Plasma exchange and intravenous immunoglobulins: mechanism of action in immune-mediated neuropathies

Immune-mediated neuropathies are a heterogeneous group of peripheral nerve disorders, which are classified by time course, clinical pattern, affected nerves and pathological features. Plasma exchange (PE) and intravenous immunoglobulins (IVIg) are mainstays in the treatment of immune-mediated neuropathies. Of all treatments currently used, IVIg has probably the widest application range in immune-mediated neuropathies and efficacy has been well documented in several randomized controlled trials for Guillain-Barré syndrome and chronic inflammatory demyelinating polyneuropathy (CIDP). Beneficial effects of IVIg have also been proven for multifocal motor neuropathy (MMN). Likewise, PE is an established treatment for GBS and CIDP, whereas it is considered to be ineffective in MMN. Different mechanisms of action are sought to be responsible for the immunemodulatory effect of PE and IVIg in autoimmune disorders. Some of those might be important for immune-mediated neuropathies, while others are probably negligible. The aim of this review is to summarize the recent advances in elucidating disease-specific mechanisms of actions of PE and IVIg in the treatment of immune-mediated neuropathies.     

Intravenous immunoglobulin in the treatment of autoimmune neuromuscular diseases: present status and practical therapeutic guidelines.

This review summarizes the current status of intravenous immunoglobulin (IVIg) in the treatment of autoimmune neuromuscular disorders and the possible mechanisms of action of the drug based on work in vivo, in vitro, and in animal models. Supply of idiotypic antibodies, suppression of antibody production, or acceleration of catabolism of immunoglobulin G (IgG) are relevant in explaining the efficacy of IVIg in myasthenia gravis (MG), Lambert-Eaton myasthenic syndrome (LEMS), and antibody-mediated neuropathies. Suppression of pathogenic cytokines has putative relevance in inflammatory myopathies and demyelinating neuropathies. Inhibition of complement binding and prevention of membranolytic attack complex (MAC) formation are relevant in dermatomyositis (DM), Guillain-Barré syndrome (GBS), and MG. Modulation of Fc receptors or T-cell function is relevant in chronic inflammatory demyelinating polyneuropathy (CIDP), GBS, and inflammatory myopathies. The clinical efficacy of IVIg, based on controlled clinical trials conducted in patients with GBS, CIDP, multifocal motor neuropathy (MMN), DM, MG, LEMS, paraproteinemic IgM anti-myelin-associated glycoprotein (anti-MAG) demyelinating polyneuropathies, and inclusion body myositis is summarized and practical issues related to each disorder are addressed. The present role of IVIg therapy in other disorders based on small controlled or uncontrolled trials is also summarized. Finally, safety issues, risk factors, adverse reactions, spurious results or serological tests, and practical guidelines associated with the administration of IVIg in the treatment of neuromuscular disorders are presented.     

IVIg in idiopathic autoimmune neuropathies: analysis in the light of the latest results

High-dose intravenous immunoglobulin (IVIg) is effective in the treatment of idiopathic autoimmune neuropathies including Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating neuropathy (CIDP) and multifocal motor neuropathy (MMN), representing a useful option or, as in MMN, the gold standard for their treatment. In GBS, two randomised, controlled trials (RCT) showed that IVIg is at least as effective as plasma exchange (PE). IVIg may however be preferred due to its low number of contraindications and complications and the fact that it can be administered at any time, in any department, including patients with contraindications to PE, or in intensive care units. In CIDP, at least four RCTs have demonstrated the efficacy of IVIg in over 60% of CIDP patients, while two additional RCTs have shown a comparable effect to steroids and PE as initial treatment. As with PE, the effects of IVIg usually last a few weeks meaning that the majority of patients require periodic maintenance infusions. The lower cost and easier administration of oral steroids compared to IVIg may be partly compensated by the safer long-term profile of IVIg over steroids. In MMN, almost 80% of patients improve with IVIg, the efficacy of which has been confirmed by four RCTs, making of IVIg the first-choice therapy in MMN, for which steroids and PE are ineffective or even detrimental. Also in these patients, IVIg induces a rapid improvement that usually lasts only a few weeks and has to be maintained with periodic IVIg infusions for long periods of time, if not indefinitely.     

Clinical trials in CIDP and chronic autoimmune demyelinating polyneuropathies

The main chronic autoimmune neuropathies include chronic inflammatory demyelinating polyneuropathy (CIDP), multifocal motor neuropathy (MMN), and anti-myelin-associated glycoprotein (MAG) demyelinating neuropathy. On the basis of randomized controlled studies, corticosteroids, intravenous immunoglobulin (IVIg), and plasmapheresis provide short-term benefits in CIDP. MMN responds only to IVIg. Because in MMN and CIDP, IVIg infusions are required every 3-6 weeks to sustain benefits or long-term remissions, there is a need for "IVIg-sparing" agents. In CIDP, immunosuppressive drugs, such as azathioprine, cyclosporine, methotrexate, mycophenolate, and cyclophosphamide, are used, but controlled trials have not shown that they are effective. Controlled trials have also not shown benefit to any agents in anti-MAG neuropathy. However, clinicians use many immunosuppressive drugs in both settings, but all have potentially serious side effects and are only effective in some patients. Thus, there is a need for new therapies in the inflammatory and paraproteinemic neuropathies. New agents targeting T cells, B cells, and transmigration and transduction molecules are discussed as potential treatment options for new trials. The need for biomarkers that predict therapeutic responses or identify patients with active disease is emphasized, and the search for better scoring tools that capture meaningful changes after response to therapies is highlighted.     

Immune mediated neuropathies

Abstract. This paper reviews recent treatment strategies of immune mediated neuropathies, in particular it includes data regarding Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyneuropathy (CIDP), multifocal motor neuropathy (MMN), neuropathy with IgM monoclonal gammopathy and other dysglobulinemic neuropathies. In the treatment of Guillain- Barré syndrome, there is no significant difference between IVIg, plasma exchange or plasma exchange followed by IVIg. However, for reasons of convenience and safety, IVIg is used as standard treatment in most centers. There is so far insufficient evidence for the use of corticosteroids in the therapy of GBS. In treating CIDP corticosteroids, intravenous immunoglobulin and plasma exchange seem to be equally effective. However, the high costs and relative lack of availability of IVIg, the only short-term benefit and the invasive nature of the plasma exchange procedure, and on the other hand serious long-term side effects of corticosteroids are the most important disadvantages of these treatments and have to be taken into consideration before a decision about therapy can be made. In multifocal motor neuropathy the intravenous immunoglobulin therapy is the only treatment that has been shown to be effective in controlled trials. However, inadequate response in a proportion of patients, high cost and variable availability of IVIg show the need for the search of adjunctive immunosuppressive therapies. Neuropathies with IgM monoclonal gammopathy may improve after treatment with chemotherapeutic agents, though the long-term effects are not known. In addition, such treatment modalities may be associated with serious side effect and even severe toxicity. Recent data support the use of a new promising drug: Rituximab, a monoclonal antibody directed against the B cell surface membrane marker CD 20.This article has been adapted from an ENS Teaching Course in Istanbul, Turkey, June 2003.     

Antiganglioside antibodies in the pathogenesis of autoimmune neuropathies]

Antiganglioside antibodies are frequently detected in sera from patients with autoimmune neuropathies, such as Guillain-Barré syndrome, Miller Fisher syndrome, IgM paraproteinemic neuropathy, chronic inflammatory demyelinating polyneuropathy, and multifocal motor neuropathy. In the acute phase sera from GBS patients, antiganglioside antibodies are detected in 60-70%. Ganglioside antigens recognized by serum antibodies are varied from case to case. IgG antibody against GQ1b ganglioside is specifically raised in sera from patients with Miller Fisher syndrome and Guillain-Barré syndrome with ophthalmoplegia. That antibody may bind to the paranodal myelin of oculomotor, trochlear and abducens nerves, where GQ1b ganglioside is specifically localized, to cause ophthalmoplegia. IgM M-protein which recognizes the disialosyl residue of GD1b is specifically associated with sensory ataxic neuropathy. The IgM M-protein may bind to the primary sensory neurons, where GD1b ganglioside is localized, to cause sensory disturbance. After we confirmed the localization of GD1b in the rabbit primary sensory neurons, we sensitized rabbits with GD1b and induced sensory ataxic neuropathy in them. This is the first established animal model of autoimmune neuropathy induced by sensitization with ganglioside. Some antiganglioside antibodies may determine the clinical phenotype of neuropathy by binding specifically to the ganglioside antigens which have unique localization.     

Localization of GM1 and GD1b antigens in the human peripheral nervous system

Serum antibodies against ganglioside GM1 and/or GD1b are frequently detected in autoimmune neuropathies such as multifocal motor neuropathy, IgM paraproteinemic neuropathy and Guillain–Barré syndrome. Some of them bind to GM1 or GD1b monospecifically but others cross-react with both of the antigens. In order to investigate the respective localizations of GM1 and GD1b antigens in the human peripheral nervous system, an immunohistochemical study was performed using two mouse monoclonal antibodies, each monospecific to GM1 and GD1b. GGR12, monospecific to GD1b, bound to neurons in dorsal root ganglia and sympathetic ganglia, and some parts of the peripheral myelin, mainly the paranodal areas. However GMB16, monospecific to GM1, did not bind to either neurons or myelin. GD1b antigen present on neurons and paranodal myelin in the peripheral nervous system can be a target antigen of serum antibodies in autoimmune neuropathies. Further effort should be made to reveal the localization of GM1 antigen in the human peripheral nervous system.     

Serological evidence for infection with Campylobacter jejuni/coli in patients with multifocal motor neuropathy

Campylobacter jejuni/coli (CJC) infection has been implicated in the immunopathogenesis of Guillain-Barré syndrome (GBS), acute motor axonal neuropathy (AMAN), and Miller Fisher syndrome (MFS). However, its role in chronic immune mediated neuropathies such as multifocal motor neuropathy (MMN) or chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is less clear. Anti-ganglioside antibodies are associated with chronic motor neuropathies such as MMN and IgM anti-GM1, and IgM anti-asialo GM1 antibodies have been shown to cross-react with CJC lipopolysaccharides. Molecular mimicry between CJC and IgG anti-GM1 antibodies has also been suggested. Therefore we have performed a retrospective assessment of anti-CJC-specific IgG, IgM, and IgA antibodies in a cohort of seven patients with clinical and electrophysiologically definite MMN. The control group consisted of 140 healthy blood donors with no history of enteric illnesses. We found elevated titres of anti-CJC-specific IgG in 5 of 7 patients, IgM in 3 of 7 and IgA in 1 of 7. At least 1 anti-CJC antibody was elevated in 6 of 7 patients, and 3 patients had elevations of both IgG and IgM antibodies. Three patients had significantly elevated titres of anti-ganglioside antibodies without a clear relationship to the anti-CJC titres. Therefore antibodies specific for CJC were found more frequently than expected in patients with MMN. Prior or ongoing infection with CJC may play a role in the actiopathogenesis of MMN.     

Treatment of immune-mediated, dysimmune neuropathies

This review focuses on the actual status and recent advances in the treatment of immune-mediated neuropathies, including: Guillain-Barre syndrome (GBS) with its subtypes acute inflammatory demyelinating polyradiculoneuropathy, acute motor axonal neuropathy, acute motor and sensory axonal neuropathy, Miller Fisher syndrome, and acute pandysautonomia; chronic inflammatory demyelinating polyneuropathy (CIDP) with its subtypes classical CIDP, CIDP with diabetes, CIDP/monoclonal gammopathy of undetermined significance (MGUS), sensory CIDP, multifocal motor neuropathy (MMN), multifocal acquired demyelinating sensory and motor neuropathy or Lewis-Sumner syndrome, multifocal acquired sensory and motor neuropathy, and distal acquired demyelinating sensory neuropathy; IgM monoclonal gammopathies with its subtypes Waldenstrom's macroglobulinemia, myelin-associated glycoprotein-associated gammopathy, polyneuropathy, organomegaly, endocrinopathy, M-protein, skin changes syndrome, mixed cryoglobulinemia, gait ataxia, late-onset polyneuropathy syndrome, and MGUS. Concerning the treatment of GBS, there is no significant difference between intravenous immunoglobulins (IVIG), plasma exchange or plasma exchange followed by IVIG. Because of convenience and absent invasiveness, IVIG are usually preferred. In treating CIDP corticosteroids, IVIG, or plasma exchange are equally effective. Despite the high costs and relative lack of availability, IVIG are preferentially used. For the one-third of patients, who does not respond, other immunosuppressive options are available. In MMN IVIG are the treatment of choice. Inadequate response in 20% of the patients requires adjunctive immunosuppressive therapies. Neuropathies with IgM monoclonal gammopathy may respond to various chemotherapeutic agents, although the long-term effects are unknown. In addition, such treatment may be associated with serious side effects. Recent data support the use of rituximab, a monoclonal antibody against the B-cell surface-membrane-marker CD20.     

Expression of chemokine receptors on peripheral blood mononuclear cells of patients with immune-mediated neuropathies treated with intravenous immunoglobulins

Intravenous immunoglobulin (IVIg) is an efficacious treatment for immune-mediated neuropathies like Guillain–Barré syndrome (GBS), chronic inflammatory demyelinating neuropathy (CIDP), and multifocal motor neuropathy (MMN). In the pathogenesis of immune-mediated neuropathies chemokines and their receptors play a crucial role. Using flow cytometry we examined whether IVIg modulates chemokine expression repertoires of T cells and monocytes. The expression of inflammatory chemokine receptors CCR1, CCR2, CCR4, CCR5, CCR6 and CXCR3 was investigated on circulating T-cell subsets, and CCR1, CCR2 and CCR5 on circulating monocytes before and after IVIg treatment in patients with immune-mediated neuropathies (MMN, n  = 7; GBS, n  = 1; CIDP, n  = 2). Furthermore, the homing potential of T cells was analyzed by the expression of CCR7, a chemokine receptor known to be utilized by mature T cells to recirculate into secondary lymphoid organs. In contrast to studies in chronic heart failure, no differences in expression patterns before and after IVIg treatment of any of the investigated chemokine receptors were found. Furthermore, the proportion of CD45RO-positive CD4⁺ or CD8⁺ T-cell subsets was not changed by IVIg treatment. Thus, we concluded that modulation of the expression of chemokine receptors on circulating leukocytes by IVIg is not a mode of action in immune-mediated neuropathies.     

Immunneuropathien

The Guillain-Barré syndrome (GBS) and chronic inflammatory demyelinating polyneuropathy (CIDP) are the most common immune-mediated polyneuropathies, which can show variable clinical and electrophysiological manifestations. Rarer immune-mediated neuropathies encompass paraproteinemic neuropathies (PPN), multifocal motor neuropathy (MMN) and vasculitic neuropathies. The diagnosis usually relies on the history of symptom evolution, distribution of nerve dysfunction and particularly on characteristic features in nerve conduction studies, aided by cerebrospinal fluid (CSF) examination and nerve biopsy findings. The therapeutic toolbox encompasses corticosteroids, immunoglobulins and plasmapheresis often accompanied by long-term immunosuppression. It is important to note that immune-mediated neuropathies selectively respond to treatment and contraindications need to be considered. Despite treatment a considerable number of patients suffer from permanent neurological deficits.     

The role of IVIg in autoimmune neuropathies: the latest evidence

Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and multifocal motor neuropathy (MMN) are the major immune neuropathies. Although a detailed understanding of the pathogenesis of these conditions is not yet available, the multiple effects of IVIg on the immune and inflammatory process recommend it as an agent worthy of investigation in these diseases. Following recent research, IVIg is now recommended as a first-line treatment option for moderate or severe GBS to be administered within two weeks of disease onset. With regard to CIDP, a Cochrane review demonstrated significant short-term improvements in disability and impairment with IVIg. The ICE (IGIV CIDP Efficacy trial) study group undertook the largest ever trial of IVIg for CIDP, which demonstrated for the first time the long-term efficacy of IVIg. The results of this ICE trial demonstrated the efficacy of IVIg in CIDP, with a significantly higher response rate versus placebo after 24 weeks of treatment (P = 0.0002). Furthermore, long-term maintenance with IVIg also significantly reduced the rate of relapse (P < 0.011). On the basis of available data, IVIg can be recommended as a first-line treatment option for GBS and CIDP. For MMN, although the evidence for IVIg is limited, there is no evidence to recommend other treatments.     

Systematic reviews of treatment for chronic inflammatory demyelinating neuropathy

Chronic inflammatory demyelinating polyradiculoneuropathies include chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), multifocal motor neuropathy (MMN) and paraprotein-associated demyelinating neuropathy. This review summarises the evidence from randomised controlled trials (RCTs) for the treatment of these conditions. It leads to the conclusions that: 1) steroids are beneficial in CIDP but not MMN and their efficacy in paraproteinaemic demyelinating neuropathy (PDN) is uncertain; 2) intravenous immunoglobulin (IVIg) produces short-term benefit in CIDP, MMN and IgM PDN. Its effect in IgG or IgA PDN has not been tested in RCTs; 3) plasma exchange (PE) also produces short-term benefit in CIDP and IgG or IgA PDN but probably not in MMN; 4) there is almost no information from RCTs concerning the possible benefits of immunosuppressive agents; and 5) volunteers are needed to write Cochrane systematic reviews of IVIg for MMN and of interventions for PDN associated with IgG and IgA.     

How useful are anti-neural IgM antibodies in the diagnosis of chronic immune-mediated neuropathies?

Antibodies against several neural antigens have been associated with different chronic immune-mediated neuropathies but their practical clinical relevance remains unclear. To determine the possible diagnostic usefulness of these antibodies we reviewed the clinical correlate of IgM antibodies to the myelin-associated glycoprotein (MAG), sulfatide, the gangliosides GM1, GM2, GD1a and GD1b in 539 consecutive patients examined for neuropathy or related diseases in our Neuropathy Clinics and tested for these antibodies in our laboratory since 1985. 302 patients (56%) had an established diagnosis of definite or possible chronic immune-mediated neuropathy while 237 had a neuropathy of non-immune-mediated origin or of unknown aetiology or a closely related disease. Antibodies to one or more antigen were more frequent (chi(2)=63.32; p<0.00001) in patients with chronic immune-mediated neuropathy (37.7%) than with other neuropathy or related diseases (7.2%) and their presence was associated in 87% of the patients with an immune-mediated neuropathy, incrementing by 31% the probability of having this form. Testing for MAG permitted to identify 24.8% of patients with an immune-mediated neuropathy, GM1 an additional 9.9%, while GM2, GD1b, GD1a and sulfatide altogether an additional 3% of the patients. Concerning clinical correlations, all 75 patients with anti-MAG IgM had neuropathy and IgM monoclonal gammopathy (PN+IgM) with a positive predictive value for this neuropathy of 100%. A similarly high predictive value for neuropathy (91.4%) was observed among 269 patients with IgM monoclonal gammopathy including 103 patients without neuropathy. Anti-sulfatide IgM, though rare, were also significantly and constantly associated with PN+IgM and permitted to identify few patients not bearing anti-MAG IgM. Anti-GM1 IgM were significantly associated with multifocal motor neuropathy (MMN) (29.2%) but where also found in a few patients with other immune or non-immune neuropathies or related diseases with a positive predictive value for MMN of 25.5%. Anti-GM2 IgM were also significantly associated with MMN and increased the sensitivity (36.2%) for MMN obtained with anti-GM1 IgM only, without affecting its specificity and positive predictive value. Anti-GD1a, GD1b, though not significantly more frequent in patients with immune-mediated neuropathy, were associated in 80 to 100% of patients with these neuropathies. In conclusion anti-neural IgM antibodies may help in identifying patients with a chronic immune-mediated neuropathy, even if only anti-MAG and anti-sulfatide IgM appear to be strictly associated with a definite clinical syndrome.     

Acute-onset multifocal motor neuropathy (AMMN): how we meet the diagnosis

Multifocal motor neuropathy (MMN) usually progresses insidiously with lower motor neuron-type weakness, minimal or no sensory symptoms. Diagnostic criteria include motor conduction block (CB) at sites not exposed to compression or entrapment. CBs may persist or reverse irrespective of clinical outcome. Acute onset with generalized weakness is uncommon. We report four patients who presented acutely areflexia, pure motor deficits without sensory disturbances, multifocal CBs persisting at the same motor nerves on serial electrophysiological studies. Three patients had preceding infections; two showed IgM reactivity against the ganglioside GM1. Intravenous immuneglobulin (IVIg) improved or stabilized symptoms. Patients 2,3,4 receive maintenance therapy with IVIg for years. Acute-onset MMN (AMMN) should be differentiated from other immune-mediated neuropathies such as acute inflammatory polyneuropathy either demyelinating (AIDP) or axonal (AMAN), acute motor conduction block neuropathy (AMCBN), acute-onset chronic inflammatory demyelinating polyneuropathy (CIDP). The correct diagnosis deserves implications for patient long-term treatment and prognosis. Moreover, the authors address the problem of defining the spectrum of MMN particularly in the acute setting.     

Multifocal motor neuropathy: current concepts and controversies

Multifocal motor neuropathy (MMN) is now a well-defined purely motor multineuropathy characterized by the presence of multifocal partial motor conduction blocks (CB), frequent association with anti-GM1 IgM antibodies, and usually a good response to high-dose intravenous immunoglobulin (IVIg) therapy. However, several issues remain to be clarified in the diagnosis, pathogenesis, and therapy of this condition including its nosological position and its relation to other chronic dysimmune neuropathies; the degree of CB necessary for the diagnosis of MMN; the existence of an axonal form of MMN; the pathophysiological basis of CB; the pathogenetic role of antiganglioside antibodies; the mechanism of action of IVIg treatments in MMN and the most effective regimen; and the treatment to be used in unresponsive patients. These issues are addressed in this review of the main clinical, electrophysiological, immunological, and therapeutic features of this neuropathy.     

Efficacy and tolerability of different brands of intravenous immunoglobulin in the maintenance treatment of chronic immune‐mediated neuropathies

High‐dose intravenous immunoglobulin (IVIg) is effective in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and multifocal motor neuropathy (MMN). Not all brands of IVIg are however licensed for these neuropathies. We reviewed six patients with CIDP and seven with MMN treated with maintenance therapy with IVIg from 2009 to 2013. In all patients, we measured the Medical Research Council (MRC) and Overall Neuropathy Limitation Scale (ONLS) scores before each infusion, registered the monthly dose and brand of IVIg, and recorded adverse events. Patients were treated for 25–60 months (mean 49 months) alternating different brands of IVIg including IgVena, Gammagard, Kiovig, and Flebogamma. Minor and transient side effects were equally observed with each brand. No difference in the MRC or ONLS scores was observed in relation to the brand of IVIg used. Chronic maintenance treatment with IVIg in patients with MMN and CIDP was not associated with a different tolerability or efficacy despite the use of different brands of IVIg.     

Office immunotherapy in chronic inflammatory demyelinating polyneuropathy and multifocal motor neuropathy

Intravenous immunoglobulin [IVIg], plasma exchange [PE], and corticosteroids are efficacious treatment in chronic inflammatory demyelinating polyneuropathy [CIDP]. IVIg is effective in multifocal motor neuropathy [MMN]. NIS, NIS‐weakness, sum scores of raw amplitudes of motor fiber (CMAPs) amplitudes, and Dyck/Rankin score provided reliable measures to detect and scale abnormality and reflect change; they are therefore ideal for office management of response‐based immunotherapy (R‐IRx) of CIDP. Using efficacious R‐IRx, a large early and late therapeutic response (≥ one‐fourth were in remission or had recovered) was demonstrated in CIDP. In MMN only an early improvement with late non‐significant worsening was observed. The difference in immunotherapy response supports a fundamental difference between CIDP (immune attack on Schwann cells and myelin) and MMN (attack on nodes of Ranvier and axons). Muscle Nerve 52: 488–497, 2015     

Acute and chronic ataxic neuropathies with disialosyl antibodies: A continuous clinical spectrum and a common pathophysiological mechanism

Acute ataxic neuropathies with disialosyl antibodies include Fisher syndrome, ataxic Guillain–Barré syndrome (GBS), and acute sensory ataxic neuropathy. Fisher syndrome and ataxic GBS are more strongly associated with IgG anti‐GQ1b and anti‐GT1a than with anti‐GD1b antibodies, whereas the association is reversed in the case of acute sensory ataxic neuropathy. Chronic ataxic neuropathy with disialosyl antibodies is associated with IgM paraprotein to GD1b and GQ1b, which occasionally reacts with GT1a. The clinical, electrophysiological, and pathological features, along with experimental findings, suggest that acute and chronic ataxic neuropathies with disialosyl antibodies form a continuous clinical and pathophysiological spectrum characterized by a complement‐mediated disruption at the nodal region and are better classified in the new category of nodo‐paranodopathies. Muscle Nerve 49 : 629–635, 2014     

CIDP - the relevance of recent advances in Schwann cell/axonal neurobiology

Early pathological studies in patients with acute and chronic inflammatory demyelinating neuropathies, and the animal model experimental autoimmune neuritis (EAN) showed similarities in the process of demyelination. These studies focused on compact myelin proteins and peptides as targets of immune attack in Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), and EAN. However, serological studies in patients with subsets of GBS highlighted the importance of gangliosides - glycolipids enriched in non-compact Schwann cell regions and the node, paranodal, and internodal axolemma. In the acute motor axonal neuropathy (AMAN) rabbit model, antibodies to the ganglioside GM1 bind in the nodal region, impair Na channel clustering and disturb Schwann cell/axon organisation. Schwann cell neurobiological studies now highlight the importance of adhesion molecules, including neurofascins, gliomedin, contactins, and NrCAM to Schwann cell/axon integrity. Changes to nodal fine structure by immune responses against such molecules may provide a mechanism for reversible conduction failure or block. Recovery of patients with CIDP or multifocal motor neuropathy (MMN) following treatment may sometimes be better explained by reversal of conduction failure than remyelination or regeneration. This review considers the importance of the intricate molecular arrangements at the nodal and paranodal regions in inflammatory neuropathies such as CIDP. Early images of compact myelin stripping and phagocytosis, may have diverted the research focus away from these vital non-compact myelin Schwann cell areas.