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Paraproteinemia and neuropathy

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Abstract

Paraproteinemia is associated with different peripheral neuropathies. The major causes of neuropathy correlated with paraproteinemia are the deposition of immunoglobulin in the myelin, represented by anti-myelin-associated glycoprotein (MAG) neuropathy; deposition of immunoglobulin or its fragment in the interstitium, represented by immunoglobulin light chain amyloidosis (AL amyloidosis); and paraneoplastic mechanisms that cannot be solely attributed to the deposition of immunoglobulin or its fragment, represented by polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin change (POEMS) syndrome. Patients with anti-MAG neuropathy and POEMS syndrome present with slowing of nerve conduction parameters. This characteristic fulfills the electrodiagnostic criteria for chronic inflammatory demyelinating polyneuropathy (CIDP) defined by the European Academy of Neurology and Peripheral Nerve Society (EAN/PNS). Although direct damage caused by the deposition of amyloid can induce axonal damage in AL amyloidosis, some patients with this condition have features fulfilling the EAN/PNS electrodiagnostic criteria for CIDP. Conventional immunotherapies for CIDP, such as steroids, intravenous immunoglobulin, and plasma exchange, offer no or only minimal-to-modest benefit. Although rituximab can reduce the level of circulating autoantibodies, it may only be effective in some patients with anti-MAG neuropathy. Drugs including melphalan, thalidomide, lenalidomide, and bortezomib for POEMS syndrome and those including melphalan, thalidomide, lenalidomide, pomalidomide, bortezomib, ixazomib, and daratumumab for AL amyloidosis are considered. Since there will be more therapeutic options in the future, thereby enabling appropriate treatments for individual neuropathies, there is an increasing need for early diagnosis.

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References

  1. Glavey SV, Leung N (2016) Monoclonal gammopathy: the good, the bad and the ugly. Blood Rev 30(3):223–231

    Article  PubMed  Google Scholar 

  2. Kyle RA, Larson DR, Therneau TM, Dispenzieri A, Kumar S, Cerhan JR, Rajkumar SV (2018) Long-term follow-up of monoclonal gammopathy of undetermined significance. N Engl J Med 378(3):241–249

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Chaudhry HM, Mauermann ML, Rajkumar SV (2017) Monoclonal gammopathy-associated peripheral neuropathy: diagnosis and management. Mayo Clin Proc 92(5):838–850

    Article  PubMed  Google Scholar 

  4. Saleun JP, Vicariot M, Deroff P, Morin JF (1982) Monoclonal gammopathies in the adult population of Finistère. France J Clin Pathol 35(1):63–68

    Article  CAS  PubMed  Google Scholar 

  5. Crawford J, Eye MK, Cohen HJ (1987) Evaluation of monoclonal gammopathies in the “well” elderly. Am J Med 82(1):39–45

    Article  CAS  PubMed  Google Scholar 

  6. Kyle RA, Therneau TM, Rajkumar SV, Larson DR, Plevak MF, Offord JR, Dispenzieri A, Katzmann JA, Melton LJ 3rd (2006) Prevalence of monoclonal gammopathy of undetermined significance. N Engl J Med 354(13):1362–1369

    Article  CAS  PubMed  Google Scholar 

  7. Vallat JM, Duchesne M, Corcia P, Richard L, Ghorab K, Magy L, Mathis S (2021) The wide spectrum of pathophysiologic mechanisms of paraproteinemic neuropathy. Neurology 96(5):214–225

    Article  PubMed  Google Scholar 

  8. Kelly JJ Jr, Kyle RA, O’Brien PC, Dyck PJ (1981) Prevalence of monoclonal protein in peripheral neuropathy. Neurology 31(11):1480–1483

    Article  PubMed  Google Scholar 

  9. Tomita M, Koike H, Kawagashira Y, Iijima M, Adachi H, Taguchi J, Abe T, Sako K, Tsuji Y, Nakagawa M, Kanda F, Takeda F, Sugawara M, Toyoshima I, Asano N, Sobue G (2013) Clinicopathological features of neuropathy associated with lymphoma. Brain 136(Pt 8):2563–2578

    Article  PubMed  Google Scholar 

  10. Latov N (1995) Pathogenesis and therapy of neuropathies associated with monoclonal gammopathies. Ann Neurol 37(Suppl 1):S32-42

    Article  PubMed  Google Scholar 

  11. Kawagashira Y, Koike H, Tomita M, Morozumi S, Iijima M, Nakamura T, Katsuno M, Tanaka F, Sobue G (2010) Morphological progression of myelin abnormalities in IgM-monoclonal gammopathy of undetermined significance anti-myelin-associated glycoprotein neuropathy. J Neuropathol Exp Neurol 69(11):1143–1157

    Article  CAS  PubMed  Google Scholar 

  12. Koike H, Mouri N, Fukami Y, Iijima M, Matsuo K, Yagi N, Saito A, Nakamura H, Takahashi K, Nakae Y, Okada Y, Tanaka F, Sobue G, Katsuno M (2021) Two distinct mechanisms of neuropathy in immunoglobulin light chain (AL) amyloidosis. J Neurol Sci 421:117305

    Article  PubMed  Google Scholar 

  13. Koike H, Iijima M, Mori K, Yamamoto M, Hattori N, Watanabe H, Tanaka F, Doyu M, Sobue G (2008) Neuropathic pain correlates with myelinated fibre loss and cytokine profile in POEMS syndrome. J Neurol Neurosurg Psychiatry 79(10):1171–1179

    Article  CAS  PubMed  Google Scholar 

  14. Ramchandren S, Lewis RA (2009) Monoclonal gammopathy and neuropathy. Curr Opin Neurol 22(5):480–485

    Article  PubMed  Google Scholar 

  15. Nobile-Orazio E, Manfredini E, Carpo M, Meucci N, Monaco S, Ferrari S, Bonetti B, Cavaletti G, Gemignani F, Durelli L et al (1994) Frequency and clinical correlates of anti-neural IgM antibodies in neuropathy associated with IgM monoclonal gammopathy. Ann Neurol 36(3):416–424

    Article  CAS  PubMed  Google Scholar 

  16. Campagnolo M, Zambello R, Nobile-Orazio E, Benedetti L, Marfia GA, Riva N, Castellani F, Bianco M, Salvalaggio A, Garnero M, Ruiz M, Mataluni G, Fazio R, Ermani M, Briani C (2017) IgM MGUS and Waldenstrom-associated anti-MAG neuropathies display similar response to rituximab therapy. J Neurol Neurosurg Psychiatry 88(12):1094–1097

    Article  PubMed  Google Scholar 

  17. Svahn J, Petiot P, Antoine JC, Vial C, Delmont E, Viala K, Steck AJ, Magot A, Cauquil C, Zarea A, Echaniz-Laguna A, Iancu Ferfoglia R, Gueguen A, Magy L, Léger JM, Kuntzer T, Ferraud K, Lacour A, Camdessanché JP (2018) Francophone anti-MAG cohort Group. Anti-MAG antibodies in 202 patients: clinicopathological and therapeutic features. J Neurol Neurosurg Psychiatry 89(5):499–505

    Article  PubMed  Google Scholar 

  18. Steck AJ, Stalder AK, Renaud S (2006) Anti-myelin-associated glycoprotein neuropathy. Curr Opin Neurol 19(5):458–463

    Article  CAS  PubMed  Google Scholar 

  19. Lunn MP, Crawford TO, Hughes RA, Griffin JW, Sheikh KA (2002) Anti-myelin-associated glycoprotein antibodies alter neurofilament spacing. Brain 125(Pt 4):904–911

    Article  PubMed  Google Scholar 

  20. Trapp BD, Quarles RH (1982) Presence of the myelin-associated glycoprotein correlates with alterations in the periodicity of peripheral myelin. J Cell Biol 92(3):877–882

    Article  CAS  PubMed  Google Scholar 

  21. Lach B, Rippstein P, Atack D, Afar DE, Gregor A (1993) Immunoelectron microscopic localization of monoclonal IgM antibodies in gammopathy associated with peripheral demyelinative neuropathy. Acta Neuropathol 85(3):298–307

    Article  CAS  PubMed  Google Scholar 

  22. Vallat JM, Magy L, Sindou P, Magdelaine C, Cros D (2005) IgG neuropathy: an immunoelectron microscopic study. J Neuropathol Exp Neurol 64(5):386–390

    Article  PubMed  Google Scholar 

  23. Vallat JM, Tabaraud F, Sindou P, Preux PM, Vandenberghe A, Steck A (2000) Myelin widenings and MGUS-IgA: an immunoelectron microscopic study. Ann Neurol 47(6):808–811

    Article  CAS  PubMed  Google Scholar 

  24. Monaco S, Bonetti B, Ferrari S, Moretto G, Nardelli E, Tedesco F, Mollnes TE, Nobile-Orazio E, Manfredini E, Bonazzi L et al (1990) Complement-mediated demyelination in patients with IgM monoclonal gammopathy and polyneuropathy. N Engl J Med 322(10):649–652

    Article  CAS  PubMed  Google Scholar 

  25. Koike H, Kadoya M, Kaida KI, Ikeda S, Kawagashira Y, Iijima M, Kato D, Ogata H, Yamasaki R, Matsukawa N, Kira JI, Katsuno M, Sobue G (2017) Paranodal dissection in chronic inflammatory demyelinating polyneuropathy with anti-neurofascin-155 and anti-contactin-1 antibodies. J Neurol Neurosurg Psychiatry 88(6):465–473

    Article  PubMed  Google Scholar 

  26. Koike H, Katsuno M (2020) Pathophysiology of chronic inflammatory demyelinating polyneuropathy: insights into classification and therapeutic strategy. Neurol Ther 9(2):213–227

    Article  PubMed  PubMed Central  Google Scholar 

  27. Kawagashira Y, Koike H, Takahashi M, Ohyama K, Iijima M, Katsuno M, Niwa JI, Doyu M, Sobue G (2020) Aberrant expression of nodal and paranodal molecules in neuropathy associated with IgM monoclonal gammopathy with anti-myelin-associated glycoprotein antibodies. J Neuropathol Exp Neurol 79(12):1303–1312

    Article  CAS  PubMed  Google Scholar 

  28. Koike H, Katsuno M (2021) Macrophages and autoantibodies in demyelinating diseases. Cells 10(4):844

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Koike H, Nishi R, Ikeda S, Kawagashira Y, Iijima M, Katsuno M, Sobue G (2018) Ultrastructural mechanisms of macrophage-induced demyelination in CIDP. Neurology 91(23):1051–1060

    Article  CAS  PubMed  Google Scholar 

  30. Koike H, Fukami Y, Nishi R, Kawagashira Y, Iijima M, Katsuno M, Sobue G (2020) Ultrastructural mechanisms of macrophage-induced demyelination in Guillain-Barré syndrome. J Neurol Neurosurg Psychiatry 91(6):650–659

    Article  PubMed  Google Scholar 

  31. Kawagashira Y, Kondo N, Atsuta N, Iijima M, Koike H, Katsuno M, Tanaka F, Kusunoki S, Sobue G (2010) IgM MGUS anti-MAG neuropathy with predominant muscle weakness and extensive muscle atrophy. Muscle Nerve 42(3):433–435

    Article  PubMed  Google Scholar 

  32. Magy L, Kaboré R, Mathis S, Lebeau P, Ghorab K, Caudie C, Vallat JM. 2015 Heterogeneity of polyneuropathy associated with anti-MAG antibodies. J Immunol Res. 2015:450391.

  33. Van den Bergh PYK, van Doorn PA, Hadden RDM, Avau B, Vankrunkelsven P, Allen JA, Attarian S, Blomkwist PH, Cornblath DR, Eftimov F, Goedee HS, Harbo T, Kuwabara S, Lewis RA, Lunn MP, Nobile-Orazio E, Querol L, Rajabally YA, Sommer C, Topaloglu HA. European Academy of Neurology/Peripheral Nerve Society Guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: report of a joint Task Force - Second Revision. J Peripher Nerv Syst. in press.

  34. Kaku DA, England JD, Sumner AJ (1994) Distal accentuation of conduction slowing in polyneuropathy associated with antibodies to myelin-associated glycoprotein and sulphated glucuronyl paragloboside. Brain 117(Pt 5):941–947

    Article  PubMed  Google Scholar 

  35. Trojaborg W, Hays AP, van den Berg L, Younger DS, Latov N (1995) Motor conduction parameters in neuropathies associated with anti-MAG antibodies and other types of demyelinating and axonal neuropathies. Muscle Nerve 18(7):730–735

    Article  CAS  PubMed  Google Scholar 

  36. Capasso M, Torrieri F, Di Muzio A, De Angelis MV, Lugaresi A, Uncini A (2002) Can electrophysiology differentiate polyneuropathy with anti-MAG/SGPG antibodies from chronic inflammatory demyelinating polyneuropathy? Clin Neurophysiol 113(3):346–353

    Article  CAS  PubMed  Google Scholar 

  37. Gondim FA, De Sousa EA, Latov N, Sander HW, Chin RL, Brannagan TH (2007) Anti-MAG/SGPG associated neuropathy does not commonly cause distal nerve temporal dispersion. J Neurol Neurosurg Psychiatry 78(8):902–904

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Nobile-Orazio E, Bianco M, Nozza A (2017) Advances in the treatment of paraproteinemic neuropathy. Curr Treat Options Neurol 19(12):43

    Article  PubMed  Google Scholar 

  39. Dalakas MC (2018) Advances in the diagnosis, immunopathogenesis and therapies of IgM-anti-MAG antibody-mediated neuropathies. Ther Adv Neurol Disord 15(11):1756285617746640

    Google Scholar 

  40. Maurer MA, Rakocevic G, Leung CS, Quast I, Lukačišin M, Goebels N, Münz C, Wardemann H, Dalakas M, Lünemann JD (2012) Rituximab induces sustained reduction of pathogenic B cells in patients with peripheral nervous system autoimmunity. J Clin Invest 122(4):1393–1402

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Dalakas MC, Rakocevic G, Salajegheh M, Dambrosia JM, Hahn AF, Raju R, McElroy B (2009) Placebo-controlled trial of rituximab in IgM anti-myelin-associated glycoprotein antibody demyelinating neuropathy. Ann Neurol 65(3):286–293

    Article  CAS  PubMed  Google Scholar 

  42. Léger JM, Viala K, Nicolas G, Créange A, Vallat JM, Pouget J, Clavelou P, Vial C, Steck A, Musset L, Marin B, RIMAG Study Group (2013) (France and Switzerland). Placebo-controlled trial of rituximab in IgM anti-myelin-associated glycoprotein neuropathy. Neurology 80(24):2217–25

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. Levine TD, Pestronk A (1999) IgM antibody-related polyneuropathies: B-cell depletion chemotherapy using Rituximab. Neurology 52(8):1701–1704

    Article  CAS  PubMed  Google Scholar 

  44. Kawagashira Y, Koike H, Ohyama K, Hashimoto R, Iijima M, Adachi H, Katsuno M, Chapman M, Lunn M, Sobue G (2015) Axonal loss influences the response to rituximab treatment in neuropathy associated with IgM monoclonal gammopathy with anti-myelin-associated glycoprotein antibody. J Neurol Sci 348(1–2):67–73

    Article  CAS  PubMed  Google Scholar 

  45. Lunn MP, Nobile-Orazio E (2016) Immunotherapy for IgM anti-myelin-associated glycoprotein paraprotein-associated peripheral neuropathies. Cochrane Database Syst Rev 10(10):CD002827

    PubMed  Google Scholar 

  46. Iancu Ferfoglia R, Guimarães-Costa R, Viala K, Musset L, Neil J, Marin B, Léger JM (2016) Long-term efficacy of rituximab in IgM anti-myelin-associated glycoprotein neuropathy: RIMAG follow-up study. J Peripher Nerv Syst 21(1):10–14

    Article  CAS  PubMed  Google Scholar 

  47. Nakanishi T, Sobue I, Toyokura Y, Nishitani H, Kuroiwa Y, Satoyoshi E, Tsubaki T, Igata A, Ozaki Y (1984) The Crow-Fukase syndrome: a study of 102 cases in Japan. Neurology 34(6):712–720

    Article  CAS  PubMed  Google Scholar 

  48. Dispenzieri A (2019) POEMS Syndrome: 2019 Update on diagnosis, risk-stratification, and management. Am J Hematol 94(7):812–827

    PubMed  Google Scholar 

  49. Suichi T, Misawa S, Beppu M, Takahashi S, Sekiguchi Y, Shibuya K, Amino H, Tsuneyama A, Suzuki YI, Nakamura K, Sato Y, Kuwabara S (2019) Prevalence, clinical profiles, and prognosis of POEMS syndrome in Japanese nationwide survey. Neurology 93(10):e975–e983

    Article  PubMed  Google Scholar 

  50. Suichi T, Misawa S, Sekiguchi Y, Shibuya K, Tsuneyama A, Suzuki YI, Nakamura K, Kano H, Kuwabara S (2020) Treatment response and prognosis of POEMS syndrome coexisting with Castleman disease. J Neurol Sci 413:116771

    Article  CAS  PubMed  Google Scholar 

  51. Adams D, Said G (1998) Ultrastructural characterisation of the M protein in nerve biopsy of patients with POEMS syndrome. J Neurol Neurosurg Psychiatry 64(6):809–812

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Watanabe O, Arimura K, Kitajima I, Osame M, Maruyama I (1996) Greatly raised vascular endothelial growth factor (VEGF) in POEMS syndrome. Lancet 347(9002):702

    Article  CAS  PubMed  Google Scholar 

  53. Kanai K, Sawai S, Sogawa K, Mori M, Misawa S, Shibuya K, Isose S, Fujimaki Y, Noto Y, Sekiguchi Y, Nasu S, Nakaseko C, Takano S, Yoshitomi H, Miyazaki M, Nomura F, Kuwabara S (2012) Markedly upregulated serum interleukin-12 as a novel biomarker in POEMS syndrome. Neurology 79(6):575–582

    Article  CAS  PubMed  Google Scholar 

  54. Sobue G, Doyu M, Watanabe M, Hayashi F, Mitsuma T (1992) Extensive demyelinating changes in the peripheral nerves of Crow-Fukase syndrome: a pathological study of one autopsied case. Acta Neuropathol 84(2):171–177

    Article  CAS  PubMed  Google Scholar 

  55. Vital C, Gherardi R, Vital A, Kopp N, Pellissier JF, Soubrier M, Clavelou P, Bellance R, Delisle MB, Ruchoux MM et al (1994) Uncompacted myelin lamellae in polyneuropathy, organomegaly, endocrinopathy, M-protein and skin changes syndrome. Ultrastructural study of peripheral nerve biopsy from 22 patients. Acta Neuropathol 87(3):302–7

    Article  CAS  PubMed  Google Scholar 

  56. Ohnishi A, Hirano A (1981) Uncompacted myelin lamellae in dysglobulinemic neuropathy. J Neurol Sci 51(1):131–140

    Article  CAS  PubMed  Google Scholar 

  57. Hashimoto R, Koike H, Takahashi M, Ohyama K, Kawagashira Y, Iijima M, Sobue G (2015) Uncompacted myelin lamellae and nodal ion channel disruption in POEMS syndrome. J Neuropathol Exp Neurol 74(12):1127–1136

    CAS  PubMed  Google Scholar 

  58. Yoshikawa H, Dyck PJ (1991) Uncompacted inner myelin lamellae in inherited tendency to pressure palsy. J Neuropathol Exp Neurol 50(5):649–657

    Article  CAS  PubMed  Google Scholar 

  59. Lagueny A, Latour P, Vital A, Le Masson G, Rouanet M, Ferrer X, Vital C, Vandenberghe A (2001) Mild recurrent neuropathy in CMT1B with a novel nonsense mutation in the extracellular domain of the MPZ gene. J Neurol Neurosurg Psychiatry 70(2):232–235

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Fujinuma Y, Asahina M, Fukushima T, Katagiri A, Yamanaka Y, Misawa S, Kuwabara S (2012) Preserved autonomic function in patients with POEMS syndrome. J Neurol Sci 318(1–2):131–134

    Article  CAS  PubMed  Google Scholar 

  61. Isose S, Misawa S, Kanai K, Shibuya K, Sekiguchi Y, Nasu S, Fujimaki Y, Noto Y, Nakaseko C, Kuwabara S (2011) POEMS syndrome with Guillan-Barre syndrome-like acute onset: a case report and review of neurological progression in 30 cases. J Neurol Neurosurg Psychiatry 82(6):678–680

    Article  CAS  PubMed  Google Scholar 

  62. Nasu S, Misawa S, Sekiguchi Y, Shibuya K, Kanai K, Fujimaki Y, Ohmori S, Mitsuma S, Koga S, Kuwabara S (2012) Different neurological and physiological profiles in POEMS syndrome and chronic inflammatory demyelinating polyneuropathy. J Neurol Neurosurg Psychiatry 83(5):476–479

    Article  PubMed  Google Scholar 

  63. Suichi T, Misawa S, Sato Y, Beppu M, Sakaida E, Sekiguchi Y, Shibuya K, Watanabe K, Amino H, Kuwabara S (2019) Proposal of new clinical diagnostic criteria for POEMS syndrome. J Neurol Neurosurg Psychiatry 90(2):133–137

    Article  PubMed  Google Scholar 

  64. Mauermann ML, Sorenson EJ, Dispenzieri A, Mandrekar J, Suarez GA, Dyck PJ, Dyck PJ (2012) Uniform demyelination and more severe axonal loss distinguish POEMS syndrome from CIDP. J Neurol Neurosurg Psychiatry 83(5):480–486

    Article  PubMed  Google Scholar 

  65. Marsh ES, Keddie S, Terris-Prestholt F, D’Sa S, Lunn MP (2021) Early VEGF testing in inflammatory neuropathy avoids POEMS syndrome misdiagnosis and associated costs. J Neurol Neurosurg Psychiatry 92(2):172–176

    Article  PubMed  Google Scholar 

  66. Sung JY, Kuwabara S, Ogawara K, Kanai K, Hattori T (2002) Patterns of nerve conduction abnormalities in POEMS syndrome. Muscle Nerve 26(2):189–193

    Article  PubMed  Google Scholar 

  67. Sekiguchi Y, Misawa S, Shibuya K, Nasu S, Mitsuma S, Iwai Y, Beppu M, Sawai S, Ito S, Hirano S, Nakaseko C, Kuwabara S (2013) Ambiguous effects of anti-VEGF monoclonal antibody (bevacizumab) for POEMS syndrome. J Neurol Neurosurg Psychiatry 84(12):1346–1348

    Article  PubMed  Google Scholar 

  68. Huang CC, Chu CC (1996) Poor response to intravenous immunoglobulin therapy in patients with Castleman’s disease and the POEMS syndrome. J Neurol 243(10):726–727

    Article  CAS  PubMed  Google Scholar 

  69. Brown R, Ginsberg L (2019) POEMS syndrome: clinical update. J Neurol 266(1):268–277

    Article  PubMed  Google Scholar 

  70. Cerri F, Falzone YM, Riva N, Quattrini A (2019) An update on the diagnosis and management of the polyneuropathy of POEMS syndrome. J Neurol 266(1):258–267

    Article  PubMed  Google Scholar 

  71. Humeniuk MS, Gertz MA, Lacy MQ, Kyle RA, Witzig TE, Kumar SK, Kapoor P, Lust JA, Hayman SR, Buadi FK, Rajkumar SV, Zeldenrust SR, Russell SJ, Dingli D, Lin Y, Leung N, Dispenzieri A (2013) Outcomes of patients with POEMS syndrome treated initially with radiation. Blood 122(1):68–73

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Kuwabara S, Hattori T, Shimoe Y, Kamitsukasa I (1997) Long term melphalan-prednisolone chemotherapy for POEMS syndrome. J Neurol Neurosurg Psychiatry 63(3):385–387

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Li J, Zhang W, Jiao L, Duan MH, Guan HZ, Zhu WG, Tian Z, Zhou DB (2011) Combination of melphalan and dexamethasone for patients with newly diagnosed POEMS syndrome. Blood 117(24):6445–6449

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Ohwada C, Sakaida E, Kawajiri-Manako C, Nagao Y, Oshima-Hasegawa N, Togasaki E, Muto T, Tsukamoto S, Mitsukawa S, Takeda Y, Mimura N, Takeuchi M, Shimizu N, Misawa S, Iseki T, Kuwabara S, Nakaseko C (2018) Long-term evaluation of physical improvement and survival of autologous stem cell transplantation in POEMS syndrome. Blood 131(19):2173–2176

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Misawa S, Sato Y, Katayama K, Nagashima K, Aoyagi R, Sekiguchi Y, Sobue G, Koike H, Yabe I, Sasaki H, Watanabe O, Takashima H, Nishizawa M, Kawachi I, Kusunoki S, Mitsui Y, Kikuchi S, Nakashima I, Ikeda S, Kohara N, Kanda T, Kira J, Hanaoka H, Kuwabara S, Japanese POEMS Syndrome for Thalidomide (J-POST) Trial Study Group (2016) Safety and efficacy of thalidomide in patients with POEMS syndrome: a multicentre, randomised, double-blind, placebo-controlled trial. Lancet Neurol 15(11):1129–37

    Article  CAS  PubMed  Google Scholar 

  76. Delforge M, Bladé J, Dimopoulos MA, Facon T, Kropff M, Ludwig H, Palumbo A, Van Damme P, San-Miguel JF, Sonneveld P (2010) Treatment-related peripheral neuropathy in multiple myeloma: the challenge continues. Lancet Oncol 11(11):1086–1095

    Article  CAS  PubMed  Google Scholar 

  77. Suichi T, Misawa S, Nagashima K, Sato Y, Iwai Y, Katayama K, Sekiguchi Y, Shibuya K, Amino H, Suzuki YI, Tsuneyama A, Nakamura K, Kuwabara S (2020) Lenalidomide treatment for thalidomide-refractory POEMS syndrome: a prospective single-arm clinical trial. Intern Med 59(9):1149–1153

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Gertz MA, Comenzo R, Falk RH, Fermand JP, Hazenberg BP, Hawkins PN, Merlini G, Moreau P, Ronco P, Sanchorawala V, Sezer O, Solomon A, Grateau G (2005) Definition of organ involvement and treatment response in immunoglobulin light chain amyloidosis (AL): a consensus opinion from the 10th International Symposium on Amyloid and Amyloidosis, Tours, France, 18–22 April 2004. Am J Hematol 79(4):319–328

    Article  PubMed  Google Scholar 

  79. Adams D (2001) Hereditary and acquired amyloid neuropathies. J Neurol 248(8):647–657

    Article  CAS  PubMed  Google Scholar 

  80. Adams D, Koike H, Slama M, Coelho T (2019) Hereditary transthyretin amyloidosis: a model of medical progress for a fatal disease. Nat Rev Neurol 15(7):387–404

    Article  CAS  PubMed  Google Scholar 

  81. Vital C, Vallat JM, Deminiere C, Loubet A, Leboutet MJ (1982) Peripheral nerve damage during multiple myeloma and Waldenstrom’s macroglobulinemia: an ultrastructural and immunopathologic study. Cancer 50(8):1491–1497

    Article  CAS  PubMed  Google Scholar 

  82. Sommer C, Schröder JM (1989) Amyloid neuropathy: immunocytochemical localization of intra- and extracellular immunoglobulin light chains. Acta Neuropathol 79(2):190–199

    Article  CAS  PubMed  Google Scholar 

  83. Koike H, Katsuno M (2019) Ultrastructure in transthyretin amyloidosis: from pathophysiology to therapeutic insights. Biomedicines 7(1):11

    Article  CAS  PubMed Central  Google Scholar 

  84. Mathis S, Magy L, Diallo L, Boukhris S, Vallat JM (2012) Amyloid neuropathy mimicking chronic inflammatory demyelinating polyneuropathy. Muscle Nerve 45(1):26–31

    Article  PubMed  Google Scholar 

  85. Hamidi Asl K, Liepnieks JJ, Nakamura M, Benson MD (1999) Organ-specific (localized) synthesis of Ig light chain amyloid. J Immunol 162(9):5556–5560

    Article  CAS  PubMed  Google Scholar 

  86. Kyle RA, Greipp PR (1983) Amyloidosis (AL). Clinical and laboratory features in 229 cases. Mayo Clin Proc 58(10):665–83

    CAS  PubMed  Google Scholar 

  87. Shimazaki C, Hata H, Iida S, Ueda M, Katoh N, Sekijima Y, Ikeda S, Yazaki M, Fukushima W, Ando Y (2018) Nationwide survey of 741 patients with systemic amyloid light-chain amyloidosis in Japan. Intern Med 57(2):181–187

    Article  CAS  PubMed  Google Scholar 

  88. Koike H, Misu K, Sugiura M, Iijima M, Mori K, Yamamoto M, Hattori N, Mukai E, Ando Y, Ikeda S, Sobue G (2004) Pathology of early- vs late-onset TTR Met30 familial amyloid polyneuropathy. Neurology 63(1):129–138

    Article  CAS  PubMed  Google Scholar 

  89. Koike H, Katsuno M (2020) Transthyretin amyloidosis: update on the clinical spectrum, pathogenesis, and disease-modifying therapies. Neurol Ther 9(2):317–333

    Article  PubMed  PubMed Central  Google Scholar 

  90. Koike H, Tanaka F, Hashimoto R, Tomita M, Kawagashira Y, Iijima M, Fujitake J, Kawanami T, Kato T, Yamamoto M, Sobue G (2012) Natural history of transthyretin Val30Met familial amyloid polyneuropathy: analysis of late-onset cases from non-endemic areas. J Neurol Neurosurg Psychiatry 83(2):152–158

    Article  PubMed  Google Scholar 

  91. Gertz MA (2020) Immunoglobulin light chain amyloidosis: 2020 update on diagnosis, prognosis, and treatment. Am J Hematol 95(7):848–860

    Article  CAS  PubMed  Google Scholar 

  92. Koike H, Okumura T, Murohara T, Katsuno, M. Multidisciplinary approaches for transthyretin amyloidosis. Cardiol Ther., in press.

  93. Klein CJ, Vrana JA, Theis JD, Dyck PJ, Dyck PJ, Spinner RJ, Mauermann ML, Bergen HR 3rd, Zeldenrust SR, Dogan A (2011) Mass spectrometric-based proteomic analysis of amyloid neuropathy type in nerve tissue. Arch Neurol 68(2):195–199

    Article  PubMed  Google Scholar 

  94. Matsuda M, Gono T, Morita H, Katoh N, Kodaira M, Ikeda S (2011) Peripheral nerve involvement in primary systemic AL amyloidosis: a clinical and electrophysiological study. Eur J Neurol 18(4):604–610

    Article  CAS  PubMed  Google Scholar 

  95. Jones NF, Hilton PJ, Tighe JR, Hobbs JR (1972) Treatment of “primary” renal amyloidosis with melphalan. Lancet 2(7778):616–619

    Article  CAS  PubMed  Google Scholar 

  96. Kyle RA, Gertz MA, Greipp PR, Witzig TE, Lust JA, Lacy MQ, Therneau TM (1997) A trial of three regimens for primary amyloidosis: colchicine alone, melphalan and prednisone, and melphalan, prednisone, and colchicine. N Engl J Med 336(17):1202–1207

    Article  CAS  PubMed  Google Scholar 

  97. Comenzo RL, Vosburgh E, Simms RW, Bergethon P, Sarnacki D, Finn K, Dubrey S, Faller DV, Wright DG, Falk RH, Skinner M (1996) Dose-intensive melphalan with blood stem cell support for the treatment of AL amyloidosis: one-year follow-up in five patients. Blood 88(7):2801–2806

    Article  CAS  PubMed  Google Scholar 

  98. Jaccard A, Moreau P, Leblond V, Leleu X, Benboubker L, Hermine O, Recher C, Asli B, Lioure B, Royer B, Jardin F, Bridoux F, Grosbois B, Jaubert J, Piette JC, Ronco P, Quet F, Cogne M, Fermand JP (2007) Myélome Autogreffe (MAG) and Intergroupe Francophone du Myélome (IFM) Intergroup. High-dose melphalan versus melphalan plus dexamethasone for AL amyloidosis. N Engl J Med 357(11):1083 93

    Article  PubMed  Google Scholar 

  99. Gertz MA, Lacy MQ, Dispenzieri A, Buadi FK, Dingli D, Hayman SR, Kumar SK, Leung N, Lust J, Rajkumar SV, Russell SJ, Suman VJ, Le-Rademacher JG, Hogan WJ (2016) Stem cell transplantation compared with melphalan plus dexamethasone in the treatment of immunoglobulin light-chain amyloidosis. Cancer 122(14):2197–2205

    Article  CAS  PubMed  Google Scholar 

  100. Obici L, Adams D (2020) Acquired and inherited amyloidosis: knowledge driving patients’ care. J Peripher Nerv Syst 25(2):85–101

    Article  PubMed  Google Scholar 

  101. Biolo A, Ramamurthy S, Connors LH, O’Hara CJ, Meier-Ewert HK, Soo Hoo PT, Sawyer DB, Seldin DC, Sam F (2008) Matrix metalloproteinases and their tissue inhibitors in cardiac amyloidosis: relationship to structural, functional myocardial changes and to light chain amyloid deposition. Circ Heart Fail 1(4):249–257

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Ward JE, Ren R, Toraldo G, Soohoo P, Guan J, O’Hara C, Jasuja R, Trinkaus-Randall V, Liao R, Connors LH, Seldin DC (2011) Doxycycline reduces fibril formation in a transgenic mouse model of AL amyloidosis. Blood 118(25):6610–6617

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. D’Souza A, Flynn K, Chhabra S, Dhakal B, Hamadani M, Jacobsen K, Pasquini M, Weihrauch D, Hari P (2017) Rationale and design of DUAL study: doxycycline to upgrade response in light chain (AL) amyloidosis (DUAL): a phase 2 pilot study of a two-pronged approach of prolonged doxycycline with plasma cell-directed therapy in the treatment of AL amyloidosis. Contemp Clin Trials Commun 24(8):33–38

    Article  Google Scholar 

  104. Griffin JM, Rosenblum H, Maurer MS (2021) Pathophysiology and therapeutic approaches to cardiac amyloidosis. Circ Res 128(10):1554–1575

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Hrncic R, Wall J, Wolfenbarger DA, Murphy CL, Schell M, Weiss DT, Solomon A (2000) Antibody-mediated resolution of light chain-associated amyloid deposits. Am J Pathol 157(4):1239–1246

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Nardelli E, Steck AJ, Barkas T, Schluep M, Jerusalem F (1988) Motor neuron syndrome and monoclonal IgM with antibody activity against gangliosides GM1 and GD1b. Ann Neurol 23(5):524–528

    Article  CAS  PubMed  Google Scholar 

  107. Eurelings M, Ang CW, Notermans NC, Van Doorn PA, Jacobs BC, Van den Berg LH (2001) Antiganglioside antibodies in polyneuropathy associated with monoclonal gammopathy. Neurology 57(10):1909–1912

    Article  CAS  PubMed  Google Scholar 

  108. Vlam L, Piepers S, Sutedja NA, Jacobs BC, Tio-Gillen AP, Stam M, Franssen H, Veldink JH, Cats EA, Notermans NC, Bloem AC, Wadman RI, van der Pol WL, van den Berg LH (2015) Association of IgM monoclonal gammopathy with progressive muscular atrophy and multifocal motor neuropathy: a case-control study. J Neurol 262(3):666–673

    Article  CAS  PubMed  Google Scholar 

  109. Carpo M, Meucci N, Allaria S, Marmiroli P, Monaco S, Toscano A, Simonetti S, Scarlato G, Nobile-Orazio E (2000) Anti-sulfatide IgM antibodies in peripheral neuropathy. J Neurol Sci 176(2):144–150

    Article  CAS  PubMed  Google Scholar 

  110. Dabby R, Weimer LH, Hays AP, Olarte M, Latov N (2000) Antisulfatide antibodies in neuropathy: clinical and electrophysiologic correlates. Neurology 54(7):1448–1452

    Article  CAS  PubMed  Google Scholar 

  111. Matà S, Borsini W, Ambrosini S, Toscani L, Barilaro A, Piacentini S, Sorbi S, Lolli F (2011) IgM monoclonal gammopathy-associated neuropathies with different IgM specificity. Eur J Neurol 18(8):1067–1073

    Article  PubMed  Google Scholar 

  112. Campagnolo M, Ferrari S, Dalla Torre C, Cabrini I, Cacciavillani M, Lucchetta M, Ruggero S, Toffanin E, Cavallaro T, Briani C (2015) Polyneuropathy with anti-sulfatide and anti-MAG antibodies: clinical, neurophysiological, pathological features and response to treatment. J Neuroimmunol 15(281):1–4

    Article  CAS  Google Scholar 

  113. Boso F, Ruggero S, Giannotta C, Benedetti L, Marfia GA, Ermani M, Campagnolo M, Salvalaggio A, Gallia F, De Michelis C, Visentin A, Bianco M, Ruiz M, Mataluni G, Nobile-Orazio E, Briani C (2017) Anti-sulfatide/galactocerebroside antibodies in immunoglobulin M paraproteinemic neuropathies. Eur J Neurol 24(11):1334–1340

    Article  CAS  PubMed  Google Scholar 

  114. Willison HJ, O’Leary CP, Veitch J, Blumhardt LD, Busby M, Donaghy M, Fuhr P, Ford H, Hahn A, Renaud S, Katifi HA, Ponsford S, Reuber M, Steck A, Sutton I, Schady W, Thomas PK, Thompson AJ, Vallat JM, Winer J (2001) The clinical and laboratory features of chronic sensory ataxic neuropathy with anti-disialosyl IgM antibodies. Brain 124(Pt 10):1968–1977

    Article  CAS  PubMed  Google Scholar 

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Funding

This work was supported in part by the Health and Labour Sciences Research Grant on Intractable Diseases (Neuroimmunological Diseases) from the Ministry of Health, Labour and Welfare of Japan (20FC1030).

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  1. Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan

    Haruki Koike & Masahisa Katsuno

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  1. Haruki Koike
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Haruki Koike conceived and wrote the first draft and Masahisa Katsuno revised it for intellectual content. All authors have read and agreed to the published version of the manuscript.

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Koike, H., Katsuno, M. Paraproteinemia and neuropathy. Neurol Sci 42, 4489–4501 (2021). https://doi.org/10.1007/s10072-021-05583-7

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