Annals of Hematology

, Volume 94, Issue 6, pp 1011–1016 | Cite as

IgM MGUS associated with anti-MAG neuropathy: a single institution experience

  • Giampaolo Talamo
  • Muhammad A. Mir
  • Manoj K. Pandey
  • Jeffrey K. Sivik
  • Divisha Raheja
Original Article


Anti-MAG neuropathy is a very rare form of acquired polyneuropathy associated with IgM monoclonal gammopathy of undetermined significance (MGUS). We conducted a retrospective review of 194 consecutive MGUS patients seen at the Penn State Hershey Cancer Institute. We identified six patients among 37 (16 %) with IgM MGUS with anti-MAG neuropathy. Interestingly, an additional patient had anti-MAG neuropathy without MGUS. Common clinical manifestations were numbness and paresthesias of the extremities and gait imbalance. All four patients treated with rituximab and none of the three untreated ones had a subjective improvement of their symptoms. We conclude that all patients with IgM MGUS and neuropathy should be screened for anti-MAG antibodies and, if positive, they should be offered treatment with rituximab.


MGUS IgM Myelin-associated glycoprotein Peripheral neuropathy Rituximab 



This research received no funding.

Conflict of interest



  1. 1.
    Vladutiu AO (1987) Prevalence of M-proteins in serum of hospitalized patients. Physicians’ response to finding M-proteins in serum protein electrophoresis. Ann Clin Lab Sci 17:157–161PubMedGoogle Scholar
  2. 2.
    Kyle RA (1994) Monoclonal gammopathy of undetermined significance. Blood Rev 8:135–141CrossRefPubMedGoogle Scholar
  3. 3.
    Kelly JJ Jr, Kyle RA, O’Brien PC, Dyck PJ (1981) Prevalence of monoclonal protein in peripheral neuropathy. Neurology 31:1480–1483CrossRefPubMedGoogle Scholar
  4. 4.
    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 354:1362–1369CrossRefPubMedGoogle Scholar
  5. 5.
    Nobile-Orazio E, Barbieri S, Baldini L, Marmiroli P, Carpo M, Premoselli S, Manfredini E, Scarlato G (1992) Peripheral neuropathy in monoclonal gammopathy of undetermined significance: prevalence and immunopathogenetic studies. Acta Neurol Scand 85:383–390CrossRefPubMedGoogle Scholar
  6. 6.
    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 36:416–424CrossRefPubMedGoogle Scholar
  7. 7.
    Steck AJ, Murray N, Meier C, Page N, Perruisseau G (1983) Demyelinating neuropathy and monoclonal IgM antibody to myelin-associated glycoprotein. Neurology 33:19–23CrossRefPubMedGoogle Scholar
  8. 8.
    Mahdi-Rogers M, Hughes RA (2014) Epidemiology of chronic inflammatory neuropathies in southeast England. Eur J Neurol 21:28–33CrossRefPubMedGoogle Scholar
  9. 9.
    Ellie E, Vital A, Steck A, Boiron JM, Vital C, Julien J (1996) Neuropathy associated with “benign” anti-myelin-associated glycoprotein IgM gammopathy: clinical, immunological, neurophysiological pathological findings and response to treatment in 33 cases. J Neurol 243:34–43CrossRefPubMedGoogle Scholar
  10. 10.
    Lunn MP, Crawford TO, Hughes RA, Griffin JW, Sheikh KA (2002) Anti-myelin-associated glycoprotein antibodies alter neurofilament spacing. Brain 125:904–911CrossRefPubMedGoogle Scholar
  11. 11.
    Hays AP, Latov N, Takatsu M, Sherman WH (1987) Experimental demyelination of nerve induced by serum of patients with neuropathy and an anti-MAG IgM M-protein. Neurology 37:242–256CrossRefPubMedGoogle Scholar
  12. 12.
    Chassande B, Leger JM, Younes-Chennoufi AB, Bengoufa D, Maisonobe T, Bouche P, Baumann N (1998) Peripheral neuropathy associated with IgM monoclonal gammopathy: correlations between M-protein antibody activity and clinical/electrophysiological features in 40 cases. Muscle Nerve 21:55–62CrossRefPubMedGoogle Scholar
  13. 13.
    Yeung KB, Thomas PK, King RH, Waddy H, Will RG, Hughes RA, Gregson NA, Leibowitz S (1991) The clinical spectrum of peripheral neuropathies associated with benign monoclonal IgM, IgG and IgA paraproteinaemia. Comparative clinical, immunological and nerve biopsy findings. J Neurol 238:383–391CrossRefPubMedGoogle Scholar
  14. 14.
    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 113:346–353CrossRefPubMedGoogle Scholar
  15. 15.
    Notermans NC, Franssen H, Eurelings M, Van der Graaf Y, Wokke JH (2000) Diagnostic criteria for demyelinating polyneuropathy associated with monoclonal gammopathy. Muscle Nerve 23:73–79CrossRefPubMedGoogle Scholar
  16. 16.
    Latov N, Sherman WH, Nemni R, Galassi G, Shyong JS, Penn AS, Chess L, Olarte MR, Rowland LP, Osserman EF (1980) Plasma-cell dyscrasia and peripheral neuropathy with a monoclonal antibody to peripheral-nerve myelin. N Engl J Med 303:618–621CrossRefPubMedGoogle Scholar
  17. 17.
    Murray N, Page N, Steck AJ (1986) The human anti-myelin-associated glycoprotein IgM system. Ann Neurol 19:473–478CrossRefPubMedGoogle Scholar
  18. 18.
    Pestronk A, Li F, Griffin J, Feldman EL, Cornblath D, Trotter J, Zhu S, Yee WC, Phillips D, Peeples DM et al (1991) Polyneuropathy syndromes associated with serum antibodies to sulfatide and myelin-associated glycoprotein. Neurology 41:357–362CrossRefPubMedGoogle Scholar
  19. 19.
    Pestronk A, Cornblath DR, Ilyas AA, Baba H, Quarles RH, Griffin JW, Alderson K, Adams RN (1988) A treatable multifocal motor neuropathy with antibodies to GM1 ganglioside. Ann Neurol 24:73–78CrossRefPubMedGoogle Scholar
  20. 20.
    Cavanna B, Carpo M, Pedotti R, Scarpini E, Meucci N, Allaria S, Scarlato G, Nobile-Orazio E (1999) Anti-GM2 IgM antibodies: clinical correlates and reactivity with a human neuroblastoma cell line. J Neuroimmunol 94:157–164CrossRefPubMedGoogle Scholar
  21. 21.
    Bollensen E, Schipper HI, Steck AJ (1989) Motor neuropathy with activity of monoclonal IgM antibody to GD1a ganglioside. J Neurol 236:353–355CrossRefPubMedGoogle Scholar
  22. 22.
    Daune GC, Farrer RG, Dalakas MC, Quarles RH (1992) Sensory neuropathy associated with monoclonal immunoglobulin M to GD1b ganglioside. Ann Neurol 31:683–685CrossRefPubMedGoogle Scholar
  23. 23.
    Carpo M, Pedotti R, Lolli F, Pitrola A, Allaria S, Scarlato G, Nobile-Orazio E (1998) Clinical correlate and fine specificity of anti-GQ1b antibodies in peripheral neuropathy. J Neurol Sci 155:186–191CrossRefPubMedGoogle Scholar
  24. 24.
    Bridel C, Horvath J, Kurian M, Truffert A, Steck A, Lalive PH (2014) Multifocal motor neuropathy with high titers of anti-MAG antibodies. J Peripher Nerv Syst 19:180-182CrossRefPubMedGoogle Scholar
  25. 25.
    Lombardi R, Erne B, Lauria G, Pareyson D, Borgna M, Morbin M, Arnold A, Czaplinski A, Fuhr P, Schaeren-Wiemers N, Steck AJ (2005) IgM deposits on skin nerves in anti-myelin-associated glycoprotein neuropathy. Ann Neurol 57:180–187CrossRefPubMedGoogle Scholar
  26. 26.
    Kyle RA, Therneau TM, Rajkumar SV, Offord JR, Larson DR, Plevak MF, Melton LJ 3rd (2002) A long-term study of prognosis in monoclonal gammopathy of undetermined significance. N Engl J Med 346:564–569CrossRefPubMedGoogle Scholar
  27. 27.
    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 83:476–479CrossRefPubMedGoogle Scholar
  28. 28.
    European Federation of Neurological Societies/Peripheral Nerve Society (2006) Guideline on management of paraproteinemic demyelinating neuropathies. Report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society. J Peripher Nerv Syst 11:9–19CrossRefGoogle Scholar
  29. 29.
    Nobile-Orazio E, Gallia F, Terenghi F, Allaria S, Giannotta C, Carpo M (2008) How useful are anti-neural IgM antibodies in the diagnosis of chronic immune-mediated neuropathies? J Neurol Sci 266:156–163CrossRefPubMedGoogle Scholar
  30. 30.
    Baldini L, Nobile-Orazio E, Guffanti A, Barbieri S, Carpo M, Cro L, Cesana B, Damilano I, Maiolo AT (1994) Peripheral neuropathy in IgM monoclonal gammopathy and Waldenstrom’s macroglobulinemia: a frequent complication in elderly males with low MAG-reactive serum monoclonal component. Am J Hematol 45:25–31CrossRefPubMedGoogle Scholar
  31. 31.
    Donfrid M, Apostolski S, Suvajdzic N, Jankovic G, Cemerikic-Martinovic V, Atkinson HD, Colovic M (2001) Monocytoid B cell lymphoma associated with antibodies to myelin-associated glycoprotein and sulphated glucuronyl paragloboside. Acta Haematol 106:130–132CrossRefPubMedGoogle Scholar
  32. 32.
    Garces-Sanchez M, Dyck PJ, Kyle RA, Zeldenrust S, Wu Y, Ladha SS, Klein CJ (2008) Antibodies to myelin-associated glycoprotein (anti-Mag) in IgM amyloidosis may influence expression of neuropathy in rare patients. Muscle Nerve 37:490–495CrossRefPubMedGoogle Scholar
  33. 33.
    Rossi D, Franceschetti S, Cerri M, Conconi A, Lunghi M, Capello D, Cantello R, Gaidano G (2007) Hairy cell leukaemia complicated by anti-MAG paraproteinemic demyelinating neuropathy: resolution of neurological syndrome after cladribrine treatment. Leuk Res 31:873–876CrossRefPubMedGoogle Scholar
  34. 34.
    Xu L, Hunter ZR, Yang G, Cao Y, Liu X, Manning R, Tripsas C, Chen J, Patterson CJ, Kluk M, Kanan S, Castillo J, Lindeman N, Treon SP (2014) Detection of MYD88 L265P in peripheral blood of patients with Waldenstrom’s macroglobulinemia and IgM monoclonal gammopathy of undetermined significance. Leukemia 28:1698–1704CrossRefPubMedGoogle Scholar
  35. 35.
    Nobile-Orazio E, Latov N, Hays AP, Takatsu M, Abrams GM, Sherman WH, Miller JR, Messito MJ, Saito T, Tahmoush A et al (1984) Neuropathy and anti-MAG antibodies without detectable serum M-protein. Neurology 34:218–221CrossRefPubMedGoogle Scholar
  36. 36.
    Lunn MP, Nobile-Orazio E (2012) Immunotherapy for IgM anti-myelin-associated glycoprotein paraprotein-associated peripheral neuropathies. Cochrane Database Syst Rev 5, CD002827PubMedGoogle Scholar
  37. 37.
    Latov N (2014) Diagnosis and treatment of chronic acquired demyelinating polyneuropathies. Nat Rev Neurol 10:435–446CrossRefPubMedGoogle Scholar
  38. 38.
    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 65:286–293CrossRefPubMedGoogle Scholar
  39. 39.
    Leger JM, Viala K, Nicolas G, Creange A, Vallat JM, Pouget J, Clavelou P, Vial C, Steck A, Musset L, Marin B (2013) Placebo-controlled trial of rituximab in IgM anti-myelin-associated glycoprotein neuropathy. Neurology 80:2217–2225CrossRefPubMedCentralPubMedGoogle Scholar
  40. 40.
    Hospital MA, Viala K, Dragomir S, Levy V, Cohen-Aubart F, Neil J, Musset L, Choquet S, Leger JM, Leblond V (2013) Immunotherapy-based regimen in anti-MAG neuropathy: results in 45 patients. Haematologica 98:e155–e157CrossRefPubMedCentralPubMedGoogle Scholar
  41. 41.
    Sala E, Robert-Varvat F, Paul S, Camdessanche JP, Antoine JC (2014) Acute neurological worsening after rituximab treatment in patients with anti-MAG neuropathy. J Neurol Sci 345:224-227Google Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Giampaolo Talamo
    • 1
  • Muhammad A. Mir
    • 1
  • Manoj K. Pandey
    • 1
  • Jeffrey K. Sivik
    • 1
  • Divisha Raheja
    • 1
  1. 1.Penn State Milton S. Hershey Medical CenterHersheyUSA

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