Autoimmune nodo-paranodopathies of peripheral nerve: the concept is gaining ground

Abstract

Peripheral neuropathies are classified as primarily demyelinating or axonal. Microstructural alterations of the nodal region are the key to understand the pathophysiology of neuropathies with antibodies to gangliosides and the new category of nodo-paranodopathy has been proposed to better characterise these disorders and overcome some inadequacies of the dichotomous classification. Recently, the research in autoimmune neuropathies has been boosted by reports of patients carrying immunoglobulin G4 antibodies against paranodal axo-glial proteins with distinct phenotypes and showing loss of transverse bands, terminal myelin loop detachment, nodal widening and axonal loss. These patients have been classified up to now as chronic inflammatory demyelinating polyradiculoneuropathy but, in our opinion, better fit into the nodo-paranodopathy category because nerve injury is due to dismantling of the paranode, segmental de-remyelination is absent and the pathogenic mechanism is not inflammatory. Evidence from nerve conductions and electron microscopy studies in patients and mutant animal models can reconcile the apparent contrast between the electrophysiological 'demyelinating' features, explainable just by the paranodal involvement and the axonal pathology. These patients broaden the autoimmune nodo-paranodopathy category and re-emphasise the usage of the term that pointing to the site of nerve injury reminds specific pathophysiological mechanisms, reconciles contrasting electrophysiological and pathological findings, and avoids misdiagnosis and taxonomic confusion. In our opinion, the nodo-paranodopathy term more adequately classifies the peripheral nerve disorders due to an autoimmune attack directed and limited to the nodal region integrating the traditional classification of peripheral neuropathies.

Antibodies to neurofascin, contactin-1, and contactin-associated protein 1 in CIDP

“…Analysis of myelinated fibers in the skin biopsy of patients with anti-Nfasc155, CNTN1, or Caspr1 IgG4 antibodies showed morphological changes of the nodes of Ranvier, including elongation of the node and loss of neurofascin and Caspr1 staining at paranodes, which were absent or less prominent in seronegative CIDP cases or in the case with anti-Nfasc155 antibodies of an undetectable isotype. These data add to other recent histopathologic and neurophysiologic observations in patients with antibodies to nodal/paranodal proteins 14,25 and indicate that isotype determination appears to be crucial to correctly identify such patients and to guide treatment.…”

Anti–neurofascin-155 IgG4 antibodies prevent paranodal complex formation in vivo

“…In keeping with this view, sural nerve biopsies from CIDP patients with anti-Nfasc155 IgG4 revealed specific alterations at paranodal regions with a loss of septate-like junctions (23)(24)(25), but did not show evidence of macrophage-mediated demyelination. The pathogenic mechanisms responsible for conduction slowing in patients with anti-Nfasc155 IgG4 thus appear different from those implicated in other CIDP patients, and further support the existence of nodo-paranodopathy (41). It is possible that paranodal demyelination, as observed in sural nerve biopsies (24,25), may also participate in conduction slowing or loss in patients with anti-Nfasc155 IgG4.…”

The conceptual introduction of the “demyelinating Schwann cell” in peripheral demyelinating neuropathies

“…The destruction of axo-glial interactions around nodal and paranodal regions alters the normal distribution of voltage-gated sodium and potassium channels, which are essential for the generation of action potentials in the nodes of Ranvier, leading to abnormal conduction of the electrical impulse (Arroyo, Sirkowski, Chitale, & Scherer, 2004;Doppler et al, 2015;Hafer-Macko et al, 1996;Pollard & Armati, 2011;Salzer et al, 2008). One of the main mechanisms that leads to paranodal demyelination is mediated by autoantibodies (Dalakas, 2011;Devaux, 2012;Querol, Devaux, Rojas-Garcia, & Illa, 2017;Uncini & Vallat, 2017). Indeed several recent studies have revealed the presence of autoantibodies against paranodal proteins such as neurofascin-155…”