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August 2002 Volume 5, Issue 2:
Neuropathy and Monoclonal Gammopathy
By By Norman Latov, M.D., Ph.D.


Peripheral neuropathy causes numbness, pain, weakness in the arms and legs, with incoordination and difficulty walking. The neuropathy can be severe and sometimes debilitating. The causes of neuropathy are diverse, but approximately 10% of patients with neuropathy of otherwise unknown etiology also have a monoclonal gammopathy, which can be non-malignant or associated with myeloma or Waldenstrom’s macroglobulinemia. Several different syndromes can be recognized based on the type of monoclonal gammopathy and neuropathy. In evaluating the neuropathy, the physician typically performs Electromyography and nerve conduction studies which measure the electrical properties of the nerves, and draws numerous blood studies to make sure that the neuropathy is related to the monoclonal gammopathy rather than to another cause. A nerve biopsy may also be needed to elucidate the pathophysiology in some cases.

Neuropathy Syndromes Associated with IgM Monoclonal Gammopathies

Sixty to seventy percent of the IgM monoclonal gammopathies that are associated with neuropathy have antibody activity to sugar-like molecules, called oligosaccharides, that are attached to fatty molecules (glycolipids) or proteins (glycoproteins), that are concentrated in the peripheral nerves. The neuropathy is these cases is thought to be caused by the antibodies attacking the peripheral nerves. The most common antibody, which is found in approximately 50% of patients, is the MAG (myelin associated glycoprotein) antibody, which is associated with demyelinating neuropathy. Other antibodies include: a) GD1b and disialosyl ganglioside antibodies, GM1 ganglioside antibodies, GD1a ganglioside antibodies, sulfatide antibodies, and GM2 ganglioside antibodies. These can be tested for by the physician. In addition, some of the monoclonal gammopathies, called cryoglobulins, can precipitate in the cold and damage the blood vessels in the nerves. In the malignant monoclonal gammopathies, the malignant cells can invade the peripheral nerves (lymphomatosis) and cause neuropathy.

Therapy is directed toward reducing the IgM concentration. The response varies between patients, depending on the degree of reduction, the type of neuropathy, and the damage already present. In general, it is easier to prevent progression than recover function, so early intervention is preferred. Several chemo-therapeutic agents have been reported to be beneficial, including chlorambucil, fludarabine, and cladrabine. In less severe cases, rituximab (RituxanTM), a humanized, recombinant monoclonal CD20 antibody directed at B cells, can result in a gradual reduction of IgM concentration and clinical improvement. The combination of fludarabine and RituxanTM is more effective than either one alone. Intra-venous gammaglobulins or plasmapheresis are beneficial in some, but not most patients.

Neuropathy Syndromes Associated with IgG or IgA Monoclonal Gammopathies

Neuropathy is associated with IgG or IgA monoclonal gammopathies in the osteosclerotic forms of myeloma, with amyloidosis, and in the POEMS syndrome where patients have polyneuropathy in addition to organomegaly, endocrinopathy, myeloma, and skin changes. Osteosclerotic myeloma constitutes approximately 3% of myelomas, but 50% of these have peripheral neuropathy. Patients with the POEMS syndrome, as well as with others myelomas, have been reported to exhibit highly elevated titers of vascular endothelial growth factor (VEGF). In primary amyloidosis, the amyloid deposits consist of fragments of monoclonal antibody light chains that can be detected in the urine as Bence Jones protein.

Treatment for myeloma-related neuropathy is directed at the underlying myeloma using melphalan and prednisone. Eradication of solitary plasmacytoma by irradiation or surgery can sometimes be curative, with substantial improvement in the neuropathy. High dose chemotherapy with stem cell transplantation may be helpful in some patients with widespread myeloma. Thalidomide, which is sometimes used to treat myeloma, can also cause neuropathy as a side effect, aggravating the condition.

Treating the Symptoms of Neuropathy, Self Help, and Education

Aside from treating the underlying cause for the neuropathy, or the monoclonal gammopathy, therapy is directed at alleviating the symptoms and helping cope. Neuropathic pain, which can be debilitating, can be treated with tricyclics such as Amitriptyline or Nortriptyline, anti-seizure agents such as Gabapentine, or opioids. Physical and occupational therapy can also help patients increase strength, walk better, and do more with their hands. Sharing information and experiences with other patients that have neuropathy helps people cope, both emotionally and in practical matters. More information about neuropathy can be obtained from The Neuropathy Association at www.neuropathy.org.

Dr. Latov is currently Professor of Neurology and Neuroscience, and Director of the Peripheral Neuropathy Center at the Weill Medical College of Cornell University. He also serves as Medical and Scientific Director, and founding Board member of The Neuropathy Association. Dr. Latov’s clinical and research interests are in the areas of peripheral neuropathy and neuroimmunology, focusing on the mechanisms and treatment of autoimmune neuropathies. His laboratory is credited with discovering antibodies as a cause peripheral neuropathy, and for developing diagnostic tests that are widely used in the evaluation and management of patients with neuropathy. He has lectured widely, and has over 200 publications, including research articles, reviews, editorials, chapters, and books.

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