Pain, Tingling, and Numbness in the Extremities With Foot Drop and Progressive Weakening of the Legs

Sumaira Nabi, MBBS; Rao Suhail, MBBS, FCPS Neurology; Shahzad Ahmed, MBBS


May 19, 2014


This patient’s serum showed findings consistent with IgM kappa monoclonal gammopathy. Therefore, the final diagnosis of paraproteinemic neuropathy associated with monoclonal gammopathy of undetermined significance (MGUS) was made.

MGUS, an asymptomatic, premalignant clonal plasma cell disorder, is the most common of the plasma cell dyscrasias. MGUS occurs in over 5.3% of persons in the general population over age 70 years, and the incidence increases with age.[1] It is more common in men than women. The disorder is typically detected incidentally when patients undergo protein electrophoresis as part of an evaluation for unrelated indications. There are 3 distinct clinical variants of MGUS: non-IgM MGUS, IgM MGUS, and light-chain MGUS.[2,3] Each of these subtypes has a small risk of progressing to a malignant plasma cell dyscrasia or lymphoproliferative disorder.[4,5]

Non-IgM and IgM MGUS are characterized by the presence of a serum M-protein at below 3 g/dL, the existence of less than 10% of monoclonal plasma cells in the bone marrow, no or only small amounts of Bence-Jones protein in the urine, and the absence of lytic bone lesions, as well as the absence of any end organ damage, such as anemia, hypercalcemia, or renal failure, related to the proliferative process.[1]

MGUS was once considered benign, but it is now known that approximately 20% of patients will in time acquire a malignant plasma cell disorder, usually myeloma. (Typically, 0.6-3.4% of cases of MGUS progress to multiple myeloma annually.[6,7]) Patients with MGUS also have an increased risk of axial bone fractures and thromboembolism, as well as the development of secondary malignancies after multiple myeloma.[8,9,10] Nonetheless, the median survival of patients with MGUS is only slightly shorter than that of the general population.

There is no known role for chemotherapy in the management of MGUS, and in fact, no treatment is recommended or required for individuals with this condition. However, because the disease may progress, patients must be followed over time, using history and clinical assessment to determine whether such progression has occurred. All patients should undergo laboratory evaluation—including assessment of serum and urinary M-protein, creatinine, and serum calcium, as well as a CBC—6 months after diagnosis.

Periodic laboratory testing should then be performed in high-risk patients. A risk stratification system can be used to determine which patients fall into this category, since not all persons with MGUS have the same risk of disease progression.[11,12,13] The management of a patient with MGUS requires an understanding of the risk of progression to symptomatic disease requiring therapy.

In addition to being incidentally discovered, MGUS is also diagnosed during the course of workup for polyneuropathies. Paraproteinemic neuropathies—which are associated with the presence of M-protein (a so-called M spike) in the serum—are thought to constitute approximately 10% of idiopathic polyneuropathies, with two thirds of all paraproteinemic neuropathy cases believed to be associated with MGUS.[14,15,16] Other conditions associated with paraproteins, including multiple myeloma, Waldenström macroglobulinemia, osteosclerotic myeloma, primary amyloidosis, cryoglobulinemia, non-Hodgkin lymphoma, Castleman disease and related lymphatic diseases, and chronic leukemias, are also typically associated with neuropathies.

M-proteins are derived from a single clone of plasma cells. Some M-proteins behave as antibodies for components of myelin and axolemma. Nerve damage from M-proteins may also be secondary to deposition of the amyloid byproduct of the circulating paraprotein. Although IgG is the most common class of paraproteins in patients with MGUS, IgM is more frequent in those with neuropathy (60%).[17,18] Patients with MGUS predominantly have a kappa light-chain component.