Elsevier

Clinical Neurophysiology

Volume 124, Issue 10, October 2013, Pages 1928-1934
Clinical Neurophysiology

Review
Nodo-paranodopathy: Beyond the demyelinating and axonal classification in anti-ganglioside antibody-mediated neuropathies

https://doi.org/10.1016/j.clinph.2013.03.025Get rights and content

Highlights

  • Anti-ganglioside antibody-mediated neuropathies share a common pathogenic mechanism of dysfunction/disruption at the node of Ranvier.

  • The classification of polyneuropathies into demyelinating or axonal may generate confusion in the electrophysiological diagnosis of neuropathies with anti-ganglioside antibodies.

  • To overcome the classification difficulties and to focus on the site of nerve injury, we propose the new category of nodo-paranodopathy.

Abstract

In some anti-ganglioside antibody-mediated neuropathies, human and experimental data suggest a common pathogenic mechanism of dysfunction/disruption at the node of Ranvier resulting in a pathophysiologic continuum from transitory nerve conduction failure to axonal degeneration. The traditional classification of polyneuropathies into demyelinating or axonal may generate some confusion in the electrophysiological diagnosis of Guillain–Barré syndrome subtypes associated with anti-ganglioside antibodies. The axonal forms show, besides axonal degeneration, promptly reversible nerve conduction failure. This may be interpreted, by a single electrophysiological study, as demyelinating conduction block or distal axonal degeneration leading to errors in classification and in establishing prognosis. Moreover the term axonal may be misleading as it is commonly associated to axonal degeneration and not to a transitory, promptly reversible, dysfunction of the excitable axolemma. To focus on the site of nerve injury and overcome the classification difficulties, we propose the new category of nodo-paranodopathy which seems appropriate to various acute and chronic neuropathies associated with anti-ganglioside antibodies and we think better systematizes the neuropathies characterized by an autoimmune attack targeting the nodal region.

Introduction

Polyneuropathies are traditionally classified into demyelinating or axonal, according to whether the pathologic process affects primarily the myelin/Schwann cells or the axon. This classification has electrophysiological correlates employed for diagnosis and to establish prognosis. Acute inflammatory demyelinating polyradiculoneuropathy (AIDP), a primary demyelinating neuropathy, it is pathologically characterized by segmental demyelination, which can begin at the node of Ranvier but usually extends to the whole internode, with variable lymphocytic inflammation and axonal degeneration (Asbury et al., 1969). AIDP is electrophysiologically characterized by nerve conduction slowing, conduction block (CB) and excessive temporal dispersion of compound muscle action potentials (CMAPs). Motor conduction slowing usually progresses up to 6–10 weeks and the resolution of CB is associated with temporal dispersion of CMAP due to remyelinating slow conducting components (Albers et al., 1985, Albers and Kelly, 1989). In addition to AIDP, Guillain–Barré syndrome (GBS) includes primary axonal polyneuropathies, acute motor axonal neuropathy (AMAN) and acute motor-sensory axonal neuropathy (AMSAN), which are strongly associated with autoantibodies to gangliosides such as GM1 or GD1a (Griffin et al., 1996a, Ho et al., 1999, Yuki et al., 1999, Ogawara et al., 2000). Whether anti-GM1 or -GD1a antibodies are present only in the axonal subtypes or may be found in AIDP has been debated for long time (Hadden et al., 1998, Ho et al., 1995, Sekiguchi et al., 2012). Related to this is the uncertainty in predicting prognosis as some studies showed that anti-GM1 or -GD1a antibodies were associated with extensive axonal loss and poor outcome whereas other studies showed no correlation (Van den Berg et al., 1992, Gregson et al., 1993, Vriesendorp et al., 1993, Rees et al., 1995). The key for the interpretation of this confused matter is the recognition that besides Wallerian-like degeneration, AMAN (but also other GBS subtypes) with antibodies to gangliosides are characterized electrophysiologically by CB/slowing, initially mimicking demyelination, which promptly resolves without the development of temporal dispersion (Kuwabara et al., 1998, Capasso et al., 2003).

In this review, which is also a personal view, we attempt to reconcile the contrasting results in the field of anti-ganglioside antibody-mediated neuropathies on the basis of the common pathogenic mechanism of primary dysfunction/disruption at the node of Ranvier resulting in a pathophysiological continuum from a transitory nerve conduction failure to axonal degeneration. To focus on the site of nerve injury and overcome the classification difficulties of these neuropathies we propose the new category of nodo-paranodopathy.

Section snippets

Acute neuropathies with anti-ganglioside antibodies

In the last three decades, the literature on dysimmune neuropathies has been dominated by studies on clinical correlates and pathophysiology of neuropathies associated with antibodies to gangliosides (Willison and Yuki, 2002). Gangliosides, composed of a ceramide attached to one or more sugars (hexoses) and containing sialic acid (N-acethylneuraminic acid) linked to the oligosaccharide core, are important components of the peripheral nerves. GM1, GD1a, GD1b, GT1a and GQ1b differ with regard to

Nodes and paranodes: targets of anti-ganglioside antibodies

The myelinated axons are organized in distinct domains including nodes of Ranvier, paranodes, juxtaparanodes, and internodes (Supplementary Figure S2). Specific molecular complexes characterize each of these domains (for more details, see Poliak and Peles, 2003). The nodes have the highest density in voltage-gated sodium (Nav) channels, providing a site for the regeneration and rapid propagation of the action potentials. Several mechanisms are responsible for the concentration of Nav channels

Nodo-paranodopathy: a new category to solve classification difficulties

The traditional classification of neuropathies into axonal or demyelinating might generate confusion in diagnosing GBS subtypes. AMAN is classified as an axonal neuropathy because the primary attack is directed towards the excitable nodal axolemma leading ultimately to axonal degeneration. However the term axonal may be misleading as in the common neurological knowledge is linked to Wallerian-like degeneration, evokes poor prognosis, and few are familiar or agree on an axonal scenario

Examples of nodo-paranodopathies

Fig. 1 summarizes the dysimmune neuropathies associated with anti-ganglioside antibodies that can be classified as nodo-paranodopathies and the evidence supporting this categorization. Results of human and experimental studies indicate that AMAN is the prototype of nodo-paranodopathies (Fig. 1), and that AMSAN and acute sensory ataxic neuropathy also belong to this category. RCF has been recognized in both motor and sensory fibers in AMSAN patients with IgG anti-GM1 antibodies (Capasso et al.,

Diagnosis of nodo-paranodopathies

The diagnosis of an acute nodo-paranodopathy, in the appropriate clinical setting, is mainly electrophysiological and can be made only by serial recordings. The following patterns are consistent with an acute nodo-paranodopathy: (1) CB or reduced distal CMAP amplitude which promptly resolves without the development of excessive temporal dispersion of CMAPs; (2) CB followed by low amplitude CMAPs from all nerve stimulation sites without persistent features of demyelination and (3) low amplitude

Conclusions and future directions

Evidence in humans and animal models point to dysfunction/disruption of the nodal region as a common pathway in acute, and possibly chronic, neuropathies associated with antibodies to gangliosides. The term nodo-paranodopathy better reflects, in our opinion, the current understanding of the pathophysiology and better systematizes these conditions than the traditional classification into demyelinating or axonal.

Future directions will be to establish reliable quantitative neurophysiologic

Acknowledgements

We thank Dr. Y.-C. Chan (Department of Medicine, National University Hospital, Singapore); Dr. N. Kokubun (Department of Neurology, Dokkyo Medical University, Japan); Dr. N. Shahrizaila (Department of Medicine, University of Malaya, Malyasia); Dr. T. Umapathi (Department of Neurology, National Neuroscience Institute, Singapore) for their critical reading of the manuscript.

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