Paraproteinemic Neuropathy: A Practical Review

Richard A. Rison; Said R. Beydoun


BMC Neurol. 2016;16(13) 

In This Article

Paraproteinemia Treatment Strategy

Many of the treatments for PPN are chemotherapy agents that may have significant impact on lifestyle. Psychological support for both the patient and family is often needed. As lifestyle modifications generally recommended in clinical practice, patients are counseled to remain as active as possible, abstain from alcohol, and stop smoking, if applicable. Several specialties may collaborate on treatment plans, including hematology for chemotherapy, neurology for pain management, radiation oncology for radiotherapy of plasmacytomas in POEMS syndrome, surgery for removal of solitary plasmacytomas in POEMS syndrome, and physical/occupational/recreational/speech/rehabilitation therapy.[17] Table 2 lists treatments directed to paraproteinemia.

The mode and method of monitoring depends on the particular condition. Treatment decisions from a neurology standpoint usually are not based only on M-protein levels but rather the clinical picture, including severity, progression, and topography of motor deficit all which are important in selecting appropriate treatment. Additionally for MGUS patients, periodic (every 6–12 months) immunoglobulin quantitation and serum immunofixation may be done to determine changes in monoclonal protein level.[8] We consider treatment (always in consult with a hematologist) when the serum monoclonal protein rises above a concentration of 1.5 g/dL.[38,39] Occasionally, serial electrodiagnostic studies are used to monitor disease response or progression.[36] Complications from the neuropathy itself include neuropathic ulcers and pain, Charcot joints, orthostasis, and predisposition to peripheral injury given lack of sensation.[40]

PPN treatment first aims for paraprotein quantity reduction and the diminishing of cells producing the paraproteins, which may lead to improvement of neurological symptoms. IgM PPN sometimes responds to immunotherapies, but the potential benefits should be balanced against possible side effects, as well as the typically slow disease progression.[18] IgG and IgA PDN may be indistinguishable from chronic inflammatory demyelinating polyradiculoneuropathy clinically, electrophysiologically, and in response to treatment. The presence of paraprotein-related vasculitis or AL may also require treatment modification.[19]

Intravenous Immune Globulin (IVIG)

A systematic Cochrane review identified seven randomized controlled trials that examined the efficacy of any form of immunotherapy in reducing disability and impairment resulting from IgM anti-MAG paraprotein-associated demyelinating peripheral neuropathy. The primary outcome measure was the change in Neuropathy Impairment scale or Modified Rankin after six months, and secondary outcomes included shorter-term changes in impairment scale scores as well as paraprotein levels after six months. None of the seven trials provided adequate evidence to support immunotherapies based on the primary outcome measured at six months.[41] However, two short-term trials of IVIG showed statistically significant improvements in Modified Rankin Scale at two weeks and 10-m walk time at four weeks (level of evidence, 2). Other studies have indicated that IVIG was effective in 15 % to 20 % of patients.[42–44] A prospective study of 22 patients indicated that IVIG induced a short-term benefit in 50 % of patients with IgM paraprotein-associated neuropathies (11 of 19 patients had elevated anti-MAG antibodies).[45] These findings suggest IVIG may provide benefit for some patients.

IVIG adverse effects may include allergic reactions, cephalgia, aseptic meningitis, hemolysis, renal adverse effects mostly in sucrose-based preparations, and hypercoagulable states (e.g., DVT, PE, and MI).

Plasmapheresis (Plasma Exchange)

This blood purification procedure removes antibodies, thereby preventing them from binding their targets. The procedure removes the blood, separates blood cells from plasma, and returns purified blood, diluted with a plasma substitute, to the circulation.[46] Plasmapheresis is used for certain patients with IgG/A MGUS-associated neuropathy and may be helpful in severe cases of cryoglobulinemia. Plasmapheresis has only short term efficacy and must be repeated to maintain effectiveness. The procedure has limited utility for treatment of IgM-associated PPN.

A systematic review of treatments for IgG or IgA paraproteinemic peripheral neuropathy identified one relevant randomized controlled trial with 18 participants. Results showed plasma exchange had modest improvement over sham plasma exchange over a short-term follow up (level of evidence: 2).[47]


A review of case reports and uncontrolled studies indicated that corticosteroids, when given in conjunction with other therapies, produced a response in about half of the patients with high anti-MAG IgM, but was seldom effective as a single therapy.[43] Corticosteroids have potential adverse effects on numerous organ systems (dermatologic, metabolic, cardiovascular, immune, gastrointestinal, central nervous system, bone), and patients receiving long-term or high doses of corticosteroids should be monitored for the development or worsening of these conditions. Long-term use (usually >3 weeks) or doses greater than physiological amounts (7.5 mg prednisone), may lead to clinically relevant suppression of the pituitary-adrenal axis, or exogenous Cushing syndrome. Corticosteroids may cause immunosuppression, which may mask signs of infection and increase patient susceptibility to infection. Patients should not receive live attenuated vaccines during therapy.[48,49]


After IVIG or corticosteroids, azathioprine is an alternative immunosuppressive treatment for CIDP.[21] The US FDA requires a boxed warning to advise of increased risk of neoplasia, particularly lymphoma (hepatosplenic T-cell lymphoma) and skin cancers associated with use of azathioprine. The drug is a purine analog that causes immune suppression and subnormal response to infections or vaccines. Infections should be treated vigorously and live vaccines avoided. There is risk of irreversible or delayed bone marrow suppression. Individuals with thiopurine methyltransferase (TPMT) deficiency may be unusually susceptible to myelosuppression. There is also a risk of pancreatitis and hepatotoxicity, which may be dose-related. A gastrointestinal hypersensitivity reaction characterized by severe nausea and vomiting has also been reported and may occur in the first few weeks of treatment. Hepatic or renal impairment may require a dose reduction. CBC, renal and liver function should be monitored periodically.


This monoclonal antibody targets the CD20 antigen on B lymphocytes and is a first-line treatment for IgM-MGUS (off-label use). A small randomized study determined the effectiveness of rituximab versus placebo on symptoms of neuropathy in patients with anti-MAG IgM demyelinating polyneuropathy. Twenty-six patients were randomized to four weekly infusions of 375 mg/m2 rituximab or placebo. After 8 months, 4 of 12 rituximab-treated patients improved by at least one INCAT score (a measure of leg disability) compared with 0 of 13 patients taking placebo (P = .036) (level of evidence, 2).[50] Another double blind placebo controlled trial of rituximab randomized 54 patients with IgM anti-MAG demyelinating neuropathy to receive rituximab or placebo. The primary outcome was the mean change in INCAT sensory score at 12 months, which showed no significant difference between treatment arms. However, with six patients in the rituximab group dropping out of the study, the per protocol analysis showed significant improvement in the rituximab group for secondary endpoints of INCAT disability scale and self-evaluation scale (P = .027 and P = .016, respectively).[51] Both trials indicate statistically significant improvement in clinical rating scales (as secondary outcomes in some cases) suggesting that the use of rituximab for patients with anti-MAG IgM demyelinating polyneuropathy may provide benefit. Although some may not improve and the worsening is part of the disease progression, some patients may worsen after rituximab, especially if IgM levels are very high, similarly as with Waldenstrom's macroglobulinemia.[52–54]


The alkylating agent chlorambucil is well tolerated by most patients but immunosuppression and bone marrow suppression may develop, which may lead to an increased susceptibility to infections or bleeding. Neutropenia can occur after the third week of chlorambucil therapy and continue for up to 10 days after the last dose. CBC should be monitored weekly.


Fludarabine is used as alternative therapy for IgM-MGUS, and the efficacy of the cytotoxic purine antimetabolite has been demonstrated in very small case series, both alone and in combination with rituximab.[55,56] Use of fludarabine can cause severe bone marrow suppression. Life-threatening and sometimes fatal autoimmune hemolytic anemia and immune thrombocytopenic purpura have been reported following one or more cycles of fludarabine therapy in approximately 5 % of patients. Nausea/vomiting during intravenous fludarabine treatment is common. CBC should be monitored weekly.


Melphalan in combination with prednisone may reduce the monoclonal protein level and even prolong survival in AL, but the specific effect of this regimen on peripheral neuropathy is not known.[57] Melphalan is used for treatment of POEMS syndrome. A study from China on 31 patients with POEMS reported that high-dose melphalan plus dexamethasone resulted in good hematologic and neurologic responses.[58] The drug may cause a secondary malignancy; melphalan is leukemogenic in humans. Myelosuppressive effects of melphalan can increase the risk of infection or bleeding. The dosage of melphalan should be reduced or therapy discontinued at the first signs of neutropenia or thrombocytopenia. CBC should be monitored closely.