Anti-MAG or Not?

Abstract & Commentary

Synopsis: Pure sensory clinical phenotype, low median and ulnar terminal latency index, and absence of M responses in the lower limbs were significantly associated with the diagnosis of MAG-PN, and indicate a moderate to large increase in probability of this diagnosis in patients with chronic dysimmune demyelinating polyneuropathies.

Source: Isoardo G, et al. Differential diagnosis of chronic dysimmune demyelinating polyneuropathies with and without anti-MAG antibodies. Muscle Nerve. 2005;31:52-58.

Can one, at the initial patient encounter, clinically differentiate chronic inflammatory demyelinating polyneuropathy (CIDP) from demyelinating neuropathy associated with anti-MAG antibodies (MAG-PN)? To answer this question, 35 CIDP patients and 14 with MAG-PN were examined by a blinded neurologist, and clinical findings and nerve conduction studies were analyzed to determine distinctive characteristics. Electrodiagnostic studies included study of bilateral median, ulnar, tibial, and peroneal motor nerves, and sural, ulnar, and median sensory nerves. Diagnosis of CIDP followed standard criteria (J Neurol Sci. 2000;173;129-139), with exclusionary criteria encompassing evidence of hereditary neuropathy, hypothyroidism, vitamin deficiency, vasculitis, amyloid, Refsum’s disease, central nervous system white matter disease, optic atrophy, or retinitis pigmentosa. MAG-PN was confirmed by both IgM paraproteinemia and anti-MAG antibody assay > 1:13,000 using immunoblot. Most patients (n = 43) underwent spinal fluid analysis. Chi-square and Fisher’s exact test, Student’s t-test, the Mann-Whitney U-test, and Spearman’s correlation coefficient provided statistical analysis.

Significant associations with MAG-PN included pure sensory neuropathy (P = 0.008), distal acquired demyelinating symmetric neuropathy (DADS) with no proximal weakness (P = 0.04), reduced median and ulnar terminal latency index (P < 0.0001) calculated as distal conduction distance (mm) / conduction velocity (m/s) X distal motor latency (ms), and unobtainable motor responses in the legs (P = 0.001). Incidence of conduction block on nerve conduction studies did not significantly differ between groups. None of the MAG-PN patients experienced a subacute onset, compared to 62.8 % (n = 22) of the CIDP group (P < 0.0001). Anti-MAG assays are likely to be positive in patients with the phenotypes noted, but the cost-effectiveness of this approach remains to be determined.

Commentary

Anti-MAG antibodies bind to molecules in both the central (CNS) and peripheral nervous system (PNS), but with considerable variation. Sera from 18 patients, 12 men and 6 women, with IgM paraproteinemia, anti-MAG antibodies, and neuropathy was tested for immunoreactivity to myelin in the CNS and PNS by ELISA and Western blot analysis (J Neurol Sci. 2003;207;43-49). Indirect peroxidase staining on cryostat sections of sural nerve was also used to examine IgM binding to nerve. MAG was detected in central myelin by all the sera on Western blot, by peroxidase immunoreactivity in myelin sheaths in 12 sera, and by Western blot in peripheral myelin in 8 sera. Staining patterns in sural nerve varied. Some showed staining of the whole cross section of the myelin sheath (n = 8), others (n = 4) showed staining in 50% of fibers, while 6 showed no myelin sheath staining whatsoever. Of these last, 5 stained the outer border of the nerve fibers. Anti-MAG IgM ELISA titers closely correlated with both immunostaining patterns of the whole myelin sheath and with PNS-Western blot results, but PNS and CNS Western blot concordance was only 44.5%. Severity of neuropathy did not significantly correlate with ELISA titers, Western blot analysis, immunostaining patterns, or IgM level. CNS and PNS MAG may differ in their glycosylation patterns explaining the antibody binding differences in CNS and PNS myelin. How this impacts on the pathogenesis of demyelinating neuropathy remains to be elucidated. — Michael Rubin

Dr. Rubin, Professor of Clinical Neurology, New York Presbyterian Hospital-Cornell Campus, is Assistant Editor of Neurology Alert.