Skip to main content
Book cover

Small Fiber Neuropathy and Related Syndromes: Pain and Neurodegeneration pp 121–129Cite as

Small Fiber Pathology in Pain Syndromes

  • 541 Accesses

Abstract

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.

Keywords

  • 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

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

Chapter
USD   29.95
Price excludes VAT (USA)
  • DOI: 10.1007/978-981-13-3546-4_11
  • Chapter length: 9 pages
  • Instant PDF download
  • Readable on all devices
  • Own it forever
  • Exclusive offer for individuals only
  • Tax calculation will be finalised during checkout
eBook
USD   59.99
Price excludes VAT (USA)
  • ISBN: 978-981-13-3546-4
  • Instant PDF download
  • Readable on all devices
  • Own it forever
  • Exclusive offer for individuals only
  • Tax calculation will be finalised during checkout
Hardcover Book
USD   79.99
Price excludes VAT (USA)
Learn about institutional subscriptions
Fig. 11.1
Fig. 11.2

References

  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.

    CAS  CrossRef  Google Scholar 

  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.

    CrossRef  Google Scholar 

  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.

    CrossRef  Google Scholar 

  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.

    CrossRef  Google Scholar 

  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.

    PubMed  Google Scholar 

  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.

    CrossRef  Google Scholar 

  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.

    CrossRef  Google Scholar 

  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.

    CAS  CrossRef  Google Scholar 

  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.

    CrossRef  Google Scholar 

  10. Kosek E, Ekholm J, Hansson P. Sensory dysfunction in fibromyalgia patients with implications for pathogenic mechanisms. Pain. 1996;68:375–83.

    CAS  CrossRef  Google Scholar 

  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.

    CrossRef  Google Scholar 

  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.

    CAS  CrossRef  Google Scholar 

  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.

    CAS  CrossRef  Google Scholar 

  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.

    CrossRef  Google Scholar 

  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.

    CrossRef  Google Scholar 

  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.

    CrossRef  Google Scholar 

  17. Caro XJ, Winter EF. Evidence of abnormal epidermal nerve fiber density in fibromyalgia: clinical and immunologic implications. Arthritis Rheumatol. 2014;66:1945–54.

    CrossRef  Google Scholar 

  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.

    CrossRef  Google Scholar 

  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.

    CrossRef  Google Scholar 

  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.

    CrossRef  Google Scholar 

  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.

    CrossRef  Google Scholar 

  22. Caro XJ, Winter EF. The role and importance of small fiber neuropathy in fibromyalgia pain. Curr Pain Headache Rep. 2015;19:55.

    CrossRef  Google Scholar 

  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.

    CAS  CrossRef  Google Scholar 

  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.

    CrossRef  Google Scholar 

  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.

    CrossRef  Google Scholar 

  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.

    CAS  CrossRef  Google Scholar 

  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.

    CAS  CrossRef  Google Scholar 

  28. Üçeyler N. Small fiber pathology-a culprit for many painful disorders? Pain. 2016;157(Suppl 1):S60–6.

    CrossRef  Google Scholar 

  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.

    CrossRef  Google Scholar 

  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.

    CrossRef  Google Scholar 

  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.

    CAS  CrossRef  Google Scholar 

  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.

    CAS  CrossRef  Google Scholar 

  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.

    CrossRef  Google Scholar 

  34. Cohen JI. Clinical practice: Herpes zoster. N Engl J Med. 2013;369:255–63.

    CAS  CrossRef  Google Scholar 

  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.

    CAS  CrossRef  Google Scholar 

  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.

    CrossRef  Google Scholar 

  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.

    CrossRef  Google Scholar 

  38. Petersen KL, Rice FL, Farhadi M, Reda H, Rowbotham MC. Natural history of cutaneous innervation following herpes zoster. Pain. 2010;150:75–82.

    CrossRef  Google Scholar 

  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.

    CAS  CrossRef  Google Scholar 

  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.

    CrossRef  Google Scholar 

  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.

    CrossRef  Google Scholar 

  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.

    CrossRef  Google Scholar 

  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.

    CrossRef  Google Scholar 

  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.

    CrossRef  Google Scholar 

  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.

    CAS  CrossRef  Google Scholar 

  46. Jaaskelainen SK, Woda A. Burning mouth syndrome. Cephalalgia. 2017;37:627–47.

    CrossRef  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Universitätsklinikum Würzburg, Würzburg, Germany

    Claudia Sommer & Nurcan Üçeyler

Authors
  1. Claudia Sommer
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nurcan Üçeyler
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Claudia Sommer .

Editor information

Editors and Affiliations

  1. Department of Neurology, National Taiwan University Hospital, Taipei, Taiwan

    Prof. Dr. Sung-Tsang Hsieh

  2. Department of Neurology, Imperial College London, Hammersmith Hospital, London, UK

    Prof. Dr. Praveen Anand

  3. Department of Neurology, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, MA, USA

    Prof. Dr. Christopher H. Gibbons

  4. Neurologische Klinik, Universitätsklinikum Würzburg , Würzburg, Germany

    Prof. Dr. Claudia Sommer

Rights and permissions

Reprints and Permissions

Copyright information

© 2019 Springer Nature Singapore Pte Ltd.

About this chapter

Verify currency and authenticity via CrossMark

Cite this chapter

Sommer, C., Üçeyler, N. (2019). Small Fiber Pathology in Pain Syndromes. 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_11

Download citation

  • DOI: https://doi.org/10.1007/978-981-13-3546-4_11

  • Published:

  • Publisher Name: Springer, Singapore

  • Print ISBN: 978-981-13-3545-7

  • Online ISBN: 978-981-13-3546-4

  • eBook Packages: MedicineMedicine (R0)