Monoclonal gammopathy of undetermined significance and polyneuropathy

Monoclonal gammopathies are heterogeneous group of disorders characterized by unregulated production and deposition of monoclonal (M) protein or paraproteins by proliferation of a clone of plasma cells or B lymphocytes. Paraproteins are consist of two same class and subclass heavy polypeptide chains (G, M, or A) and two same type light polypeptide chains (kappa or lambda). IgG is the most common paraproteins, and less than 15% is IgM. Monoclonal gammopathy without any association with plasma cell dyscrasia occurs in 1% of general population and increases to 10% in older than 80 years. Monoclonal gammopathy with undetermined significance (MGUS) is the most common type of gammopathies which occurs in the absence of malignancy but multiple myeloma and Waldenstrom's macroglobulinemia occur in the context of systemic malignant disorder. Neuropathies are defined as damage to or degeneration of sensory, motor, or autonomic nerves, and association of monoclonal gammopathy and neuropathy is commonly seen in clinical practice. Neuropathy is highly prevalent in MGUS, and estimated 30-50% in IgM, 10-15% in IgA, and 5% in IgG paraproteins. Symmetrical paresthesia, tingling and numbness of the hands and feet in a socks and gloves pattern are the common presentation features. There is large body of evidences that IgM paraproteins induced neuropathy is an immune-mediated neuropathy, and IgM antibodies may bind directly to myelin-associated glycoprotein (MAG) and disrupt interactions between Schwann cells and axons. Peripheral neuropathy is highly variable in IgM MGUS neuropathy, but a phenotypically characteristic IgM MGUS neuropathy progresses slowly and first involves longest nerves symmetrically, and then may progress to proximal nerves. This is the classic description of distal acquired demyelinating symmetric (DADS) sensory and motor neuropathy. In about half of IgM MGUS patients, the IgM M protein binds to carbohydrate moiety of MAG and results in widening of myelin lamella. Anti- MAG antibody induced neuropathy is less common in other monoclonal gammopathies. Motor neuropathies present with muscle cramps, tremors or weakness, and are less frequent than sensory neuropathies. Diabetes mellitus, alcohol abuse, vitamin deficiencies, and viral infections are predisposing factors which may aggravate IgM MGUS neuropathies. A history of already existing neuropathy is a strong risk factor for IgM MGUS neuropathy. Identification of IgM paraproteins by serum protein electrophoresis and presence of high titer (more than 1:6400) anti-MAG antibody are diagnostic of IgM MGUS neuropathy. Sensory action potentials are severely attenuated in electrophysiological studies. Motor nerve conduction velocity is significantly decreased and can be quantified by the terminal latency index which is highly specific for anti-MAG neuropathies. In about 80% of patients CSF protein is increased with normal cellularity. In electron microscopy, there is deposition of IgM on nerve myelin, and myelin lamella is widely open. Serum level of IgM shows correlation with anti-MAG antibodies, and appearance of axonal degeneration in skin nerve biopsies. Patients with IgG/IgA neuropathies have more motor weakness, and less balance problem. The presence of demyelination in nerve conduction studies, the absence of anti- MAG antibodies, and higher age at the onset of disease are three different prognostic factors which can help to classify patients. Patients with demyelinating IgM MGUS neuropathy have more severe nervous symptoms than MAG-positive patients. It has been shown that the disease progress reach at a plateau phase after 10-15 years, and treatment modalities should start at the first 10 years of disease duration. Treatment should target lowering IgM paraproteins levels. It is appropriate to start treatment in younger patients, but timing of treatment is not clear in older patients. Plasma exchange, cytotoxic alkylating drugs, nucleoside analogs, IVIg, and rituximab are tested modalities but no randomized clinical trial supports any of them. IVIg has termbenefs, but studies showed that targeting the B-cell surface antigen CD20 by rituximab is promising. Rituximab may improve or stabilize the anti-MAG antibody neuropathy, and has direct correlation with its serum levels. However, rituximab increase progressive multifocal leukoencephalopathy, and it is prudent to check serum antibodies to JC virus before starting treatment.