The polyneuropathy associated with monoclonal gammopathy affects mainly, but not exclusively, males in the sixth and seventh decades of life. The onset is insidious over weeks and months or more, with numbness and paresthesias of the feet and then of the hands, followed by a relatively symmetrical weakness and slight wasting of these muscles. In some patients, sensory signs predominate. The tendon reflexes, eventually lost or diminished, may be preserved in the early phases of the illness. The course is usually slowly progressive, sometimes static after a year or so, and rarely remitting and relapsing. The CSF typically shows an elevation of the protein in the range of 50 to 100 mg/dL, and this is not due to passive diffusion of the excess paraprotein into the CSF.
The majority of cases of polyneuropathy with monoclonal gammopathy have a demyelinating or mixed axonal–demyelinating pattern on the EMG and nerve conduction study, but once the illness is well established, most will have predominantly axonal features. With few exceptions we have been unable to distinguish the axonal and demyelinating groups on clinical grounds or by their response to therapy (Gorson et al 1997, Ropper and Gorson 1998). Sural nerve biopsies show a loss of myelinated fibers of all sizes; unmyelinated fibers are mostly spared; hypertrophic changes, reflecting cycles of demyelination and remyelination with fibrosis are present in about half the cases according to Smith and colleagues. They found the monoclonal IgM antibody bound to surviving myelin sheaths and Latov and coworkers have shown that the serum IgM fraction often displays antimyelin activity.
Typically, the monoclonal protein in the blood is present in a concentration much less than 2 g/dL and there is no evidence of multiple myeloma or other malignant blood dyscrasia. It should be emphasized that routine serum protein electrophoresis (SPEP) fails to detect the majority of these paraproteins; immunoelectrophoresis (IEP) or the more sensitive immunofixation testing is required. The bone marrow aspirate shows a normal or only mildly increased proportion of plasma cells, which are the source of the paraprotein and the plasma cells are not morphologically atypical as they are in myeloma. Insofar as myeloma becomes manifest in perhaps one-quarter of patients many years after the gammopathy has been recognized, the condition is termed monoclonal gammopathy of undetermined significance (MGUS), although the older term benign monoclonal gammopathy is less cumbersome.
The importance of excess immunoglobulin as a cause of neuropathy can be appreciated by noting that 6 percent of patients referred to the Mayo Clinic with chronic polyneuropathy of unknown cause and as many as 20 percent in our clinical material and in other series have proved to have a monoclonal paraproteinemia (of course, the majority of patients with a blood paraprotein do not develop neuropathy).
Despite the fact that IgG is the most frequent paraprotein in adults, a polyneuropathy is associated somewhat more often with the IgM class. Combining three large series of patients with neuropathy and monoclonal paraproteinemias (62 patients of Yeung et al, Gosselin et al, and our patients as reported by Simovic et al), 60 percent had IgM, 30 percent IgG, and 10 percent with IgA subclass paraproteins. An identical but infrequent condition exists in which only the light chain component of an immunoglobulin is overproduced by the plasma cells and is found exclusively in the urine (similar to the Bence Jones protein of multiple myeloma).