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Monoclonal gammopathy and neuropathy.

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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
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