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Archive for June, 2017

Anti-neurofascin-155 antibodies: dissecting peripheral nerve abnormalities in CIDP

20 Jun, 17 | by Dr Jose Manuel Matamala, JNNP web editor.


In the June JNNP issue, Koike and colleagues have reported the morphological changes in sural nerve biopsies of patients with chronic inflammatory demyelinating polyneuropathy (CIDP) who have autoantibodies against paranodal structures.

CIDP is an immune-mediated neuropathy that develops over 8 week, which manifests with progressive proximal and distal weakness and is associated with sensory disturbances. Clinically, CIDP encompasses a heterogeneous group of subtypes, including MADSAM, DADS, pure sensory CIDP, pure motor CIDP and more focal forms. In addition, treatment responses are varied, suggesting that the pathophysiological mechanisms involved in the disease are diverse. In recent years, the discovery of particular autoantibodies against nerve and glial structures has revolutionized the field.

In this study, the authors studied the morphological characteristics of sural nerve biopsies using light and electron microscopy techniques in 9 patients with CIDP how had anti-neurofascin-155 and 1 patient with anti-contactin-1 antibodies. The results were compared with 13 patients with CIDP who did not have autoantibodies. In the patients with anti-neurofascin-155 antibodies, the authors found a reduction in myelinated fibre density, without macrophage-mediated demyelination or onion bulbs. Segmental demyelination was also found in patients with large axonal degeneration. Moreover, electron microscopy of longitudinal sections showed detachment of the terminal myelin loop from the axonal membrane (figure 1), a finding that correlated with axonal degeneration.


Figure 1. CIDP with anti-neurofascin-155 antibodies. (A) Electron microscopy finding in longitudinal sections from patients with anti-neurofascin-155 antibodies. Large spaces were observed between the terminal loops and the axolemma (arrows). (B) Antibodies against NF155 disrupt paranodal morphology; NF155, neurofascin-155.










Myelinated peripheral nervous system fibres are divided into four compartments: (i) nodes, (ii) paranodes, (iii) juxtaparanodes and (iv) internodes. Each has a specific function in nerve physiology, essential for the safety of action potential propagation. Neurofascin-155 is expressed on the myelin side of the paranode and is attached to contactin-1 (axonal membrane), which is critical for axonal-Schwann cell interaction. The paranode compartment works as an isolator, which is crucial for saltatory conduction. From a pathological point of view, these autoantibodies produce detachment of myelin terminal loops, generating a leak in current and conduction failure, and secondary axonal degeneration. The morphological characterization of CIDP patients with anti-neurofascin-155 antibodies is a crucial step in the understanding of this complex disease and for future development of targeted treatments. Patients with such autoantibodies are known to display particular clinical features, such us sensory ataxia and tremor, and have a poor response to IVIg treatment. These peripheral neuropathies that compromise primarily the nodal and paranodal regions have recently been called “nodopathy”, a novel concept, that allows the classification of this unique group of patients. Further studies should be focused in development of optimal treatments to avoid axonal degeneration due to axo-glial disjunction.


As such, this is a very interesting study, which provides valuable insights into the pathophysiology of CIDP with autoantibodies against paranodal structures.







Corpus callosum dysfunction in ALS: more than just connecting two sides

2 Jun, 17 | by Dr Jose Manuel Matamala, JNNP web editor.


In the May JNNP issue, Zhang and colleagues have published a study investigating the changes in structural and functional connectivity in patients with ALS.

ALS is one of the most complex neurodegenerative diseases, which affects the motor system. It is characterized by concomitant degeneration of the upper and lower motor neurons, producing progressive weakness and muscle atrophy. Even though it was initially conceived that just the motor cortex and anterior horn cells were affected, in recent years substantial evidence supports the compromise of extra-motor brain structures, such us the corpus callosum (CC).


In this study, the authors have explored interhemispheric connectivity in 38 patients with ALS and 35 controls using diffusion tensor imaging (DTI) and resting state functional MRI (rfMRI). Indices of interhemispheric structural and functional neural connectivity were compared between groups. The rfMRI revealed a reduction in homotopic connectivity in ALS patients, specifically between the precentral and postcentral gyrus, the paracentral lobule, the superior temporal gyrus, the middle cingulate gyrus, the putamen and the superior parietal lobule, suggesting an extensive dysfunction in interhemispheric functional connectivity. In addition, DTI analysis in ALS patients showed a reduction in structural connectivity through the CC, specifically affecting subregions II, III and V. Finally, the combination of structural and functional data suggest that the central motor cortical interhemispheric fibres were the most affected in ALS.


Abnormal interhemispheric homotopic connectivity in ALS


This interesting article extends and confirms previous results that suggest dysfunction in interhemispheric communication, proposing a preferential involvement of the CC in ALS. Previous DTI studies in ALS have shown a reduction on fractional anisotropy in the CC extending to the primary motor cortex. On the other hand, electrophysiological studies have also supported the compromise of the CC. Specifically, transcranial magnetic stimulation (TMS) has provided evidence of functional impairment of the CC, showing a reduction in the interhemispheric inhibition. Clinically, a typical feature of ALS is focal clinical onset and regional spreading of neuronal degeneration. These clinical features indicate that neurodegeneration in ALS is an orderly propagating process, which seems to share the signature of a seeded self-propagation, such as prions. Interestingly, TDP-43, the major pathological protein in ALS, forms insoluble fibrillar aggregates in vitro and theoretically can act as seeds to trigger the aggregation of native proteins. This cumulative evidence allows us to question the contribution of the CC in spreading of disease and its potential use as a therapeutic target in the future.








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