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.