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The Role and Importance of Small Fiber Neuropathy in Fibromyalgia Pain


Serious investigators of fibromyalgia (FM) realize the profound implications of finding features of small fiber neuropathy (SFN) in this disorder. For the first time, an easily reproducible and generally agreed upon, peripheral tissue lesion has been reported from multiple investigative centers. Understanding how this discovery relates to other features of FM, and how one might utilize it to better comprehend, and care for, afflicted patients’ painful complaints remains a challenge, however. In this article we review how the SFN seen in FM may be placed in context, and suggest how such a tissue abnormality might be used to better understand the pathophysiology of FM, and plan for its effective treatment. We also suggest how finding SFN in FM implies the need for continued focused research within the area of neuropathic disease in FM.

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Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.

    Doppler K, Rittner HL, Deckart M, Sommer C. Reduced dermal nerve fiber diameter in skin biopsies of patients with fibromyalgia. Pain. 2015.

  2. 2.

    Levine TD, Saperstein DS. Routine use of punch biopsy to diagnose small fiber neuropathy in fibromyalgia patients. Clin Rheumatol. 2015;34:413–7.

    PubMed Central  Article  PubMed  Google Scholar 

  3. 3.

    Kosmidis ML, Koutsogeorgopoulou L, Alexopoulos H, Mamali I, Vlachoyiannopoulos PG, Voulgarelis M, et al. Reduction of intraepidermal nerve fiber density (IENFD) in the skin biopsies of patients with fibromyalgia: a controlled study. J Neurol Sci. 2014;347(1–2):143–7.

    Article  PubMed  Google Scholar 

  4. 4.•

    Caro XJ, Winter EF. Evidence of abnormal epidermal nerve fiber density in fibromyalgia: clinical and immunologic implications. Arthritis Rheumatol. 2014;66:1945–54. This study demonstrates a measureable immune component to the SFN seen in fibromyalgia.

    Article  PubMed  Google Scholar 

  5. 5.

    Giannoccaro MP, Donadio V, Incensi A, Avoni P, Liguori R. Small nerve fiber involvement in patients referred for fibromyalgia. Muscle Nerve. 2014;49:757–9.

    Article  PubMed  Google Scholar 

  6. 6.

    Oaklander AL, Herzog ZD, Downs HM, Klein MM. Objective evidence that small-fiber polyneuropathy underlies some illnesses currently labeled as fibromyalgia. Pain. 2013;154:2310–6.

    Article  PubMed  Google Scholar 

  7. 7.•

    Üçeyler N, Zeller D, Kahn AK, Kewenig S, Kittel-Schneider S, Schmid A, et al. Small fibre pathology in patients with fibromyalgia syndrome. Brain. 2013;136:1857–67. This ambitious study surveys SFN and function using a variety of approaches.

    Article  PubMed  Google Scholar 

  8. 8.

    Blumenstiel K, Gerhardt A, Rolke R, Bieber C, Tesarz J, Friederich HC, et al. Quantitative sensory testing profiles in chronic back pain are distinct from those in fibromyalgia. Clin J Pain. 2011;27(8):682–90.

    Article  PubMed  Google Scholar 

  9. 9.

    Thieme K, Turk DC. Heterogeneity of psychophysiological stress responses in fibromyalgia syndrome patients. Arthritis Res Ther. 2006;8:R9.

    PubMed Central  Article  PubMed  Google Scholar 

  10. 10.

    Donadio V, Liguori R. Microneurographic recording from unmyelinated nerve fibers in neurological disorders: an update. Clin Neurophysiol. 2015;126(3):437–45.

    CAS  Article  PubMed  Google Scholar 

  11. 11.•

    Serra J, Collado A, Solà R, Antonelli F, Torres X, Salgueiro M, et al. Hyperexcitable C nociceptors in fibromyalgia. Ann Neurol. 2014;75(2):196–208. This study demonstrates that the SFN lesion in FM is not merely anatomical, but functional as well.

    CAS  Article  PubMed  Google Scholar 

  12. 12.

    Caro XJ. Immunofluorescent detection of IgG at the dermal-epidermal junction in patients with apparent primary fibrositis syndrome. Arthritis Rheum. 1984;27:1174–9.

    CAS  Article  PubMed  Google Scholar 

  13. 13.

    Caro XJ, Wolfe F, Johnston WH, Smith AL. A controlled and blinded study of immunoreactant deposition at the dermal-epidermal junction of patients with primary fibrositis syndrome. J Rheumatol. 1986;13:1086–92.

    CAS  PubMed  Google Scholar 

  14. 14.

    Caro XJ. Is there an immunologic component to the fibrositis syndrome? Rheum Dis Clin N Am. 1989;15:169–86.

    CAS  Google Scholar 

  15. 15.•

    Caro XJ, Winter EF, Dumas A. A subset of fibromyalgia patients have findings suggestive of chronic inflammatory demyelinating polyneuropathy (CIDP) and appear to respond to IVIg. Rheumatology (Oxford). 2008;47:208–11. This study is the first to show large nerve involvement in FM and potential responsiveness to IVIg treatment.

    CAS  Article  Google Scholar 

  16. 16.

    Dinerman H, Goldenberg DL, Felson DT. A prospective evaluation of 118 patients with fibromyalgia syndrome: prevalence of Raynaud’s phenomenon, sicca symptoms, ANA, low complement, and Ig deposition at the dermal-epidermal junction. J Rheumatol. 1986;13:368–73.

    CAS  PubMed  Google Scholar 

  17. 17.

    Smart PA, Waylonis GW, Hackshaw KV. Immunologic profile of patients with fibromyalgia. Am J Phys Med Rehabil. 1997;76:231–4.

    CAS  Article  PubMed  Google Scholar 

  18. 18.•

    Salemi S, Rethage J, Wollina U, et al. Detection of interleukin 1 beta (IL-1beta), IL-6, and tumor necrosis factor-alpha in skin of patients with fibromyalgia. J Rheumatol. 2003;30:146–50. This study demonstrates abundant, local inflammatory markers in FM skin samples suggesting immune participation in FM skin pathology.

    CAS  PubMed  Google Scholar 

  19. 19.

    Hernanz W, Valenzuela A, Quijada J, et al. Lymphocyte subpopulations in patients with primary fibromyalgia. J Rheumatol. 1994;21:2122–4.

    CAS  PubMed  Google Scholar 

  20. 20.

    Wallace DJ, Bowman RL, Wormsley SB, Peter JB. Cytokines and immune regulation in patients with fibrositis. Arthritis Rheum. 1989;32:1334–5.

    CAS  Article  PubMed  Google Scholar 

  21. 21.

    Wilson RB, Gluck OS, Tesser JR, Rice JC, Meyer A, Bridges AJ. Antipolymer antibody reactivity in a subset of patients with fibromyalgia correlates with severity. J Rheumatol. 1999;26:402–7.

    CAS  PubMed  Google Scholar 

  22. 22.

    Shanklin DR, Stevens MV, Hall MF, Smalley DL. Environmental immunogens and T-cell-mediated responses in fibromyalgia: evidence for immune dysregulation and determinants of granuloma formation. Exp Mol Pathol. 2000;69:102–18.

    CAS  Article  PubMed  Google Scholar 

  23. 23.

    Macedo JA, Hesse J, Turner JD, Ammerlaan W, Giesens A, Hellhamer DH, et al. Adhesion molecules and cytokine expression in fibromyalgia patients: increased L-selectin on monocytes and neutrophils. J Neuroimmunol. 2007;188:159–66.

    CAS  Article  PubMed  Google Scholar 

  24. 24.

    Burda CD, Cox FR, Osborne P. Histocompatibility antigens in the fibrositis (fibromyalgia) syndrome. Clin Exp Rheumatol. 1986;4:355–8.

    CAS  PubMed  Google Scholar 

  25. 25.••

    Bazzichi L, Rossi A, Massimetti G, Giannaccini G, Guiliano T, De Feo F, et al. Cytokine patterns in fibromyalgia and their correlations with clinical manifestations. Clin Exp Rheumatol. 2007;25:225–30. This comprehensive study surveys multiple inflammatory markers in FM and suggests their elevation is more than coincidental.

    CAS  PubMed  Google Scholar 

  26. 26.

    Wallace DJ, Margolin K, Waller P. Fibromyalgia and interleukin-2 therapy for malignancy. Ann Intern Med. 1988;108:909.

    CAS  Article  PubMed  Google Scholar 

  27. 27.••

    Uceyler N, Kafke W, Riediger N, He L, Necula G, Toyka KV, et al. Elevated proinflammatory cytokine expression in affected skin in small fiber neuropathy. Neurology. 2010;74:1806–13. Subjects with length dependent SFN had significantly higher cytokine gene expression in affected skin, suggesting a role in pain production.

    CAS  Article  PubMed  Google Scholar 

  28. 28.•

    Parambil JG, Tavee JO, Zhou L, Pearson KS, Culver DA. Efficacy of intravenous immunoglobulin for small fiber neuropathy associated with sarcoidosis. Respir Med. 2011;105(1):101–5. This paper suggests that SFN may be successfully treated with IVIg.

    Article  PubMed  Google Scholar 

  29. 29.

    Sheikh KA, Zhang G, Gong Y, Schnaar RL, Griffin JW. An anti-ganglioside antibody-secreting hybridoma induces neuropathy in mice. Ann Neurol. 2004;56(2):228–39.

    CAS  Article  PubMed  Google Scholar 

  30. 30.•

    Grant IA. Cryptogenic sensory polyneuropathy. In: Dyck PJ, Thomas PK, editors. Peripheral neuropathy. Philadelphia: Elsevier; 2005. p. 2321–33. Excellent general review of SFN.

    Chapter  Google Scholar 

  31. 31.

    Phillips K, Clauw DJ. Central pain mechanisms in chronic pain states: maybe it is all in their head. Best Pract Res Clin Rheumatol. 2011;25:141–54.

    PubMed Central  Article  PubMed  Google Scholar 

  32. 32.•

    Staud R, Smitherman ML. Peripheral and central sensitization in fibromyalgia: pathogenetic role. Curr Pain Headache Rep. 2002;6(4):259–66. A comprehensive discussion of the potential role of undiagnosed peripheral pain generators, feeding central sensitization, in FM.

    Article  PubMed  Google Scholar 

  33. 33.

    Katz RS, Wolfe F, Michaud K. Fibromyalgia diagnosis: a comparison of clinical, survey, and American College of Rheumatology criteria. Arthritis Rheum. 2006;54(1):169–76.

    Article  PubMed  Google Scholar 

  34. 34.

    Wolfe F, Smythe HA, Yunus MB, Bennett RM, Bombardier C, Goldenberg DL, et al. The American College of Rheumatology 1990 criteria for the classification of fibromyalgia: report of the multicenter criteria committee. Arthritis Rheum. 1990;33:160–72.

    CAS  Article  PubMed  Google Scholar 

  35. 35.

    Wolfe F, Clauw DJ, Fitzcharles MA, Goldenberg DL, Katz RS, Mease P, et al. The American College of Rheumatology preliminary diagnostic criteria for fibromyalgia and measurement of symptom severity. Arthritis Care Res. 2010;62(5):600–10.

    Article  Google Scholar 

  36. 36.•

    Tavee J, Zhou L. Small fiber neuropathy: a burning problem. Cleve Clin J Med. 2009;76(5):297–305. A very readable review of SFN; excellent for the clinician.

    Article  PubMed  Google Scholar 

  37. 37.•

    Caro XJ. Fibromyalgia: evaluation and therapy of a neuroimmune disorder. In: Mahmoudi M, editor. Challenging cases in rheumatology and diseases of the immune system. New York: Springer; 2013. p. 257–84. The author shows how to use ENFD (skin biopsy) in the evaluation of FM. Case examples are presented.

    Chapter  Google Scholar 

  38. 38.

    Melzack R, Katz J. Pain assessment in adult patients. In: McMahon SB, Koltzenburg M, editors. Wall and Melzack’s textbook of pain. 5th ed. Philadelphia: Elsevier; 2005. p. 291–304.

    Google Scholar 

  39. 39.

    Martinez-Lavin M, Lopez S, Medina M, Nava A. Use of the Leeds assessment of neuropathic symptoms and signs questionnaire in patients with fibromyalgia. Semin Arthritis Rheum. 2003;32:407–11.

    Article  PubMed  Google Scholar 

  40. 40.

    Simms RW, Goldenberg DL. Symptoms mimicking neurologic disorders in fibromyalgia syndrome. J Rheumatol. 1988;15:1271–3.

    CAS  PubMed  Google Scholar 

  41. 41.

    Katirji B. Clinical assessment in neuromuscular disorders. In: Katirji B, Kaminski HJ, Preston DC, Ruff RL, Shapiro BE, editors. Neuromuscular disorders. Boston: Butterworth Heinemann; 2002. p. 3–19.

    Google Scholar 

  42. 42.

    DeJong RN. The neurologic examination: incorporating the fundamentals of neuroanatomy and neurophysiology. 4th ed. Cambridge: Harper & Row; 1979. p. 44–9. 67–8.

    Google Scholar 

  43. 43.••

    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. Excellent study of the pathophysiology of SFN and how its neuropathology translates into clinical findings.

    PubMed Central  Article  PubMed  Google Scholar 

  44. 44.

    Ersoz M. Nerve conduction tests in patients with fibromyalgia: comparison with normal controls. Rheumatol Int. 2003;23:166–70.

    Article  PubMed  Google Scholar 

  45. 45.

    Caro XJ, Winter E. Nerve conduction tests in patients with fibromyalgia syndrome. Rheumatol Int. 2005;25(1):77–8.

    Article  PubMed  Google Scholar 

  46. 46.

    Ersoz M. Nerve conduction tests in patients with fibromyalgia: comparison with normal controls. Rheumatol Int. 2005;25(1):79–80.

    Article  Google Scholar 

  47. 47.

    Caro XJ, Galbraith RG, Winter EF. Is there peripheral large nerve involvement in fibromyalgia? A systematic EMG / nerve conduction study evaluation of 55 consecutive FM patients [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10).

  48. 48.

    Hays AP. Utility of skin biopsy to evaluate peripheral neuropathy. Curr Neurol Neurosci Rep. 2010;10:101–7.

    Article  PubMed  Google Scholar 

  49. 49.

    Kennedy WR, Wendelschafer-Crabb G, Polydefkis M, McArthur JC. Chapter 34: pathology and quantitation of cutaneous innervation. In: Dyck PJ, Thomas PK, editors. Peripheral neuropathy. 4th ed. Philadelphia: Elsevier Saunders; 2005. p. 869–95.

    Chapter  Google Scholar 

  50. 50.

    Polydefkis M, Griffin JW, McArthur J. New insights into diabetic polyneuropathy. JAMA. 2003;290(10):1371–6.

    CAS  Article  PubMed  Google Scholar 

  51. 51.

    Rehman HU. Re: vitamin B12 deficiency. BMJ. 2014;349:g5226.

    Article  Google Scholar 

  52. 52.•

    Scadding JW, Koltzenburg M. Painful peripheral neuropathies. In: McMahon SB, Koltzenburg M, editors. Wall and Melzack’s textbook of pain. 6th ed. Philadelphia: Elsevier Churchill Livingstone; 2013. p. 926–51. A comprehensive review of peripheral neuropathic pain mechanisms.

    Google Scholar 

  53. 53.

    Dyck PJ, Lambert EH, O’Brien PC. Pain in peripheral neuropathy related to rate and kind of fiber degeneration. Neurology. 1976;26:466–71.

    CAS  Article  PubMed  Google Scholar 

  54. 54.

    Gilron I, Baron R, Jensen T. Neuropathic pain: principles of diagnosis and treatment. Mayo Clin Proc. 2015;90(4):532–45.

    CAS  Article  PubMed  Google Scholar 

  55. 55.

    Davis-Richardson AG, Triplett EW. A model for the role of gut bacteria in the development of autoimmunity for type 1 diabetes. Diabetologia. 2015;58(7):1386–93.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  56. 56.

    Gomez A, Luckey D, Taneja V. The gut microbiome in autoimmunity: sex matters. Clin Immunol. 2015;6:S1521–6616.

    Google Scholar 

  57. 57.

    Rogier R, Koenders MI, Abdollahi-Roodsaz S. Toll-like receptor mediated modulation of T cell response by commensal intestinal microbiota as a trigger for autoimmune arthritis. J Immunol Res. 2015;2015:527696.

    PubMed Central  Article  PubMed  Google Scholar 

  58. 58.

    Van Praet JT, Donovan E, Vanassche I, Drennan MB, Windels F, Dendooven A, et al. Commensal microbiota influence systemic autoimmune responses. EMBO J. 2015;34(4):466–74.

    Article  PubMed  Google Scholar 

  59. 59.

    Geuking MB, Köller Y, Rupp S, McCoy KD. The interplay between the gut microbiota and the immune system. Gut Microbes. 2014;5(3):411–8.

    PubMed Central  Article  PubMed  Google Scholar 

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Correspondence to Xavier J. Caro.

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This article is part of the Topical Collection on Neuropathic Pain

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Caro, X.J., Winter, E.F. The Role and Importance of Small Fiber Neuropathy in Fibromyalgia Pain. Curr Pain Headache Rep 19, 55 (2015).

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  • Fibromyalgia
  • Chronic pain
  • Chronic widespread pain
  • Neuropathic pain
  • Small fiber neuropathy
  • Epidermal nerve fiber density