Monoclonal Immunoglobulins and Peripheral Neuropathy: Causative Agent or Coincidental Finding?

Abstract

Patients who have peripheral neuropathies and monoclonal immunoglobulins (Igs) detectable in their sera present a difficult clinical problem to neurologists and hemato-oncologists alike. However, there are 2 principal considerations when assessing such patients. In the first instance, it is necessary to consider whether the monoclonal Igs are directly responsible for the neuropathy, which in most instances will be a result of autoantibody activity directed against known neural antigens, or do they merely represent a coincidental finding? The second factor to consider is the underlying pathologic diagnosis and cause of the monoclonal Ig. When assessing a potential pathologic role for monoclonal immunoglobulins, it is important to consider the heavy chain isotype. Immunoglobulin M (IgM) monoclonal proteins are frequently associated with demonstrable autoantibody activity directed against a variety of neural antigens such as myelin-associated glycoprotein, sulfatide, and gangliosides such as GalNacGD1a, GM1, GM2, and GD1b.1-5 The autoantibody specificity, to a certain extent, determines the clinical phenotype and electrophysiologic findings.2-5 However, approximately 30% of patients with peripheral neuropathy and an IgM monoclonal protein lack clear evidence of neural antigen autoantibody specificity. Neuropathy in at least a proportion of these patients may be a result of reactivity against unknown neural antigens or indeed amyloid deposition, even though this appears to be rare in IgM gammopathies.4,6,7 Evidence of a clear pathologic role for IgG and IgA monoclonal proteins is generally lacking, and they may therefore represent merely a coincidental finding in patients who might otherwise be diagnosed with chronic inflammatory demyelinating polyneuropathy (CIDP).810 However, it is interesting to note the recent report by Favereaux et al, who demonstrated autoantibody specificity directed against the P0 dimer and P0-related protein in 17 of 55 patients with peripheral neuropathy and IgG monoclonal gammopathy.11 It is of considerable importance to identify the underlying pathologic diagnosis in these patients, and a bone marrow examination should be considered in most patients and is essential in all patients considered for cytoreductive or monoclonal antibody therapy. In patients with IgM proteins, the underlying pathologic diagnosis will be monoclonal gammopathy of undetermined significance (MGUS) or a B-cell lymphoproliferative disorder, most commonly Waldenstrom’s macroglobulinemia (WM).12 Monoclonal IgG or IgA secretion will result from MGUS, multiple myeloma, or rarely, a B-cell lymphoproliferative disorder. Patients with symptomatic neuropathies and monoclonal Igs present a considerable therapeutic challenge. However, it is important to note that many patients do not require any therapy, whereas others gain symptomatic benefit from simple analgesic agents and agents such as gabapentin, and the provision of appropriate physical aids and therapy.13,14 However, if more definitive therapy is contemplated because of progressive neurologic impairment, it is essential to consider the evidence of a direct pathologic role for the monoclonal Ig and the underlying pathologic diagnosis. It may not be appropriate to institute cytoreductive therapy in patients with no definitive causal link between the monoclonal Ig and the neuropathy and a pathologic diagnosis of MGUS. This is particularly pertinent to those patients with IgG and IgA proteins whose condition mimics CIDP and who may respond to intravenous Ig, plasmapheresis, or corticosteroids.9,13 There is certainly no rationale for the use of rituximab in this situation, because terminally differentiated plasma cells lack CD20 expression. Patients with IgM proteins with evidence of autoantibody activity similarly present a therapeutic challenge. Individuals with an underlying lymphoproliferative disorder, most commonly WM, may be treated with alkylating agents, purine analogues, or rituximab.4,14-16 However, treatment decisions in patients with IgM MGUS are much less straightforward, even though cytoreductive and/or monoclonal antibody therapy is advocated by a number of clinicians.The rationale for this approach has been the assumption that IgM MGUS represents a form of occult WM with a clonal B-cell component showing differentiation to plasma cells. However, there is no clear pathologic evidence to support this assumption, and the overall incidence of progression in IgM MGUS appears to be low.17 There are very limited published data on the activity of alkylating agents, purine analogues, and rituximab in this setting, and the results are generally disappointing.13,18-21 These results are likely in part to reflect the low rate of complete response seen with these agents. It may therefore be appropriate in some patients to increase the intensity of treatment with the aim of achieving an immunofixationnegative complete response. Autologous transplantation with stem cell support may therefore be applicable to a subgroup of patients with progressive disability.22 Monoclonal Immunoglobulins and Peripheral Neuropathy: Causative Agent or Coincidental Finding? Commentary