Four-fifths of patients have had a kappa light chain component, as mentioned previously, although lambda light chain has special significance as discussed further on in relation to plasmacytoma and the polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes (POEMS) syndrome. In our experience and in that of others, patients with IgM paraprotein more often have severe sensory findings and a demyelinative type of nerve conduction abnormality when compared with the IgG group. However, with the exception of the special anti-MAG syndrome (see later), we have not found the extent of difference in clinical features and response to treatment between the immunoglobulin subclasses that has been reported by others (Simovic et al).
Although more than a dozen specific antibodies against myelin and other components of nerve have been identified among the paraproteins, the ones that give rise to the most distinctive clinical syndromes, present in 50 to 75 percent of patients with IgM-associated neuropathies, are those that react with a MAG, related glycolipids, or sulfatide components of myelin (the latter are referred to as sulfate-3-glucuronyl paragloboside [SGPG] and related sulfatides). Proprioceptive sensory loss with gait imbalance, tremor, and the Romberg sign are typical findings in the group with anti-MAG activity, while weakness and atrophy tend to appear later in the illness. Other IgM antineural antibodies have a more tentative connection to polyneuropathy. It is reasonable to assume that IgG monoclonal gammopathies are also capable of causing chronic neuropathies, but the evidence is less compelling and based mainly on the frequency of their presence in cases of otherwise unexplained polyneuropathy. Indeed, it has been suggested that in many reported instances the association with neuropathy with IgG paraproteinemia is coincidental. The anti-MAG illnesses are relentlessly progressive at various rates in most patients but in about 15 percent of our patients with anti-MAG antibody the illness has been mild and static for years at a time, even without treatment.
Because of the risk of myeloma or Waldenström disease, bone marrow examination is generally performed some time in the course and particularly if the concentration of the paraprotein exceeds 3 g/dL or climbs progressively over years, or if other hematologic changes such as unexplained anemia or thrombocytopenia develop.
Treatment In most cases of uncomplicated monoclonal gammopathy with polyneuropathy that are associated with IgG or IgA paraproteins, particularly if not of long standing, plasma exchange may produce transient improvement for several weeks to months (Dyck et al, 1991). The treatment regimen generally is a total volume of approximately 200 to 250 mL/kg exchanged in each of 4 to 6 treatments over about 10 days and the removed plasma replaced with a mixture of albumin and saline.
In patients who have IgM serum activity against specific components of myelin (particularly anti-MAG), the results of treatment have been inconsistent and generally less favorable. Plasma exchange alone has effected transient improvement in half of cases but sustained improvement in only 10 to 20 percent of our patients. Series of plasma exchanges every 2 to 4 months has sometimes resulted in transient responses. According to some reports, the response to immunosuppression with intravenous cyclophosphamide or fludarabine, mycophenolate, or oral chlorambucil, when coupled with plasma exchanges, has been somewhat better, at times allowing a reduction in the frequency of exchanges but our experience has generally not affirmed this. Rituximab, which has the appeal of having a preferential effect on the B-cell lymphocyte population, after initial enthusiasm based on small series, has given conflicting and generally negative results in several trials, including of anti-MAG neuropathy, but it may be reasonable to try in intractable cases.