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Fibromyalgia and small fiber neuropathy: the plot thickens!

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Abstract

Several groups of investigators have described the presence of small fiber neuropathy in fibromyalgia patients. This writing discusses how this new finding could renovate fibromyalgia concept, diagnosis, and treatment. Predominant rheumatology thinking proposes fibromyalgia as a “centralized pain syndrome.” An alternative hypothesis views fibromyalgia as a stress-related dysautonomia with neuropathic pain features. Dorsal root ganglia may be the key autonomic-nociceptive short-circuit sites. The recent recognition of small fiber neuropathy in a large subgroup of fibromyalgia patients reinforces the dysautonomia-neuropathic hypothesis and validates fibromyalgia pain. These new findings support fibromyalgia as a primarily neurological entity, nevertheless, rheumatologist will likely remain the best equipped specialist to diagnose fibromyalgia and differentiate it from other multi-symptomatic rheumatic syndromes. Skin biopsy and corneal confocal microscopy will probably become useful fibromyalgia diagnostic tests. Dorsal root ganglia sodium channel blockers are potential fibromyalgia analgesic medications. Subgroups of young girls with “autoimmune neuropathic fibromyalgia” may respond to immunoglobulin therapy. Multimodal intervention directed to regain autonomic nervous system resilience will likely remain the cornerstone for fibromyalgia therapy.

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References

  1. Uceyler N, Zeller D, Kahn AK, Kewenig S, Kittel-Schneider S, Schmid A et al (2013) Small fibre pathology in patients with fibromyalgia syndrome. Brain 136(Pt 6):1857–1867

    Article  Google Scholar 

  2. Oaklander AL, Herzog ZD, Downs HM, Klein MM (2013) Objective evidence that small-fiber polyneuropathy underlies some illnesses currently labeled as fibromyalgia. Pain 154:2310–2316

    Article  Google Scholar 

  3. Serra J, Collado A, Sola R, Antonelli F, Torres X, Salgueiro M et al (2014) Hyperexcitable C nociceptors in fibromyalgia. Ann Neurol 75:196–208

    Article  CAS  Google Scholar 

  4. Giannoccaro MP, Donadio V, Incensi A, Avoni P, Liguori R (2014) Small nerve fiber involvement in patients referred for fibromyalgia. Muscle Nerve 49:757–759

    Article  Google Scholar 

  5. Caro XJ, Winter EF (2014) Evidence of abnormal epidermal nerve fiber density in fibromyalgia: clinical and immunologic implications. Arthritis Rheum 66:1945–1954

    Article  Google Scholar 

  6. Kosmidis ML, Koutsogeorgopoulou L, Alexopoulos H, Mamali I, Vlachoyiannopoulos PG, Voulgarelis M, Moutsopoulos HM, Tzioufas AG, Dalakas MC (2014) Reduction of Intraepidermal Nerve Fiber Density (IENFD) in the skin biopsies of patients with fibromyalgia: a controlled study. J Neurol Sci 347:143–147

    Article  Google Scholar 

  7. Ramírez M, Martínez-Martínez LA, Hernández-Quintela E, Velazco-Casapía J, Vargas A, Martínez-Lavín M (2015) Small fiber neuropathy in women with fibromyalgia. An in vivo assessment using corneal confocal bio-microscopy. Semin Arthritis Rheum 45:214–219

    Article  Google Scholar 

  8. 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 37:205–210

    Article  Google Scholar 

  9. Martínez-Lavín M (2013) Fibromyalgia. How stress becomes real pain and what to do about it. E-book Amazon Kindle Edition. USA

  10. Clauw DJ (2015) Fibromyalgia and related conditions. Mayo Clin Proc 90:680–692

    Article  Google Scholar 

  11. Yunus MB (2007) Fibromyalgia and overlapping disorders: the unifying concept of central sensitivity syndromes. Semin Arthritis Rheum 36:339–356

    Article  Google Scholar 

  12. Martinez-Lavin M (2007) Biology and therapy of fibromyalgia. Stress, the stress response system, and fibromyalgia. Arthritis Res Ther 9:216–219

    Article  Google Scholar 

  13. Martínez-Lavín M, Hermosillo AG (2000) Autonomic nervous system dysfunction may explain the multisystem features of fibromyalgia. Semin Arthritis Rheum 29:197–199

    Article  Google Scholar 

  14. Martínez-Lavín M, Vidal M, Barbosa RE, Pineda C, Casanova JM, Nava A (2002) Norepinephrine-evoked pain in fibromyalgia. A randomized pilot study ISCRTN 70707830. BMC Musculoskelet Disord 2:3 (16 Jan 2002)

    Google Scholar 

  15. Vargas-Alarcon G, Alvarez-Leon E, Fragoso JM, Vargas A, Martinez A, Vallejo M, Martinez-Lavin M (2012) A SCN9A gene-encoded dorsal root ganglia sodium channel polymorphism associated with severe fibromyalgia. BMC Musculoskeletal Dis. https://doi.org/10.1186/1471-2474-13-23

  16. Martinez-Lavin M, Infante O, Lerma C (2008) Hypothesis: the chaos and complexity theory may help our understanding of fibromyalgia and similar maladies. Semin Arthritis Rheum 37:260–264

    Article  Google Scholar 

  17. Reyes-Manzano CF, Lerma C, Echeverría JC, Martínez-Lavín M, Martinez-Martínez LA, Infante O, Guzmán-Vargas L (2018) Multifractal analysis reveals decreased nonlinearity and stronger anticorrelations in heart period fluctuations of fibromyalgia patients. Front Physiol. https://doi.org/10.3389/fphys.2018.01118

  18. Martinez-Lavin M (2012) Fibromyalgia when distress becomes (un)sympathetic pain. Pain Res Treat 2012:1–6. https://doi.org/10.1155/2012/981565

    Article  Google Scholar 

  19. Tavee J, Zhou L (2009) Small fiber neuropathy: a burning problem. Cleve Clin J Med 76:297–305

    Article  Google Scholar 

  20. Tavakoli M, Ferdousi M, Petropoulos IN, Morris J, Pritchard N, Zhivov A, Ziegler D, Pacaud D, Romanchuk K, Perkins BA, Lovblom LE, Bril V, Singleton JR, Smith G, Boulton AJ, Efron N, Malik RA (2015) Normative values for corneal nerve morphology assessed using corneal confocal microscopy: a multinational normative data set. Diabetes Care 38:838–843

    Article  Google Scholar 

  21. Faber CG, Hoeijmakers JG, Ahn HS, Cheng X, Han C, Choi JS et al (2012) Gain of function Nav1.7 mutations in idiopathic small fiber neuropathy. Ann Neurol 71:26–39

    Article  CAS  Google Scholar 

  22. Chen SS, Zhang JM (2015) Progress in sympathetically mediated pathological pain. J Anesth Perioper Med 2:216–225

    Article  Google Scholar 

  23. Martinez-Lavin M, Solano C (2009) Dorsal root ganglia sodium channels and fibromyalgia sympathetic pain. Med Hypotheses 72:64–66

    Article  CAS  Google Scholar 

  24. Clauw DJ (2015) What is the meaning of “small fiber neuropathy” in fibromyalgia? Pain 156:2115–2116

    Article  Google Scholar 

  25. Wolfe F, Walitt B, Rasker JJ, Häuser W (2018) Primary and secondary fibromyalgia are the same: the Universality of Polysymptomatic Distress. J Rheumatol. https://doi.org/10.3899/jrheum.180083

  26. Suokas K, Palmio J, Sandell S, Udd B, Hietaharju A (2018) Pain in SCN4A mutated P.A1156T muscle sodium channelopathy-a postal survey. Muscle Nerve 57:1014–1017. https://doi.org/10.1002/mus.26050

    Article  CAS  PubMed  Google Scholar 

  27. Castoro R, Simmons M, Ravi V, Huang D, Lee C, Sergent J, Zhou L, Li J (2018) SCN11A Arg225Cys mutation causes nociceptive pain without detectable peripheral nerve pathology. Neurol Genet 4:e255. https://doi.org/10.1212/NXG.0000000000000255. eCollection

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  29. Benarroch EE (2012) Postural tachycardia syndrome: a heterogeneous and multifactorial disorder. Mayo Clin Proc 87:1214–1225

    Article  Google Scholar 

  30. Blitshteyn S, Brook J (2017) Postural tachycardia syndrome (POTS) with anti-NMDA receptor antibodies after human papillomavirus vaccination. Immunol Res 65:282–284

    Article  Google Scholar 

  31. Haensch CA, Tosch M, Katona I, Weis J, Isenmann S (2014) Small-fiber neuropathy with cardiac denervation in postural tachycardia syndrome. Muscle Nerve 50:956–961

    Article  CAS  Google Scholar 

  32. Fedorowski A, Li H, Yu X, Koelsch KA, Harris VM, Liles C, Murphy TA, Quadri SMS, Scofield RH, Sutton R, Melander O, Kem DC (2017) Antiadrenergic autoimmunity in postural tachycardia syndrome. Europace 19(7):1211–1219

    Article  Google Scholar 

  33. Martínez-Lavín M, Amezcua-Guerra L (2017) Serious adverse events after HPV vaccination: a critical review of randomized trials and post-marketing case series. Clin Rheumatol 36:2169–2217

    Article  Google Scholar 

  34. Blitshteyn S (2014) Postural tachycardia syndrome following human papillomavirus vaccination. Eur J Neurol 21:135–139

    Article  CAS  Google Scholar 

  35. Kinoshita T, Abe RT, Hineno A, Tsunekawa K, Nakane S, Ikeda S (2014) Peripheral sympathetic nerve dysfunction in adolescent Japanese girls following immunization with the human papillomavirus vaccine. Intern Med 53:2185–2200

    Article  Google Scholar 

  36. Hendrickson JE, Tormey CA (2016) Human papilloma virus vaccination and dysautonomia: considerations for autoantibody evaluation and HLA typing. Vaccine 34:4468. https://doi.org/10.1016/j.vaccine.2016.05.029

    Article  PubMed  Google Scholar 

  37. Schofield JR, Hendrickson JE (2017) Autoimmunity, autonomic neuropathy, and the HPV vaccination: a vulnerable subpopulation. Clin Pediatr (Phila) 57:603–606. https://doi.org/10.1177/0009922817728701

    Article  Google Scholar 

  38. Martínez-Lavin M (2018) HPV vaccination syndrome: a clinical mirage, or a new tragic fibromyalgia model. Reumatol Clin (English Edition) 14:211–214. https://doi.org/10.1016/j.reumae.2018.01.001

    Article  Google Scholar 

  39. Choi BY, Oh HJ, Lee YJ, Song YW (2016) Prevalence and clinical impact of fibromyalgia in patients with primary Sjögren’s syndrome. Clin Exp Rheumatol 34(Suppl 96):S9–S13

    PubMed  Google Scholar 

  40. Pavlakis PP, Alexopoulos H, Kosmidis ML, Mamali I, Moutsopoulos HM, Tzioufas AG, Dalakas MC (2012) Peripheral neuropathies in Sjögren's syndrome: a critical update on clinical features and pathogenetic mechanisms. J Autoimmun 39:27–33. https://doi.org/10.1016/j.jaut.2012.01.003

    Article  CAS  PubMed  Google Scholar 

  41. Oomatia A, Fang H, Petri M, Birnbaum J (2014) Peripheral neuropathies in systemic lupus erythematosus: clinical features, disease associations, and immunologic characteristics evaluated over a twenty-five-year study period. Arthritis Rheum 66:1000–1009

    Article  CAS  Google Scholar 

  42. Zakrzewska JM, Palmer J, Morisset V, Giblin GM, Obermann M, Ettlin DA, Cruccu G, Bendtsen L, Estacion M, Derjean D, Waxman SG, Layton G, Gunn K, Tate S (2017) Safety and efficacy of a Nav1.7 selective sodium channel blocker in patients with trigeminal neuralgia: a double-blind, placebo-controlled, randomised withdrawal phase 2a trial. Lancet Neurol 16:291–300. https://doi.org/10.1016/S1474-4422(17)30005-4

    Article  CAS  PubMed  Google Scholar 

  43. Li M, Wu Y, Zou B, Wang X, M L, Yu H (2018) Identification of WB4101, an α1-adrenoceptor antagonist, as a sodium channel blocker. Mol Pharm 94:896–906. https://doi.org/10.1124/mol.117.111252

    Article  CAS  Google Scholar 

  44. Yang Y, Mis MA, Estacion M, Dib-Hajj SD, Waxman SG (2018) NaV1.7 as a pharmacogenomic target for pain: moving toward precision medicine. Trends Pharmacol Sci 39:258–275. https://doi.org/10.1016/j.tips.2017.11.010

    Article  CAS  PubMed  Google Scholar 

  45. Oaklander AL (2016) Immunotherapy prospects for painful small-fiber sensory neuropathies and Ganglionopathies. Neurotherapeutics 13:108–117. https://doi.org/10.1007/s13311-015-0395-1

    Article  CAS  PubMed  Google Scholar 

  46. Schofield JR, Blitshteyn S, Shoenfeld Y, Hughes GR (2014) Postural tachycardia syndrome (POTS) and other autonomic disorders in antiphospholipid (Hughes) syndrome (APS). Lupus 23:697–702

    Article  CAS  Google Scholar 

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Martínez-Lavín, M. Fibromyalgia and small fiber neuropathy: the plot thickens!. Clin Rheumatol 37, 3167–3171 (2018). https://doi.org/10.1007/s10067-018-4300-2

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