Monoclonal Gammopathy and Neuropathy Norman Latov, MD, PhD In examining the clinical and electrophysiological features of the neuropathies associated with monoclonal gammopathy of undetermined significance (MGUS), D r Gosselin and associates postulate that if “the mechanism for IgM-MGUS is different than it is in neuropathies with other monoclonal gammopathies, the natural history and characteristics of the neuropathy might reflect this difference.” They find that the “type and severity of neuropathy were not significantly different between IgM-MGUS neuropathies, with or without antiMAG Ab,” and conclude that “the role of anti-MAG Ab in causing neuropathy gains no support from the present study” 111. A more likely interpretation of their data would be that analysis of only the natural history and electrophysiological features, without further pathological and immunological investigation, can no more distinguish between the pathogenesis of neuropathies associated with various monoclonal gammopathies than they can distinguish between the pathogenesis of diabetic, uremic, or toxic neuropathies in the absence of the appropriate laboratory data. The authors ignore the extensive immunopdthohgical evidence for the heterogeneity of these disorders, and would lump together the demyelinating neuropathies associated with anti-MAG antibodies [2], the axonal neuropathies associated with anti-chondroitin sulfate antibodies { 31,the motor neuropathies associared with anti-GM1 antibodies [ 4 ] ,and the sensory neuropathies associated with anti-sulfatide antibodies 151. They then compare these disorders t o other syndromes that are equally heterogeneous. Predictably, the results are uninterpretable. The discussion of the role of the monoclonal anti-MAG Ab in the pathogenesis of the neuropathy is also unbalanced and misleading. The authors quote several older, unrevealing studies but omit references to more recent studies from several independent laboratories which show that intraneural or systemic transfer of anti-MAG antibodies into experimental animals induced demyelination, conduction block, and splitting of the myelin lamellae, which are characteristic findings in patients with the disease C6-91. The term MGUS was proposed by Kyle [lo] to replace “benign monoclonal gammopathy” in asymptomatic patients who did not have myeloma or macroglobulinemia. H e suggested that the earlier term was a “misnomer” because in some cases there was progression to the malignant disease. When applied to patients with neuropathy, however, the term MGUS loses its usefulness and may itself be a misnomer. There is a great deal that is still to be learned about these syndromes, but most investigators would agree that the monoclonal gammopathies associated with neuropathy are of some significance (MGSS). It would be more useful to state whether the gamrnopathy is malignant or nonmalignant, and to describe the associated disease; i.e., nonmalignant IgM monoclonal gammopathy with demyelinating neuropath y and anti-MAG antibody activity. The diagnosis should be made after considering not only the clinical course and the electrophysiological characteristics of the disease, but also the results

690 Annals of Neurology

Vol 31

No 6 June 1992

of pathological, immunocytochemical, and immunological investigations. Department of Neurologl Columbia University New Yo& N Y

References 1. Gosselin S, Kyle RA, Dyik PJ. Neuropathies associateci with monoclonal gammopathies of undetermined significance Ann Neurol 199 13034-6 1 2. Vital A, Vital C, Julien J. et al. Polvneuropathy associated with IgM monoclonal gammopathy : immunological and pathological study in 31 patients. Acta Neuropathol 1987 3. Y e e WC, Hahn AF, Hearri SA, et al. Neuropathy in IgM paraproteinemia: immunoreactivity to neural proteins and chondroitin sulfate. Acta Neuropathol 1989;’8:57-64 4. Nobile-Orazio E, Legnamr G, Daverio R, et al. Motor n8zuron disease in a patient with ;i monoclonal IgMk directed againsr GMI, GDlb, and high molecular weight neural specific glycoproteins. Ann Nrurol 1990;28: 190-194 5 . Pestronk A, Li F, Griffin 1, er al. Polyneuropathy syndromes associated with serum antibodies to sulfatide and myelin associated glycoprotein. Neurology 1991;41:357-362 6. Hays AP, Latov N, Takatsu M, et al. Experimental demyelination of nerve induced by serum o f parients wirh neuropathy and anti-MAG M-proteins Neurology 1987;1’:242-256 7. Willison HJ, Trapp BD, I3acher J D , ec al. Demyelination induced by intraneural injecfion of human anti-myelin associated glycoprotein antibodirs. Muscle N e r v e 1788;ll : I 100-1 176 8. Trojaborg W, Galassi G, Hays AP, et al. Elt.ctrophysic,logIc study of experimental demyelinatlon induced by serum of patients wirh IgM M-proteins and neuropathy. Neurology 1989;39:1581-1586 9. Tatum AH. Experimental IgM anti-myelin parapr’rjteindemyehating neuropathv: ultrastructural characterizxion. AIH) Neurol 1989;26:298 10. Kyle RA. Benign monoclorial gammopathy: a misnomer?J.AMA 1984;25 1 :1849- 1854

Reply

Sylvie Gosselin, MD, Robert A. Kyle, MD, and Peter James Dyck, M D

It is not surprising that both Latov and Pestronk would write in response to our article on the natural history of monoclonal protein associated neuropathies { 11, because our results d o not fulfill their expectations that the presence of anti-MAG antibodies influences the expression of neuropathy. The following responds to the important issues they raise. Latov performed the assays for anti-MAG activity using ELISA. We maintain that, if one wants to know whether anti-MAG antibodies influence the expression and severity of neuropathy in IgM-MGUS patients with neuropathy, comparisons should be made in such patients between those with and without anti-MAG antibodies. If significant difference between groups cannot be shown in symptoms, neuropathic deficits, or attributes of nerve conduction-the results we found-it is reasonable to conclude, as we did, that our observations provided no support for the concept that antiMAG antibodies influence the clinical and electrophysiological characteristics of IgM-MGUS neuropathy. We did not