Demyelination without nodo-paranodopathy: is there any

evidence?

L. MAGYService et Laboratoire de Neurologie

Centre de Référence "Neuropathies Périphériques Rares"

What is a nodo(paranodo)pathy?

• A neuropathy with lesions involving the node/paranode?

• A neuropathy with lesions starting at the node/paranode?

• Whatever the consequence are (demyelination or axon involvement)?

• A neuropathy involving specific structures of the node?

What is so specific to the nodal/paranodal structure?

Neurophysiological perspective

• Clustering of ion channels with high specificity

• High speed saltatory conduction

• Propensity to develop (reversible) conduction failure if targeted by any deleterious agent (toxins, immune attack)

Molecular perspective

• Clustering of specific proteins/glycolipids

• That are important to maintain the nodal/paranodalarchitecture

• Known from several KO animal models

• That are important for ion channel anchoring and proper axon/myelin interaction/maintenance

Uncini & Kuwabara JNNP 2015

Uncini & Kuwabara JNNP 2015

Physical perspective (not so far explored)• Physical constraints are likely to differ between

nodes/paranodes/juxtaparanodes/internodes

• A region of particular weakness at the axon/myelin interaction?

• Do antibodies/complement/immune cells have the same access to each compartment?

So, where does demyelination start (and end) in acquired (immune-mediated) demyelinating neuropathies?

The longitudinal vs transversal perspective• Most of the nerve samples are cut (and studied)

transversally for diagnostic purpose

• Advantages• People are used to see samples in this way!• A global view of the different nerve compartments• it's easier to check for fiber loss• It's (relatively easy to check for demyelination/remyelination

• Disadvantage• No clear view of some anomalies like axonal mitochondria AND

NODAL/PARANODAL region

The longitudinal vs transversal perspective• The "classic" teasing

From Dyck & Thomas 2005

The longitudinal vs transversal perspective• Electron microscopic examination may offer a much

clearer view of the node/paranode region

So, let's think in 3D!

Anti-MAG antibody associated neuropathy• Chronic demyelinating neuropathy of adulthood• IgM monoclonal gammopathy• Anti-Myelin Associated Glycoprotein antibodies

• Typically a sensory ataxic neuropathy

• Demyelination predominates in distal segments according to NCS

• Widening of myelin lamellae

The likely scenario of demyelination in anti-MAG neuropathy:Starting at paranode!

Demyelinating Guillain-Barrésyndrome• Defined by an acute (<1 month) ascending flaccid

paralysis followed by a plateau phase then a recovery phase of variable duration

• Frequently triggered by an infection (molecular mimicry demonstrated for C Jejuni)

• Nerve conduction findings suggestive of multifocal demyelination with axon loss

• Frequent albuminocytologic dissociation

Chronic inflammatory demyelinating polyradiculoneuropathy• A chronic acquired demyelinating neuropathy• The chronic counterpart of GBS

• Pathologically defined by segmental demyelination (macrophage-associated demyelination) with variable degree of axon loss

• Thought to be autoimmune in origin (mostly T cell-driven)

• Quite good response to immunotherapy

• Probably a heterogeneous condition

Whatever scenario (nodal attack or internodalpenetration of macrophages):

paranodal loops might be affected at any point

Conclusions

• The "longitudinal perspective" provides the opportunity to look differently at nerve fibers in the context of peripheral neuropathy

• In most of demyelinating neuropathies, the paranodal region seems to be involved at some point

• A definition of nodo-paranodopathy should take this into account