Combined Central and Peripheral Demyelination With IgM Anti–Neurofascin 155 Antibodies

Discussion

We reported herein an instructive case with (1) a peripheral clinical picture of CIDP with ataxia and tremor associated with simultaneous acute relapse of cervical myelitis leading to CCPD diagnosis, (2) a positivity of IgM anti-NF155 Ab without IgG4, and (3) an effectiveness of corticosteroid and rituximab treatment. CIDP associated with IgG4 anti-NF155 Ab is rare (5%–10% of CIDP cases) and presents specific clinical characteristics: young age at onset, distal motor lower limb weakness, sensory ataxia, tremor, poor response to IVIg, and good response to corticosteroids and rituximab.¹ NF155 protein is expressed in both the central and peripheral nervous systems explaining the CCPD due to anti-NF155 Ab (up to half the cases of CCPD reported in a Japanese study).¹

IgM anti-NF155 Abs have also been rarely described, and their pathogenicity remains unknown. Most IgM anti-NF155 Abs have been associated with IgG4 in patients with neuropathies,^3,-,5 but some were found isolated.^4,-,7 Isolated IgM anti-NF155 Abs have been reported in only 20 patients: 10 with CIDP (3 with tremor), 2 with Guillain-Barré syndrome, 4 with axonal neuropathies, 2 with CMT, 1 with upper trunk brachial plexopathy, and 1 with facial numbness with normal ENMG, none in CCPD.^4,-,7

We are unable to demonstrate a pathophysiologic link between this case of CCPD and IgM anti-NF155 Ab; however, few elements can be discussed. First, the clinical presentation resembles the previously reported cases of CIDP with IgG4 anti-NF155 Ab, notably regarding ataxia, tremor, and associated demyelinating lesion in the CNS,¹ although other cases of neuropathies with IgM anti-NF155 Ab have been described with various heterogeneous characteristics.^4,-,7 Second, the patient presented an IgM-MGUS, an immune disease, and an antibody with IgM isotype, as in anti-MAG neuropathies, and chronic ataxic neuropathy, ophthalmoplegia, IgM paraprotein, cold agglutinins, and disialosyl antibodies, in which this pathophysiologic link is already known. Finally, an enhancement and prolongation of experimental autoimmune neuritis has been reported in rats after injection of anti-neurofascin IgM, suggesting a pathogenicity of these IgM anti-NF155 Ab.³

In published studies, several techniques have been used to detect IgM anti-NF155 Ab (e.g., cell-based assay [CBA], flow cytometry, ELISA, and Western blot), sometimes with unspecific rat-NF155, which can explain the clinical heterogeneity of patients, especially considering the possible false-positive results.^4,-,8 Some authors recommend another confirming technique (e.g., ELISA and immunohistochemistry) associated with CBA (the gold standard technique) because this technique yields a 5.6% false-positive rate in a cohort of 108 patients with inherited neuropathies; in addition, the authors advise against the use of rat-NF155 (leading to false-positive results) and recommend the use of human-NF155.⁸ Anti-CD20 is a classical treatment of multiple sclerosis and is sometimes effectively used in CIDP, especially with IgG4 anti-NF155, and has been found effective in CCPD.¹

Our study presents some limitations. Only 1 method of detection was used without confirming technique. Also, the search for IgM anti-NF155 Ab in the CSF was not performed, neither was nerve biopsy to investigate the presence of disruption of myelin paranodal loops. Moreover, the titers of IgM anti-NF155 Ab remained unchanged after treatment, despite clinical improvement.

In conclusion, this patient presented a CCPD with concomitant peripheral relapse and cervical myelitis leading to find isolated IgM anti-NF155 Ab and responded well to corticosteroids and rituximab. Prospective studies are necessary to demonstrate a pathophysiologic link between IgM anti-NF155 Ab and CCPD and assess the prevalence of this Ab in CCPD.