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February 2001 Volume 4, Issue 3:
By Robert A. Kyle, MD
MGUS and Peripheral Neuropathy
MGUS and Peripheral Neuropathy

Monoclonal gammopathy of undetermined significance (MGUS) is characterized by the presence of an M (monoclonal) protein in persons without evidence of multiple myeloma, macroglobulinemia, amyloidis or other related disorders. It is characterized by the presence of a serum M-protein consentratioin <3g/dL, <10% plasma cells in the bone marrow, none or only a small amount of M-protein (light chain, Bence Jones protein) in the urine and the absence of lytic bone lesions. Anemia, elevated serum calcium and kidney insufficiency are absent. Most importantly, the stability of the M-protein and the failure of development of other abnormalities during long-term follow-up of the patient are necessary for diagnosis. Almost two-thirds of newly-diagnosed patients at the Mayo Clinic with an M-protein have MGUS. It is found in 3% of persons older than 70 years and in approximately 1% of persons >50 years of age.

Peripheral neuropathy is characterized by paresthesias (tingling, burning pain), numbness or weakness of the limbs. The toes, feet and legs are more commonly involved than the fingers and hands. These symptoms are usually bilateral and symmetric and progressive. The nerves to the bowel may also be involved and lead to constipation, diarrhea, abdominal distention, nausea, vomiting, and loss of weight.

The presence of an M-protein (IgG, IgA or IgM) in the serum of a patient with peripheral neuropathy raises the suspicion of primary amyloidosis (AL), POEMS syndrome (osteosclerotic myeloma) as well as Waldenstrom's macroglobulinemia, other lymphoproliferative disorders such as lymphoma or, rarely, multiple myeloma. If these diseases are excluded by appropriate diagnostic studies, the patient most likely has an MGUS. One must keep in mind that neuropathies in all patients with MGUS may not be related to the presence of the MGUS. It is necessary therefore to consider other causes of the neuropathy, the course, electrophysiologic features, cerebrospinal fluid findings et cetera to decide whether it is likely to be an MGUS-related neuropathy. 

During a one-year period nearly 700 patients with clinically apparent neuropathy were identified at the Mayo Clinic. About one-half had a systemic disease known to cause neuropathies such as diabetes mellitus, alcoholism or connective tissue disorders. In the remaining patients, 10% had a monoclonal protein associated with MGUS, primary amyloidosis or related disorders. 

Typically, MGUS neuropathy has the following features: 

  1. It is associated with the occurrence of a monoclonal protein in the serum; 
  2. amyloidosis, POEMS syndrome or related disorders are absent; 
  3. A symmetric sensorimotor polyneuropathy that begins insidiously and usually slowly progresses; 
  4. occurs in the sixth or seventh decade of life; 
  5. It affects males more frequently than females; 
  6. Parathesias (numbness and tingling), ataxia (decrease in balance), and pain may be prominent; and 
  7. Cranial nerves are involved. 

Neuropathy in MGUS usually involves patients over 50 years of age. Men are more frequently involved than women. IgM is the most frequent type of monoclonal protein followed by IgG and IgA. Symptoms usually begin in the toes and extend to the feet and legs. The lower extremities are involved in almost 90% of patients. The majority have decreased or altered sensation, paresthesias, unsteadiness of gait and muscle weakness. The muscle stretch reflexes are decreased or absent but Babinski signs (pathological reflexes) are never found. Chronic progression of symptoms occurs in most of the patients.

In a comparison of IgM with IgG and IgA associated peripheral neuropathies the IgM group has more sensory ataxia, reduction in nerve conduction and more frequent dispersion of the compound muscle action potential. The results show a greater slowing of peroneal nerve conduction velocity in the IGM patients. 
Electromyographic studies are a measure of nerve and muscle function. Nerve conduction is abnormal in both motor and sensory fibers in the upper and lower extremities. The conduction velocity of motor fibers is decreased. The amplitude of the compound muscle action potential is markedly decreased. Frequently, responses from the sensory fibers of the upper and lower limb nerves cannot be elicited. Needle electromyography reveals demyelination in the majority of patients. Both demyelination and axonal degeneration are seen. The sural nerve (major nerve in lower limbs) is usually more severely involved that the median nerve in the arms. 

Appoximately one-half of patients with peripheral neuropathy and an IgM monoclonal protein have IgM antibodies that bind to myelin-associated glycoprotein (MAG) in the myelin sheath of nerves. However, there is no apparent difference in the clinical pattern of patients with or without MAG antibody activity. Furthermore, there is no correlation with the course of the disease or reponse to therapy in the MAG positive or negative patients. In addition to the MAG determinants, other antigens in the nerves such as glycolipids, gangliosides, chondroitin sulfate and sulphatide have been found but do not relate to any specific clinical features or response to treatment. 

Differential Diagnosis 

MGUS neuropathy must be distinguished from chronic inflammatory demyelinating polyneuropathy (CIDP), amyloidosis, osteosclerotic myeloma, myeloma, T-cell and B-cell lymphomas as well as metabolic, hereditary and toxic neuropathies. CIDP occurs at any age and some feel that these patients have more severe weakness, less vibration loss in the hands and are more likely to have a relapsing course than MGUS-associated neuropathy patients. In addition, impairment appears to develop more slowly in the MGUS patients then in CIDP. Motor symptoms tend to predominate in CIDP and, of course, these patients do not have an M-protein in the serum.

MGUS neuropathies differ from those associated with primary amyloidosis in the following respects: 

  1. In MGUS the lower extremities are preferentially affected but upper and lower limbs tend to be affected to greater degree in amyloidosis; 
  2. The course in amyloidosis is always slowly progressive; 
  3. Although amyloidosis may present as a sensorimotor neuropathy, autonomic features such as a light-headedness from low blood pressure (postural hypotension), loss of bowel or urine control and lack of sweating may occur. 

In addition, heart or kidney failure are not a part of MGUS neuropathy. Biopsy of the sural nerve is often necessary to exclude the possibility of amyloidosis. It is important to make this distinction because peripheral neuropathy associated with amyloidosis rarely responds to therapy.

POEMS syndrome must be considered in the differential diagnosis. These patients present with peripheral neuropathy in which muscle weakness is prominent. Autonomic symptoms are not found. In contrast to multiple myeloma, bone pain and fractures rarely occur. The liver and spleen are enlarged in half the cases. Increased pigmentation of the skin or excessive tanning may be prominent. Increased hair growth on the extremities may be seen. Enlargement of the breasts and atrophy of the testes may occur. Increased fluid in the abdomen or chest cavities may be present. Ninety percent of patients have s solitary sclerotic lesion or multiple lesions in the bones. Papilledema (swelling of the optic discs) may be present. Protein in the cerebrospinal fluid is elevated. It is important to make the diagnosis because radiation to a localized sclerotic lesion often produces dramatic improvement.


Treatment of patients with MGUS neuropathy has shown some promise. Plasma exchange consists of removal of 3-4 liters of the patient's blood and replacing it with the patient's red cells, serum albumin and saline. The plasma which contains the M-protein is discarded. In a randomized trial, 39 patients with MGS and peripheral neuropathy were assigned to receive either plasma exchange twice weekly or sham plasma exchange in a double-blind trial at the Mayo Clinic. The average neuropathy disability score improved by 12 points in the plasma exchange group and only 2 points in the sham exchange group. In the open trial patients who initially under-went sham exchange were then treated with plasma exchange and the neuropathy score and weakness score improved more with plasma exchange than with sham exchange. In both double-blind and open trials, IgG or IgA MGUS had a better response to plasma exchange than those with IgM MGUS.

Rituximab (Rituxan) produced improvement in all 5 patients with neuropathy and IgM antibody to MAG or Gm1 ganglioside. Rituxan is a monoclonal antibody directed against CD20 which is a common surface membrane marker in lymphoproliferative disorders. The patients received 4 weekly infusions of Rituximab without major side effects. 

We have used chlorambucil for patients with IgM monoclonal gammopathy and melphalan for those with IgG and IgA monoclonal gammopathies and peripheral neuropathy. Some of these patients have had a gratifying response to therapy. The use of prednisone and/or cyclophosphamide or azathioprine may be helpful in some instances. Fludarabine, a purine analog, was reported to produce improvement in 3 of 4 patients an IgM monoclonal protein and peripheral neuropathy. In another report, 7 of 10 patients with an IgM monoclonal protein and neuropathy responded to fludarabine. The use of intravenous gamma globulin has been beneficial in some patients with CIDP but has generally been disappointing for patients with MGUS-associated peripheral neuropathy.

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