Antiganglioside antibodies in Guillain-Barré syndrome and its related conditions

Guillain-Barré syndrome (GBS) is typically classified into two major subtypes: acute inflammatory demyelinating neuropathy and acute motor axonal neuropathy. Its most recognizable variant is Fisher syndrome. The last two decades have seen considerable advances in our understanding of GBS. Of note, various autoantibodies against ganglioside antigens have been identified and found to have significant associations with the axonal forms of GBS and Fisher syndrome. In this article, we discuss the different clinical presentations in GBS and the role of antiganglioside antibodies in their underlying pathogenesis. We also discuss the impact that antiganglioside antibodies have had in the development of experimental models and treatment modalities in GBS.     

Primary cytomegalovirus infection in patients with Guillain-Barré syndrome

Guillain-Barré syndrome (GBS) is frequently associated with the presence of CMV-specific IgM-antibodies or CMV-DNA in serum. Detection of IgM-antibodies or viremia may indicate primary infection, but also reactivation or reinfection. We identified 46 GBS patients with detectable CMV-specific IgM- or IgG-antibodies, or both. Sera from these patients were tested for the presence of CMV-specific, low-avidity IgG-antibodies, which indicate primary infection that occurred <6 months before sample collection, and for the presence of CMV-DNA by polymerase chain reaction (PCR). Primary infection was identified by the presence of low-avidity IgG-antibodies in 9/46 (20%) or by detection of IgM-antibodies in the absence of IgG-antibodies in 1/46 (2%) patients. CMV-DNA was detectable in 17/46 (37%) sera. In contrast, CMV-DNA was detected in only 2% of sera from 46 age-matched patients with neuroborreliosis. The likelihood of viremia decreased in GBS patients significantly with increasing antibody-avidity (P=0.041). Detection of IgM-antibodies correlated with that of CMV-DNA in patients with low-avidity IgG-antibodies (P=0.048) but not in those with high-avidity IgG-antibodies (P=0.543). In 45 age-matched healthy controls, low-avidity IgG-antibodies and CMV-DNA were detected in only 2% and 0% of sera, respectively. Our findings further strengthen evidence for an association between CMV infection and GBS. Primary CMV infection was identified in almost one-fourth of patients with detectable CMV-specific antibodies. Nevertheless, endogenous reactivation and reinfection have to be considered also as relevant events associated with GBS.     

An adolescent with pharyngeal-cervical-brachial variant of Guillain-Barré syndrome after cytomegalovirus infection

A 15-year-old Japanese girl developed bulbar palsy and upper limb-dominant muscle weakness 2 weeks after the onset of an upper respiratory tract infection due to cytomegalovirus (CMV). Her symptoms resembled that seen in the pharyngeal-cervical-brachial variant (PCB) of Guillain-Barré syndrome (GBS). Although bulbar palsy usually continues for several months in PCB, her bulbar palsy was very mild and improved rapidly before intravenous immunoglobulin therapy was instituted. Serum anti-GT1a IgG antibody titer was elevated at the acute phase of the disease and gradually decreased. The bulbar palsy-dominant GBS is thought to relate to anti-GT1a antibody and Campylobacter jejuni infection in adult patients. Our Case report suggests that CMV can also induce the production of anti-GT1a antibody, thereby resulting in PCB. When one sees acute onset bulbar palsy and limb muscle weakness, the possibility of PCB, even in children, should be considered, thus compelling the need for serum anti-ganglioside antibody measurement.     

Guillain-Barré syndrome after a jellyfish sting

This is the case of a jellyfish sting associated with the rare development of Guillain-Barré syndrome. The patient, a 66-year-old woman, was stung by a jellyfish on the right thigh while swimming in the Atlantic Ocean, off Charleston, SC. Ten days later, she developed low back and right thigh pain followed by progressive numbness and weakness in all extremities. These symptoms reached their peak in 30 days and slowly began to improve. Initial neurologic examination showed areflexia, weakness, absent vibration and position sense, and hyperesthesia to pin and light touch in the mid to distal region of all four extremities. Serial electromyography and nerve conductions were consistent with an improving predominantly demyelinating polyneuropathy. Spinal fluid analysis showed no cells, elevated protein (108), gammaglobulin 6 (normal less than 5.4), and immunoglobulin G 8.2 (normal less than 6). The only treatment was gabapentin for neuropathy pain. The patient made an excellent recovery in less than 1 year with minimal residual numbness in both thumbs, index fingers, and middle toes.     

Guillain-Barré syndrome and optic neuritis after Mycoplasma pneumoniae infection

We report the case of a 12-year-old girl who developed Guillain-Barré syndrome (GBS) and optic neuritis (ON) following Mycoplasma pneumoniae infection.Her symptoms, including bilateral vision impairment and tingling in her hands and right foot, were resolved after methylprednisolone pulse therapy. Serum anti-galactocerebroside (Gal-C) IgM antibodies were detected in our patient.This is the first report of a child with GBS and ON associated with M. pneumoniae infection.     

Intravenous immunoglobulins neutralize blocking antibodies in Guillain-Barré syndrome

Intravenous immunoglobulin (IVIg) treatment ameliorates the course of Guillain-Barré syndrome (GBS), but its specific mode of action is unknown. We attempted to delineate the effect of IVIg on neuromuscular blocking antibodies in GBS. A total of seven GBS serum samples were examined for blocking antibodies and the effect of IVIg with a macro-patch-clamp technique in mouse hemidiaphragms. First, serum was tested before and after treatment with IVIg. Second, we investigated with coincubation experiments whether the IVIg was capable of neutralizing neuromuscular blocking antibodies in GBS serum or affinity-purified immunoglobulin G (IgG) fractions. Finally, the mechanism of the neutralizing effect was studied by the coincubation of active blocking GBS IgG with Fab and Fc fragments prepared from IVIg. All GBS sera (two adults and two children) and GBS IgG fractions (three adults) taken before treatment with IVIg blocked evoked quantal release by approximately 90%. Blocking activity was markedly reduced in sera obtained after treatment with IVIg. Coincubation of the pretreatment blocking serum with the posttreatment serum, or with the IVIg preparation used for treatment, reduced the blocking activity of the pretreatment GBS serum. When GBS IgG was coincubated with IVIg, the blocking activity of GBS IgG was diminished dose-dependently. Monovalent and divalent Fab fragments prepared from the IVIg were as effective as whole IVIg, but Fc fragments were ineffective. Therapeutic IVIg is capable of neutralizing neuromuscular blocking antibodies in GBS by a dose-dependent, antibody-mediated mechanism. This may, in part, explain its therapeutic efficacy.     

Anti-GT1a IgG antibodies in a child with severe Guillain-Barré syndrome

This report describes a male, age 8 years 10 months, with severe Guillain-Barré syndrome after Campylobacter jejuni infection. The patient developed fulminant muscle weakness, external ophthalmoplegia, bulbar palsy, and respiratory distress. A high level of serum monospecific anti-GT1a immunoglobulin G antibody was detected. He was treated with intravenous immunoglobulins and artificial ventilation. Two years after the onset, the patient still suffered from residual leg weakness and foot drop. After 3 years and clinical recovery, the antibody was no longer detectable. This report presents the first case in childhood suggesting an association between a severe Guillain-Barré syndrome after C. jejuni enteritis with monospecific anti-GT1a immunoglobulin G antibody.     

Origin of ganglioside complex antibodies in Guillain-Barré syndrome

The origin of antibodies to ganglioside complexes, as new immunotargets for Guillain-Barré syndrome (GBS), is unknown. This was investigated in 21 GBS patients from which Campylobacter jejuni was isolated. Two of these patients had serum IgG to the GM1/GD1a complex and two other patients had IgG to the GQ1b/GD1a complex. These pairs of patients were clinically distinct. These antibodies all cross-reacted to lipo-oligosaccharides (LOS) from the autologous C. jejuni strain. Previous mass spectrometry studies on these LOS showed the presence of oligosaccharides with a similar structure, further supporting the hypothesis that in these patients LOS induced the ganglioside complex antibodies.     

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.     

Guillain-Barré syndrome in an immunocompromised patient and coccidioidomycosis infection

A 70-year-old man was referred for evaluation of a 2-week history of numbness and progressive weakness in his lower and upper extremities and subsequently diagnosed with Guillain-Barré syndrome. The patient had been taking mycophenolate mofetil 500 mg twice daily and tacrolimus 6 mg daily for immunosuppression following a kidney transplant 2 years earlier. However, 5 weeks prior to presentation he had been diagnosed with pneumonia due to coccidioidomycosis and his tacrolimus dose was reduced to 1 mg daily to prevent a drug interaction with fluconazole, which was prescribed to treat the coccidioidomycosis infection. The authors surmise that the reduced tacrolimus dose, coupled with a relatively low maintenance dose of mycophenolate mofetil, left the patient less immunosuppressed and therefore able to mount an immune response to the coccidioidomycosis infection, resulting in Guillain-Barré syndrome. This is the first known report of an association between coccidioidomycosis infection and Guillain-Barré syndrome.     

Anti-GT1a IgG in Guillain-Barré syndrome

OBJECTIVE: To investigate the presence of serum anti-GT1a IgG in Guillain-Barré syndrome (GBS) and its relation to clinical manifestations. BACKGROUND: Several patients with GBS and bulbar palsy have been reported to have serum anti-GT1a IgG. Most, however, also have anti-GQ1b IgG. A previous study failed to detect GT1a in human cranial nerves, but GQ1b was abundant in human ocular motor nerves. Whether anti-GT1a IgG itself determines the clinical manifestations is not yet clear. METHODS: The association of clinical manifestations with the presence of anti-GT1a IgG and with its cross reactivity was investigated. An immunochemical study was performed to determine whether GT1a is present in human cranial nerves. RESULTS: Anti-GT1a and anti-GQ1b IgG were positive in 10% and 9% respectively of 220 consecutive patients with GBS. Patients with anti-GT1a IgG often had cranial nerve palsy (ophthalmoparesis, 57%; facial palsy, 57%; bulbar palsy, 70%), and 39% needed artificial ventilation. These features were also seen in patients with anti-GQ1b IgG. There was no significant difference between the two groups with respect to the frequency of clinical findings. An enzyme-linked immunosorbent assay showed that anti-GT1a IgG cross reacted with GQ1b in 75% of the patients, GD1a in 30%, GM1 in 20%, and GD1b in 20%. All five patients who carried anti-GT1a IgG that did not cross react with GQ1b had bulbar palsy, neck weakness, absence of sensory disturbance, and positive Campylobacter jejuni serology. Thin-layer chromatography with immunostaining showed that GT1a is present in human oculomotor and lower cranial nerves. CONCLUSIONS: These findings provide further evidence that anti-GT1a IgG itself can determine clinical manifestations. The distinctive clinical features of patients with anti-GT1a IgG without anti-GQ1b activity distinguish a specific subgroup within GBS.     

Pharyngeal-cervical-brachial variant Guillain-Barré syndrome in a child

The pharyngeal-cervical-brachial variant of Guillain-Barré syndrome is uncommon but well recognized in the adult literature. Patients have weakness in a pharyngeal-cervical-brachial distribution with relative lower limb sparing. We describe a 12-year-old boy with predominantly pharyngeal-cervical-brachial weakness and subsequent respiratory failure. Owing to prominent bulbar symptoms, he was initially misdiagnosed as having epiglottitis. This case illustrates that the clinical spectrum of Guillain-Barré syndrome in children includes the pharyngeal-cervical-brachial variant, which is distinct from Miller-Fisher syndrome. Atypical Guillain-Barré syndrome should be considered in the differential diagnosis of a child presenting with bulbar palsy and/or respiratory failure.     

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.