Paraproteinaemic neuropathies

Paraproteinaemia and neuropathy are each relatively frequent and may be associated by chance. However, a number of significant relationships have to be ruled out in the differential diagnosis. Malignant gammopathy should be excluded: multiple myeloma can lead to compression of the spinal cord or cauda equina; primary amyloidosis is occasionally involved; the rare but intriguing POEMS syndrome, consisting of polyneuropathy, organomegaly, endocrinopathy, M-protein and skin changes, usually accompanies osteosclerotic myeloma. It can be associated with angio-follicular lymph node hyperplasia and needs to be recognized because radioablative therapy is curative. The 'benign' monoclonal gammopathies of undetermined significance, known as MGUS, are much more frequent. There is an IgM MGUS group with predominantly distal sensorimotor demyelinating polyneuropathy and another rather heterogeneous group with IgG or IgA MGUS and a tendency to a favourable response to plasmapheresis. The role of the monoclonal IgG and IgA antibodies is unclear. This chapter has focused on the pathogenetic mechanisms of neuropathies associated with IgM MGUS. In the majority of cases, monoclonal autoantibodies specific for particular carbohydrate epitopes bind to myelin and are now recognized as the primary cause of the disease manifestations, including widening of the myelin lamellae. While the autoantibodies have been shown to bind complement, the presence of inhibitors is invoked to explain the absence of acute inflammatory changes. The epitopes recognized with the highest affinity by the auto-antibodies are present on the myelin-associated glycoprotein (MAG) and could interfere with cell adhesion and cellular signally processes. In addition, binding to antigenically similar glycoproteins, such as PO, PMP-22 and some acidic glycolipids, may be a contributory factor. It is generally accepted that the anti-MAG autoantibodies are inducing a progressive demyelinating polyneuropathy by modifying axon-Schwann cell interactions.