Paraproteinemic Neuropathy: A Practical Review

Richard A. Rison; Said R. Beydoun

Disclosures

BMC Neurol. 2016;16(13) 

In This Article

Background

Paraproteinemia

Paraproteins are immunoglobulins that are produced in excess by an abnormal clonal proliferation of B-lymphocytes or plasma cells. These monoclonal proteins exist as heavy chain subtypes (IgG, IgA, IgG, and less commonly IgD or IgE) and light chain subtypes (kappa or lambda).[1] Clonal proliferation may occur in the context of a hematologic malignancy or a premalignancy. Commonly associated disorders include multiple myeloma, cryoglobulinemia, lymphoma, amyloidosis, Waldenstrom macroglobulinemia, and POEMS (polyneuropathy, organomegaly, endocrinopathy, M-protein spike, and skin manifestations) syndrome.[6]

Despite the range of associated hematologic disorders, paraproteins most commonly occur as a monoclonal gammopathy of undetermined significance (MGUS).[7,8] MGUS is a common, age-related medical condition characterized by an accumulation of bone marrow plasma cells derived from a single abnormal clone without proliferation of malignant cells.[8–10] Three criteria define MGUS: A monoclonal paraprotein band less than 30 g/L (3 g/dL); plasma cells less than 10 % on bone marrow examination; and no evidence of bone lesions, anemia, hypercalcemia, or renal insufficiency related to the paraprotein.[11] MGUS-associated neuropathies are generally not treated, except in the case of a disabling IgM monoclonal gammopathy or when associated with chronic inflammatory demyelinating neuropathy (CIDP), as in certain cases of IgG or IgA monoclonal gammopathy. CIDP-MGUS (non-IgM) has the same clinical and electrodiagnostic characteristics as pure CIDP and has the same treatment choice and algorithms (please note however that many neurologists still try standard CIDP treatments first before considering immunosuppression, even though they are not as effective as in idiopathic CIDP).[12] In the case of IgG monoclonal gammopathy, studies have shown improvement on impairment measures following treatment with rituximab, cyclophosphamide/prednisone, or fludarabine.[11–13]

Multiple myeloma is part of the spectrum of diseases ranging from MGUS to plasma cell leukemia, and similar to MGUS, is characterized by proliferation of a plasma cell clone and subsequent overabundance of monoclonal paraprotein (M protein).[13]

Paraproteinemic Neuropathy (PPN)

Several disorders of the peripheral nervous system are closely associated with the presence of excessive amounts of abnormal immunoglobulins in the blood.[14] PPN may be caused by interaction of antibodies with specific antigenic targets on peripheral nerves or by deposition of immunoglobulins or amyloid. The clinical presentation, treatment, and prognosis of PPN differs based on the subtype and associated disorders.[3] There are three major clinical PPN subtypes:

  • Distal demyelinating symmetric neuropathy

  • Chronic inflammatory demyelinating polyneuropathy (CIDP) –like

  • Axonal sensorimotor peripheral neuropathy

Approximately 10 % of patients with a chronic sensorimotor neuropathy of unknown origin have an associated serum monoclonal gammopathy, and two-thirds of such cases are initially classified as MGUS.[15,16]

Clinical presentation of peripheral neuropathy associated with monoclonal proteins includes general symptoms of foot numbness, paresthesias, imbalance, gait ataxia, dysesthesia, and lancinating pain. In early stages, general signs include abnormal sensation in the legs referable to conduction in large fibers (touch, joint position, vibration). As the illness progresses, weakness in distal muscles with variable atrophy occurs.[15,17]

Paraproteins are detected in the serum of approximately 1 % of the general population.[1,7] The prevalence of paraproteinemia rises with age, up to 5.3 % among individuals over 70 years and up to 10 % in people older than 80 years.[10] Among patients with cryptogenic neuropathy, the prevalence of paraproteinemia is 10 %. PPN is most commonly observed with IgM gammopathy (48 %), followed by IgG (37 %), and IgA (15 %). African Americans have a higher prevalence of monoclonal gammopathy.[5]

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