Demyelinating Neuropathy and Antineurofilament Antibodies
Abstract & Commentary
Source: Stubbs EB Jr, et al. Anti-neurofilament antibodies in neuropathy with monoclonal gammopathy of undetermined significance produce experimental motor nerve conduction block. Acta Neuropathol. 2003;105:109-116.
Among patients with plasma cell dyscrasias and polyneuropathy, most have monoclonal gammopathy of undetermined significance (MGUS), of which 50% are IgM in type. Most of these demonstrate activity against myelin-associated glycoprotein (MAG). Other IgM antibodies are reactive against acidic glycolipids, GM1 and GD1b gangliosides, intermediate filaments, chondroitin sulfate C, sulfatide, and neurofilament. Segmental demyelination is seen with most of these, but chondroitin sulfate C, sulfatide, and neurofilament demonstrate axonal degeneration. Although it is tempting to attribute the neuropathy to the antibody, a definite cause-and-effect relationship has yet to be established for any of the associations, though it is strongest for anti-MAG demyelinating polyneuropathy.
Sixteen patients presenting with distal symmetric polyneuropathy and preserved strength had IgG MGUS on laboratory evaluation. All had normal serum IgM and IgA levels, normal bone marrow biopsy, and absence of diabetes, toxin exposure, Bence-Jones proteinuria, lytic bone lesions, anemia, hypercalcemia, amyloidosis, organomegaly, or renal insufficiency. Four of the 16 patients’ sera contained elevated polyclonal IgG antibodies. On immunoblot, the IgG reacted with a high molecular mass protein which, when sequenced, was confirmed to be high-molecular-weight neurofilament (NFH) protein. Demyelinating neuropathy was seen on nerve conduction studies in 2 of the 4 patients, with an axonal and a mixed axonal-demyelinating neuropathy in 1 each. None of 10 control sera demonstrated these antibody activities and the 4 patients’ own IgG monoclonal antibodies were nonreactive as well. When NFH was injected into rat sciatic nerve endoneurium together with complement-supplemented sera, motor nerve conduction block was documented electrophysiologically with no evidence of temporal dispersion. Injection of NFH alone, without complement-supplemented sera, failed to produce conduction block. Injection of complement-supplemented sera alone was similarly nonpathogenic. Pathologic study of the NFH-complement injected nerve revealed axonal shrinkage, with myelin vesiculation, ovoid formation, and edema. Polyclonal NFH antibody activity may be causally related to IgG MGUS demyelinating neuropathy.
Commentary
Polyclonal antibodies are nonpathogenic.1 Association between IgG or IgA MGUS and polyneuropathy is tenuous. Hence, this report is doubly intriguing and raises several questions. Patients demonstrated normal strength, indicating an absence of significant conduction block, yet the rat model showed evidence of just such pathology. Nerve conduction results were similarly predominantly demyelinating, but whether they involved motor or sensory nerves, or both, remained unstated. Numbers were small (n = 4) and 1 patient with a mixed axonal-demyelinating neuropathy "developed a smoldering multiple myeloma." Confirmation of these results in other, larger, series will be desirable to confirm or contradict its findings. — Michael Rubin
Dr. Rubin Professor of Clinical Neurology, New York Presbyterian Hospital-Cornell Campus.
Reference
1. Gorson KC, et al. Neurology. 1997;49:1747.
Among patients with plasma cell dyscrasias and polyneuropathy, most have monoclonal gammopathy of undetermined significance (MGUS), of which 50% are IgM in type. Most of these demonstrate activity against myelin-associated glycoprotein (MAG).You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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