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Pathogenesis and Treatment of Anti-MAG Neuropathy

Opinion statement

Polyneuropathies associated with IgM monoclonal gammopathies comprise a distinct entity. In spite of the apparent pathogenicity of the IgM antibodies and the specific immunoreactivity to myelin antigens, the disease has been difficult to treat. This review describes the clinical phenotype, addresses recent data on immunoreactivity of IgM to various nerve antigens, and discusses the latest progress on treatment.

Most of these patients present with paresthesias and sensory ataxia followed by a varying degree of sensorimotor deficits. In more than 75% of the patients, the monoclonal IgM recognizes myelin-associated glycoprotein (MAG) and sulfoglucuronyl glycosphingolipid (SGPG), best detected by ELISA, or other peripheral nerve glycolipids. Recent experiments have demonstrated that animals immunized with SGPG develop sensory ataxia, suggesting a pathogenic role for this antigen. Although cladribine, cyclophosphamide with prednisone, and intravenous immunoglobulin have offered transient benefits to some patients, most have remained treatment-resistant. Open label studies and a recent randomized controlled trial indicate that rituximab is emerging as the best agent available, providing long-term benefits to almost half of these patients. Rituximab appears to work by suppressing the IgM as well as the anti-MAG antibodies and by inducing immunoregulatory T cells. Patients with more sensory deficits and higher anti-MAG antibodies are more likely to respond but may require re-treatment after several months.

These encouraging results need confirmation with a larger trial. Data on long-term efficacy and immune markers associated with response to therapy or need for re-treatment are still needed.

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References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance, •• Of major importance

  1. 1.

    Kelly JJ, Kyle RA, O’Brien PC, Dyck PJ: The prevalence of monoclonal gammopathy in peripheral neuropathy. Neurology 1981, 31:1480–1483.

    PubMed  Google Scholar 

  2. 2.•

    Kelly JJ: Peripheral neuropathies associated with monoclonal gammopathies of undetermined significance. Rev Neurol Dis 2008, 5(2):14–22. This nice review provides an up-to-date assessment of the topic.

    Google Scholar 

  3. 3.

    Kyle RA, Therneau TM, Rajkumar SV, et al.: Prevalence of monoclonal gammopathy of undetermined significance. N Engl J Med 2006, 354:1362–1369.

    Article  CAS  PubMed  Google Scholar 

  4. 4.

    Latov N, Hays A, Sherman WH: Peripheral neuropathy and anti-MAG antibodies. Crit Rev Neurobiol 1988, 3:301–332.

    CAS  PubMed  Google Scholar 

  5. 5.

    Dalakas MC, Engel WK: Polyneuropathy and monoclonal gammopathy: studies of 11 patients. Ann Neurol 1981, 10:45–52.

    Article  CAS  PubMed  Google Scholar 

  6. 6.•

    Dalakas MC: Autoimmune peripheral neuropathies. In Clinical Immunology: Principles and Practice, edn 3. Edited by Rich RR, Fleisher TA, Shearer WT, et al.: Philadelphia: Mosby Elsevier; 2008:977–994. This nice review provides an up-to-date assessment on the topic and examines the immunopathology and immunoreactivity of IgM in the paraproteinemic neuropathies.

  7. 7.

    Latov N: Pathogenesis and therapy of neuropathies associated with monoclonal gammopathies Ann Neurol 1995, 37:S32–S42.

    Article  PubMed  Google Scholar 

  8. 8.

    Nobile-Orazio E, Meucci N, Baldini L, et al.: Long-term prognosis of neuropathy associated with anti-MAG IgM M-proteins and its relationship to immune therapies. Brain 2000, 123(Pt 4):710–717.

    Article  PubMed  Google Scholar 

  9. 9.

    Dalakas MC: Chronic idiopathic ataxic neuropathy. Ann Neurol 1986, 19:545–554.

    Article  CAS  PubMed  Google Scholar 

  10. 10.

    Dalakas MC, Teravinen H, Engel WK: Tremor as a feature of chronic relapsing and dysgammaglobulinemic polyneuropathies: incidence and management. Arch Neurol 1984, 41:711–714.

    CAS  PubMed  Google Scholar 

  11. 11.

    Dalakas MC, Papadopoulos NM: Paraproteins in the spinal fluid of patients with paraproteinemic polyneuropathies. Ann Neurol 1984, 15:590–593.

    Article  CAS  PubMed  Google Scholar 

  12. 12.

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

    Article  PubMed  Google Scholar 

  13. 13.•

    Lupu VD, Mora CA, Dambrosia J, et al.: Terminal latency index in neuropathy with antibodies against myelin-associated glycoproteins. Muscle Nerve 2007, 35(2):196–202. This useful electrophysiologic study confirms that the terminal latency index is specific for anti-MAG neuropathy and differentiates it from hereditary sensorimotor neuropathy type 1 (HMSN1).

  14. 14.

    Latov N, Braun PE, Gross RB, et al.: Plasma cell dyscrasia and peripheral neuropathy: identification of the myelin antigens that react with human paraproteins. Proc Natl Acad Sci U S A 1981, 78(11):7139–7142.

    Article  CAS  PubMed  Google Scholar 

  15. 15.

    Ilyas AA, Quarles RH, McIntosh TD, et al.: IgM in a human neuropathy related to paraproteinemia binds to a carbohydrate determinant in the myelin-associated glycoprotein and to a ganglioside. Proc Natl Acad Sci U S A 1984, 81:1225–1229.

    Article  CAS  PubMed  Google Scholar 

  16. 16.

    Ilyas AA, Quarles RH, Dalakas MC, Brady RO: Polyneuropathy with monoclonal gammopathy: glycolipids are frequently antigens for IgM paraproteins. Proc Natl Acad Sci U S A 1985, 82:6697–6700.

    Article  CAS  PubMed  Google Scholar 

  17. 17.

    Mendell JR, Sahenk Z, Whitaker JN, et al.: Polyneuropathy and monoclonal gammopathy: studies on the pathogenetic role of anti-myelin-associated glycoprotein antibody. Ann Neurol 1985, 17:243–254.

    Article  CAS  PubMed  Google Scholar 

  18. 18.•

    Kuijf ML, Eurelings M, Tio-Gillen AP, et al.: Detection of anti-MAG antibodies in polyneuropathy associated with IgM monoclonal gammopathy. Neurology 2009, 73(9):688–695. This very useful study confirms with a large number of samples that ELISA is the preferred method of testing for anti-MAG antibodies.

    Google Scholar 

  19. 19.

    Ilyas AA, Li SC, Chou DKH, et al.: Gangliosides GM2, IV4Gal NaC GM1B, and IV4Gal NaC GD1a as antigens for monoclonal immunoglobulin M neuropathy associated with gammopathy. J Biol Chem 1988, 263:4369–4373.

    CAS  PubMed  Google Scholar 

  20. 20.

    Duane GC, Farrer RG, Dalakas MC, Quarles RH: Sensory neuropathy associated with monoclonal IgM to GD1b ganglioside. Ann Neurol 1992, 31:683–685.

    Article  Google Scholar 

  21. 21.

    Dalakas MC, Quarles RH: Autoimmune ataxic neuropathies (sensory ganglionopathies): Are glycolipids the responsible autoantigens? Ann Neurol 1996, 39:419–422.

    Article  CAS  PubMed  Google Scholar 

  22. 22.

    Quarles RH, Dalakas MC: Do antiganglioside antibodies cause human peripheral neuropathies? J Clin Invest 1996, 97:1136–1137.

    Article  CAS  PubMed  Google Scholar 

  23. 23.

    Monaco S, Bonetti B, Ferrari S, et al.: Complement dependent demyelination in patients with IgM monoclonal gammopathy and polyneuropathy. N Engl J Med 1990, 322:844–852.

    Article  Google Scholar 

  24. 24.

    Lombardi R, Erne B, Lauria G, et al.: IgM deposits on skin nerves in antimyelin-associated glycoprotein neuropathy. Ann Neurol 2005, 57:180–187.

    Article  CAS  PubMed  Google Scholar 

  25. 25.

    Willison HJ, Trapp BD, Bacher JD, et al.: Demyelination induced by intraneural injection of human antimyelin associated glycoprotein antibodies. Muscle Nerve 1988, 11:1169–1176.

    Article  CAS  PubMed  Google Scholar 

  26. 26.

    Tatum AH: Experimental paraprotein neuropathy, demyelination by passive transfer of human IgM anti-MAG. Ann Neurol 1993, 33:502–506.

    Article  CAS  PubMed  Google Scholar 

  27. 27.••

    Ilyas AA, Gu Y, Dalakas MC, et al.: Induction of experimental ataxic sensory neuronopathy in cats by immunization with purified SGPG. J Neuroimmunol 2008, 193(1–2):87–93. This novel study indicates for the first time that immunization of cats with SGPG produces an ataxic neuronopathy (sensory ganglionopathy), clinically similar to MAG neuropathy.

    Google Scholar 

  28. 28.

    Farrer RG, Dalakas MC, Quarles RH: Multiple antibodies to nerve glycoconjugates in an unusual patient with neuropathy and monoclonal IgA gammopathy. J Neuroimmunol 1996, 66(1–2):71–76.

    Article  CAS  PubMed  Google Scholar 

  29. 29.

    Nobile-Orazio E: Treatment of dysimmune neuropathies. J Neurol 2005, 252:385–395.

    Article  CAS  PubMed  Google Scholar 

  30. 30.

    Lunn MP, Nobile-Orazio E: Immunotherapy for IgM anti-myelin-associated glycoprotein paraprotein-associated peripheral neuropathies. Cochrane Database Syst Rev 2006, (2):CD002827.

  31. 31.

    Joint Task Force of EFNS and the PNS: European Federation of Neurological Societies/Peripheral Nerve Society 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 2006, 11(1):9–19.

    Article  Google Scholar 

  32. 32.

    Dalakas MC, Flaum MA, Rick M, et al.: Treatment of polyneuropathy in Waldenström’s macroglobulinemia. Role of paraproteinemia and immunological studies. Neurology 1983, 33:1406–1410.

    CAS  PubMed  Google Scholar 

  33. 33.

    Niermeijer JM, Eurelings M, van der Linden MW, et al.: Intermittent cyclophosphamide with prednisone versus placebo for polyneuropathy with IgM monoclonal gammopathy. Neurology 2007, 69(1):50–59.

    Article  CAS  PubMed  Google Scholar 

  34. 34.

    Wilson HC, Lunn MP, Schey S, Hughes RA: Successful treatment of IgM paraproteinaemic neuropathy with fludarabine. J Neurol Neurosurg Psychiatry 1999, 66(5):575–580.

    Article  CAS  PubMed  Google Scholar 

  35. 35.

    Niermeijer JM, Eurelings M, Lokhorst H, et al.: Neurologic and hematologic response to fludarabine treatment in IgM MGUS polyneuropathy. Neurology 2006, 67(11):2076–2079.

    Article  CAS  PubMed  Google Scholar 

  36. 36.

    Cook D, Dalakas M, Galdi A, et al.: High-dose intravenous immunoglobulin in the treatment of demyelinating neuropathy associated with monoclonal gammopathy. Neurology 1990, 40:212–214.

    CAS  PubMed  Google Scholar 

  37. 37.

    Dalakas MC, Quarles RH, Farrer RG, et al.: A controlled study of intravenous immunoglobulin in demyelinating neuropathy with IgM gammopathy. Ann Neurol 1996, 40:792–795.

    Article  CAS  PubMed  Google Scholar 

  38. 38.

    Comi G, Roveri L, Swan A, et al.: A randomised controlled trial of intravenous immunoglobulin in IgM paraprotein associated demyelinating neuropathy. J Neurol 2002, 249(10):1370–1377.

    Article  CAS  PubMed  Google Scholar 

  39. 39.•

    Attarian S, Boucraut J, Hubert AM, et al.: Chronic ataxic neuropathies associated with anti-GD1b IgM antibodies: response to IVIg therapy. J Neurol Neurosurg Psychiatry 2010, 81(1):61–64. This interesting, multicenter (but uncontrolled) study shows some responses to IVIG of the non-MAG/SGPG but anti-glycolipid antibody-mediated ataxic neuropathy. The main concern is the uncontrolled nature of the study. The encouraging news is that even the ataxic neuropathy, often a ganglionopathy, can be potentially treatable, at least for some patients.

    Google Scholar 

  40. 40.••

    Dalakas MC: B cells as therapeutic targets in autoimmune neurological disorders. Nat Clin Pract Neurol 2008, 4(10):557–567. This up-to-date review on B-cell therapies in neurology identifies the various B-cell targets and the new emerging drugs currently being tested in controlled trials in various autoimmune diseases.

  41. 41.

    Kosmidis M, Dalakas MC: Rituximab in the treatment of neurological disorders. Ther Adv Neurol Disord 2010 (in press).

  42. 42.

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

    CAS  PubMed  Google Scholar 

  43. 43.

    Pestronk A, Florence J, Miller T, et al.: Treatment of IgM antibody associated polyneuropathies using rituximab. J Neurol Neurosurg Psychiatry 2003, 74:485–489.

    Article  CAS  PubMed  Google Scholar 

  44. 44.

    Renaud S, Gregor M, Fuhr P, et al.: Rituximab in the treatment of polyneuropathy associated with anti-MAG antibodies. Muscle Nerve 2003, 27:611–615.

    Article  CAS  PubMed  Google Scholar 

  45. 45.

    Renaud S, Fuhr P, Gregor M, et al.: High-dose rituximab and anti-MAG associated polyneuropathy Neurology 2006, 66:742–744.

    Article  CAS  PubMed  Google Scholar 

  46. 46.

    Broglio L, Lauria G: Worsening after rituximab treatment in anti-mag neuropathy [letter]. Muscle Nerve 2005, 32(3):378–379.

    Article  PubMed  Google Scholar 

  47. 47.

    Benedetti L, Briani C, Grandis M, et al.: Predictors of response to rituximab in patients with neuropathy and anti-myelin associated glycoprotein immunoglobulin J Periph Nerv Syst 2007, 12:102–107.

    Article  CAS  Google Scholar 

  48. 48.•

    Benedetti L, Briani C, Franciotta D, et al.: Long term effect of rituximab in anti-MAG polyneuropathy. Neurol 2008, 71(18):1742–1744. In an extension of their previous study, this new report provides additional and very useful data on the long-term efficacy of rituximab in anti-MAG neuropathies. Relapses appear to correlate with high anti-MAG titers. Whether these are a marker of disease activity, as proposed, remains to be determined.

    Google Scholar 

  49. 49.••

    Dalakas MC, Rakocevic G, Salajegheh M, et al.: Placebo-controlled trial of rituximab in IgM anti-myelin-associated glycoprotein antibody demyelinating neuropathy. Ann Neurol 2009, 65(3):286–293. This is the first randomized trial of rituximab in anti-MAG neuropathies and is the largest today in this disease. It presents the means of action of rituximab with immunologic measurements.

    Google Scholar 

  50. 50.•

    Steck AJ, Czaplinski A, Renaud S: Inflammatory demyelinating neuropathies and neuropathies with monoclonal gammopathies: treatment update. Neurotherapeutics 2008, 5:528–534. This excellent and up-to-date review provides useful and practical guidelines on how best to treat this disease.

    Google Scholar 

  51. 51.

    Bonavita S, Conforti R, Russo A, et al.: Infratentorial progressive multifocal leukoencephalopathy in a patient treated with fludarabine and rituximab. Neurol Sci 2008, 29(1):37–39.

    Article  PubMed  Google Scholar 

  52. 52.

    FDA Safety Alerts for Human Medical Products: Rituxan (rituximab)—PML. Available at http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm187791.htm. Accessed January 6, 2010.

  53. 53.•

    McMaster J, Gibson G, Castro-Prado F, et al.: Neurosurgical treatment of tremor in anti-myelin-associated glycoprotein neuropathy. Neurology 2009, 73(20):1707–1708. This is the first study that treats the disabling tremor in patients with anti-MAG neuropathy. Although it presents a single case report, the information is useful to start a trial.

    Google Scholar 

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Correspondence to Marinos C. Dalakas MD.

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Dalakas, M.C. Pathogenesis and Treatment of Anti-MAG Neuropathy. Curr Treat Options Neurol 12, 71–83 (2010). https://doi.org/10.1007/s11940-010-0065-x

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Keywords

  • Monoclonal Gammopathy
  • Demyelinating Polyneuropathy
  • Chronic Inflammatory Demyelinating Polyradiculoneuropathy
  • Sural Nerve Biopsy
  • Myelin Lamella