Small Fiber Pathology in Pain Syndromes

  • Claudia SommerEmail author
  • Nurcan Üçeyler


Evidence of functional and morphological changes in small nerve fibers has been shown in several painful disorders that do not have the clinical characteristics of small fiber neuropathy. The role of the small fiber pathology in these disorders remains to be defined, in particular the question whether it is causative to the pain in the disorders or whether it is a secondary phenomenon that needs to be answered. Skin innervation is reduced in the complex regional pain syndrome (CRPS). CRPS is a disorder that occurs after trauma, mostly a bone fracture, and where part of the acute pathophysiology consists in exaggerated inflammation with edema. At later stages, trophic changes are present. Since the intraepidermal nerve fibers are in a constant neuroplastic process, such changes in their environment may well induce a lack of regeneration and thus decrease their density. Fibromyalgia syndrome (FMS) is characterized by chronic widespread pain, mostly localized to deep tissues, and associated symptoms like morning stiffness, depression, and unrefreshing sleep. The finding of small fiber pathology in the skin in these patients was unexpected; however, it was independently confirmed by researchers in different geographical areas. Furthermore, pathologic function of small fibers and their afferent tracts has been shown by using specialized evoked potentials, quantitative sensory testing, and microneurography. The relation of small fiber pathology to FMS symptoms needs to be explored. The findings in diverse small fiber tests are not specific for one or the other diagnosis and can be found also in other painful conditions such as postherpetic neuralgia or postsurgical pain. Here, the underlying mechanisms and the relation of small fiber pathology to the respective pain syndrome are even less well explored and understood.


Complex regional pain syndrome Fibromyalgia syndrome Postherpetic neuralgia Postsurgical pain Ehlers-Danlos syndrome Quantitative sensory testing Pain related evoked potentials Skin biopsy Corneal confocal microscopy Microneurography Growth-associated protein 43 


  1. 1.
    Birklein F, Riedl B, Sieweke N, Weber M, Neundorfer B. Neurological findings in complex regional pain syndromes—analysis of 145 cases. Acta Neurol Scand. 2000;101:262–9.CrossRefGoogle Scholar
  2. 2.
    Üçeyler N, Eberle T, Rolke R, Birklein F, Sommer C. Differential expression patterns of cytokines in complex regional pain syndrome. Pain. 2007;132:195–205.CrossRefGoogle Scholar
  3. 3.
    Gierthmühlen J, Maier C, Baron R, Tölle T, Treede RD, Birbaumer N, et al. Sensory signs in complex regional pain syndrome and peripheral nerve injury. Pain. 2012;153:765–74.CrossRefGoogle Scholar
  4. 4.
    Oaklander AL, Fields HL. Is reflex sympathetic dystrophy/complex regional pain syndrome type I a small-fiber neuropathy? Ann Neurol. 2009;65:629–38.CrossRefGoogle Scholar
  5. 5.
    Kharkar S, Venkatesh YS, Grothusen JR, Rojas L, Schwartzman RJ. Skin biopsy in complex regional pain syndrome: case series and literature review. Pain Physician. 2012;15:255–66.PubMedGoogle Scholar
  6. 6.
    van der Laan L, ter Laak HJ, Gabreels-Festen A, Gabreels F, Goris RJ. Complex regional pain syndrome type I (RSD): pathology of skeletal muscle and peripheral nerve. Neurology. 1998;51:20–5.CrossRefGoogle Scholar
  7. 7.
    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.CrossRefGoogle Scholar
  8. 8.
    Hurtig IM, Raak RI, Kendall SA, Gerdle B, Wahren LK. Quantitative sensory testing in fibromyalgia patients and in healthy subjects: identification of subgroups. Clin J Pain. 2001;17:316–22.CrossRefGoogle Scholar
  9. 9.
    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;27:682–90.CrossRefGoogle Scholar
  10. 10.
    Kosek E, Ekholm J, Hansson P. Sensory dysfunction in fibromyalgia patients with implications for pathogenic mechanisms. Pain. 1996;68:375–83.CrossRefGoogle Scholar
  11. 11.
    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.CrossRefGoogle Scholar
  12. 12.
    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.CrossRefGoogle Scholar
  13. 13.
    Leinders M, Doppler K, Klein T, Deckart M, Rittner H, Sommer C, et al. Increased cutaneous miR-let-7d expression correlates with small nerve fiber pathology in patients with fibromyalgia syndrome. Pain. 2016;157:2493–503.CrossRefGoogle Scholar
  14. 14.
    Ramirez M, Martinez-Martinez LA, Hernandez-Quintela E, Velazco-Casapia J, Vargas A, Martinez-Lavin M. Small fiber neuropathy in women with fibromyalgia. An in vivo assessment using corneal confocal bio-microscopy. Semin Arthritis Rheum. 2015;45:214–9.CrossRefGoogle Scholar
  15. 15.
    da Silva LA, Kazyiama HH, Teixeira MJ, de Siqueira SR. Quantitative sensory testing in fibromyalgia and hemisensory syndrome: comparison with controls. Rheumatol Int. 2013;33:2009–17.CrossRefGoogle Scholar
  16. 16.
    de Tommaso M, Nolano M, Iannone F, Vecchio E, Ricci K, Lorenzo M, et al. Update on laser-evoked potential findings in fibromyalgia patients in light of clinical and skin biopsy features. J Neurol. 2014;261:461–72.CrossRefGoogle Scholar
  17. 17.
    Caro XJ, Winter EF. Evidence of abnormal epidermal nerve fiber density in fibromyalgia: clinical and immunologic implications. Arthritis Rheumatol. 2014;66:1945–54.CrossRefGoogle Scholar
  18. 18.
    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.CrossRefGoogle Scholar
  19. 19.
    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;347:143–7.CrossRefGoogle Scholar
  20. 20.
    Martinez-Martinez LA, Mora T, Vargas A, Fuentes-Iniestra M, Martinez-Lavin M. Sympathetic nervous system dysfunction in fibromyalgia, chronic fatigue syndrome, irritable bowel syndrome, and interstitial cystitis: a review of case-control studies. J Clin Rheumatol. 2014;20:146–50.CrossRefGoogle Scholar
  21. 21.
    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.CrossRefGoogle Scholar
  22. 22.
    Caro XJ, Winter EF. The role and importance of small fiber neuropathy in fibromyalgia pain. Curr Pain Headache Rep. 2015;19:55.CrossRefGoogle Scholar
  23. 23.
    Gao WQ, Shinsky N, Ingle G, Beck K, Elias KA, Powell-Braxton L. IGF-I deficient mice show reduced peripheral nerve conduction velocities and decreased axonal diameters and respond to exogenous IGF-I treatment. J Neurobiol. 1999;39:142–52.CrossRefGoogle Scholar
  24. 24.
    Hoffmann JN, Montag AG, Dominy NJ. Meissner corpuscles and somatosensory acuity: the prehensile appendages of primates and elephants. Anat Rec A Discov Mol Cell Evol Biol. 2004;281:1138–47.CrossRefGoogle Scholar
  25. 25.
    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.CrossRefGoogle Scholar
  26. 26.
    Oudejans L, He X, Niesters M, Dahan A, Brines M, van Velzen M. Cornea nerve fiber quantification and construction of phenotypes in patients with fibromyalgia. Sci Rep. 2016;6:23573.CrossRefGoogle Scholar
  27. 27.
    Serra J, Collado A, Sola R, Antonelli F, Torres X, Salgueiro M, et al. Hyperexcitable C nociceptors in fibromyalgia. Ann Neurol. 2014;75:196–208.CrossRefGoogle Scholar
  28. 28.
    Üçeyler N. Small fiber pathology-a culprit for many painful disorders? Pain. 2016;157(Suppl 1):S60–6.CrossRefGoogle Scholar
  29. 29.
    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.CrossRefGoogle Scholar
  30. 30.
    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 (Hoboken). 2010;62:600–10.CrossRefGoogle Scholar
  31. 31.
    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.CrossRefGoogle Scholar
  32. 32.
    Eich W, Bar KJ, Bernateck M, Burgmer M, Dexl C, Petzke F. et al. [Definition, classification, clinical diagnosis and prognosis of fibromyalgia syndrome: updated guidelines 2017 and overview of systematic review articles]. Schmerz. 2017;31:231–8.CrossRefGoogle Scholar
  33. 33.
    Dworkin RH, Gnann JW Jr, Oaklander AL, Raja SN, Schmader KE, Whitley RJ. Diagnosis and assessment of pain associated with herpes zoster and postherpetic neuralgia. J Pain. 2008;9:S37–44.CrossRefGoogle Scholar
  34. 34.
    Cohen JI. Clinical practice: Herpes zoster. N Engl J Med. 2013;369:255–63.CrossRefGoogle Scholar
  35. 35.
    Buonocore M, Gatti AM, Amato G, Aloisi AM, Bonezzi C. Allodynic skin in post-herpetic neuralgia: histological correlates. J Cell Physiol. 2012;227:934–8.CrossRefGoogle Scholar
  36. 36.
    Üçeyler N, Valet M, Kafke W, Tölle TR, Sommer C. Local and systemic cytokine expression in patients with postherpetic neuralgia. PLoS One. 2014;9:e105269.CrossRefGoogle Scholar
  37. 37.
    Truini A, Haanpaa M, Provitera V, Biasiotta A, Stancanelli A, Caporaso G, et al. Differential myelinated and unmyelinated sensory and autonomic skin nerve fiber involvement in patients with ophthalmic postherpetic neuralgia. Front Neuroanat. 2015;9:105.CrossRefGoogle Scholar
  38. 38.
    Petersen KL, Rice FL, Farhadi M, Reda H, Rowbotham MC. Natural history of cutaneous innervation following herpes zoster. Pain. 2010;150:75–82.CrossRefGoogle Scholar
  39. 39.
    Truini A, Galeotti F, Haanpaa M, Zucchi R, Albanesi A, Biasiotta A, et al. Pathophysiology of pain in postherpetic neuralgia: a clinical and neurophysiological study. Pain. 2008;140:405–10.CrossRefGoogle Scholar
  40. 40.
    Pfau DB, Krumova EK, Treede RD, Baron R, Toelle T, Birklein F, et al. Quantitative sensory testing in the German Research Network on Neuropathic Pain (DFNS): reference data for the trunk and application in patients with chronic postherpetic neuralgia. Pain. 2014;155:1002–15.CrossRefGoogle Scholar
  41. 41.
    Bischoff JM, Ringsted TK, Petersen M, Sommer C, Uceyler N, Werner MU. A capsaicin (8%) patch in the treatment of severe persistent inguinal postherniorrhaphy pain: a randomized, double-blind, placebo-controlled trial. PLoS One. 2014;9:e109144.CrossRefGoogle Scholar
  42. 42.
    Cazzato D, Castori M, Lombardi R, Caravello F, Bella ED, Petrucci A, et al. Small fiber neuropathy is a common feature of Ehlers-Danlos syndromes. Neurology. 2016;87:155–9.CrossRefGoogle Scholar
  43. 43.
    Laurencin C, Andre-Obadia N, Camdessanche JP, Mauguiere F, Ong E, Vukusic S, et al. Peripheral small fiber dysfunction and neuropathic pain in patients with Morvan syndrome. Neurology. 2015;85:2076–8.CrossRefGoogle Scholar
  44. 44.
    Lauria G, Majorana A, Borgna M, Lombardi R, Penza P, Padovani A, et al. Trigeminal small-fiber sensory neuropathy causes burning mouth syndrome. Pain. 2005;115:332–7.CrossRefGoogle Scholar
  45. 45.
    Puhakka A, Forssell H, Soinila S, Virtanen A, Roytta M, Laine M, et al. Peripheral nervous system involvement in primary burning mouth syndrome—results of a pilot study. Oral Dis. 2016;22:338–44.CrossRefGoogle Scholar
  46. 46.
    Jaaskelainen SK, Woda A. Burning mouth syndrome. Cephalalgia. 2017;37:627–47.CrossRefGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  1. 1.Universitätsklinikum WürzburgWürzburgGermany

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