Neurofascin-155 Immunoglobulin Subtypes: Clinicopathologic Associations and Neurologic Outcomes

Background and objective: Multiple studies highlighting diagnostic utility of neurofascin 155 (NF155)-IgG4 in chronic demyelinating inflammatory polyradiculoneuropathy (CIDP) have been published. However, few studies comprehensively address the long-term outcomes, or clinical utility of NF155-IgM or NF155-IgG, in the absence of NF155-IgG4. In this study we evaluate phenotypic and histopathological 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: In this study, neuropathy patient sera seen 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 patients (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 CASS 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 2^nd and 3^rd 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 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 patients. NF155-IgG4 but not IgM or IgG patients 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 typical CIDP patients, present with distal more than proximal muscle weakness, positive sensory symptoms, and gait ataxia.