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Disruption of nodes of Ranvier and paranodal region. Longitudinal sections of large myelinated fibres exhibiting lengthening of nodes of Ranvier (white arrows in A and B; normal -black arrowhead in A) and myelin splitting at paranodes (black arrows in A and B). Compare with normal width of nodes of Ranvier (black arrowhead in A). Remnants of a degenerating myelinated fibre with myelin debris lying in ovoids (white arrowhead in B). There is no evidence of segmental demyelination. Semi-thin plastic section, thionine and basic fuchsin stain, bar = 37m.
Source publication
Background:
Miller Fisher syndrome is a regional variant of Guillain-Barre syndrome with a characteristic clinical triad of ophthalmoplegia, areflexia and ataxia and occasionally distal limb sensory loss. 90% of patients have associated antibodies to the GQ1b ganglioside. The pathophysiology of antibody-mediated peripheral nerve impairment remains...
Citations
... Interestingly, similar findings have been reported in patients with IgG4 antibodies to neurofascin-155, contactin-1, and Caspr (14). In our study, 2 patients had antibodies to disialosyl gangliosides, which are expressed on paranodal axolemma (12,39,40). Three patients with anti-MAG neuropathy were also grouped into cluster 2. MAGs are present on terminal myelin loops (paranode) and Schmidt-Lantermann incisures (internode). ...
Immune-mediated neuropathies are a heterogenous group of inflammatory peripheral nerve disorders. They can be classified according to the domain where the autoimmune process begins: the internode, paranode, or node. However, conventional diagnostic tools, electrodiagnosis (EDX), and autoantibody testing do not fully address this issue. In this institutional cohort study, we investigated the value of dermal myelinated fiber analysis for target domain-based classification. Twenty-seven consecutive patients with immune-mediated neuropathies underwent skin biopsies. The sections were stained with antibodies representative of myelinated fiber domains and were scanned using a confocal microscope. Clinical and pathological features of each patient were reviewed comprehensively. Quantitative morphometric parameters were subjected to clustering analysis, which stratified patients into 3 groups. Cluster 1 ("internodopathy") was characterized by prominent internodal disruption , intact nodes and paranodes, demyelinating EDX pattern, and absence of nodal-paranodal antibodies. Cluster 2 ("paranodopathy") was characterized by paranodal disruption and corresponding antibodies. Morphological changes were restricted to the nodes in cluster 3; we designated this cluster as "nodopathy." This report highlights the utility of skin biopsy as a diagnostic aid to gain pathogenic insight and classify patients with immune-mediated neuropathies.
... Otherwise, in 2014, Yuki and Uncini suggested that acute and chronic ataxic peripheral neuropathies (such as MFS or CANDA) might belong to a clinical spectrum in which they included some other peripheral neuropathies associated with anti-GM1 antibodies (such as AMAN or AMSAN); they hypothesized that such peripheral neuropathies could be characterized by a common pathophysiological mechanism and actually classified them as 'nodo-paranodopathies' rather than 'axonal' or 'demyelinating' peripheral neuropathies; but, in their paper, Yuki and Uncini did not show any microscopical evidence of the nodal or paranodal disruption [1]. In 2014, Miller et al described, for the first time, on semi-thin sections of a nerve biopsy of a MFS patient, that macrophages invade the paranodal area between the axon and the axolemma, producing myelin splitting which causes conduction failureF [11]. In our two cases, macrophages disrupting the paranodes were ultrastructurally identical to those which dissociate the internodal myelin lamellae, as it has been described by many authors in acute inflammatory demyelinating polyradiculoneuropathy (AIDP, GBS) and typical CIDP [12]. ...
Objective
To study the pathological characteristics of acute and chronic ataxic peripheral neuropathy at the level of the node of Ranvier.
Study design and setting
We performed the pathological study (nerve biopsy of a sural nerve) of two patients, one with an acute form of ataxic peripheral neuropathy called ‘Miller Fisher syndrome’ (MFS), the other one with a chronic form called ‘chronic ataxic neuropathies with disialosyl antibodies’ (CANDA).
Results
A dysimmune process involving peripheral nerves commences in myelin, at the internodal area or/and in the paranodal and nodal regions. Our electron microscopic observations suggest that both patients present lesions in favor of a paranodopathy.
Conclusion
Many of the immune-mediated peripheral neuropathies are now classified as nodoparanodopathies. This subtype of auto-immune neuropathy may present various clinical phenotypes such as ‘Acute Motor Axonal Neuropathy’ (AMAN), ‘Acute Motor and Sensory Neuropathy’ (AMSAN) or ‘chronic inflammatory demyelinating polyradiculoneuropathy’ (CIDP), and are associated with anti-disialosyl antibodies. In our two cases, some paranodes seem to be associated with macrophages and we hypothesized that these lesions are in favor of a complement-mediated dysfunction/disruption of the nodal region due to disialosyl antibodies against gangliosides which are mainly located at the level of the axolemma of the paranode.
... The potential mechanisms of dysesthesia associated with anti-GQ1b antibodies has been supported by previous studies in patients with FS, in which the decreased level of sensory nerve action potential in NCS and the axonal damage in a nerve biopsy was demonstrated. 12,13 In addition, this was the first study to show that consciousness disturbance exhibited an earlier improvement in anti-GQ1b antibody-positive BBE compared with antibody-negative BBE. ...
Objective:
To clarify the differences in clinical characteristics between anti-GQ1b antibody-positive and antibody-negative Bickerstaff brainstem encephalitis (BBE).
Methods:
We compared 73 anti-GQ1b antibody-positive BBE cases with 10 antibody-negative cases. Their clinical information and sera were collected from various hospitals throughout Japan between 2014 and 2017. The anti-GQ1b antibody was examined in each serum sample by ELISA.
Results:
We identified the distinctive findings of anti-GQ1b antibody-positive BBE compared with the antibody-negative cases: (1) upper respiratory infection and sensory disturbance were more common, (2) the cell count or protein concentration was lower in the CSF, (3) the abnormal findings on brain MRI were less, and (4) the consciousness disturbance disappeared earlier. Furthermore, IV immunoglobulin (IVIG) was more frequently administered to the anti-GQ1b antibody-positive cases of BBE compared with the antibody-negative cases.
Conclusions:
BBE with anti-GQ1b antibody has homogeneous features. IVIG is the treatment used prevalently for BBE with anti-GQ1b antibody in Japan.
... Anti-ganglioside antibodies attack nerve axon primarily.) 34,35 whereas AIDP and AMAN shared common clinical symptom (e.g. limb motor weakness) 2,36 . ...
Guillain–Barré syndrome (GBS) is an acute fatal progressive disease caused by autoimmune mechanism mainly affecting peripheral nervous system. Although the syndrome is clinically sub-classified into several variants, specific biomarker and exact pathomechanism of each subtypes are not well elucidated yet. In current study, integrative metabolomic and lipidomic profiles were acquisitioned from cerebrospinal fluid samples of 86 GBS from three variants and 20 disease controls. And the data were systematically compared to our previous result on inflammatory demyelination disorders of central nervous system (IDDs) and healthy controls. Primary metabolite profiles revealed unique metabolic traits in which 9 and 7 compounds were specifically changed in GBS and IDD, respectively. Next, the biomarker panel with 10 primary metabolites showed a fairly good discrimination power among 3 GBS subtypes, healthy controls, and disease controls (AUCs ranged 0.849–0.999). The robustness of the biomarker panel was vigorously validated by multi-step statistical evaluation. Subsequent lipidomics revealed GBS variant-specific alteration where the significant elevations of lyso-phosphatidylcholines and sphingomyelins were unique to AIDP (acute inflammatory demyelinating polyneuropathy) and AMAN (acute motor axonal neuropathy), respectively. And metabolome-wide multivariate correlation analysis identified potential clinical association between GBS disability scale (Hughes score) and CSF lipids (monoacylglycerols, and sphingomyelins). Finally, Bayesian network analysis of covarianced structures of primary metabolites and lipids proposed metabolic hub and potential biochemical linkage associated with the pathology.
... As pure Fisher syndrome is relatively benign, post-mortem studies are not available and biopsies of affected parts of the peripheral nervous system are impractical, so that the underlying pathology has not been extensively studied. In one pathological case report, sural biopsy did show lengthening of nodes of Ranvier, myelin splitting and macrophage internodal axonal invasion without any features of segmental demyelination (Miller et al., 2014). GQ1b has been localized by immunohistology with anti-GQ1b antibodies to both paranodal Schwann cell membranes and motor nerve terminals of human extraocular nerves (Chiba et al., 1997;Liu et al., 2009), indicating that both sites may be vulnerable to immune attack. ...
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In 1916, during the Battle of the Somme, Guillain, Barré and Strohl described two soldiers with severe generalised weakness and loss of sensation. Hughes et al . mark the centenary of this first account of ‘Guillain-Barré syndrome’ by examining its subtypes, pathophysiology and epidemiology, including recent Zika virus-associated epidemics.
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In 1916, during the Battle of the Somme, Guillain, Barré and Strohl described two soldiers with severe generalised weakness and loss of sensation. Hughes et al . mark the centenary of this first account of ‘Guillain-Barré syndrome’ by examining its subtypes, pathophysiology and epidemiology, including recent Zika virus-associated epidemics.
... If the immunopathological process progresses, axonal degeneration may occur. There is growing opinion that many features of the antiganglioside antibody-mediated neuropathies can be encompassed in a new categorisation referred to as the nodo-paranodopathy [32,33]. As our experimental knowledge grows, it is becoming increasing difficult to clinically and electrophysiologically distinguish reversible axonal conduction block from that caused by paranodal demyelination, especially since both may occur concurrently in the same nerve fibre. ...
A wide range of autoantibodies have been described in immune-mediated nerve disorders that target glycans borne by glycolipids and glycoproteins enriched in the peripheral nerves. Their use as diagnostic biomarkers is very widespread, despite some limitations on sensitivity and specificity, and the lack of standardized assays and access to quality assurance schemes. Although many methods have been applied to measurement, ELISA, in the form of commercial kits or in-house assays, still remains the most widely available and convenient assay methodology.
Some antibodies have a particularly robust and widely appreciated clinical significance. Thus, the anti-MAG IgM antibodies that are found in IgM paraprotein related neuropathies define a relatively uniform clinical and prognostic phenotype. IgG antibodies against gangliosides GM1 and GD1a are strongly associated with motor axonal variants of Guillain-Barré syndrome, and anti-GQ1b with Miller Fisher syndrome. In other chronic neuropathies, antibodies against disialylated gangliosides including GD1b and GD3 are detected in ataxic neuropathies, usually associated with an IgM paraprotein, and antibodies against GM1 and the complex GM1:GalC are frequently found in multifocal motor neuropathy. Unfortunately, autoantibodies strongly associated with the diagnosis of chronic inflammatory demyelinating polyneuropathies and with demyelinating forms of GBS are still lacking.
Identification of autoantibodies that map onto a specific clinical phenotype not only allows for improved classification, but also provides better understanding of the pathophysiology of inflammatory neuropathies and the potential for therapeutic interventions.
... 48 49 The sensory nerve biopsy of an anti-GQ1b ganglioside positive patient with Miller-Fisher syndrome showed lengthening of nodes of Ranvier, myelin splitting and macrophage invasion of the internodal axon without any features of demyelination, strikingly similar to the pathological features found in AMAN motor fibres. 50 Chronic ataxic neuropathy patients with disialosyl antibodies may have a relapsing remitting clinical course; relapses have been reported to improve and resolve within a few days with immunotherapy and in some patients persistent multifocal motor CB has been also described. 51 All these findings suggest that neuropathies with antiganglioside antibodies belong to a continuous spectrum with a common pathophysiological mechanism focused to the nodal region. ...
Peripheral nerve diseases are traditionally classified as demyelinating or axonal. It has been recently proposed that microstructural changes restricted to the nodal/paranodal region may be the key to understanding the pathophysiology of antiganglioside antibody mediated neuropathies. We reviewed neuropathies with different aetiologies (dysimmune, inflammatory, ischaemic, nutritional, toxic) in which evidence from nerve conductions, excitability studies, pathology and animal models, indicate the involvement of the nodal region in the pathogenesis. For these neuropathies, the classification in demyelinating and axonal is inadequate or even misleading, we therefore propose a new category of nodopathy that has the following features: (1) it is characterised by a pathophysiological continuum from transitory nerve conduction block to axonal degeneration; (2) the conduction block may be due to paranodal myelin detachment, node lengthening, dysfunction or disruption of Na(+) channels, altered homeostasis of water and ions, or abnormal polarisation of the axolemma; (3) the conduction block may be promptly reversible without development of excessive temporal dispersion; (4) axonal degeneration, depending on the specific disorder and its severity, eventually follows the conduction block. The term nodopathy focuses to the site of primary nerve injury, avoids confusion with segmental demyelinating neuropathies and circumvents the apparent paradox that something axonal may be reversible and have a good prognosis.
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The nodes of Ranvier (NoR) are essential domains for nerve conduction and their disruption plays a key role in the pathophysiology of immune-mediated neuropathies. Our understanding of the specialised nodal regions and the immune mechanisms that affect them is growing and has led to the update of peripheral neuropathy classification to include the autoimmune nodopathies, defined by the site of the autoimmune attack. Autoantibodies directed against molecules of the nodal region (as neurofascin-140/186, neurofascin-155, contactin-1, contactin-associated protein 1, contactin-associated protein 2, gangliosides, LGI4 or myelin-associated glycoprotein), macrophage-induced paranodal demyelination, and phenotypic changes of the nodal domains of Schwann cells have been identified as key mechanisms in the pathogenesis of the autoimmune neuropathies. This review explores the current knowledge of the autoimmune vulnerability of the NoR, including the underlying mechanisms leading to dysfunction in the diverse autoimmune disorders. This article is protected by copyright. All rights reserved.
Background and aims:
Autoimmune neuropathies are classified, on the basis of pathophysiology, as demyelinating or axonal. The term nodo-paranodopathy, introduced in 2013 to better categorize the neuropathies with antiganglioside antibodies and later expanded to include neuropathies with antibodies to nodal and paranodal axoglial complexes, characterizes disorders in which the nodal region is critical in the pathogenesis. These neuropathies, although presenting electrophysiologic demyelinating features do not show pathologic evidence of segmental demyelination, or, although being classified as axonal, can show reversible nerve conduction failure and rapid recovery contrary with the communal concept of an axonal neuropathy.
Methods:
In this personal view is reported, with a splitting approach, an update on autoimmune nodo-paranodopathies, classified according to the domains of peripheral nerve fiber, the target antigens and the antibody class and subclass involved. The clinical features, the electrophysiologic findings, the results of the immunopathological and ultrastructural studies, the pathophysiology and treatment are also described.
Results and interpretation:
The nodo-paranodopathy category integrates the clinical classification of autoimmune neuropathies and expands the traditional dichotomous demyelinating and axonal classification. It helps to a better systematization pointing to the domain and target antigens of the autoimmune process, it resolves conflicting pathologic and electrophysiologic findings, reconciles the contradiction that axonal neuropathies may be rapidly reversible, avoids taxonomical confusion and possible misdiagnoses. Finally this categorization, through the identification of the specific antibody and its prevalent class and subclass, clarifies the pathophysiological mechanisms and addresses to a more targeted therapeutic approach.
Autoimmune neuropathies are named by eponyms, by descriptive terminology or because of the presence of specific antibodies and are traditionally classified, on the basis of pathology and electrophysiology, as primary demyelinating or axonal. However, autoimmune disorders targeting specific molecules of the nodal region, although not showing pathological evidence of demyelination, can exhibit all the electrophysiological changes considered characteristic of a demyelinating neuropathy and acute neuropathies with antiganglioside antibodies, classified as axonal and due to nodal dysfunction, can present with reversible conduction failure and prompt recovery that appear contradictory with the common view of an axonal neuropathy. These observations bring into question the concepts of demyelinating and axonal nerve conduction changes and the groundwork of the classical dichotomous classification.
We propose a classification of autoimmune neuropathies based on the involved domains of the myelinated fibre and, when known, on the antigen. This classification, in our opinion, helps to better systematise autoimmune neuropathies because points to the site and molecular target of the autoimmune attack, reconciles some contrasting pathological and electrophysiological findings, circumvents the apparent paradox that neuropathies labelled as axonal may be promptly reversible and finally avoids taxonomic confusion and possible misdiagnosis.
