Axonal Guillain-Barré syndrome: relation to anti-ganglioside antibodies and Campylobacter jejuni infection in Japan

To clarify the relations of the axonal form of Guillain-Barré syndrome (GBS) to anti-ganglioside antibodies and Campylobacter jejuni infection, 86 consecutive Japanese GBS patients were studied. Electrodiagnostic criteria showed acute inflammatory demyelinating polyneuropathy in 36% of the patients and acute motor axonal neuropathy (AMAN) in 38%. Frequent anti-ganglioside antibodies were of the IgG class and against GM1 (40%), GD1a (30%), GalNAc-GD1a (17%), and GD1b (21%). Identified infections were C. jejuni (23%), cytomegalovirus (10%), Mycoplasma pneumoniae (6%), and Epstein-Barr virus (3%). There was a strong association between AMAN and IgG antibodies against GM1, GD1a, GalNAc-GD1a, or GD1b. Almost all the patients with at least one of these antibodies had the AMAN pattern or rapid resolution of conduction slowing/block possibly because of early-reversible changes on the axolemma. C. jejuni infection was frequently associated with AMAN or anti-ganglioside antibodies, but more than half of the patients with AMAN or anti-ganglioside antibodies were C. jejuni-negative. These findings suggest that the three phenomena "axonal dysfunctions (AMAN or early-reversible conduction failure)," "IgG antibodies against GM1, GD1a, GalNAc-GD1a, or GD1b," and "C. jejuni infection" are closely associated but that microorganisms other than C. jejuni frequently trigger an anti-ganglioside response and elicit axonal GBS.     

Detection of anti-ganglioside antibodies in Guillain-Barré syndrome and its variants by the agglutination assay

Sera from 40 patients with Guillain-Barré syndrome (GBS), including the subtypes acute inflammatory demyelinating polyneuropathy (AIDP), acute motor axonal neuropathy (AMAN), acute motor and sensory axonal neuropathy (AMSAN), and Miller Fisher syndrome (MFS) were examined for the presence of anti-ganglioside antibodies using the ganglioside agglutination assay, and the enzyme-linked immunosorbent assay (ELISA). In the ELISA system, sera were tested for IgM and IgG antibodies to GM1, GM2, GD1a, GD1b, GT1b, and GQ1b gangliosides. Antibodies to gangliosides were detected in 21 (53%) of the GBS patients by agglutination assay and in 17 (43%) of the patients by ELISA. Some of the sera reacted with more than one ganglioside. Antibodies were not found in the control sera that were studied. The agglutination assay may be useful for rapid screening of GBS sera for antibodies to multiple gangliosides.     

Dysfunction of nodes of Ranvier: a mechanism for anti-ganglioside antibody-mediated neuropathies

Autoantibodies against gangliosides GM1 or GD1a are associated with acute motor axonal neuropathy (AMAN) and acute motor-sensory axonal neuropathy (AMSAN), whereas antibodies to GD1b ganglioside are detected in acute sensory ataxic neuropathy (ASAN). These neuropathies have been proposed to be closely related and comprise a continuous spectrum, although the underlying mechanisms, especially for sensory nerve involvement, are still unclear. Antibodies to GM1 and GD1a have been proposed to disrupt the nodes of Ranvier in motor nerves via complement pathway. We hypothesized that the disruption of nodes of Ranvier is a common mechanism whereby various anti-ganglioside antibodies found in these neuropathies lead to nervous system dysfunction. Here, we show that the IgG monoclonal anti-GD1a/GT1b antibody injected into rat sciatic nerves caused deposition of IgG and complement products on the nodal axolemma and disrupted clusters of nodal and paranodal molecules predominantly in motor nerves, and induced early reversible motor nerve conduction block. Injection of IgG monoclonal anti-GD1b antibody induced nodal disruption predominantly in sensory nerves. In an ASAN rabbit model associated with IgG anti-GD1b antibodies, complement-mediated nodal disruption was observed predominantly in sensory nerves. In an AMAN rabbit model associated with IgG anti-GM1 antibodies, complement attack of nodes was found primarily in motor nerves, but occasionally in sensory nerves as well. Periaxonal macrophages and axonal degeneration were observed in dorsal roots from ASAN rabbits and AMAN rabbits. Thus, nodal disruption may be a common mechanism in immune-mediated neuropathies associated with autoantibodies to gangliosides GM1, GD1a, or GD1b, providing an explanation for the continuous spectrum of AMAN, AMSAN, and ASAN.     

Axonal Guillain-Barré syndrome: carbohydrate mimicry and pathophysiology

Abstract   Acute motor axonal neuropathy (AMAN), an axonal subtype of Guillain-Barré syndrome (GBS), is characterized by pure motor involvement, frequent antecedent infection by Campylobacter jejuni , association with anti-GM1 or anti-GD1a immunoglobulin G (IgG) antibodies, and the electrophysiological features of axonal degeneration and reversible conduction block. Molecular mimicry exists between GM1 and GD1a gangliosides and lipooligosaccharides (LOSs) of C. jejuni isolates from AMAN. Sensitization of rabbits with GM1 or C. jejuni LOS induces anti-GM1 IgG antibodies and subsequent flaccid paralysis. Pathological changes seen in rabbit model peripheral nerves are identical to those in human AMAN. Immunohistochemistry of AMAN rabbits shows disruption of nodal sodium channel clusters and detachment of paranodal myelin terminal loops, similar to paranodal demyelination, which would significantly reduce the safety factor for impulse transmission and might be responsible for the rapidly reversible conduction block frequently present in human AMAN. C. jejuni sialyltransferase (Cst-II), which functions in the biosynthesis of ganglioside-like LOSs, determines the transferase activity. Strains with cst-II (Thr51) express GM1 and GD1a epitopes, whereas GBS patients infected with cst-II (Thr51) strains have anti-GM1 or anti-GD1a IgG antibodies. The cst-II gene is responsible for the development of GBS. Immunological, pathological, electrophysiological, and bacteriological studies have provided strong evidence of carbohydrate mimicry being a cause of AMAN and clarified the mechanisms of nerve conduction failure in AMAN.     

Fine specificities of anti-LM1 IgG antibodies in Guillain-Barré syndrome

We investigated the prevalence of anti-LM1 IgG antibody and its fine specificity in Guillain-Barré syndrome (GBS). Anti-LM1 IgG and IgM antibodies from sera of 47 patients with GBS--19 with acute inflammatory demyelinating polyneuropathy (AIDP), 27 with acute motor axonal neuropathy (AMAN), and 1 with acute motor-sensory axonal neuropathy (AMSAN)--were tested. Anti-LM1 IgG antibody was detected in only one patient with AIDP, whereas it was present in seven with AMAN and in one with AMSAN. Sera from the eight IgG anti-LM1-positive patients with AMAN/AMSAN also had IgG activity against the gangliosides GM1, GM1b, GD1a, GalNAc-GD1a, GD1b, or GQ1b. Anti-LM1 IgG antibodies from the AMAN/AMSAN patients cross-reacted with other gangliosides, whereas IgG antibody from the AIDP patient was monospecific against LM1. Anti-LM1 IgG antibody therefore, cannot be a marker of AIDP. In addition, whether monospecific anti-LM1 IgG antibody is associated with AIDP remains to be concluded. Larger studies are needed to verify whether monospecific anti-LM1 IgG antibody could be a marker of AIDP.     

Ganglioside mimicry as a cause of Guillain-Barré syndrome

Guillain-Barré syndrome (GBS), characterized by acute progressive limb weakness and areflexia, is the prototype of postinfectious autoimmune diseases. Campylobacter jejuni is the most frequently identified agent of infection in GBS patients, often preceding acute motor axonal neuropathy (AMAN), a variant of GBS. Anti-GM1, anti-GM1b, anti-GD1a, and anti-GalNAc-GD1a IgG antibodies are associated with AMAN. Carbohydrate mimicry [Galbeta1-3GalNAcbeta1-4(NeuAcalpha2-3)Galbeta1-] was seen between the lipo-oligosaccharide of C. jejuni isolated from an AMAN patient and human GM1 ganglioside. Sensitization with the lipo-oligosaccharide of C. jejuni induces AMAN in rabbits as does sensitization with GM1 ganglioside. Paralyzed rabbits have pathological changes in their peripheral nerves identical to changes seen in human GBS. C. jejuni infection may induce anti-ganglioside antibodies by molecular mimicry, eliciting AMAN. This is the first verification of the causative mechanism of molecular mimicry in an autoimmune disease. To express ganglioside mimics, C. jejuni requires specific gene combinations that function in sialic acid biosynthesis or transfer. The knockout mutants of these landmark genes of GBS show reduced reactivity with GBS patients' sera, and fail to induce an anti-ganglioside antibody response in mice. These genes are crucial for the induction of neuropathogenic cross-reactive antibodies. An approach for evaluating intravenous immune globulin, a treatment for GBS, based on our animal model of AMAN is also discussed in this review, and recent advances made in this field are described.     

Subclass distribution and the secretory component of serum IgA anti-ganglioside antibodies in Guillain-Barré syndrome after Campylobacter jejuni enteritis.

Previously, we reported that IgA anti-GM1 antibody is more closely associated with preceding Campylobacter jejuni enteritis in Guillain-Barré syndrome (GBS) than are IgG and IgM antibodies. However, the mechanism of the induction of IgA anti-ganglioside antibodies is not clear. In this study, serum IgA antibodies against GM1, GM1b, and GD1a, and GalNAc-GD1a were examined in 152 GBS patients. In GBS, antecedent C. jejuni infection is closely associated with IgA antibodies, other than GM1, against GM1b. The IgA subclass distribution is completely restricted to IgA1, no secretory IgA anti-ganglioside antibody being detected. This result does not support the hypothesis that the serum IgA antibodies present in GBS after C. jejuni enteritis originate at mucosal sites, such as the gut mucosal immune system. Seventeen (85%) of 20 patients with IgA anti-ganglioside antibodies had serological evidence of C. jejuni infection and/or a history of antecedent diarrhea. Moreover, a motor nerve conduction study showed that patients with IgA antibodies frequently had axonal neuropathy, whereas none had demyelinating neuropathy. This may support the previous report that IgA isotype anti-GM1 antibodies are more closely associated with poor outcome than are the IgG or IgM isotypes. The induction mechanism of IgA anti-ganglioside antibodies must be clarified by determining whether concentrations of cytokines, which increase the IgA class switch, are elevated in patients with GBS after C. jejuni enteritis.     

Guillain-Barré syndrome

Guillain-Barré syndrome (GBS) is currently divided into the two major subtypes: acute inflammatory demyelinating polyneuropathy (AIDP) and acute motor axonal neuropathy (AMAN). This review highlights relevant recent publications, particularly on the pathophysiology of AMAN. Molecular mimicry of the bacterial lipo-oligosaccharide by the human gangliosides is now considered an important cause of AMAN. Gangliosides GM1, GM1b, GD1a, and GalNAc-GD1a expressed on the motor axolemma are likely to be the epitopes for antibodies in AMAN. At the nodes or paranodes, deposition of antiganglioside antibodies initially cause reversible conduction block followed by axonal degeneration. Electrodiagnostic findings support this process. Disruption of glycolipids, which are important to maintain ion channel clustering at the nodes and paranode, may impair nerve conduction. Genetic polymorphisms of Campylobacter jejuni determine the expression of the gangliosides on the bacterial wall. In contrast, target molecules in AIDP have not yet been identified. Meta-analyses show efficacy of plasmapheresis and immunoglobulin therapy, but not corticosteroids, in hastening recovery.     

Association of antibodies to ganglioside complexes and conduction blocks in axonal Guillain‐Barré syndrome presenting as acute motor conduction block neuropathy

A close relationship between acute motor conduction block neuropathy and antibodies against the complex of GM1 and GalNAc‐GD1a has been reported. This study investigates the hypothesis that conduction block at the early phase of axonal Guillain‐Barré syndrome (GBS) is also associated with such ganglioside complexes. Sera were obtained from seven French patients with initial evidence of isolated conduction blocks that resolved or progressed to acute motor axonal neuropathy. Serum IgG to asialo‐GM1 and gangliosides of LM1, GM1, GM1b, GD1a, GalNAc‐GD1a, GD1b, GT1a, GT1b, and GQ1b as well as their complexes were measured. Five of seven patients progressed within the first month of disease to AMAN. One patient had IgG antibodies against the complex of asialo‐GM1 and each of the other ganglioside antigens. Another patient carried IgG antibodies against GM1 complex with GM1b, GD1a, and GT1a as well as asialo‐GM1 complex with GD1a and GT1a. None had IgG antibodies against GM1/GalNAc‐GD1a complex. Six patients had IgG against single antigens GM1, GD1a, GalNAc‐GD1a, GD1b, and asialo‐GM1. In three patients, a reduced reaction against GM1/GalNAc‐GD1a complex was observed. The presence of conduction block in axonal GBS is not always associated with anti‐GM1/GalNAc‐GD1a complex antibodies.     

The immunobiology of Guillain-Barré syndromes

This presentation highlights aspects of the immunobiology of the Guillain-Barré syndromes (GBS), the world's leading cause of acute autoimmune neuromuscular paralysis. Understanding the key pathophysiological pathways of GBS and developing rational, specific immunotherapies are essential steps towards improving the clinical outcome of this devastating disorder. Much of the research into GBS over the last decade has focused on the forms mediated by anti-ganglioside antibodies, and we have made substantial progress in our understanding in several related areas. Particular highlights include (a) the emerging correlations between anti-ganglioside antibodies and specific clinical phenotypes, notably between anti-GM1/anti-GD1a antibodies and the acute motor axonal variant and anti-GQ1b/anti-GT1a antibodies and the Miller Fisher syndrome; (b) the identification of molecular mimicry between GBS-associated Campylobacter jejuni oligosaccharides and GM1, GD1a, and GT1a gangliosides as a mechanism for anti-ganglioside antibody induction; (c) the development of rodent models of GBS with sensory ataxic or motor phenotypes induced by immunisation with GD1b or GM1 gangliosides, respectively. Our work has particularly studied the motor nerve terminal as a model site of injury, and through combined active and passive immunisation paradigms, we have developed murine neuropathy phenotypes mediated by anti-ganglioside antibodies. This has been achieved through use of glycosyltransferase and complement regulator knock-out mice, both for cloning anti-ganglioside antibodies and inducing disease. Through such studies, we have proven a neuropathogenic role for murine anti-ganglioside antibodies and human GBS-associated antisera and identified several determinants that influence disease expression including (a) the level of immunological tolerance to microbial glycans that mimic self-gangliosides; (b) the ganglioside density in target tissue; (c) the level of complement activation and the neuroprotective effects of endogenous complement regulators; and (d) the role of calcium influx through complement pores in mediating axonal injury. Such studies provide us with clear information on an antibody-mediated pathogenesis model for GBS and should lead to rational therapeutic testing of agents that are potentially suitable for use in humans.     

Prevalence of Anti-Ganglioside Antibodies and Their Clinical Correlates with Guillain-Barré Syndrome in Korea: A Nationwide Multicenter Study

Background and Purpose

No previous studies have investigated the relationship between various anti-ganglioside antibodies and the clinical characteristics of Guillain-Barré syndrome (GBS) in Korea. The aim of this study was to determine the prevalence and types of anti-ganglioside antibodies in Korean GBS patients, and to identify their clinical significance.

Methods

Serum was collected from patients during the acute phase of GBS at 20 university-based hospitals in Korea. The clinical and laboratory findings were reviewed and compared with the detected types of anti-ganglioside antibody.

Results

Among 119 patients, 60 were positive for immunoglobulin G (IgG) or immunoglobulin M antibodies against any type of ganglioside (50%). The most frequent type was IgG anti-GM1 antibody (47%), followed by IgG anti-GT1a (38%), IgG anti-GD1a (25%), and IgG anti-GQ1b (8%) antibodies. Anti-GM1-antibody positivity was strongly correlated with the presence of preceding gastrointestinal infection, absence of sensory symptoms or signs, and absence of cranial nerve involvement. Patients with anti-GD1a antibody were younger, predominantly male, and had more facial nerve involvement than the antibody-negative group. Anti-GT1a-antibody positivity was more frequently associated with bulbar weakness and was highly associated with ophthalmoplegia when coupled with the coexisting anti-GQ1b antibody. Despite the presence of clinical features of acute motor axonal neuropathy (AMAN), 68% of anti-GM1- or anti-GD1a-antibody-positive cases of GBS were diagnosed with acute inflammatory demyelinating polyradiculoneuropathy (AIDP) by a single electrophysiological study.

Conclusions

Anti-ganglioside antibodies were frequently found in the serum of Korean GBS patients, and each antibody was correlated strongly with the various clinical manifestations. Nevertheless, without an anti-ganglioside antibody assay, in Korea AMAN is frequently misdiagnosed as AIDP by single electrophysiological studies.     

Anti‐ganglioside antibodies in Guillain–Barré syndrome and chronic inflammatory demyelinating polyneuropathy in Chinese patients

Introduction: In this study we investigated the relationships between anti‐ganglioside antibodies and Guillain–Barré syndrome (GBS) and chronic inflammatory demyelinating polyneuropathy (CIDP). Methods: Samples from 48 Chinese patients diagnosed with GBS and 18 patients diagnosed with CIDP were retrospectively reviewed. Results: In the GBS patients, 62.5% were classified as having acute inflammatory demyelinating polyneuropathy (AIDP), 27.1% were found to have acute motor axonal neuropathy (AMAN), and 10.4% were unclassified. Serum IgG anti‐ganglioside antibodies were detected in 46.2% of the AMAN patients and in 6.7% of the AIDP patients (P < 0.05); 5.6% of the 18 CIDP patients were IgG antibody positive, and 27.8% were IgM antibody positive. Facial palsy and sensory impairment were significantly associated with IgM antibodies. Conclusions: These results suggest that IgG anti‐GM1 antibodies are associated with AMAN, but not with AIDP, and that IgM antibodies against GM1, GM2, and GM3 are associated with facial nerve palsy. Muscle Nerve 55 : 470–475, 2017     

Patología axonal en la fase precoz del síndrome de Guillain-Barré

IntroductionGuillain-Barré syndrome (GBS) is an acute-onset, immune-mediated disease of the peripheral nervous system. It may be classified into 2 main subtypes: demyelinating (AIDP) and axonal (AMAN). This study aims to analyse the mechanisms of axonal damage in the early stages of GBS (within 10 days of onset).DevelopmentWe analysed histological, electrophysiological, and imaging findings from patients with AIDP and AMAN, and compared them to those of an animal model of myelin P2 protein-induced experimental allergic neuritis. Inflammatory oedema of the spinal nerve roots and spinal nerves is the initial lesion in GBS. The spinal nerves of patients with fatal AIDP may show ischaemic lesions in the endoneurium, which suggests that endoneurial inflammation may increase endoneurial fluid pressure, reducing transperineurial blood flow, potentially leading to conduction failure and eventually to axonal degeneration. In patients with AMAN associated with anti-ganglioside antibodies, nerve conduction block secondary to nodal sodium channel dysfunction may affect the proximal, intermediate, and distal nerve trunks. In addition to the mechanisms involved in AIDP, active axonal degeneration in AMAN may be associated with nodal axolemma disruption caused by anti-ganglioside antibodies.ConclusionInflammatory oedema of the proximal nerve trunks can be observed in early stages of GBS, and it may cause nerve conduction failure and active axonal degeneration.     

Anti-ganglioside antibody and neuropathy: review of our research

Some patients developed Guillain-Barré syndrome (GBS) after the administration of bovine gangliosides. Patients with GBS subsequent to Campylobacter jejuni enteritis frequently have IgG antibody to GM1 ganglioside. Fisher's syndrome (FS), a variant of GBS, is associated with IgG antibody to GQ1b ganglioside. We showed the existence of molecular mimicry between GM1 and lipopolysaccharide (LPS) of C. jejuni isolated from a GBS patient, and that between GQ1b and C. jejuni LPSs from FS patients. Several lines of evidence suggest a pathogenic role for anti-ganglioside antibodies. Some patients developed sensorimotor polyneuropathy after anti-GD2 antibody administration. Anti-GM1 antibody can block motor nerve conduction. The molecular mimicry between infectious agents and gangliosides may function in the production of anti-ganglioside antibodies and the development of GBS and FS. Anti-GQ1b IgG antibody is detected also in Bickerstaff's brainstem encephalitis and acute ophthalmoparesis, which suggests that these conditions are categorized as autoimmune diseases related to FS. Since a tryptophan-immobilized column effectively adsorb anti-GQ1b IgG antibody, immunoadsorption with the column should be considered as an alternative form of plasmapheresis for the anti-GQ1b IgG antibody syndrome.     

Anti-GM1b IgG antibody is associated with acute motor axonal neuropathy and Campylobacter jejuni infection

Anti-GM1 and anti-GM1b antibodies are frequently present in patients with Guillain-Barré syndrome (GBS) and accordingly, the two antibodies often coexist in the same patient. In order to study clinical and laboratory features of anti-GM1b-positive GBS, we analyzed the data of patients with anti-GM1b IgG antibody but no anti-GM1 IgG antibody. Of 86 consecutive patients, 10 had anti-GM1b antibody alone and frequently had acute motor axonal neuropathy (AMAN, 80%) and Campylobacter jejuni infection (60%). Of 10 patients with anti-GM1 antibody alone, four had AMAN, and two had C. jejuni infection. These results showed that GM1b could be a target molecule of autoantibody in the AMAN form of GBS subsequent to C. jejuni infection.     

Anti-GD1a antibody is associated with axonal but not demyelinating forms of Guillain-Barré syndrome

Immunopathological studies suggest that the target of immune attack is different in the subtypes of Guillain-Barré syndrome (GBS). In acute motor axonal neuropathy (AMAN), the attack appears directed against the axolemma and nodes of Ranvier. In acute inflammatory demyelinating polyneuropathy (AIDP), the attack appears directed against a component of the Schwann cell. However, the nature of the antigenic targets is still not clear. We prospectively studied 138 Chinese GBS patients and found that IgG anti-GD1a antibodies were closely associated with AMAN but not AIDP. With a cutoff titer of greater than 1:100, 60% of AMAN versus 4% of AIDP patients had IgG anti-GD1a antibodies; with a cutoff titer of greater than 1:1,000, 24% of AMAN patients and none of the AIDP patients had IgG anti-GD1a antibodies. In contrast, low levels of IgG anti-GM1 antibodies (>1:100) were detected in both the AMAN and the AIDP forms (57% vs 35%, NS). High titers of IgG anti-GM1 (>1:1,000) were more common in the AMAN form (24% vs 8%, NS). Serological evidence of recent Campylobacter infection was detected in 81% of AMAN and 50% of AIDP patients, and anti-ganglioside antibodies were common in both Campylobacter-infected and noninfected patients. Our results suggest that IgG anti-GD1a antibodies may be involved in the pathogenesis of AMAN. Ann Neurol 1999;45:168–173     

Guillain-Barré syndrome: An update

Guillain-Barré syndrome (GBS) is an acute polyneuropathy consisting of different subtypes. Acute inflammatory demyelinating polyradiculoneuropathy, the classic demyelinating form of GBS, accounts for 90% of all GBS cases in the Western world. Acute motor axonal neuropathy (AMAN) and acute motor and sensory axonal neuropathy (AMSAN) are axonal forms of GBS that are more prevalent in Asia, South and Central America, often preceded by infection by Campylobacter jejuni. AMAN and AMSAN may be mediated by specific anti-ganglioside antibodies that inhibit transient sodium ion (Na⁺) channels. The efficacy of plasmapheresis and intravenous immunoglobulin has been established in large international randomised trials, with corticosteroids proven ineffective. Although axonal demyelination is an established pathophysiological process in GBS, the rapid improvement of clinical deficits with treatment is consistent with Na⁺ channel blockade by antibodies or other circulating factors, such as cytokines. This review provides an update on the epidemiology, clinical features, diagnosis, pathogenesis and treatment of GBS.     

Ganglioside mimicry and peripheral nerve disease

Four criteria must be satisfied to conclude that a given microorganism causes Guillain-Barré (GBS) or Fisher (FS) syndrome associated with anti-ganglioside antibodies: (1) an epidemiological association between the infecting microbe and GBS or FS; (2) isolation in the acute progressive phase of illness of that microorganism from GBS or FS patients with associated anti-ganglioside IgG antibodies; (3) identification of a microbial ganglioside mimic; and (4) a GBS or FS with associated anti-ganglioside antibodies model produced by sensitization with the microbe itself or its component, as well as with ganglioside. Campylobacter jejuni is a definitive causative microorganism of acute motor axonal neuropathy and may cause FS and related conditions. Haemophilus influenzae and Mycoplasma pneumoniae are possible causative microorganisms of acute motor axonal neuropathy or FS. Acute and chronic inflammatory demyelinating polyneuropathies may be produced by mechanisms other than ganglioside mimicry.     

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.     

Temporal profile of anti-ganglioside antibodies and their relation to clinical parameters and treatment in Guillain-Barré syndrome

Elevated anti-ganglioside antibody levels mainly of anti-GM1 and anti-GD1a specificities have been reported in THE serum of patients with Guillain–Barré syndrome (GBS). The relevance of anti-ganglioside antibodies other than anti-GM1 and anti-GD1a IgG antibodies and the temporal profile of anti-ganglioside antibodies in GBS is less clear. We studied serum antibodies to GM1, GD1a, GD1b, GQ1b, sulfatide and cardiolipin of the IgM, IgG and IgA classes over the course of GBS in patients who were untreated or treated with highdose intravenous immunoglobulin (IvIg). Antibodies to GD1b, GQ1b, sulfatide and cardiolipin were not detected in the sera of the GBS patients examined in this study. Anti-GM1 IgG titers peaked around 40 days and anti-GD1a IgM around 90 days after GBS onset. Titers of anti-GM1 IgG antibodies decreased following IvIg treatment. Patients with antibody peaks, defined as fivefold or higher increase in antibody titer compared to the lowest antibody titer over the course of GBS, had higher disability scores during the first two weeks of GBS and a worse clinical outcome (anti-GM1 IgG and anti-GD1a IgM antibody peaks) and axonal damage (anti-GD1a IgM antibody peaks), compared to patients without peak antibody titers. Anti-GM1 IgG and anti-GD1a IgM antibodies are thus strongly associated with more severe- and predominantly axonal cases of GBS. The appearance of anti-GM1 IgG and anti-GD1a antibody peaks in the serum after the termination of the acute phase of GBS suggests that these antibodies are produced secondary to nerve damage in GBS. The data does not exclude the possibility that secondarily secreted anti-GM1 IgG and anti-GD1a IgM antibodies may themselves be biologically active and play a role in disease propagation and/or recovery from disease in some patients with GBS.