IgG1 pan-neurofascin antibodies identify a severe yet treatable neuropathy with a high mortality

Fehmi, J.; Davies, A. J.; Walters, R. J.; Lavin, T.; Keh, R.; Rossor, A. M.; Munteanu, T.; Delanty, N.; Roberts, R.; Bäumer, D.; Lennox, G.; Rinaldi, S.

Guillain-Barre syndrome and chronic inflammatory demyelinating polyneuropathy are umbrella terms for a number of pathologically distinct diseases involving disabling, immune-mediated injury to peripheral nerves. Current treatments involve non-specific immunomodulation. Prospective identification of patients with specific disease mechanisms should increasingly inform the use of more targeted disease modifying therapies and may lead to improved outcomes. In this cohort study, we tested serum for antibodies directed against nodal/paranodal protein antigens. The clinical characteristics of antibody positive and seronegative patients were then compared. Eight patients with IgG1-subclass antibodies directed against both isoforms of the nodal/paranodal cell-adhesion molecule neurofascin were identified. All developed rapidly progressive tetraplegia. Cranial nerve deficits (100% versus 26%), autonomic dysfunction (75% versus 13%) and respiratory involvement (88% versus 14%) were more common than in seronegative patients. The response to intravenous immunoglobulin, steroids and/or plasmapheresis was poor. Four patients received the B-cell-depleting therapy rituximab. After several weeks, these patients began to show progressive functional improvements, became seronegative, and were ultimately discharged home. Four patients who did not receive rituximab did not improve and died following the development of infectious complications and/or withdrawal of intensive care support. IgG1 pan-neurofascin antibodies define a very severe autoimmune neuropathy. We urgently recommend trials of targeted immunotherapy for this serologically-classified patient group.