Skip to main content

Advertisement

SpringerLink
Log in

The puzzle of fibromyalgia between central sensitization syndrome and small fiber neuropathy: a narrative review on neurophysiological and morphological evidence

  • Review Article
  • Published:
Neurological Sciences Aims and scope Submit manuscript

Abstract

Fibromyalgia (FM) is a condition characterized by chronic widespread pain whose pathogenesis is still not fully defined. Evidence based on structural and functional neuroimaging methods, electrophysiological, and morphological – skin biopsy – features demonstrated a central and peripheral nervous system involvement. A dysfunction in nociceptive inputs processing at the central level was highlighted as the primary cause of FM, but other data coming from different laboratories contributed to emphasize again the peripheral origin of FM. In fact, small fibers neuropathy (SFN) was observed in a large number of patients submitted to skin biopsy. The complex interaction between central and peripheral factors is opening a new scenario about the management of this neurological disorder. Whether proximal SFN is an initiating event leading to FM or is the consequence of stress-related insular hyper excitability remains unclear. Mild sufferance of peripheral afferents could function as a trigger for an exaggerated response of the so-called “salience matrix” in predisposed individuals. On the other side, the intriguing hypothesis rising from animal models could indicate that the cortical hyper function could cause peripheral small afferent damage. The research should go on the genetic origin of such peripheral and central abnormalities, the acquired facilitating factors, and the presence of different phenotypes in order to search for efficacious treatments, which are still lacking.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Data availability

Not applicable.

Code availability

Not applicable.

References

  1. Mikkelsson M, Latikka P, Kautiainen H et al (1992) Muscle and bone pressure pain threshold and pain tolerance in fibromyalgia patients and controls. Arch Phys Med Rehabil 73:814–818

    CAS  PubMed  Google Scholar 

  2. Kosek E,9 Ekholm J, Hansson P. (1995) Increased pressure pain sensibility in fibromyalgia patients is located deep to the skin but not restricted to muscle tissue. Pain. Dec;63(3):335–339. doi: https://doi.org/10.1016/0304-3959(95)00061-5.

  3. Staud R (2011) Brain imaging in fibromyalgia syndrome. Clin Exp Rheumatol 29(6 Suppl 69):S109–S117

    CAS  PubMed  Google Scholar 

  4. Wolfe F, Smythe HA, Yunus MB, et al. (1990) The American College of Rheumatology 1990 Criteria for the Classification of Fibromyalgia. Report of the Multicenter Criteria Committee. Arthritis and Rheumatism. Feb;33(2):160–72. https://doi.org/10.1002/art.1780330203

  5. Staud R (2011) Peripheral pain mechanisms in chronic widespread pain. Best Pract Res Clin Rheumatol. Apr;25(2):155–64. https://doi.org/10.1016/j.berh.2010.01.010

  6. Yunus MB (2015) (2015) Editorial review: an update on central sensitivity syndromes and the issues of nosology and psychobiology. Curr Rheumatol Rev 11(2):70–85

    Article  Google Scholar 

  7. Wolfe F, Clauw DJ, Fitzcharles MA et al (2010) The American College of Rheumatology preliminary diagnostic criteria for fibromyalgia and measurement of symptom severity. Arthritis Care Res 62:600–610. https://doi.org/10.1002/acr.20140

    Article  Google Scholar 

  8. Grayston R, Czanner G, Elhadd K et al (2019) A systematic review and meta-analysis of the prevalence of small fiber pathology in fibromyalgia: implications for a new paradigm in fibromyalgia etiopathogenesis. Semin Arthritis Rheum 48(5):933–940. https://doi.org/10.1016/j.semarthrit.2018.08.003

    Article  PubMed  Google Scholar 

  9. Wolfe F, Walitt B (2013) Culture, science and the changing nature of fibromyalgia. Nat Rev Rheumatol 9(12):751–755

    Article  Google Scholar 

  10. Palmer S, Bailey J, Brown C, Jones A, McCabe CS (2019) Sensory function and pain experience in arthritis, complex regional pain syndrome, fibromyalgia syndrome, and pain-free volunteers: a cross-sectional study. Clin J Pain 35(11):894–900

    Article  Google Scholar 

  11. Gracely Rh, Petzke F, Wolf JM, Clauw DJ (2002) Functional magnetic resonance imaging evidence of augmented pain processing in fibromyalgia. Arthritis Rheum 46:1333–1343. https://doi.org/10.1002/art.10225

    Article  PubMed  Google Scholar 

  12. Williams DA, Gracely RH (2006) Biology and therapy of fibromyalgia. Functional magnetic resonance imaging findings in fibromyalgia. Arthritis Res Ther. 8(6):224.

  13. Burgmer M, Pfleiderer B, Maihöfner C, Gaubitz M, Wessolleck E, Heuft G, Pogatzki-Zahn E (2012) Cerebral mechanisms of experimental hyperalgesia in fibromyalgia. Eur J Pain 16(5):636–647. https://doi.org/10.1002/j.1532-2149.2011.00058.x

    Article  CAS  PubMed  Google Scholar 

  14. Craggs JG, Staud R, Robinson ME, Perlstein WM, Price DD (2012) Effective connectivity among brain regions associated with slow temporal summation of C-fiber-evoked pain in fibromyalgia patients and healthy controls. J Pain 13(4):390–400. https://doi.org/10.1016/j.jpain.2012.01.002

    Article  PubMed  PubMed Central  Google Scholar 

  15. Pujol J, Macià D, Garcia-Fontanals A, Blanco-Hinojo L, López-Solà M, Garcia-Blanco S, Poca-Dias V, et al. (20 The contribution of sensory system functional connectivity reduction to clinical pain in fibromyalgia. Pain. 155(8):1492–1503.

  16. Bosma RL, Mojarad EA, Leung L, Pukall C, Staud R, Stroman PW (2016) FMRI of spinal and supra-spinal correlates of temporal pain summation in fibromyalgia patients. Hum Brain Mapp 37(4):1349–1360

    Article  Google Scholar 

  17. Schreiber KL, Loggia ML, Kim J, Cahalan CM, Napadow V, Edwards RR (2017) Painful after-sensations in fibromyalgia are linked to catastrophizing and differences in brain response in the medial temporal lobe. J Pain 18(7):855–867. https://doi.org/10.1016/j.jpain.2017.02.437

    Article  PubMed  PubMed Central  Google Scholar 

  18. Ellingson LD, Stegner AJ, Schwabacher IJ, Lindheimer JB, Cook DB (2018) Catastrophizing interferes with cognitive modulation of pain in women with fibromyalgia. Pain Med 19(12):2408–2422. https://doi.org/10.1093/pm/pny008

    Article  PubMed  PubMed Central  Google Scholar 

  19. Sandström A, Ellerbrock I, Tour J, Kadetoff D, Jensen KB, Kosek E (2020) Neural correlates of conditioned pain responses in fibromyalgia subjects indicate preferential formation of new pain associations rather than extinction of irrelevant ones. Pain 161(9):2079–2088

    Article  Google Scholar 

  20. Hubbard CS, Lazaridou A, Cahalan CM, Kim J, Edwards RR, Napadow V, Loggia ML (2020) Aberrant salience? Brain hyperactivation in response to pain onset and offset in fibromyalgia. Arthritis Rheumatol 72(7):1203–1213. https://doi.org/10.1002/art.41220

    Article  PubMed  PubMed Central  Google Scholar 

  21. Truini A, Tinelli E, Gerardi MC, Calistri V, Iannuccelli C, La Cesa S, Tarsitani L, Mainero C, Sarzi-Puttini P, Cruccu G, Caramia F, Di Franco M (2016) Abnormal resting state functional connectivity of the periaqueductal grey in patients with fibromyalgia. Clin Exp Rheumatol 34(2 Suppl 96):S129–S133 PMID: 27157397

    PubMed  Google Scholar 

  22. Coulombe MA, St Lawrence K, Moulin DE, Morley-Forster P, Shokouhi M, Nielson WR, Davis KD (2017) Lower functional connectivity of the periaqueductal gray is related to negative affect and clinical manifestations of Front Neuroanat 11:47. https://doi.org/10.3389/fnana.2017.00047

    Article  PubMed  Google Scholar 

  23. Harper DE, Ichesco E, Schrepf A, Hampson JP, Clauw DJ, Schmidt-Wilcke T, Harris RE, Harte SE (2018) Resting functional connectivity of the periaqueductal gray is associated with normal inhibition and pathological facilitation in conditioned pain modulation. J Pain 19(6):635.e1-635.e15. https://doi.org/10.1016/j.jpain.2018.01.001

    Article  Google Scholar 

  24. Čeko M, Frangos E, Gracely J, Richards E, Wang B, Schweinhardt P, Catherine Bushnell M (2020) Default mode network changes in fibromyalgia patients are largely dependent on current clinical pain. Neuroimage 1(216):116877. https://doi.org/10.1016/j.neuroimage.2020.116877

    Article  Google Scholar 

  25. Ichesco E, Puiu T, Hampson JP, Kairys AE, Clauw DJ, Harte SE, Peltier SJ, Harris RE, Schmidt-Wilcke T (2016) Altered fMRI resting-state connectivity in individuals with fibromyalgia on acute pain stimulation. Eur J Pain 20(7):1079–1089. https://doi.org/10.1002/ejp.832

    Article  CAS  PubMed  Google Scholar 

  26. Jarrahi B, Martucci KT, Nilakantan AS, Mackey S (2017) Investigating the BOLD spectral power of the intrinsic connectivity networks in fibromyalgia patients: a resting-state fMRI study. Annu Int Conf IEEE Eng Med Biol Soc 2017:497–500

    PubMed  Google Scholar 

  27. Jarrahi B, Martucci KT, Nilakantan AS, Mackey S (2018) Cold water pressor test differentially modulates functional network connectivity in fibromyalgia patients compared with healthy controls. Annu Int Conf IEEE Eng Med Biol Soc 2018:578–582

    PubMed  Google Scholar 

  28. López-Solà M, Woo CW, Pujol J, Deus J, Harrison BJ, Monfort J, Wager TD (2017) Towards a neurophysiological signature for fibromyalgia. Pain 158(1):34–47

    Article  Google Scholar 

  29. Kaplan CM, Schrepf A, Vatansever D, Larkin TE, Mawla I, Ichesco E, Kochlefl L, Harte SE, Clauw DJ, Mashour GA, Harris RE (2019) Functional and neurochemical disruptions of brain hub topology in chronic pain. Pain 160(4):973–983

    Article  Google Scholar 

  30. Ledermann K, Jenewein J, Sprott H, Hasler G, Schnyder U, Warnock G, Johayem A, Kollias S, Buck A, Martin C (2016) Relation of dopamine receptor 2 binding to pain perception in female fibromyalgia patients with and without depression--A [11C] racloprid Eur Neuropsychopharmacol. 26(2):320–330. https://doi.org/10.1016/j.euroneuro.2015.12.007

  31. Pomares FB, Roy S, Funck T, Feier NA, Thiel A, Fitzcharles MA, Schweinhardt P (2020) Upregulation of cortical GABAA receptor concentration in fibromyalgia. Pain 161(1):74–82

    Article  CAS  Google Scholar 

  32. Albrecht DS, Forsberg A, Sandström A, Bergan C, Kadetoff D, Protsenko E, Lampa J, Lee YC, Höglund CO, Catana C, Cervenka S, Akeju O, Lekander M, Cohen G, Halldin C, Taylor N, Kim M, Hooker JM, Edwards RR, Napadow V, Kosek E, Loggia ML (2018) Brain glial activation in fibromyalgia - a multi-site positron emission tomography investigation. Brain Behav Immun 75:72–83. https://doi.org/10.1016/j.bbi.2018.09.018

    Article  PubMed  PubMed Central  Google Scholar 

  33. Üçeyler N, Buchholz HG, Kewenig S, Ament SJ, Birklein F, Schreckenberger M, Sommer C (2020) Cortical binding potential of opioid receptors in patients with fibromyalgia syndrome and reduced systemic interleukin-4 levels - a pilot study. Front Neurosci 14:512. https://doi.org/10.3389/fnins.2020.00512

    Article  PubMed  PubMed Central  Google Scholar 

  34. Cagnie B, Coppieters I, Denecker S, Six J, Danneels L, Meeus M (2014) Central sensitization in fibromyalgia? A systematic review on structural and functional brain MRI. Semin Arthritis Rheum 44(1):68–75. https://doi.org/10.1016/j.semarthrit.2014.01.001

    Article  PubMed  Google Scholar 

  35. Kim H, Kim J, Loggia ML, Cahalan C, Garcia RG, Vangel MG, Wasan AD, Edwards RR, Napadow V (2015) Fibromyalgia is characterized by altered frontal and cerebellar structural covariance brain networks. Neuroimage Clin 7:667–677. https://doi.org/10.1016/j.nicl.2015.02.022

    Article  PubMed  PubMed Central  Google Scholar 

  36. Robinson ME, O’Shea AM, Craggs JG, Price DD, Letzen JE, Staud R (2015) Comparison of machine classification algorithms for fibromyalgia: neuroimages versus self-report. J Pain 16(5):472–477

    Article  Google Scholar 

  37. Sundermann B, Nayyeri MD, Pfleiderer B, Stahlberg K, Jünke L, Baie L, Dieckmann R, Liem D, Happe T, Burgmer M (2019) Subtle changes of gray matter volume in fibromyalgia reflect chronic musculoskeletal pain rather than disease-specific effects. Eur J Neurosci 50(12):3958–3967. https://doi.org/10.1111/ejn.14558

    Article  PubMed  Google Scholar 

  38. McCrae CS, O’Shea AM, Boissoneault J, Vatthauer KE, Robinson ME, Staud R, Perlstein WM, Craggs JG (2015) Fibromyalgia patients have reduced hippocampal volume compared with healthy controls. J Pain Res 30(8):47–52. https://doi.org/10.2147/JPR.S71959

    Article  Google Scholar 

  39. Feraco P, Nigro S, Passamonti L, Grecucci A, Caligiuri ME, Gagliardo C, Bacci A (2020) Neurochemical correlates of brain atrophy in fibromyalgia syndrome: a magnetic resonance spectroscopy and cortical thickness study. Brain Sci 10(6):395. https://doi.org/10.3390/brainsci10060395

    Article  CAS  PubMed Central  Google Scholar 

  40. Gibson SJ, Littlejohn GO, Gorman MM, Helme RD, Granges G (1994) Altered heat pain thresholds and cerebral event-related potentials following painful CO2 laser stimulation in subjects with fibromyalgia syndrome. Pain 58(2):185–193

    Article  CAS  Google Scholar 

  41. de Tommaso M, Federici A, Santostasi R et al (2011) Laser-evoked potentials habituation in fibromyalgia. J Pain 12(1):116–124. https://doi.org/10.1155/2017/9747148

    Article  PubMed  Google Scholar 

  42. de Tommaso M (2008) Laser-evoked potentials in primary headaches and cranial neuralgias. Expert Rev Neurother 8(9):1339–1345. https://doi.org/10.1586/14737175.8.9.1339

    Article  PubMed  Google Scholar 

  43. de Tommaso M, Ambrosini A, Brighina F et al (2014) Altered processing of sensory stimuli in patients with migraine. Nat Rev Neurol 10(3):144–155

    Article  Google Scholar 

  44. Üçeyler N, Zeller D, Kahn AK, Kewenig S, Kittel-Schneider S, Schmid A, Casanova-Molla J, Reiners K, Sommer C (2013) Small fiber pathology in patients with fibromyalgia syndrome. Brain 136(Pt 6):1857–1867. https://doi.org/10.1093/brain/awt053

    Article  PubMed  Google Scholar 

  45. Van Assche DCF, Plaghki L, Masquelier E, Hatem SM (2020) Fibromyalgia syndrome-a laser-evoked potentials study unsupportive of small nerve fibre involvement. Eur J Pain 24(2):448–456. https://doi.org/10.1002/ejp.1501

    Article  CAS  PubMed  Google Scholar 

  46. Fasolino A, Di Stefano G, Leone C, Galosi E, Gioia C, Lucchino B, Terracciano A, Di Franco M, Cruccu G, Truini A (2020) Small-fibre pathology has no impact on somatosensory system function in patients with fibromyalgia. Pain 161(10):2385–2393

    Article  CAS  Google Scholar 

  47. Vecchio E, Lombardi R, Paolini M, Libro G, Delussi M, Ricci K, Quitadamo SG, Gentile E, Girolamo F, Iannone F, Lauria G, de Tommaso M (2020) Peripheral and central nervous system correlates in fibromyalgia. Eur J Pain. 6(1).

  48. Evdokimov D, Frank J, Klitsch A, Unterecker S, Warrings B, Serra J, Papagianni A, Saffer N, Altenschildesche MZ, C, Kampik D, Malik RA, Sommer C, Üçeyler N, (2019) Reduction of skin innervation is associated with a severe fibromyalgia phenotype. Ann Neurol 86(4):504–516. https://doi.org/10.1002/ana.25565

    Article  CAS  PubMed  Google Scholar 

  49. de Tommaso M, Santostasi R, Devitofrancesco V, Franco G, Vecchio E, Delussi M, Livrea P, Katzarava Z (2011) A comparative study of cortical responses evoked by transcutaneous electrical vs CO(2) laser stimulation. Clin Neurophysiol 122(12):2482–2487. https://doi.org/10.1016/j.clinph.2011.05.006

    Article  PubMed  Google Scholar 

  50. González-Roldán AM, Cifre I, Sitges C, Montoya P (2016) Altered dynamic of EEG oscillations in fibromyalgia patients at rest. Pain Med 17(6):1058–1068. https://doi.org/10.1093/pm/pnw023

    Article  PubMed  Google Scholar 

  51. Pascual-Marqui RD, Esslen M, Kochi K, Lehmann D (2002) Functional imaging with low-resolution brain electromagnetic tomography (LORETA): a review. Methods Find Exp Clin Pharmacol 24(suppl C):91–95

    PubMed  Google Scholar 

  52. Vanneste S, Ost J, Van Havenbergh T, De Ridder D (2017) Resting state electrical brain activity and connectivity in fibromyalgia. PLoS ONE 12(6):e0178516. https://doi.org/10.1371/journal.pone.0178516

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Fallon N, Chiu Y, Nurmikko T, Stancak A (2018) Altered theta oscillations in resting EEG of fibromyalgia syndrome patients. Eur J Pain 22(1):49–57. https://doi.org/10.1002/ejp.1076

    Article  CAS  PubMed  Google Scholar 

  54. Choe MK, Lim M, Kim JS, Lee DS, Chung CK (2018) Disrupted resting state network of fibromyalgia in theta frequency. Sci Rep 8(1):2064

    Article  Google Scholar 

  55. González-Villar AJ, Triñanes Y, Gómez-Perretta C, Carrillo-de-la-Peña MT (2010) Patients with fibromyalgia show increased beta connectivity across distant networks and microstates alterations in resting-state electroencephalogram. Neuroimage. https://doi.org/10.1016/j.neuroimage.2020.117266

    Article  Google Scholar 

  56. Ploner M, Sorg C, Gross J (2017) Brain rhythms of pain. Trends Cogn Sci 21(2):100–110. https://doi.org/10.1016/j.tics.2016.12.001

    Article  PubMed  PubMed Central  Google Scholar 

  57. Uceyler N, Zeller D, Kahn AK, Kewenig S, Kittel-Schneider S, Schmid A, Sommer C (2013) Small fibre pathology in patients with fibromyalgia syndrome. Brain 136(6):1857–1867. https://doi.org/10.1093/brain/awt053

    Article  PubMed  Google Scholar 

  58. Oaklander AL, Klein MM (2013) Evidence of small-fiber polyneuropathy in unexplained, juvenile-onset, widespread pain syndromes. Pediatrics 131(4):e1091–e1100. https://doi.org/10.1542/peds.2012-2597

    Article  PubMed  PubMed Central  Google Scholar 

  59. de Tommaso M, Nolano M, Iannone F, Vecchio E, Ricci K, Lorenzo M, Delussi M, Girolamo F, Lavolpe V, Provitera V, Stancanelli A, Lapadula G, Livrea P (2014) Update on laser-evoked potential findings in fibromyalgia patients in light of clinical and skin biopsy features. J Neurol 261(3):461–472

    Article  Google Scholar 

  60. Giannoccaro MP, Donadio V, Incensi A, Avoni P, Liguori R (2014) Small nerve fiber involvement in patients referred for fibromyalgia. Muscle Nerve 49(5):757–759. https://doi.org/10.1002/mus.24156

    Article  PubMed  Google Scholar 

  61. Kosmidis ML, Koutsogeorgopoulou L, Alexopoulos H et al (2014) Reduction of intraepidermal nerve fiber density (IENFD) in the skin biopsies of patients with fibromyalgia: a controlled study. J Neurol Sci 347(1–2):143–147. https://doi.org/10.1016/j.jns.2014.09.035

    Article  PubMed  Google Scholar 

  62. Serra J, Collado A, Solà R, Antonelli F, Torres X, Salgueiro M, Quiles C, Bostock H (2014) Hyperexcitable C nociceptors in fibromyalgia. Ann Neurol 75(2):196–208

    Article  CAS  Google Scholar 

  63. Doppler K, Rittner HL, Deckart M, Sommer C (2015) Reduced dermal nerve fiber diameter in skin biopsies of patients with fibromyalgia. Pain 156(11):2319–2325

    Article  CAS  Google Scholar 

  64. Solmaz V, Yavuz S, İnanr A, Aksoy D, Pektaş E, Tekataş A, Kurt SG (2017) Investigation of nerve conduction studies of carpal tunnel syndrome cases with different risk factors: an electrodiagnostic study. J Clin Neurophysiol 34(2):139–143

    Article  Google Scholar 

  65. Klaver-Krol EG, Rasker JJ, Klaver MM, Ten Klooster PM, Zwarts MJ (2019) Fibromyalgia: increased reactivity of the muscle membrane and a role of central regulation. Clin Neurophysiol 130(1):12–19

    Article  CAS  Google Scholar 

  66. Caro XJ, Galbraith RG, Winter EF (2018) Evidence of peripheral large nerve involvement in fibromyalgia: a retrospective review of EMG and nerve conduction findings in 55 FM subjects. Eur J Rheumatol 5(2):104–110

    Article  Google Scholar 

  67. Lawson VH, Grewal J, Hackshaw KV, Mongiovi PC, Stino AM (2018) Fibromyalgia syndrome and small fiber, early or mild sensory polyneuropathy. Muscle Nerve 58(5):625–630. https://doi.org/10.1002/mus.26131

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Donadio V, Liguori R (2015) Microneurographic recording from unmyelinated nerve fibers in neurological disorders: an update. Clin Neurophysiol 126(3):437–445. https://doi.org/10.1016/j.clinph.2014.10.009

    Article  CAS  PubMed  Google Scholar 

  69. Tavakoli M, Marshall A, Pitceathly R, Fadavi H, Gow D, Roberts ME et al (2010) () Corneal confocal microscopy: a novel means to detect nerve fibre damage in idiopathic small fibre neuropathy. Exp Neurol 223:245–250. https://doi.org/10.1016/j.expneurol.2009.08.033

    Article  PubMed  Google Scholar 

  70. Ramirez M, Martinez-Martinez LA, Hernandez-Quintela E, Velazco-Casapia J, Varga A & Martinez-Lavin M (2015). Small fiber neuropathy in women with fibromyalgia. An in vivo assessment using corneal confocal bio-microscopy. Semin Arthritis Rheum, 45(2), 214–219. https://doi.org/10.1016/j.semarthrit.2015.03.003

  71. Oudejans L, He X, Niesters M, Dahan A, Brines M, van Velzen M (2016) Cornea nerve fiber quantification and construction of phenotypes in patients with fibromyalgia. Sci Rep 6:23573

    Article  CAS  Google Scholar 

  72. Erkan Turan K, Kocabeyoglu S, Unal-Cevik I, Bezci F, Akinci A, Irkec M (2018) Ocular surface alterations in the context of corneal in vivo confocal microscopic characteristics in patients with fibromyalgia. Cornea 37(2):205–210

    Article  Google Scholar 

  73. van de Donk T, van Velzen M, Dahan A (2019) Niesters M (2019) Cornea nerve fibre state determines analgesic response to tapentadol in fibromyalgia patients without effective endogenous pain modulation. Eur J Pain 23(9):1586–1595. https://doi.org/10.1002/ejp.1435

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Klitsch A, Evdokimov D, Frank J, Thomas D, Saffer N, Altenschildesche MZ, C, Sisignano M, Kampik D, Malik RA, Sommer C, Üçeyler N, (2020) Reduced association between dendritic cells and corneal sub-basal nerve fibers in patients with fibromyalgia syndrome. J Peripher Nerv Syst 25(1):9–18. https://doi.org/10.1111/jns.12360

    Article  CAS  PubMed  Google Scholar 

  75. Ramírez M, Guerra-Juárez A, Miyake DY, Sebastian-Arellano C, Estrada-Mata AG, González-Moyotl NJ, Rodríguez-Aguayo AM, Martínez-Lavin M, Martínez-Martínez LA (2020) Correlation between corneal nerve density and symptoms of small fiber neuropathy in patients with fibromyalgia: the confounding role of severe anxiety or depression. J Clin Rheumatol. 10.

  76. Leinders M, Doppler K, Klein T, Deckart M, Rittner H, Sommer C, Üçeyler N (2016) Increased cutaneous miR-let-7d expression correlates with small nerve fiber pathology in patients with fibromyalgia syndrome. Pain 157(11):2493–2503

    Article  CAS  Google Scholar 

  77. Lodahl, M., Treister, R., & Oaklander, A. L. (2018). Specific symptoms may discriminate between fibromyalgia patients with vs without objective test evidence of small-fiber polyneuropathy. Pain Rep 3(1):e633

  78. Boneparth A, Chen S, Horton DB, Moorthy LN, Farquhar I, Downs HM, Lee H, Oaklander AL (2020). Epidermal neurite density in skin biopsies from patients whith juvenile fibromyalgia. J Rheumatol. 15:jrheum.200378. https://doi.org/10.3899/jrheum.200378

  79. Kleykamp BA, Ferguson MC, McNicol E, Bixho I, Arnold LM, Edwards RR et al (2021) The prevalence of psychiatric and chronic pain comorbidities in fibromyalgia: an ACTTION systematic review. Semin Arthritis Rheum 51(1):166–174. https://doi.org/10.1016/j.semarthrit.2020.10.006

    Article  PubMed  Google Scholar 

  80. Arendt-Nielsen L, Morlion B, Perrot S et al (2018) Assessment and manifestation of central sensitisation across different chronic pain conditions. Eur J Pain 22(2):216–241. https://doi.org/10.1002/ejp.1140

    Article  CAS  PubMed  Google Scholar 

  81. Aydede M, Shriver A (2018) Recently introduced definition of “nociplastic pain” by the International Association for the Study of Pain needs better formulation. Pain 159(6):1176–1177

    Article  Google Scholar 

  82. Meacham K, Shepherd A, Mohapatra DP, Haroutounian S. (2017) Neuropathic pain: central vs. peripheral mechanisms. Curr Pain Headache Rep. 21(6):28. https://doi.org/10.1007/s11916-017-0629-5

  83. Hüllemann P, von der Brelie C, Manthey G et al (2017) Reduced laser-evoked potential habituation detects abnormal central pain processing in painful radiculopathy patients. Eur J Pain 21(5):918–926. https://doi.org/10.1002/ejp.994

    Article  PubMed  Google Scholar 

  84. Lee, Y.C., Lu, B., Bathon, J.M., Haythornthwaite, J.A., Smith, M.T, Page GG, Edwards RR (2011). Pain sensitivity and pain reactivity in osteoarthritis. Arthritis Care Res (Hoboken)63, 320–327. https://doi.org/10.1002/acr.20373

  85. Martinez-Lavin M (2018) Fibromyalgia and small fiber neuropathy: the plot thickens! Clin Rheumatol 37(12):3167–3171

    Article  Google Scholar 

  86. Nolano M, Manganelli F, Provitera V et al (2015) Small nerve fiber involvement in CMT1A. Neurology 84(4):407–414. https://doi.org/10.1212/WNL.0000000000001188

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Nolano M, Provitera V, Crisci C et al (2001) Small fibers involvement in Friedreich’s ataxia. Ann Neurol 50(1):17–25. https://doi.org/10.1002/ana.1283

    Article  CAS  PubMed  Google Scholar 

  88. Nolano M, Provitera V, Donadio V et al (2016) Cutaneous sensory and autonomic denervation in CADASIL. Neurology 86(11):1039–1044. https://doi.org/10.1212/WNL.0000000000002468

    Article  PubMed  Google Scholar 

  89. Nolano M, Provitera V, Estraneo A et al (2008) Sensory deficit in Parkinson’s disease: evidence of a cutaneous denervation. Brain 131(Pt 7):1903–1911. https://doi.org/10.1093/brain/awn102

    Article  PubMed  Google Scholar 

  90. Nolano M, Provitera V, Manganelli F et al (2017) Non-motor involvement in amyotrophic lateral sclerosis: new insight from nerve and vessel analysis in skin biopsy. Neuropathol Appl Neurobiol 43(2):119–132. https://doi.org/10.1111/nan.12332

    Article  CAS  PubMed  Google Scholar 

  91. Goebel A, Krock E, Gentry C, Israel MR, Jurczak A, Urbina CM, et al. (2021) Passive transfer of fibromyalgia symptoms from patients to mice. J Clin Invest. 1;131(13):e144201. doi: https://doi.org/10.1172/JCI144201.

  92. Harte SE, Clauw DJ, Hayes JM, Feldman EL, St Charles IC & Watson CJ (2017) Reduced intraepidermal nerve fiber density after a sustained increase in insular glutamate: a proof-of-concept study examining the pathogenesis of small fiber pathology in fibromyalgia. Pain Rep, 2(3), e590.

  93. Hsieh PC, Tseng MT, Chao CC, Lin YH, Tseng WI, Liu KH et al (2015) (2015) Imaging signatures of altered brain responses in small-fiber neuropathy: reduced functional connectivity of the limbic system after peripheral nerve degeneration. Pain 156(5):904–916. https://doi.org/10.1097/j.pain.0000000000000128

    Article  PubMed  Google Scholar 

  94. Macfarlane GJ, Kronisch C, Dean LE et al (2017) EULAR revised recommendations for the management of fibromyalgia. Ann Rheum Dis 76(2):318–328. https://doi.org/10.1136/annrheumdis-2016-209724

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

There are no specific funds for this submission

Author information

Authors and Affiliations

  1. Applied Neurophysiology and Pain Unit, SMBNOS Department, Bari Aldo Moro University, Policlinico General Hospital, Bari, Italy

    Marina de Tommaso, Eleonora Vecchio & Maria Nolano

  2. IRCSS Fondazione Maugeri, Telese, Napoli, Italy

    Marina de Tommaso, Eleonora Vecchio & Maria Nolano

Authors
  1. Marina de Tommaso
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Eleonora Vecchio
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Maria Nolano
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Marina de Tommaso.

Ethics declarations

Ethical approval

None.

Consent to participate (include appropriate statements)

Not applicable.

Consent for publication (include appropriate statements)

Not applicable.

Conflict of interest/Competing interests

The authors declare no competing interests.

Additional information

Publisher's note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

de Tommaso, M., Vecchio, E. & Nolano, M. The puzzle of fibromyalgia between central sensitization syndrome and small fiber neuropathy: a narrative review on neurophysiological and morphological evidence. Neurol Sci 43, 1667–1684 (2022). https://doi.org/10.1007/s10072-021-05806-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10072-021-05806-x

Keywords

Search

Navigation