Neurofascin-155 Immunoglobulin Subtypes Clinicopathologic Associations and Neurologic Outcomes

Shahar Shelly, Christopher J. Klein, James P.B. Dyck, Pritikanta Paul, Michelle L. Mauermann, Sarah E. Berini, Benjamin Howe, James P. Fryer, Eati Basal, Hammami M. Bakri, Ruple S. Laughlin, Andrew McKeon, Sean J. Pittock, John Mills, Divyanshu Dubey

Research output: Contribution to journalArticlepeer-review


Background and Objective Multiple studies highlighting the diagnostic utility of neurofascin-155 (NF155)–immunoglobulin G4 (IgG4) in chronic demyelinating inflammatory polyradiculoneuropathy (CIDP) have been published. However, few studies comprehensively address the long-term outcomes or clinical utility of NF155–immunoglobulin M (IgM) or NF155–immunoglobulin G (IgG) in the absence of NF155-IgG4. We evaluated phenotypic and histopathologic specificity and differences in outcomes between these NF155 antibody isotypes or IgG subclasses. We also compare NF155-IgG4-seropositive cases to other seropositive demyelinating neuropathies. Methods Neuropathy patient sera at Mayo Clinic were tested for NF155-IgG4, NF155-IgG, and NF155-IgM autoantibodies. Demographic and clinical data of all seropositive cases were reviewed. Results We identified 32 NF155 cases (25 NF155-IgG-positive [20 NF155-IgG4-positive], 7 NF155-IgM-seropositive). NF155-IgG4-seropositive patients clinically presented with distal more than proximal muscle weakness, positive sensory symptoms (prickling, asymmetric paresthesia, neuropathic pain), and gait ataxia. Cranial nerve involvement (11/20 [55%]) and papilledema (4/12 [33%]) occurred in many. Electrodiagnostic testing (EDX) demonstrated demyelinating polyradiculoneuropathy (19/20 [95%]). Autonomic involvement occurred in 45% (n = 9, median composite autonomic scoring scale score 3.5, range 1–7). Nerve biopsies from the NF155-IgG4 patients (n = 11) demonstrated grouped segmental demyelination (50%), myelin reduplication (45%), and paranodal swellings (50%). Most patients needed second- and third-line immunosuppression but had favorable long-term outcomes (n = 18). Among 14 patients with serial EDX over 2 years, all except one demonstrated improvement after treatment. NF155-IgG-positive, NF155-IgG4-negative (NF155-IgG-positive) and NF155-IgM-positive patients were phenotypically different from NF155-IgG4-seropositive patients. Sensory ataxia, neuropathic pain, cerebellar dysfunction, and root/plexus MRI abnormalities were significantly more common in NF155-IgG4-positive compared to myelin-associated glycoprotein (MAG)–IgM neuropathy. Chronic immune sensory polyradiculopathy (CISP)/CISP-plus phenotype was more common among contactin-1 neuropathies compared to NF155-IgG4-positive cases. NF155-IgG4-positive cases responded favorably to immunotherapy compared to MAG-IgM-seropositive cases with distal acquired demyelinating symmetric neuropathy (p < 0.001) and had better long-term clinical outcomes compared to contactin-1 IgG (p = 0.04). Discussion We report long-term follow-up and clinical outcome of NF155-IgG4 cases. NF155-IgG4 but not IgM or IgG cases have unique clinical–electrodiagnostic signature. We demonstrate NF155-IgG4-positive patients, unlike classical CIDP with neuropathic pain and dysautonomia common at presentation. Long-term outcomes were favorable. Classification of Evidence This study provides Class III evidence that NF155-IgG4-seropositive patients, compared to patients with typical CIDP, present with distal more than proximal muscle weakness, positive sensory symptoms, and gait ataxia.

Original languageEnglish (US)
Pages (from-to)E2392-E2403
Issue number24
StatePublished - Dec 14 2021

ASJC Scopus subject areas

  • Clinical Neurology


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