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

Abstract

Objectives: We aimed to define the clinical and serological characteristics of pan-neurofascin antibody-positive patients.

Methods: We tested serum from patients with suspected immune-mediated neuropathies for antibodies directed against nodal/paranodal protein antigens using a live cell-based assay and solid-phase platform. The clinical and serological characteristics of antibody-positive and seronegative patients were then compared. Sera positive for pan-neurofascin were also tested against live myelinated human stem cell-derived sensory neurons for antibody binding.

Results: 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% vs 26%), autonomic dysfunction (75% vs 13%) and respiratory involvement (88% vs 14%) were more common than in seronegative patients. Four patients died despite treatment with one or more modalities of standard immunotherapy (intravenous immunoglobulin, steroids and/or plasmapheresis), whereas the four patients who later went on to receive the B cell-depleting therapy rituximab then began to show progressive functional improvements within weeks, became seronegative and ultimately became functionally independent.

Conclusions: IgG₁ pan-neurofascin antibodies define a very severe autoimmune neuropathy. We urgently recommend trials of targeted immunotherapy for this serologically classified patient group.

Keywords: neuroimmunology; neuropathy.

Figure 1

Serological, radiological and histological findings. (A) Cell-based assays using HEK293T cells transiently transfected to overexpress neurofascin-155 (NF155) (upper panels) or neurofascin-186 (NF186) (lower panels). Neurofascin (red) expression in the cell membrane is revealed by a commercial polyclonal antibody, and colocalises with human IgG (green) after exposure to acute-phase serum from the patients described in this series. (B) IgG (green) from two pan-neurofascin antibody-positive patient sera (left, P1; right, P6) is deposited at the node of Ranvier (arrowhead) after exposure to myelinating co-cultures. Axons (neurofilament-heavy, NF200, blue) were also observed weakly labelled with punctate IgG deposition in P1. Neither nodal or axonal labelling was observed in sera from healthy controls (data not shown). Myelin basic protein (MBP, red) defines the myelinated internode. (C, D) MRI of the lumbar spine, with coronal short tau inversion recovery (C) and post-contrast T1 (D) sequences, shows diffuse symmetric thickening and enhancement of lumbosacral plexus nerve roots (arrowhead), and enhancement of paraspinal, psoas, pelvic and proximal leg skeletal muscles (arrow). (E) Nerve biopsy from P6 stained for NFP shows reduced numbers of NFP positive axons (more clearly seen in the inset panels), and dense patches of staining, consistent with axonal degeneration. ‘Near normal’ NFP staining (F) is shown for comparison.