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Correspondence to Dr Janev Fehmi, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford OX3 9DU, UK; [email protected]
Introduction
Overview
The so called ‘inflammatory’ neuropathies have historically been classified on clinical and electrophysiological grounds, though this categorisation does not necessarily reflect common underlying pathogenic mechanisms or predict response to treatment. Antibodies targeting the node and paranode of myelinated peripheral nerves predominantly occur in patients initially meeting diagnostic criteria for Guillain-Barré syndrome (GBS) or chronic inflammatory demyelinating polyneuropathy (CIDP), often in combination with additional clinical features and poor response to conventional therapies. There is increasing evidence that these ‘nodo-paranodopathies’ may better be considered as pathologically distinct disease entities. They may have limited evidence of inflammation or demyelination, and more targeted immunotherapies, such as the B cell depleting monoclonal antibody rituximab, may be of greater benefit. Increasing knowledge of the origins and immunopathogenic mechanisms of these antibodies will undoubtedly provide insight into the determinants of clinical phenotype and response to treatment in these disabling but treatable disorders.
Molecular targets of the node of Ranvier
The node and paranode are highly specialised domains of the peripheral nerve. Here, a dense array of communicating proteins facilitate adhesion of myelin to axon and help maintain the correct localisation of voltage-gated sodium and potassium channels (figure 1), thus promoting effective saltatory conduction. Predominantly immunoglobulin G4 (IgG4) antibodies, specifically targeting nodal neurofascin 186 (NF186), or the paranodal molecules neurofascin 155 (NF155), contactin-1 (CNTN1) and contactin-associated protein-1 (Caspr1) have recently been identified in phenotypically distinct groups of patients.
The practicalities of testing for paranodal/nodal antibodies
Who and when to test
We suggest that it may be more appropriate to base therapeutic choices in patients presenting with a rapidly progressive neuropathy on suspicion or identification of the likely pathological cause, rather than solely relying on ‘time to nadir’, as is usually the case in distinguishing GBS (within 4 weeks) from CIDP (over 8 weeks). The umbrella terms GBS and CIDP encompass numerous subgroups and ‘atypical’ variants, in many cases reflecting pathologically distinct processes. Identifying these as early as possible should enable the prompt initiation of the most appropriate treatment with the aim of preventing further disability. Serological testing for paranodal/nodal antibodies (PNAbs) is increasingly accessible, and these assays now run weekly in our laboratory....