density at the ankle, and/or abnormal quantitative sensory testing

  • SFN can be associated with systemic diseases, with an immune-mediated basis proposed in some cases; however, the cause remains unclear in a substantial number of patients

  • Mutations in SCN9A, which encodes the sodium channel Nav1.7, were found to underlie SFN in a subset of patients

  • Therapy for SFN focuses mainly on pain relief, management of autonomic dysfunction, and disease modification where possible

  • Future studies into therapies for SFN should address the efficacy of immunomodulating agents and selective sodium channel blockers

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Evidence of denervation in the skin of patients with SFN.
Figure 2: SFN-associated variants in the NaV1.7 sodium channel.

Similar content being viewed by others

References

  1. Langerhans, P. Über die nerven der menschlichen haut [German]. Virchows Arch. 44, 325–337 (1868).

    Article  Google Scholar 

  2. Weddell, G., Palmer, E. & Pallie, W. Nerve endings in mammalian skin. Biol. Rev. Camb. Philos. Soc. 30, 159–195 (1955).

    Article  Google Scholar 

  3. Lauria, G. Innervation of the human epidermis. A historical review. Ital. J. Neurol. Sci. 20, 63–70 (1999).

    Article  CAS  PubMed  Google Scholar 

  4. Erlanger, J. & Gasser, H. S. The compound nature of the action current of nerve as disclosed by the cathode ray oscillograph. Am. J. Physiol. 70, 624–666 (1924).

    Article  Google Scholar 

  5. Grant, G. The 1932 and 1944 Nobel Prizes in physiology or medicine: rewards for ground-breaking studies in neurophysiology. J. Hist. Neurosci. 15, 341–357 (2006).

    Article  PubMed  Google Scholar 

  6. McGlone, F. & Reilly, D. The cutaneous sensory system. Neurosci. Biobehav. Rev. 34, 148–159 (2010).

    Article  PubMed  Google Scholar 

  7. Boulton, A. J., Malik, R. A., Arezzo, J. C. & Sosenko, J. M. Diabetic somatic neuropathies. Diabetes Care 27, 1458–1486 (2004).

    Article  PubMed  Google Scholar 

  8. Freeman, R. Autonomic peripheral neuropathy. Lancet 365, 1259–1270 (2005).

    Article  CAS  PubMed  Google Scholar 

  9. Faber, C. G. et al. Gain of function Nav1.7 mutations in idiopathic small fiber neuropathy. Ann. Neurol. 71, 26–39 (2012).

    Article  CAS  PubMed  Google Scholar 

  10. Tesfaye, S. et al. Diabetic neuropathies: update on definitions, diagnostic criteria, estimation of severity, and treatments. Diabetes Care 33, 2285–2293 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  11. Devigili, G. et al. The diagnostic criteria for small fibre neuropathy: from symptoms to neuropathology. Brain 131, 1912–1925 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  12. Holland, N. R. et al. Small-fiber sensory neuropathies: clinical course and neuropathology of idiopathic cases. Ann. Neurol. 44, 47–59 (1998).

    Article  CAS  PubMed  Google Scholar 

  13. Gorson, K. C. et al. Non-length dependent small fibre neuropathy/ganglionopathy. J. Neurol. Neurosurg. Psychiatry 79, 163–169 (2008).

    Article  CAS  PubMed  Google Scholar 

  14. Lauria, G. Small fibre neuropathies. Curr. Opin. Neurol. 18, 591–597 (2005).

    Article  PubMed  Google Scholar 

  15. Polydefkis, M. et al. Subclinical sensory neuropathy in late-onset restless legs syndrome. Neurology 55, 1115–1121 (2000).

    Article  CAS  PubMed  Google Scholar 

  16. Stewart, J. D., Low, P. A. & Fealey, R. D. Distal small fiber neuropathy: results of tests of sweating and autonomic cardiovascular reflexes. Muscle Nerve 15, 661–665 (1992).

    Article  CAS  PubMed  Google Scholar 

  17. Lacomis, D. Small-fiber neuropathy. Muscle Nerve 26, 173–188 (2002).

    Article  PubMed  Google Scholar 

  18. Hoitsma, E. et al. Small fiber neuropathy: a common and important clinical disorder. J. Neurol. Sci. 227, 119–130 (2004).

    Article  CAS  PubMed  Google Scholar 

  19. Gorson, K. C. & Ropper, A. H. Idiopathic distal small fiber neuropathy. Acta Neurol. Scand. 92, 376–382 (1995).

    Article  CAS  PubMed  Google Scholar 

  20. Estacion, M. et al. Intra- and interfamily phenotypic diversity in pain syndromes associated with a gain-of-function variant of Nav1.7. Mol. Pain 7, 92 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Brannagan, T. H. 3rd et al. Small-fiber neuropathy/neuronopathy associated with celiac disease: skin biopsy findings. Arch. Neurol. 62, 1574–1578 (2005).

    Article  PubMed  Google Scholar 

  22. Gemignani, F. et al. Non-length dependent small fiber neuropathy. A prospective case series. J. Peripher. Nerv. Syst. 15, 57–62 (2010).

    Article  PubMed  Google Scholar 

  23. Gibbels, E. et al. Severe polyneuropathy in Tangier disease mimicking syringomyelia or leprosy. Clinical, biochemical, electrophysiological, and morphological evaluation, including electron microscopy of nerve, muscle, and skin biopsies. J. Neurol. 232, 283–294 (1985).

    Article  CAS  PubMed  Google Scholar 

  24. Pareyson, D. Diagnosis of hereditary neuropathies in adult patients. J. Neurol. 250, 148–160 (2003).

    Article  PubMed  Google Scholar 

  25. Burlina, A. P. et al. Early diagnosis of peripheral nervous system involvement in Fabry disease and treatment of neuropathic pain: the report of an expert panel. BMC Neurol. 11, 61 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  26. Biegstraaten, M. et al. The relation between small nerve fibre function, age, disease severity and pain in Fabry disease. Eur. J. Pain 15, 822–829 (2011).

    Article  PubMed  Google Scholar 

  27. Plante-Bordeneuve, V. & Said, G. Familial amyloid polyneuropathy. Lancet Neurol. 10, 1086–1097 (2011).

    Article  CAS  PubMed  Google Scholar 

  28. Bakkers, M. et al. Intraepidermal nerve fiber density and its application in sarcoidosis. Neurology 73, 1142–1148 (2009).

    Article  CAS  PubMed  Google Scholar 

  29. Malik, R. et al. Small fiber neuropathy: role in the diagnosis of diabetic sensorimotor polyneuropathy. Diabetes Metab. Res. Rev. 27, 678–684 (2011).

    Article  CAS  PubMed  Google Scholar 

  30. Boulais, N. & Misery, L. The epidermis: a sensory tissue. Eur. J. Dermatol. 18, 119–127 (2008).

    PubMed  Google Scholar 

  31. Thompson, R. J., Doran, J. F., Jackson, P., Dhillon, A. P. & Rode, J. PGP 9.5—a new marker for vertebrate neurons and neuroendocrine cells. Brain Res. 278, 224–228 (1983).

    Article  CAS  PubMed  Google Scholar 

  32. 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. 261, 25–33 (1990).

    Article  CAS  PubMed  Google Scholar 

  33. Lauria, G. 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. 17, 903–912 (2010).

    Article  CAS  PubMed  Google Scholar 

  34. McCarthy, B. G. et al. Cutaneous innervation in sensory neuropathies: evaluation by skin biopsy. Neurology 45, 1848–1855 (1995).

    Article  CAS  PubMed  Google Scholar 

  35. Lauria, G. et al. Intraepidermal nerve fiber density at the distal leg: a worldwide normative reference study. J. Peripher. Nerv. Syst. 15, 202–207 (2010).

    Article  PubMed  Google Scholar 

  36. Chien, H. F. et al. Quantitative pathology of cutaneous nerve terminal degeneration in the human skin. Acta Neuropathol. (Berl.) 102, 455–461 (2001).

    Article  CAS  Google Scholar 

  37. Goransson, L. G., Mellgren, S. I., Lindal, S. & Omdal, R. The effect of age and gender on epidermal nerve fiber density. Neurology 62, 774–777 (2004).

    Article  CAS  PubMed  Google Scholar 

  38. Lauria, G. et al. Morphometry of dermal nerve fibers in human skin. Neurology 77, 242–249 (2011).

    Article  CAS  PubMed  Google Scholar 

  39. Vlckova-Moravcova, E., Bednarik, J., Dusek, L., Toyka, K. V. & Sommer, C. Diagnostic validity of epidermal nerve fiber densities in painful sensory neuropathies. Muscle Nerve 37, 50–60 (2008).

    Article  PubMed  Google Scholar 

  40. Tschachler, E. et al. Sheet preparations expose the dermal nerve plexus of human skin and render the dermal nerve end organ accessible to extensive analysis. J. Invest. Dermatol. 122, 177–182 (2004).

    Article  CAS  PubMed  Google Scholar 

  41. Chao, C. C., Sun, H. Y., Chang, Y. C. & Hsieh, S. T. Painful neuropathy with skin denervation after prolonged use of linezolid. J. Neurol. Neurosurg. Psychiatry 79, 97–99 (2008).

    Article  PubMed  Google Scholar 

  42. Tan, C. H. et al. Painful neuropathy due to skin denervation after metronidazole-induced neurotoxicity. J. Neurol. Neurosurg. Psychiatry 82, 462–465 (2011).

    Article  PubMed  Google Scholar 

  43. Penza, P., Lombardi, R., Camozzi, F., Ciano, C. & Lauria, G. Painful neuropathy in subclinical hypothyroidism: clinical and neuropathological recovery after hormone replacement therapy. Neurol. Sci. 30, 149–151 (2009).

    Article  PubMed  Google Scholar 

  44. Ruts, L. et al. Unmyelinated and myelinated skin nerve damage in Guillain–Barré syndrome: correlation with pain and recovery. Pain 153, 399–409 (2012).

    Article  CAS  PubMed  Google Scholar 

  45. Sumner, C. J., Sheth, S., Griffin, J. W., Cornblath, D. R. & Polydefkis, M. The spectrum of neuropathy in diabetes and impaired glucose tolerance. Neurology 60, 108–111 (2003).

    Article  CAS  PubMed  Google Scholar 

  46. Smith, A. G., Ramachandran, P., Tripp, S. & Singleton, J. R. Epidermal nerve innervation in impaired glucose tolerance and diabetes-associated neuropathy. Neurology 57, 1701–1704 (2001).

    Article  CAS  PubMed  Google Scholar 

  47. Tseng, M. T. et al. Skin denervation and cutaneous vasculitis in systemic lupus erythematosus. Brain 129, 977–985 (2006).

    Article  PubMed  Google Scholar 

  48. Chao, C. C., Hsieh, S. T., Shun, C. T. & Hsieh, S. C. Skin denervation and cutaneous vasculitis in eosinophilia-associated neuropathy. Arch. Neurol. 64, 959–965 (2007).

    Article  PubMed  Google Scholar 

  49. Lombardi, R. et al. IgM deposits on skin nerves in anti-myelin-associated glycoprotein neuropathy. Ann. Neurol. 57, 180–187 (2005).

    Article  CAS  PubMed  Google Scholar 

  50. Simone, D. A., Nolano, M., Johnson, T., Wendelschafer-Crabb, G. & Kennedy, W. R. Intradermal injection of capsaicin in humans produces degeneration and subsequent reinnervation of epidermal nerve fibers: correlation with sensory function. J. Neurosci. 18, 8947–8959 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Polydefkis, M. et al. The time course of epidermal nerve fibre regeneration: studies in normal controls and in people with diabetes, with and without neuropathy. Brain 127, 1606–1615 (2004).

    Article  PubMed  Google Scholar 

  52. Rajan, B., Polydefkis, M., Hauer, P., Griffin, J. W. & McArthur, J. C. Epidermal reinnervation after intracutaneous axotomy in man. J. Comp. Neurol. 457, 24–36 (2003).

    Article  PubMed  Google Scholar 

  53. Ebenezer, G. J. et al. Impaired neurovascular repair in subjects with diabetes following experimental intracutaneous axotomy. Brain 134, 1853–1863 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  54. Ebenezer, G. J. et al. Denervation of skin in neuropathies: the sequence of axonal and Schwann cell changes in skin biopsies. Brain 130, 2703–2714 (2007).

    Article  PubMed  Google Scholar 

  55. Hahn, K., Triolo, A., Hauer, P., McArthur, J. C. & Polydefkis, M. Impaired reinnervation in HIV infection following experimental denervation. Neurology 68, 1251–1256 (2007).

    Article  CAS  PubMed  Google Scholar 

  56. Kennedy, W. R., Nolano, M., Wendelschafer-Crabb, G., Johnson, T. L. & Tamura, E. A skin blister method to study epidermal nerves in peripheral nerve disease. Muscle Nerve 22, 360–371 (1999).

    Article  CAS  PubMed  Google Scholar 

  57. Panoutsopoulou, I. G., Wendelschafer-Crabb, G., Hodges, J. S. & Kennedy, W. R. Skin blister and skin biopsy to quantify epidermal nerves: a comparative study. Neurology 72, 1205–1210 (2009).

    Article  PubMed  Google Scholar 

  58. Dyck, P. J. et al. Introduction of automated systems to evaluate touch-pressure, vibration, and thermal cutaneous sensation in man. Ann. Neurol. 4, 502–510 (1978).

    Article  CAS  PubMed  Google Scholar 

  59. Fruhstorfer, H., Lindblom, U. & Schmidt, W. C. Method for quantitative estimation of thermal thresholds in patients. J. Neurol. Neurosurg. Psychiatry 39, 1071–1075 (1976).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Yarnitsky, D. & Sprecher, E. Thermal testing: normative data and repeatability for various test algorithms. J. Neurol. Sci. 125, 39–45 (1994).

    Article  CAS  PubMed  Google Scholar 

  61. Reulen, J. P., Lansbergen, M. D., Verstraete, E. & Spaans, F. Comparison of thermal threshold tests to assess small nerve fiber function: limits vs. levels. Clin. Neurophysiol. 114, 556–563 (2003).

    Article  CAS  PubMed  Google Scholar 

  62. Hoitsma, E. et al. Abnormal warm and cold sensation thresholds suggestive of small-fiber neuropathy in sarcoidosis. Clin. Neurophysiol. 114, 2326–2333 (2003).

    Article  CAS  PubMed  Google Scholar 

  63. Chong, P. S. & Cros, D. P. Technology literature review: quantitative sensory testing. Muscle Nerve 29, 734–747 (2004).

    Article  PubMed  Google Scholar 

  64. Shy, M. E. et al. Quantitative sensory testing: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 60, 898–904 (2003).

    Article  CAS  PubMed  Google Scholar 

  65. Bakkers, M. et al. Temperature threshold testing and its clinical value in polyneuropathies: a systematic review. J. Peripher. Nerv. Syst. 16, S8 (2011).

    Google Scholar 

  66. Oliveira-Soto, L. & Efron, N. Morphology of corneal nerves using confocal microscopy. Cornea 20, 374–384 (2001).

    Article  CAS  PubMed  Google Scholar 

  67. Jalbert, I., Stapleton, F., Papas, E., Sweeney, D. F. & Coroneo, M. In vivo confocal microscopy of the human cornea. Br. J. Ophthalmol. 87, 225–236 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Malik, R. A. et al. Corneal confocal microscopy: a non-invasive surrogate of nerve fibre damage and repair in diabetic patients. Diabetologia 46, 683–688 (2003).

    Article  CAS  PubMed  Google Scholar 

  69. Hossain, P., Sachdev, A. & Malik, R. A. Early detection of diabetic peripheral neuropathy with corneal confocal microscopy. Lancet 366, 1340–1343 (2005).

    Article  PubMed  Google Scholar 

  70. Quattrini, C. et al. Surrogate markers of small fiber damage in human diabetic neuropathy. Diabetes 56, 2148–2154 (2007).

    Article  CAS  PubMed  Google Scholar 

  71. Gemignani, F. et al. Non-length-dependent small fibre neuropathy. Confocal microscopy study of the corneal innervation. J. Neurol. Neurosurg. Psychiatry 81, 731–733 (2010).

    Article  CAS  PubMed  Google Scholar 

  72. Lalive, P. H., Truffert, A., Magistris, M. R., Landis, T. & Dosso, A. Peripheral autoimmune neuropathy assessed using corneal in vivo confocal microscopy. Arch. Neurol. 66, 403–405 (2009).

    PubMed  Google Scholar 

  73. Tavakoli, M. et al. Corneal confocal microscopy: a novel means to detect nerve fibre damage in idiopathic small fibre neuropathy. Exp. Neurol. 223, 245–250 (2010).

    Article  PubMed  Google Scholar 

  74. Tavakoli, M. et al. Corneal confocal microscopy: a novel noninvasive means to diagnose neuropathy in patients with Fabry disease. Muscle Nerve 40, 976–984 (2009).

    Article  PubMed  Google Scholar 

  75. Katsarava, Z. et al. A novel method of eliciting pain-related potentials by transcutaneous electrical stimulation. Headache 46, 1511–1517 (2006).

    Article  PubMed  Google Scholar 

  76. Casanova-Molla, J., Grau-Junyent, J. M., Morales, M. & Valls-Sole, J. On the relationship between nociceptive evoked potentials and intraepidermal nerve fiber density in painful sensory polyneuropathies. Pain 152, 410–418 (2011).

    Article  PubMed  Google Scholar 

  77. Atherton, D. D. et al. Use of the novel contact heat evoked potential stimulator (CHEPS) for the assessment of small fibre neuropathy: correlations with skin flare responses and intra-epidermal nerve fibre counts. BMC Neurol. 7, 21 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  78. Obermann, M. et al. Correlation of epidermal nerve fiber density with pain-related evoked potentials in HIV neuropathy. Pain 138, 79–86 (2008).

    Article  PubMed  Google Scholar 

  79. Inui, K. & Kakigi, R. Pain perception in humans: use of intraepidermal electrical stimulation. J. Neurol. Neurosurg. Psychiatry 83, 551–556 (2011).

    Article  PubMed  Google Scholar 

  80. Bromm, B., Jahnke, M. T. & Treede, R. D. Responses of human cutaneous afferents to CO2 laser stimuli causing pain. Exp. Brain Res. 55, 158–166 (1984).

    Article  CAS  PubMed  Google Scholar 

  81. Magerl, W., Ali, Z., Ellrich, J., Meyer, R. A. & Treede, R. D. C- and Aδ-fiber components of heat-evoked cerebral potentials in healthy human subjects. Pain 82, 127–137 (1999).

    Article  CAS  PubMed  Google Scholar 

  82. Dotson, R. M. Clinical neurophysiology laboratory tests to assess the nociceptive system in humans. J. Clin. Neurophysiol. 14, 32–45 (1997).

    Article  CAS  PubMed  Google Scholar 

  83. Lefaucheur, J. P. & Creange, A. Neurophysiological testing correlates with clinical examination according to fibre type involvement and severity in sensory neuropathy. J. Neurol. Neurosurg. Psychiatry 75, 417–422 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  84. Truini, A., Romaniello, A., Galeotti, F., Iannetti, G. D. & Cruccu, G. Laser evoked potentials for assessing sensory neuropathy in human patients. Neurosci. Lett. 361, 25–28 (2004).

    Article  CAS  PubMed  Google Scholar 

  85. Agostino, R. et al. Dysfunction of small myelinated afferents in diabetic polyneuropathy, as assessed by laser evoked potentials. Clin. Neurophysiol. 111, 270–276 (2000).

    Article  CAS  PubMed  Google Scholar 

  86. Granovsky, Y., Matre, D., Sokolik, A., Lorenz, J. & Casey, K. L. Thermoreceptive innervation of human glabrous and hairy skin: a contact heat evoked potential analysis. Pain 115, 238–247 (2005).

    Article  PubMed  Google Scholar 

  87. Arendt-Nielsen, L. & Chen, A. C. Lasers and other thermal stimulators for activation of skin nociceptors in humans. Neurophysiol. Clin. 33, 259–268 (2003).

    Article  CAS  PubMed  Google Scholar 

  88. Chen, A. C., Niddam, D. M. & Arendt-Nielsen, L. Contact heat evoked potentials as a valid means to study nociceptive pathways in human subjects. Neurosci. Lett. 316, 79–82 (2001).

    Article  CAS  PubMed  Google Scholar 

  89. Mueller, D. et al. Electrically evoked nociceptive potentials for early detection of diabetic small-fiber neuropathy. Eur. J. Neurol. 17, 834–841 (2010).

    Article  CAS  PubMed  Google Scholar 

  90. Serra, J., Campero, M., Bostock, H. & Ochoa, J. Two types of C nociceptors in human skin and their behavior in areas of capsaicin-induced secondary hyperalgesia. J. Neurophysiol. 91, 2770–2781 (2004).

    Article  PubMed  Google Scholar 

  91. Serra, J. et al. Double and triple spikes in C-nociceptors in neuropathic pain states: an additional peripheral mechanism of hyperalgesia. Pain 152, 343–353 (2011).

    Article  PubMed  Google Scholar 

  92. Serra, J. et al. Microneurographic identification of spontaneous activity in C-nociceptors in neuropathic pain states in humans and rats. Pain 153, 42–55 (2012).

    Article  CAS  PubMed  Google Scholar 

  93. Serra, J. et al. C-nociceptors sensitized to cold in a patient with small-fiber neuropathy and cold allodynia. Pain 147, 46–53 (2009).

    Article  PubMed  Google Scholar 

  94. Hilz, M. J. & Dutsch, M. Quantitative studies of autonomic function. Muscle Nerve 33, 6–20 (2006).

    Article  PubMed  Google Scholar 

  95. 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. 12, 98–101 (2007).

    Article  PubMed  Google Scholar 

  96. Gibbons, C. H., Illigens, B. M., Wang, N. & Freeman, R. Quantification of sweat gland innervation: a clinical-pathologic correlation. Neurology 72, 1479–1486 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  97. Nolano, M. et al. Quantification of pilomotor nerves: a new tool to evaluate autonomic involvement in diabetes. Neurology 75, 1089–1097 (2010).

    Article  CAS  PubMed  Google Scholar 

  98. Novak, V. et al. Autonomic impairment in painful neuropathy. Neurology 56, 861–868 (2001).

    Article  CAS  PubMed  Google Scholar 

  99. Low, P. A. Evaluation of sudomotor function. Clin. Neurophysiol. 115, 1506–1513 (2004).

    Article  PubMed  Google Scholar 

  100. England, J. D. et al. Evaluation of distal symmetric polyneuropathy: The role of autonomic testing, nerve biopsy, and skin biopsy (an evidence-based review). Muscle Nerve 39, 106–115 (2009).

    Article  CAS  PubMed  Google Scholar 

  101. Liguori, R. et al. Microneurographic evaluation of sympathetic activity in small fiber neuropathy. Clin. Neurophysiol. 122, 1854–1859 (2011).

    Article  PubMed  Google Scholar 

  102. Bickel, A. et al. C-fiber axon reflex flare size correlates with epidermal nerve fiber density in human skin biopsies. J. Peripher. Nerv. Syst. 14, 294–299 (2009).

    Article  CAS  PubMed  Google Scholar 

  103. Bickel, A. et al. Assessment of the neurogenic flare reaction in small-fiber neuropathies. Neurology 59, 917–919 (2002).

    Article  CAS  PubMed  Google Scholar 

  104. Luo, K. R. et al. Quantitation of sudomotor innervation in skin biopsies of patients with diabetic neuropathy. J. Neuropathol. Exp. Neurol. 70, 930–938 (2011).

    Article  PubMed  Google Scholar 

  105. Luo, K. R., Chao, C. C., Hsieh, P. C., Lue, J. H. & Hsieh, S. T. Effect of glycemic control on sudomotor denervation in type 2 diabetes. Diabetes Care 35, 612–616 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  106. Lacomis, D., Giuliani, M. J., Steen, V. & Powell, H. C. Small fiber neuropathy and vasculitis. Arthritis Rheum. 40, 1173–1177 (1997).

    Article  CAS  PubMed  Google Scholar 

  107. Polydefkis, M. et al. Reduced intraepidermal nerve fiber density in HIV-associated sensory neuropathy. Neurology 58, 115–119 (2002).

    Article  CAS  PubMed  Google Scholar 

  108. Scott, L. J. et al. Quantitative analysis of epidermal innervation in Fabry disease. Neurology 52, 1249–1254 (1999).

    Article  CAS  PubMed  Google Scholar 

  109. Zambelis, T., Karandreas, N., Tzavellas, E., Kokotis, P. & Liappas, J. Large and small fiber neuropathy in chronic alcohol-dependent subjects. J. Peripher. Nerv. Syst. 10, 375–381 (2005).

    Article  PubMed  Google Scholar 

  110. McManis, P. G., Windebank, A. J. & Kiziltan, M. Neuropathy associated with hyperlipidemia. Neurology 44, 2185–2186 (1994).

    Article  CAS  PubMed  Google Scholar 

  111. Hoitsma, E. et al. Small fibre neuropathy in sarcoidosis. Lancet 359, 2085–2086 (2002).

    Article  CAS  PubMed  Google Scholar 

  112. Gondim, F. A., Brannagan, T. H. 3rd, Sander, H. W., Chin, R. L. & Latov, N. Peripheral neuropathy in patients with inflammatory bowel disease. Brain 128, 867–879 (2005).

    Article  CAS  PubMed  Google Scholar 

  113. Houlden, H., Blake, J. & Reilly, M. M. Hereditary sensory neuropathies. Curr. Opin. Neurol. 17, 569–577 (2004).

    Article  CAS  PubMed  Google Scholar 

  114. Bednarik, J. et al. Etiology of small-fiber neuropathy. J. Peripher. Nerv. Syst. 14, 177–183 (2009).

    Article  PubMed  Google Scholar 

  115. Smith, A. G. & Singleton, J. R. Impaired glucose tolerance and neuropathy. Neurologist 14, 23–29 (2008).

    Article  PubMed  Google Scholar 

  116. Weis, J. et al. Small-fiber neuropathy in patients with ALS. Neurology 76, 2024–2029 (2011).

    Article  CAS  PubMed  Google Scholar 

  117. Rossi, A., Giovenali, P., Benvenuti, M., Di Iorio, W. & Calabresi, P. Skin biopsy: a new diagnostic tool for autonomic dysfunctions in Parkinson's disease? Lancet Neurol. 6, 848–849 (2007).

    Article  PubMed  Google Scholar 

  118. Manganelli, F. et al. Small-fiber involvement in spinobulbar muscular atrophy (Kennedy's disease). Muscle Nerve 36, 816–820 (2007).

    Article  PubMed  Google Scholar 

  119. Oaklander, A. L. et al. Evidence of focal small-fiber axonal degeneration in complex regional pain syndrome-I (reflex sympathetic dystrophy). Pain 120, 235–243 (2006).

    Article  PubMed  Google Scholar 

  120. Lauria, G. et al. Trigeminal small-fiber sensory neuropathy causes burning mouth syndrome. Pain 115, 332–337 (2005).

    Article  PubMed  Google Scholar 

  121. Penza, P. et al. “Burning tongue” and “burning tip”: the diagnostic challenge of the burning mouth syndrome. Clin. J. Pain 26, 528–532 (2010).

    Article  PubMed  Google Scholar 

  122. Feldman, E. L. Oxidative stress and diabetic neuropathy: a new understanding of an old problem. J. Clin. Invest. 111, 431–433 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Parry, G. J. & Brown, M. J. Selective fiber vulnerability in acute ischemic neuropathy. Ann. Neurol. 11, 147–154 (1982).

    Article  CAS  PubMed  Google Scholar 

  124. Malik, R. A. et al. Hypoxic neuropathy: relevance to human diabetic neuropathy. Diabetologia 33, 311–318 (1990).

    Article  CAS  PubMed  Google Scholar 

  125. Anand, P. et al. The role of endogenous nerve growth factor in human diabetic neuropathy. Nat. Med. 2, 703–707 (1996).

    Article  CAS  PubMed  Google Scholar 

  126. Krishnan, A. V. & Kiernan, M. C. Uremic neuropathy: clinical features and new pathophysiological insights. Muscle Nerve 35, 273–290 (2007).

    Article  CAS  PubMed  Google Scholar 

  127. Marchand, F., Perretti, M. & McMahon, S. B. Role of the immune system in chronic pain. Nat. Rev. Neurosci. 6, 521–532 (2005).

    Article  CAS  PubMed  Google Scholar 

  128. Pace, M. C. et al. Neurobiology of pain. J. Cell Physiol. 209, 8–12 (2006).

    Article  CAS  PubMed  Google Scholar 

  129. Uceyler, N. et al. Elevated proinflammatory cytokine expression in affected skin in small fiber neuropathy. Neurology 74, 1806–1813 (2010).

    Article  CAS  PubMed  Google Scholar 

  130. Chamberlain, J. L. et al. Peripherin-IgG association with neurologic and endocrine autoimmunity. J. Autoimmun. 34, 469–477 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Dabby, R., Weimer, L. H., Hays, A. P., Olarte, M. & Latov, N. Antisulfatide antibodies in neuropathy: clinical and electrophysiologic correlates. Neurology 54, 1448–1452 (2000).

    Article  CAS  PubMed  Google Scholar 

  132. Chiang, M. C. et al. Cutaneous innervation in chronic inflammatory demyelinating polyneuropathy. Neurology 59, 1094–1098 (2002).

    Article  PubMed  Google Scholar 

  133. Adams, D. Hereditary and acquired amyloid neuropathies. J. Neurol. 248, 647–657 (2001).

    Article  CAS  PubMed  Google Scholar 

  134. Waxman, S. G., Brill, M. H., Geschwind, N., Sabin, T. D. & Lettvin, J. Y. Probability of conduction deficit as related to fiber length in random-distribution models of peripheral neuropathies. J. Neurol. Sci. 29, 39–53 (1976).

    Article  CAS  PubMed  Google Scholar 

  135. Mellion, M., Gilchrist, J. M. & de la Monte, S. Alcohol-related peripheral neuropathy: nutritional, toxic, or both? Muscle Nerve 43, 309–316 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Koike, H. et al. Alcoholic neuropathy is clinicopathologically distinct from thiamine-deficiency neuropathy. Ann. Neurol. 54, 19–29 (2003).

    Article  PubMed  Google Scholar 

  137. Cregg, R., Momin, A., Rugiero, F., Wood, J. N. & Zhao, J. Pain channelopathies. J. Physiol. 588, 1897–1904 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Alessandri-Haber, N. et al. Transient receptor potential vanilloid 4 is essential in chemotherapy-induced neuropathic pain in the rat. J. Neurosci. 24, 4444–4452 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Koivisto, A. et al. Inhibiting TRPA1 ion channel reduces loss of cutaneous nerve fiber function in diabetic animals: sustained activation of the TRPA1 channel contributes to the pathogenesis of peripheral diabetic neuropathy. Pharmacol. Res. 65, 149–158 (2011).

    Article  PubMed  CAS  Google Scholar 

  140. Drenth, J. P. & Waxman, S. G. Mutations in sodium-channel gene SCN9A cause a spectrum of human genetic pain disorders. J. Clin. Invest. 117, 3603–9 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Davis, M. D. et al. Histopathologic findings in primary erythromelalgia are nonspecific: special studies show a decrease in small nerve fiber density. J. Am. Acad. Dermatol. 55, 519–522 (2006).

    Article  PubMed  Google Scholar 

  142. Schiffmann, R. et al. Enzyme replacement therapy improves peripheral nerve and sweat function in Fabry disease. Muscle Nerve 28, 703–710 (2003).

    Article  CAS  PubMed  Google Scholar 

  143. Schiffmann, R. et al. Enzyme replacement therapy and intraepidermal innervation density in Fabry disease. Muscle Nerve 34, 53–56 (2006).

    Article  CAS  PubMed  Google Scholar 

  144. Dabby, R., Gilad, R., Sadeh, M., Lampl, Y. & Watemberg, N. Acute steroid responsive small-fiber sensory neuropathy: a new entity? J. Peripher. Nerv. Syst. 11, 47–52 (2006).

    Article  PubMed  Google Scholar 

  145. Souayah, N. et al. Effect of intravenous immunoglobulin on cerebellar ataxia and neuropathic pain associated with celiac disease. Eur. J. Neurol. 15, 1300–1303 (2008).

    Article  CAS  PubMed  Google Scholar 

  146. Attal, N. et al. EFNS guidelines on the pharmacological treatment of neuropathic pain: 2010 revision. Eur. J. Neurol. 17, 1113–e88 (2010).

    Article  CAS  PubMed  Google Scholar 

  147. Magri, F. et al. Intraepidermal nerve fiber density reduction as a marker of preclinical asymptomatic small-fiber sensory neuropathy in hypothyroid patients. Eur. J. Endocrinol. 163, 279–284 (2010).

    Article  CAS  PubMed  Google Scholar 

  148. Chai, J., Herrmann, D. N., Stanton, M., Barbano, R. L. & Logigian, E. L. Painful small-fiber neuropathy in Sjögren syndrome. Neurology 65, 925–927 (2005).

    Article  CAS  PubMed  Google Scholar 

  149. Oki, Y. et al. Ataxic vs painful form of paraneoplastic neuropathy. Neurology 69, 564–572 (2007).

    Article  CAS  PubMed  Google Scholar 

  150. Lund, C. et al. Histopathological and clinical findings in leprosy patients with chronic neuropathic pain: a study from Hyderabad, India. Lepr. Rev. 78, 369–380 (2007).

    Article  PubMed  Google Scholar 

  151. Bennett, J. L., Mahalingam, R., Wellish, M. C. & Gilden, D. H. Epstein–Barr virus-associated acute autonomic neuropathy. Ann. Neurol. 40, 453–455 (1996).

    Article  CAS  PubMed  Google Scholar 

  152. Giannoccaro, M. P. et al. Somatic and autonomic small fiber neuropathy induced by bortezomib therapy: an immunofluorescence study. Neurol. Sci. 32, 361–363 (2011).

    Article  PubMed  Google Scholar 

  153. Heckmann, J. G., Dutsch, M. & Schwab, S. Linezolid-associated small-fiber neuropathy. J. Peripher. Nerv. Syst. 13, 157–158 (2008).

    Article  PubMed  Google Scholar 

  154. Burakgazi, A. Z., Polydefkis, M. & Hoke, A. Skin biopsy-proven flecainide-induced neuropathy. Muscle Nerve 45, 144–146 (2012).

    Article  PubMed  Google Scholar 

  155. Tan, I. L., Polydefkis, M. J., Ebenezer, G. J., Hauer, P. & McArthur, J. C. Peripheral nerve toxic effects of nitrofurantoin. Arch. Neurol. 69, 265–268 (2012).

    Article  PubMed  Google Scholar 

  156. Bergmann, I. et al. Selective degeneration of sudomotor fibers in Ross syndrome and successful treatment of compensatory hyperhidrosis with botulinum toxin. Muscle Nerve 21, 1790–1793 (1998).

    Article  CAS  PubMed  Google Scholar 

  157. Wouthuis, S. F., van Deursen, C. T., te Lintelo, M. P., Rozeman, C. A. & Beekman, R. Neuromuscular manifestations in hereditary haemochromatosis. J. Neurol. 257, 1465–1472 (2010).

    Article  CAS  PubMed  Google Scholar 

  158. Chao, C. C. et al. Skin denervation and its clinical significance in late-stage chronic kidney disease. Arch. Neurol. 68, 200–206 (2011).

    Article  PubMed  Google Scholar 

  159. Pan, C. L. et al. Cutaneous innervation in Guillain–Barré syndrome: pathology and clinical correlations. Brain 126, 386–397 (2003).

    Article  PubMed  Google Scholar 

  160. Tembl, J. I. et al. Neurologic complications associated with hepatitis C virus infection. Neurology 53, 861–864 (1999).

    Article  CAS  PubMed  Google Scholar 

  161. Younger, D. S. & Orsher, S. Lyme neuroborreliosis: preliminary results from an urban referral center employing strict CDC criteria for case selection. Neurol. Res. Int. 2010, 525206 (2010).

    PubMed  PubMed Central  Google Scholar 

  162. Bernstein, A. L. Vitamin B6 in clinical neurology. Ann. NY Acad. Sci. 585, 250–260 (1990).

    Article  CAS  PubMed  Google Scholar 

  163. Nolano, M. et al. Small fibers involvement in Friedreich's ataxia. Ann. Neurol. 50, 17–25 (2001).

    Article  CAS  PubMed  Google Scholar 

  164. Chen, S. F. et al. Neuromuscular abnormality and autonomic dysfunction in patients with cerebrotendinous xanthomatosis. BMC Neurol. 11, 63 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Contributions

All authors contributed equally to researching data for the article, discussion of content, writing the article, and to the editing and review of the manuscript before submission.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hoeijmakers, J., Faber, C., Lauria, G. et al. Small-fibre neuropathies—advances in diagnosis, pathophysiology and management. Nat Rev Neurol 8, 369–379 (2012). https://doi.org/10.1038/nrneurol.2012.97

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrneurol.2012.97

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing