Immunoadsorption and Plasma Exchange in Seropositive and Seronegative Immune-Mediated Neuropathies

Abstract

The inflammatory neuropathies are disabling conditions with diverse immunological mechanisms. In some, a pathogenic role for immunoglobulin G (IgG)-class autoantibodies is increasingly appreciated, and immunoadsorption (IA) may therefore be a useful therapeutic option. We reviewed the use of and response to IA or plasma exchange (PLEx) in a cohort of 41 patients with nodal/paranodal antibodies identified from a total of 573 individuals with suspected inflammatory neuropathies during the course of routine diagnostic testing (PNAb cohort). 20 patients had been treated with PLEx and 4 with IA. Following a global but subjective evaluation by their treating clinicians, none of these patients were judged to have had a good response to either of these treatment modalities. Sequential serology of one PNAb+ case suggests prolonged suppression of antibody levels with frequent apheresis cycles or adjuvant therapies, may be required for effective treatment. We further retrospectively evaluated the serological status of 40 patients with either Guillain-Barré syndrome (GBS) or chronic inflammatory demyelinating polyneuropathy (CIDP), and a control group of 20 patients with clinically-isolated syndrome/multiple sclerosis (CIS/MS), who had all been treated with IgG-depleting IA (IA cohort). 32 of these patients (8/20 with CIDP, 13/20 with GBS, 11/20 with MS) were judged responsive to apheresis despite none of the serum samples from this cohort testing positive for IgG antibodies against glycolipids or nodal/paranodal cell-adhesion molecules. Although negative on antigen specific assays, three patients' pre-treatment sera and eluates were reactive against different components of myelinating co-cultures. In summary, preliminary evidence suggests that GBS/CIDP patients without detectable IgG antibodies on routine diagnostic tests may nevertheless benefit from IA, and that an unbiased screening approach using myelinating co-cultures may assist in the detection of further autoantibodies which remain to be identified in such patients.

Keywords: Guillain-Barré syndrome; Inflammatory neuropathy; chronic inflammatory demyelinating polyneuropathy; immunoadsorption; multiple sclerosis; paranodal antibodies; plasma exchange; plasmapheresis.

Figure 1

Physician-reported subjective evaluation of response to plasma exchange or immuno-adsorption in paranodal antibody positive and negative patients. Paranodal antibody positive patients treated with (A) plasma exchange (n = 17), (B) immunoadsorption (n = 4), or (C) either modality (n = 21), compared to (D) paranodal antibody negative patients (n = 33) (all treated with plasma exchange).

Figure 2

Serological results of NF155 antibody positive patient at baseline and during IA treatment. (A) Serum contains IgG (green) which binds to the cell membrane of NF155-transfected HEK293T cells, and co-localises with a commercial pan-neurofascin antibody (red). No signal is seen with NF186 or CNTN1/Caspr1-transfected cells. (B) The predominant IgG subclass of the NF155 antibodies is IgG4, with IgG1>IgG2 also represented. (C) The antibody signal intensity at 1:100 before, during and immediately after the first cycle of IA shows a progressive decline. (D) NF155 antibody titre (red) and total IgG levels (blue) over 2 cycles of IA, before and after rituximab.

Figure 3

Antibody titres and outcome/disability measures during treatment of a patient with an NF155-antibody-mediated neuropathy. (A) Patient global rating of change after treatment with dexamethasone, IVIg, IA and rituximab. (B) NF155 antibody titre. (C) Inflammatory neuropathy Rasch-built Overall Disability Score. (D) Sensory sum score. (E) Overall neuropathy limitations score.

Figure 4

Nodal/paranodal cell-based assays. (A) MS/CIS eluate weakly positive on the neurofascin-155 CBA at 1:100 (Score 2+, end-point titre 1:200) and (B) negative on the neurofascin-186 CBA. (C) Strong positive at 1:100 (Score 4+, end-point titre 1:3200) from the antibody positive CIDP cohort shown for comparison.

Figure 5

IgG deposition in myelinated co-cultures. (A) IgG concentration of dilution-adjusted eluates used for screening on myelinated cultures. (B–D) Immunofluorescence images of IgG binding patterns in myelinating co-cultures of IA eluates (1:50) from three patients with neurological disease identified in the screening assay: B) GBS (patient 07), C) CIDP (patient 11), and D) MS/CIS (patient 13) (arrow indicates IgG deposition at the node of Ranvier). (E) IgG labelling in myelinated co-cultures of serum (1:50) sampled from the CIDP (patient 11) before (Pre-treatment) and after IA (Follow-up). Note all IgG immunoreactivity is lost at follow-up. NF200, neurofilament 200; MBP, myelin basic protein.