anti-GQ1b Ganglioside Antibodies Research Articles

Case Report: Isolated, unilateral oculomotor palsy with anti-GQ1b antibody following COVID-19 vaccination

Neurological complications following vaccinations are extremely rare, but cannot be eliminated. Here, we report the first case of unilateral oculomotor nerve palsy (ONP) with anti-GQ1b antibody after receiving the Pfizer-BioNTech COVID-19 (BNT162b2) mRNA vaccine. A 65-year-old man developed diplopia and ptosis in the right eye 17 days after vaccination, without preceding infection. Neurological examination revealed mild blepharoptosis, limitation of adduction, and vertical gaze on the right side. Increased levels of anti-GQ1b ganglioside antibody in the serum and albuminocytologic dissociation in the cerebrospinal fluid were detected. Cranial magnetic resonance imaging showed swelling and enhancement of the right oculomotor nerve. The patient was diagnosed with right ONP accompanied with anti-GQ1b antibody, and intravenous immunoglobulin (IVIG) therapy for 5 days was administered. The limitation of adduction and vertical gaze improved, and ptosis markedly resolved after IVIG treatment. Given the temporal sequence of disease progression, laboratory findings, and a favorable response to IVIG, a causal relationship cannot be ruled out between the occurrence of ONP and COVID-19 immunization. Since immunomodulatory treatments significantly hasten the recovery and minimize the residual symptoms in anti-GQ1b antibody syndrome, clinicians should be aware of this clinical condition following COVID-19 vaccination.

P-PN007. A case presenting with clinical and laboratory characteristics of fisher syndrome and lambert-eaten myasthenic syndrome (LEMS)

Introduction . Although Fisher syndrome and LEMS are classified into autoimmune neuromuscular diseases, we cannot find the coincidence of them in a single patient in the previous literature. Results . A 70-year-old female was admitted to our hospital because of bilateral hand numbness, double vision and unsteadiness which had developed 2 weeks. She had no history of preceding infection and/or related illness. On admission, her condition was characterized by mydriasis, extraocular muscle weakness, mild proximal muscle weakness and truncal ataxia. In addition, the tendon reflexes were absent at rest, and improved with brief exercise. Motor nerve conduction studies showed significantly low compound muscle action potentials (CMAPs) and increments of more than 200% after brief exercise (post-exercise facilitation) in several nerves. Sensory nerve conduction studies showed significantly low sensory nerve action potential (SNAPs) of median and ulnar nerves, and normal SNAPs of sural nerves. We also demonstrated the impairment of neuromuscular transmission in several muscles based on abnormal decrements in the repetitive nerve stimulation (RNS) test and abnormal jitter in the single-fiber electromyography (SFEMG). Both anti-GQ1b and GT1a ganglioside antibodies and P/Q-type voltage-gated calcium channel (VGCC) antibodies were positive in her sera. Her conditions improved spontaneously. She accomplished walking alone in six weeks, and paralysis of the eye muscles recovered in five months. Median and ulnar SNAPs returned to normal in accordance with recovery of clinical findings. On the other hand, low CMAPs with post-exercise facilitation remained after complete recovery. Positron emission tomography and gastrointestinal endoscopy did not show any malignancy. Conclusion . Some electrophysiological studies revealed the impairment of neuromuscular transmission using RNS and/or SFEMG in patients with Fisher syndrome. Also, it has been known that autoimmune neurological phenotypes are diverse among patients with P/Q-type VGCC antibodies. This may be the first case who showed clinical and laboratory characteristics of Fisher syndrome and LEMS simultaneously.

Determining the Utility of the Guillain-Barré Syndrome Classification Criteria.

Background and PurposeSeveral variants of Guillain-Barré syndrome (GBS) and Miller Fisher syndrome (MFS) exist, but their frequencies vary in different populations and do not always meet the inclusion criteria of the existing diagnostic criteria. However, the GBS classification criteria by Wakerley and colleagues recognize and define the clinical characteristics of each variant. We applied these criteria to a GBS and MFS cohort with the aim of determining their utility.MethodsConsecutive GBS and MFS patients presenting to our center between 2010 and 2020 were analyzed. The clinical characteristics, electrophysiological data, and antiganglioside antibody profiles of the patients were utilized in determining the clinical classification.ResultsThis study classified 132 patients with GBS and its related disorders according to the new classification criteria as follows: 64 (48.5%) as classic GBS, 2 (1.5%) as pharyngeal-cervical-brachial (PCB) variant, 7 (5.3%) as paraparetic GBS, 29 (22%) as classic MFS, 3 (2.3%) as acute ophthalmoparesis, 2 (1.5%) as acute ataxic neuropathy, 2 (1.5%) as Bickerstaff brainstem encephalitis (BBE), 17 (12.9%) as GBS/MFS overlap, 4 (3%) as GBS/BBE overlap, 1 (0.8%) as MFS/PCB overlap, and 1 (0.8%) as polyneuritis cranialis. The electrodiagnosis was demyelinating in 55% of classic GBS patients but unclassified in 79% of classic MFS patients. Anti-GM1, anti-GD1a, anti-GalNAc-GD1a, and anti-GD1b IgG ganglioside antibodies were more commonly detected in the axonal GBS subtype, whereas the anti-GQ1b and anti-GT1a IgG ganglioside antibodies were more common in classic MFS and its subtypes.ConclusionsMost of the patients in the present cohort met the criteria of either classic GBS or MFS, but variants were seen in one-third of patients. These findings support the need to recognize variants of both syndromes in order to achieve a more-complete case ascertainment in GBS.

Clinical Characteristic Analysis of Seven Children With Bickerstaff Brainstem Encephalitis in China.

Objective: To summarize the clinical, electrophysiological, neuroimaging, and immunological characteristics of seven cases of Bickerstaff brainstem encephalitis (BBE) in China and to determine whether certain clinical features suggestive of BBE can facilitate diagnosis and treatment.Patients and Methods: The clinical data of seven BBE patients treated at the Children's Hospital of Fudan University between 2016 and 2019 were retrospectively analyzed. The clinical and laboratory characteristics of the BBE patients were studied.Results: The seven patients in this study included four females and three males, and the median age at diagnosis was 5.3 years (interquartile range: 3.0–7.1 years). All seven patients had an acute onset with a preinfection history. Seven cases of acute extraocular paralysis, ataxia, and an impaired level of consciousness, two cases of tendon hyperreflexia, one case of positive pathology, and five cases of cranial nerve involvement (the facial nerve and oculomotor nerve) were noted. Cerebrospinal fluid (CSF) examination of five patients showed albuminocytologic dissociation. Electromyography (EMG) was used to examine seven patients; the results were normal in four patients, showed axonal involvement in two patients, and showed demyelination in one patient. The head magnetic resonance imaging (MRI) results of all seven patients were normal. Electroencephalogram (EEG) background activity in the five monitored patients was slowed down. Seven patients underwent serum antibody testing, three of whom were positive for anti-GQ1b antibody, while one was positive for anti-GM1 antibody. Three patients received glucocorticoid combined with intravenous immunoglobulin (IVIG) therapy, and four received only IVIG therapy. One patient required a nasal catheter for oxygen during the disease course, and left upper limb muscle dysfunction (grade III muscle strength of the left upper limb) was observed during the 6-month follow-up. The other six patients had a good prognosis and no dysfunction.Conclusion: Our study identified clinical, imaging, and treatment characteristics that may have prognostic value for pediatric BBE. The positive rate of head MRI was low, the positive rate of serum anti-GQ1b ganglioside antibody was low, and the therapeutic effect of IVIG therapy was good.

Acute Sensory Neuropathy and Progressive Dysphagia with Anti-GQ1b Antibody Positive: A Case Report

Anti-GQ1b ganglioside antibody is associated with ophthalmoplegia, ataxia, and areflexia, resulting in the development of Miller Fisher Syndrome (MFS), Guillain-BarrA© Syndrome (GBS) with ophthalmoplegia and Bickerstaff brainstem encephalitis...

Bilateral abducens palsy in a case of cytomegalovirus-associated Guillain–Barré syndrome

Ophthalmoparesis in cytomegalovirus (CMV)-associated Guillain-Barré syndrome (GBS) is rare. We treated a 37-year-old woman with CMV-GBS who presented with an acute onset of generalized weakness and numbness in the extremities, followed by facial diplegia, which led to mechanical ventilation. She had increased IgM and IgG-type antibodies against CMV in the serum and increased IgM-type serum anti-GM2 ganglioside antibody was also noted, whereas anti-GQ1b ganglioside antibody was not found. She then developed the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). After recovery of consciousness due to SIADH, she exhibited bilateral abducens palsy, together with the recurrence of limb weakness and facial diplegia. Her neurological signs gradually recovered after high-dose intravenous administrations of immunoglobulin. CMV infection should be listed in the differential diagnosis of GBS patients who present with ophthalmoparesis.

Eculizumab prevents anti-ganglioside antibody-mediated neuropathy in a murine model

Anti-GQ1b ganglioside antibodies are the serological hallmark of the Miller Fisher syndrome (MFS) variant of the paralytic neuropathy, Guillain-Barré syndrome, and are believed to be the principal pathogenic mediators of the disease. In support of this, we previously showed in an in vitro mouse model of MFS that anti-GQ1b antibodies were able to bind and disrupt presynaptic motor nerve terminals at the neuromuscular junction (NMJ) as one of their target sites, thereby causing muscle paralysis. This injury only occurred through activation of complement, culminating in the formation and deposition of membrane attack complex (MAC, C5b-9) in nerve membranes. Since this step is crucial to the neuropathic process and an important convergence point for antibody and complement mediated membrane injury in general, it forms an attractive pharmacotherapeutic target. Here, we assessed the efficacy of the humanized monoclonal antibody eculizumab, which blocks the formation of human C5a and C5b-9, in preventing the immune-mediated motor neuropathy exemplified in this model. Eculizumab completely prevented electrophysiological and structural lesions at anti-GQ1b antibody pre-incubated NMJs in vitro when using normal human serum (NHS) as a complement source. In a novel in vivo mouse model of MFS generated through intraperitoneal injection of anti-GQ1b antibody and NHS, mice developed respiratory paralysis due to transmission block at diaphragm NMJs, resulting from anti-GQ1b antibody binding and complement activation. Intravenous injection of eculizumab effectively prevented respiratory paralysis and associated functional and morphological hallmarks of terminal motor neuropathy. We show that eculizumab protects against complement-mediated damage in murine MFS, providing the rationale for undertaking clinical trials in this disease and other antibody-mediated neuropathies in which complement activation is believed to be involved.

Complement inhibition abrogates nerve terminal injury in Miller Fisher syndrome

A large body of clinical and experimental data indicate that complement activation is an important mechanism for neuronal and glial injury in Guillain-Barré syndromes. Inhibition of complement activation therefore might be expected to limit the progression of the disease. Using in vitro and in vivo models of the Guillain-Barré syndrome variant, Miller Fisher syndrome, we have shown previously that anti-GQ1b ganglioside antibodies target the presynaptic motor nerve terminal axon and surrounding perisynaptic Schwann cells, thereby mediating destructive injury through deposition of membrane attack complex. Here, we have used this model to investigate the effects of a novel therapeutic inhibitor of complement activation, APT070 (Mirococept), both in vitro and in vivo. In these models, APT070 completely prevents membrane attack complex formation, and thereby has a major neuroprotective effect at the nerve terminal, as assessed by immunohistology of perisynaptic Schwann cell and axonal integrity. These data provide a rationale for considering clinical trials of APT070 in Guillain-Barré syndrome, its variant forms, and other complement dependent neuromuscular disorders.

Electrophysiological evidence by single fibre electromyography of neuromuscular transmission impairment in a case of Miller Fisher syndrome

Miller Fisher syndrome is an autoimmune neuropathy characterised by ataxia, areflexia and ophthalmoplegia, with minimal if any limb weakness, and in the majority of cases by high titres of IgG anti-GQ1b ganglioside antibodies. In vitro electrophysiological experiments have demonstrated that these antibodies induce a transmission blockade at neuromuscular junction either pre- or post-synaptically. We report the case of a 63-year-old man with MFS that shows blood serum negative for anti-GQ1b but presents an impairment of neuromuscular transmission detected by single fibre electromyography. To the best of our knowledge, this represents the first case in the literature using jitter technique and suggests that other antibodies may be involved in the function of motor end plates by bindings to the synaptic membranes.

Anti-GQ1b ganglioside antibody in peripheral nervous system disorders: pathophysiologic role and clinical relevance.

The recent literature about autoimmune peripheral neuropathies has been dominated by the discovery of antibodies to a variety of glycosphingolipids. Gangliosides are important carbohydrate determinants for autoimmune activity, and several studies have suggested that serum antibodies against gangliosides are responsible for some forms of acute and chronic neuropathy syndromes. However, this view is disputable, and despite substantial progress in understanding the potential pathogenic effects of antiganglioside antibodies, many central issues remain unresolved across the whole pathogenic process. Miller Fisher syndrome has been classified as a variant of Guillain-Barré syndrome that comprises the clinical triad of ataxia, areflexia, and ophthalmoplegia. It has been considered the archetypal antiganglioside antibody-mediated human neuropathy because anti-GQ1b ganglioside antibody is detected in most patients with Miller Fisher syndrome, decays rapidly with clinical recovery, and is not found in normal and disease control serum samples. The only other case in which this antibody is found is in patients with related conditions, which might share the same pathogenic mechanism, such as Bickerstaff brainstem encephalitis. The strength of this close serologic-clinical association is such that measurement of anti-GQ1b antibody in suspected cases of Miller Fisher syndrome is a useful diagnostic marker for clinicians. This article reviews the occurrence, the pathophysiologic role, and the clinical background of anti-GQ1b ganglioside antibody in Miller Fisher syndrome and related disorders.

Calpain inhibitors protect against axonal degeneration in a model of anti-ganglioside antibody-mediated motor nerve terminal injury.

Miller Fisher syndrome-associated anti-GQ1b ganglioside antibodies produce an acute complement-dependent neuroexocytic effect at the mouse neuromuscular junction (NMJ) that closely resembles the effect of alpha-latrotoxin (LTx). This pathophysiological effect is accompanied by morphological disruption of the nerve terminal involving the loss of major cytoskeletal components, including neurofilament. Both LTx and the membrane attack complex of complement form membrane pores that allow free ionic movement and we have previously hypothesized that Ca2+ ingress and the subsequent activation of Ca2+-dependent proteases, calpains, may lead to substrate degradation resulting in structural disorganization of the terminal. Here, we treated mouse NMJs in hemidiaphragm preparations with anti-GQ1b antibodies and complement, or with LTx in the presence and absence of extracellular Ca2+, and studied possible neuroprotective effects of the calpain inhibitors calpeptin and calpain inhibitor V. Both Ca2+ depletion and calpain inhibition protected the cytoskeleton from degradation, as assessed by immunohistological and ultrastructural analysis. Calpain inhibitors may therefore be useful therapeutically in limiting nerve terminal and axonal injury in autoimmune peripheral neuropathy and in human latrodectism.

Anti-GQ1b ganglioside antibodies mediate complement-dependent destruction of the motor nerve terminal.

Miller-Fisher syndrome is an autoimmune neuropathy characterized by ataxia, areflexia and ophthalmoplegia, and in the majority of cases the presence of high titres of anti-GQ1b ganglioside antibodies. In an ex vivo model, human and mouse anti-GQ1b antibodies have been shown previously to induce a complement-dependent alpha-latrotoxin-like effect on the murine motor endplate, i.e. they bring about massive quantal release of acetylcholine and eventually block neuromuscular transmission. Using immunofluorescence microscopy with image analysis, we show here that the late stages of this electrophysiological effect temporally coincide with the loss of heavy neurofilament (200 kDa) and type III beta-tubulin immunostaining and structural breakdown of the nerve terminal, as demonstrated by electron microscopy. Ultrastructurally, axon terminals were disorganized, depleted of vesicles, and subdivided by the infiltrating processes of capping Schwann cells. These findings provide clear pathological evidence to support a role for anti-ganglioside antibodies in mediating nerve terminal injury and further advance the view that this site may be of importance as a target in some human neuropathies.

Monoclonal antibodies raised against Guillain-Barré syndrome-associated Campylobacter jejuni lipopolysaccharides react with neuronal gangliosides and paralyze muscle-nerve preparations.

Guillain-Barré syndrome and its variant, Miller-Fisher syndrome, are acute, postinfectious, autoimmune neuropathies that frequently follow Campylobacter jejuni enteritis. The pathogenesis is believed to involve molecular mimicry between sialylated epitopes on C. jejuni LPSs and neural gangliosides. More than 90% of Miller-Fisher syndrome cases have serum anti-GQ1b and anti-GT1a ganglioside antibodies that may also react with other disialylated gangliosides including GD3 and GD1b. Structural studies on LPS from neuropathy-associated C. jejuni strains have revealed GT1a-like and GD3-like core oligosaccharides. To determine whether this structural mimicry results in pathogenic autoantibodies, we immunized mice with GT1a/GD3-like C. jejuni LPS and then cloned mAb's that reacted with both the immunizing LPS and GQ1b/GT1a/GD3 gangliosides. Immunohistology demonstrated antibody binding to ganglioside-rich sites including motor nerve terminals. In ex vivo electrophysiological studies of nerve terminal function, application of antibodies either ex vivo or in vivo via passive immunization induced massive quantal release of acetylcholine, followed by neurotransmission block. This effect was complement-dependent and associated with extensive deposits of IgM and C3c at nerve terminals. These data provide strong support for the molecular mimicry hypothesis as a mechanism for the induction of cross-reactive pathogenic anti-ganglioside/LPS antibodies in postinfectious neuropathies.

Anti-GQ1b ganglioside antibody and ophthalmoplegia of undetermined cause

BACKGROUND/AIMSerum antibody against ganglioside GQ1b is reported to be closely associated with immune mediated ophthalmoplegia in the Fisher and Guillain-Barré syndromes. Its presence against glycolipids, in particular ganglioside GQ1b, was...

Fisher syndrome associated with IgG anti-GQ 1b antibody following infection by a specific serotype of Campylobacter jejuni

Objective The purpose of the study was to describe clinical and serologic features of Fisher syndrome associated with IgG anti-GQ 1b ganglioside antibody following Campylobacter jejuni enteritis. Design A clinical trial. Participants Four consecutive patients with Fisher syndrome were studied. Intervention Samples of sera from four patients were tested for reactivity to GQ 1b ganglioside by enzyme-linked immunosorbent assay (ELISA). Campylobacter jejuni strains isolated from samples of stool from three patients were serotyped by the method of Penner and Hennessy and that of Lior. Main outcome measures Serum IgG anti-GQ 1b antibody titer and serotypes of C. jejuni. Results Diplopia occurred 8 to 14 days after the onset of diarrhea. Campylobacter jejuni was isolated from samples of stool from all of the patients. ELISA revealed a high serum IgG anti-GQ 1b antibody titer for all four patients. Two patients had high serum titers of other antiganglioside antibodies frequently related to Guillain-Barré syndrome. These two patients developed limb weakness following the onset of ophthalmoplegia. The C. jejuni serotype was Penner’s serotype 2 for all three of the patients tested. Conclusions These findings suggest that C. jejuni, especially Penner’s serotype 2, enteritis could trigger development of Fisher syndrome associated with IgG anti-GQ 1b antibody.

Immunoadsorption therapy for fisher syndrome associated with IgG Anti-GQ 1b antibody

To describe the effects of immunoadsorption therapy with a tryptophan-immobilized column on Fisher syndrome associated with IgG anti-GQ1b ganglioside antibody. Three patients with Fisher syndrome and with a high serum IgG anti-GQ1b antibody titer underwent four to nine sessions of immunoadsorption therapy with a tryptophan-immobilized column. Using enzyme-linked immunosorbent assay (ELISA), we determined the differences in IgG anti-GQ1b antibody titers. ELISA disclosed that the IgG anti-GQ1b antibody titers of the serum samples collected from the inlet of the column were markedly higher than those collected from the outlet for all three patients. Moreover, after completion of the immunoadsorption therapy, the patients' serum IgG anti-GQ1b antibody titers were markedly lower than they were before the immunoadsorption therapy. The patients' ophthalmoparesis decreased in severity during the therapy. These findings suggest that immunoadsorption therapy with the tryptophan-immobilized column is an effective method for removing IgG anti-GQ1b antibody from serum.

Mechanisms of action of anti-GM1 and anti-GQ1b ganglioside antibodies in Guillain-Barré syndrome.

Anti-GM1 and anti-GQ1b ganglioside antibodies are found in association with acute and chronic peripheral neuropathies, including Guillain-Barré syndrome. They are believed to arise as a result of molecular mimicry with immunogenic microbial polysaccharides. Although anti-ganglioside antibodies are suspected to play a causal role in neuropathy pathogenesis, the details of this have yet to be proven. The approach in this laboratory to solving this issue has been to generate anti-GM1 and anti-GQ1b monoclonal antibodies from peripheral blood lymphocytes of affected patients and to study their immunolocalization in peripheral nerve and their electrophysiologic effects in animal models in which peripheral nerve sites are exposed to anti-ganglioside antibodies. These data show that anti-ganglioside antibody-reactive epitopes are widely distributed in peripheral nerve and can cause electrophysiologic abnormalities in a variety of model systems; thus, these data support the view that anti-ganglioside antibody-reactive epitopes may directly contribute to neuropathy pathogenesis.

The Spectrum and Pathogenesis of Antibody-mediated Neuropathies

Antibodies reacting with carbohydrate epitopes on neural glycoconjugates are present in several forms of neuropathy. These include monoclonal antibodies to the myelin-associated glycoprotein (MAG) and to gan gliosides in patients with neuropathy in association with IgM gammopathy, as well as polyclonal antibodies to gangliosides in inflammatory polyneuropathies, such as Guillain-Barré syndrome and multifocal motor neuropathy. There are several correlations between antibody specificity and clinical symptoms, including anti-MAG antibodies with demyelinating sensory or sensorimotor neuropathy, anti-GM1 ganglioside anti bodies with motor nerve disorders, anti-GQ1b ganglioside antibodies with Miller-Fisher syndrome, and antibodies to gangliosides containing disialosyl moieties with sensory ataxic neuropathy. This review will emphasize recent developments concerning the origins of the anti-glycoconjugate antibodies in patients, pathogenic mechanisms by which the antibodies may cause the neuropathies, and the implications of these findings for therapy. NEUROSCIENTIST 3:195-204, 1997

Myasthenia gravis and the Miller-Fisher variant of Guillain-Barré syndrome.

This review primarily concerns two issues. First, in myasthenia gravis, what mechanisms are likely to underlie the low threshold for extraocular muscle involvement in this disease? Second, what is the likely importance of anti-GQ1b ganglioside antibodies in the diagnosis and causation of Miller-Fisher syndrome?

Miller Fisher syndrome is associated with serum antibodies to GQ1b ganglioside.

A recent report described serum anti-GQ1b ganglioside antibodies in Miller Fisher syndrome (MFS), a clinical variant of Guillain-Barré syndrome (GBS). Four consecutive cases of MFS all had high titre anti-GQ1b antibodies which were absent from all control sera including those of patients with GBS.