Monoclonal Gammopathies Of Undetermined Significance

Pathogenesis and Pathophysiology. A heterogenous group of peripheral neuropathies has been associated with the presence of an MGUS. However, the precise relationship of the monoclonal (M-) protein to the peripheral nerve disorder remains unclear. By definition, MGUS indicates the presence of an M-protein of less than 3 g/dl in concentration, with less than 5 percent plasma cells in bone marrow, none or only a very small amount of M-protein in the urine, and the absence of other abnormalities, including lytic or sclerotic bone lesions, anemia, hypercalcemia, and renal insufficiency. Furthermore, the M-protein should remain at stable and low concentrations over time.y The natural history of MGUS indicates that with advancing time specific hematological and lymphoproliferative disorders, such as multiple myeloma, Waldenstrom's macroglobulinemia, amyloidosis, and lymphoma, may develop. Nevertheless, most patients who undergo a comprehensive evaluation for an M-protein in their serum ultimately will have it attributed to MGUS. MGUS is rather common, occurring in up to 1.7 percent of patients older than age 50 and in 3 percent of patients older than age 70. y

Acquired SD polyneuropathies with features similar to that of CIDP have been observed in MGUS with IgG, IgA, and IgM M-proteins. These observations, coupled with the response of these disorders to the typical therapeutic interventions used for CIDP, have fostered the belief that these disorders are also immune mediated. However, the only strong evidence to support this theory is found in the MGUS neuropathy associated with IgM M-protein. In this disorder, the M-protein binds and reacts to myelin and to an oligosaccharide determinant that is shared by the myelin glycoproteins myelin-associated glycoprotein (MAG) and P o , and the glycolipids sulfated glucuronyl paragloboside (SGPG) and sulfated glucuronyl lactosaminyl paragloboside (SGLPG). y Approximately 50 percent of patients with IgM MGUS neuropathy have anti-MAG antibodies. Many of these patients demonstrate specific clinical and EDX features that distinguish them from the more heterogenous group of polyneuropathies associated with MGUS. The finding of deposits of anti-MAG M-protein and complement on affected myelin sheaths, the presence of widening of myelin lamellae at the sites of antibody deposition, and the experiments that document the development of polyneuropathy in animals following passive transfer of patients' serum support the concept that the IgM M-protein with anti-MAG activity plays an important pathogenetic role in the development of the polyneuropathy. y Other observations, however, have detracted from this theory, including the fact that the concentration of the IgM M-protein may not always correlate with the severity of the polyneuropathy nor with the clinical response after treatment. '34]

Similar to CIDP, the demyelinating polyneuropathy associated with MGUS typically produces physiological alterations suggestive of an acquired SD polyradiculoneuropathy, often accompanied by a modest degree of axon loss. MGUS can also produce a pure axonal sensorimotor polyneuropathy. y , y

Epidemiology and Risk Factors. MGUS polyneuropathy tends to occur later in life than CIDP, with the mean age of onset in the mid to late sixth decade. In most large series, a distinct male predominance is noted. There are no other particular risk factors, and MGUS neuropathy seldom occurs in women of childbearing age. y ,

Clinical Features and Associated Disorders. In general, the MGUS polyneuropathies associated with IgG, IgA, and IgM without anti-MAG activity conform to a symmetrical sensorimotor polyneuropathy that shares many clinical features with CIDP including predominant proximal weakness. Nonetheless, there may be some differences. Sensory symptoms usually are more prominent than in CIDP. In addition, the initial phase of the disorder often progresses much slower than it does in CIDP, and the course is less likely to be cyclical or relapsing. Also, cranial nerve involvement and autonomic involvement are rare. Nevertheless, clinical syndromes indistinguishable from CIDP may be seen with MGUS polyneuropathy.

The clinical syndrome seen with MGUS IgM polyneuropathy associated with anti-MAG antibodies appears to differ from that seen both with CIDP and with MGUS polyneuropathy associated with IgG, IgA, and IgM without anti-MAG activity. y With this disorder, sensory symptoms may be even more prominent and can be the initial presenting feature. Typically, progressive sensory impairment is followed later by motor involvement. Sensory ataxia, particularly affecting the gait, is a common finding, as are tremors of the upper extremities that resemble essential tremor. y Similar to the other MGUS polyneuropathies, the clinical features tend to progress more slowly and are less severe than the initial symptoms associated with CIDP. Moreover, relapsing and cyclical courses are not seen, and cranial nerve or autonomic involvement rarely are encountered.


There is no definitive evidence that other disorders, particularly other immune-mediated disorders, are present to a greater extent in patients with MGUS polyneuropathy. It should be emphasized, however, that the diagnosis of MGUS depends on the stability of the M-protein concentration. Because a significant number of patients with MGUS will later develop malignant forms of monoclonal gammopathy, these patients require repeated evaluations and monitoring of the M-protein over time.

Differential Diagnosis. The differential diagnosis of MGUS polyneuropathy producing acquired SD changes on EDX examination is identical to that of CIDP. It is key to exclude the other causes for monoclonal gammopathy, including multiple myeloma, isolated plasmacytoma, Waldenstrom's macroglobulinemia, osteosclerotic myeloma (including the POEMS syndrome), heavy chain diseases, malignant lymphoma, and amyloidosis. It should also be noted that MGUS polyneuropathy may manifest as an axon loss polyneuropathy and, consequently, should be included in the differential diagnosis of axon loss sensorimotor polyneuropathy discussed elsewhere.y y y

Evaluation. The EDX examination shows changes suggestive of a chronic, acquired SD polyradiculoneuropathy. Searching for an M-protein is an important component in the evaluation of any patient with a significant sensorimotor polyneuropathy. As noted earlier, if the serum protein electrophoresis is negative or unrevealing, additional testing should be performed using immunoelectrophoresis or immunofixation techniques. These methods are more sensitive in detecting small amounts of M-protein that may be important in the identification of MGUS polyneuropathy. '32' Once an M-protein is detected in the setting of a sensorimotor polyneuropathy, a careful evaluation must follow to assess for a lymphoproliferative disorder. This evaluation typically entails routine laboratory studies to assess for anemia, hypercalcemia, and renal insufficiency. In addition, M-protein should be sought in the urine, and a skeletal bone survey should be obtained to assess for multiple myeloma, isolated plasmacytomas, or osteosclerotic changes typical of osteosclerotic myeloma. Although radionuclide bone scans may be valuable in this assessment, the skeletal plain x-ray study is more sensitive for the detection of osteosclerotic lesions. A bone marrow aspirate should also be performed. HIV testing also should be performed in patients at risk, with guidelines similar to those noted for CIDP.

Routine laboratory studies in MGUS polyneuropathy typically are unremarkable. The CSF protein is consistently increased in a fashion similar to that seen with CIDP. Sural nerve biopsy may also disclose features of inflammation and SD with some axon loss, which are very similar to the pathological changes noted in CIDP. None of these findings, however, is specific for MGUS polyneuropathy, and none serves to differentiate it from CIDP and other related disorders.

Because MGUS polyneuropathy associated with IgM and anti-MAG antibodies may represent a clinically distinct disorder, patients with IgM M-proteins should be screened for anti-MAG activity. This is sometimes performed in conjunction with assessment for anti-SGPG and anti-SGLPG antibodies. There is some evidence to suggest that this subset of MGUS polyneuropathies can be distinguished from CIDP and other MGUS polyneuropathies by its EDX features: the absence of substantial conduction block, and the prominent slowing of sensory and motor nerve conduction in the distal nerve segments. y

Management. The data regarding benefits of therapeutic intervention with steroids, immunosuppressants, plasma exchange, and IVIg are largely anecdotal but tend to indicate that MGUS polyneuropathy responds in a fashion similar to CIDP. '34] A controlled trial of plasma exchange did disclose efficacy in MGUS polyneuropathy but appeared to demonstrate greater improvement in polyneuropathies associated with IgG and IgA M-proteins compared with those associated with IgM M-proteins.[37] Although convincing data are lacking, there is general agreement that these patients should be treated following the same guidelines used for CIDP. However, because MGUS polyneuropathy tends to be a more slowly progressive disorder than CIDP, it may be more difficult to define a precise threshold when treatment is indicated. Furthermore, treatment must be aggressive and sustained to provide ample time to observe a clinical response.

Prognosis and Future Perspectives. In comparison to CIDP, the prognosis in patients with MGUS polyneuropathy as a group may be less favorable. Despite the fact that the initial severity of weakness and sensory impairment is considerably less in MGUS polyneuropathy compared with cyclical relapses of CIDP or to the peak of a monophasic course of CIDP, MGUS polyneuropathy tends to be slowly progressive and ultimately, if the condition is left untreated, may result in more severe clinical deficits and disability. '311 Also, MGUS polyneuropathy, overall, is somewhat less responsive to therapy than CIDP. Patients with MGUS polyneuropathy who have prominent features of acquired SD on EDX testing appear to have the greatest chance for significant improvement following therapeutic intervention. Those patients with IgM anti-MAG polyneuropathy may be less responsive to plasma exchange and other interventions. In a study of 25 treated patients with MGUS polyneuropathy who had a mean duration of illness of 6.6 years and were followed for a minimum of 24 months, 12 percent were asymptomatic and another 60

percent had either minimal, nondisabling symptoms or minor symptoms that caused only modest restrictions in their lifestyle. y

Very fundamental nosological issues regarding MGUS polyneuropathies need to be clarified. Does the presence of an M-protein in the setting of a SD polyneuropathy mimicking CIDP indicate a separate and distinct clinical entity? What is the pathogenetic role of the M-protein in the genesis of MGUS polyneuropathy? Is the subset of MGUS polyneuropathy associated with IgG and IgA M-proteins distinct clinically and pathogenetically from that associated with an IgM M-protein? More specifically, does the presence of anti-MAG antibodies in IgM MGUS polyneuropathy signify a distinct clinical and pathogenetic disorder that can be separated from CIDP and the other MGUS polyneuropathies? And finally, what are the natural histories of these disorders and what represents optimal therapies for the various types of MGUS polyneuropathy?


Peripheral Neuropathy Natural Treatment Options

Peripheral Neuropathy Natural Treatment Options

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