Antiganglioside antibody frequency in routine clinical care settings.

BACKGROUND AND PURPOSE: Antiganglioside antibodies (AGAs) might be involved in the etiopathogenesis of many neurological diseases, such as Miller-Fisher syndrome (MFS) and Guillain-Barré syndrome (GBS). Available comprehensive reference data regarding AGA positivity rates and cross-responsiveness among AGAs (where one line immunoblot is positive for ≥1 AGA) during routine clinical care are scant. METHODS: In this 10-year monocentric retrospective study, 3560 immunoglobulin (Ig) G and IgM line blots (GA Generic Assays' Anti-Ganglioside Dot kit) obtained using cerebrospinal fluid (CSF) and serum samples from 1342 patients were analyzed for AGA positivity in terms of 14 diagnosis categories and AGA cross-responsiveness. RESULTS: Of all 3560 line blots 158 (4.4%) and of all CSF samples 0.4% (4/924) CSF line blots were AGA positive. For serum IgG, blots with positivity rates higher than the standard deviation of 15.6% were associated with MFS (GD3, GD1a, GT1a and GQ1b) and acute motor axonal neuropathy (AMAN) (GM1, GD1a and GT1a). For serum IgM, blots with positivity rates higher than the standard deviation of 8.1% were associated with AMAN (GM2, GT1a and GQ1b), MFS (GM1, GT1a and GQ1b), multifocal motor neuropathy (MMN) (GM1, GM2 and GQ1b) and chronic inflammatory demyelinating polyneuropathy (CIDP) (GM1). Cross-responsiveness was observed in 39.6% of all positive serum AGA. CONCLUSIONS: Testing for AGAs during routine clinical care rarely led to positive findings, both in serum and even less in CSF, except for the diagnoses AMAN, MFS, MMN and CIDP. Nonspecific findings found as cross-responsiveness between different AGA samples occur frequently, impacting the positivity of most AGA subtypes.

Cholesterol-added antigens can enhance antiglycolipid antibody activity: Application to antibody testing.

We analysed the effect of adding cholesterol to glycolipid antigens on antibody activity with enzyme-linked immunosorbent assay in 123 subjects consisting of 96 patients with Guillain-Barré syndrome, 25 Miller Fisher syndrome, and two Bickerstaff brainstem encephalitis. The use of cholesterol-added GM1 antigens increased anti-GM1 activity in 11 out of 23 anti-GM1-positive patients and resulted in six out of 100 anti-GM1-negative patients becoming anti-GM1-positive. Enhancement of anti-GM1 activity by cholesterol addition was significantly associated with antecedent gastrointestinal infection. The use of cholesterol-added glycolipid antigens can increase the detection rate of anti-glycolipid antibodies and accurately evaluate the anti-glycolipid antibody activity in vivo.

Antiparanodal antibodies and IgG subclasses in acute autoimmune neuropathy.

OBJECTIVE: To determine whether IgG subclasses of antiparanodal autoantibodies are related to disease course and treatment response in acute- to subacute-onset neuropathies, we retrospectively screened 161 baseline serum/CSF samples and 66 follow-up serum/CSF samples. METHODS: We used ELISA and immunofluorescence assays to detect antiparanodal IgG and their subclasses and titers in serum/CSF of patients with Guillain-Barré syndrome (GBS), recurrent GBS (R-GBS), Miller-Fisher syndrome, and acute- to subacute-onset chronic inflammatory demyelinating polyradiculoneuropathy (A-CIDP). We evaluated clinical data retrospectively. RESULTS: We detected antiparanodal autoantibodies with a prevalence of 4.3% (7/161), more often in A-CIDP (4/23, 17.4%) compared with GBS (3/114, 2.6%). Longitudinal subclass analysis in the patients with GBS revealed IgG2/3 autoantibodies against Caspr-1 and against anti-contactin-1/Caspr-1, which disappeared at remission. At disease onset, patients with A-CIDP had IgG2/3 anti-Caspr-1 and anti-contactin-1/Caspr-1 or IgG4 anti-contactin-1 antibodies, IgG3 being associated with good response to IV immunoglobulins (IVIg). In the chronic phase of disease, IgG subclass of one patient with A-CIDP switched from IgG3 to IgG4. CONCLUSION: Our data (1) confirm and extend previous observations that antiparanodal IgG2/3 but not IgG4 antibodies can occur in acute-onset neuropathies manifesting as monophasic GBS, (2) suggest association of IgG3 to a favorable response to IVIg, and (3) lend support to the hypothesis that in some patients, an IgG subclass switch from IgG3 to IgG4 may be the correlate of a secondary progressive or relapsing course following a GBS-like onset.

[Anti-GQ1b syndrome. A child with Miller-Fisher-Bickerstaff syndrome]. / Síndrome anti-GQ1b en un niño con síndrome de Miller-Fisher-Bickerstaff.

Miller-Fisher syndrome and Bickerstaff brainstem encephalitis, among others, constitute the anti-GQ1b syndrome, with a common immune pathophysiologic pathway characterized by the presence of anti-GQ1b antibodies, which react against the different nervous system GQ1b sites according to their different accessibility. The Miller-Fisher syndrome has a prevalence of 0.09 cases per 100 000 people-year but there are not epidemiological studies about Bickerstaff brainstem encephalitis, that it seems to be less frequent. In spite of having a good natural outcome, the immunoglobulin administration has been established as efficacious at improving it. A twelveyear- old boy suffering from Miller-Fisher-Bickerstaff syndrome after an acute Campylobacter jejuni diarrhea with positive titers of anti-GQ1b and anti-QGT1a antibodies is presented. We communicate a very uncommon pediatric disease with the aim of warning about the importance of its early suspicion and the need of specific laboratory determinations.

El síndrome anti-GQ1b reúne el síndrome de Miller-Fisher y la encefalitis del tronco cerebral de Bickerstaff, entre otras entidades. Tienen etiopatogenia común, constituida por la presencia de anticuerpos anti-GQ1b que reaccionan contra los sitios GQ1b del sistema nervioso según sea su accesibilidad. La prevalencia anual del síndrome de Miller-Fisher es de 0,09 casos por 100 000 habitantes por año y no existen estudios epidemiológicos sobre la encefalitis del tronco cerebral de Bickerstaff, que sería menos frecuente. De evolución natural hacia la mejoría, se beneficia del tratamiento con gammaglobulina endovenosa. Se presenta a un paciente de 12 años con síndrome de Miller- Fisher­Bickerstaff tras un episodio de diarrea aguda por Campylobacter jejuni en el que los anticuerpos anti-GQ1b resultaron positivos. Es nuestro objetivo comunicar sobre un síndrome de presentación poco habitual en pediatría a fin de advertir acerca de la necesidad de su sospecha precoz y solicitud de estudios de laboratorio específicos.

Antecedent infections in Fisher syndrome: sources of variation in clinical characteristics.

The clinical features of Guillain-Barré syndrome (GBS) are highly variable, according to the type of antecedent infection. Although a major GBS phenotype, Fisher syndrome (FS), has been shown to be preceded by infections similar to those preceding GBS, whether or not the clinical features in FS also vary according to antecedent infection remains unclarified. Frequent antecedent infections among this study of 70 FS patients included Haemophilus influenzae [n = 15 (21%)], Campylobacter jejuni [n = 10 (14%)], and cytomegalovirus (CMV) [n = 6 (8.6%)]. Compared with other FS patients, H. influenzae-seropositive FS patients more frequently had a history of prior upper respiratory tract infection; double vision as the initial symptom; and, except for oculomotor disturbance, more rarely showed cranial nerve involvement. C. jejuni-related FS occurred predominantly in younger male patients and characteristically presented with blurred vision. According to GBS disability scale, CMV-related FS tended to be more severe, although every patient received immunotherapy. Serum anti-GQ1b IgG antibodies were detected in most cases, regardless of antecedent infection type. At the nadir of illness, the most frequent diagnosis in H. influenzae-related cases was "pure FS" without limb weakness or central nervous system involvement (71%), in C. jejuni-related cases "incomplete FS" such as acute ophthalmoparesis with or without ataxia (60%), and in CMV-related cases (50%) advanced conditions such as GBS overlap and Bickerstaff brainstem encephalitis. These findings indicate that the type of preceding infection determined the neurological features of FS. CMV-related FS appeared to be similar to H. influenzae- and C. jejuni-related FS regarding anti-GQ1b antibody-mediated pathogenesis, as opposed to CMV-related GBS.

Clinical characterization of anti-GQ1b antibody syndrome in Korean children.

Anti-GQ1b antibody syndrome encompasses Miller Fisher syndrome and its related disorders. We retrospectively identified 11 pediatric patients (5.4-18 years old) with anti-GQ1b antibody syndrome. Diagnoses of patients included acute ophthalmoparesis (n = 6), classical Miller Fisher syndrome (n = 2), Miller Fisher syndrome/Guillain-Barré syndrome (n = 1), acute ataxic neuropathy (n = 1), and pharyngeal-cervical-brachial weakness (n = 1). Nine patients (81.8%) fully recovered. Maturational change in GQ1b antigen expression and the accessibility of anti-GQ1b antibodies might be the cause of the difference of clinical manifestations in children with anti-GQ1b antibody syndrome.

Atypical clinical manifestations of Miller Fisher syndrome.

Miller Fisher syndrome (MFS) is characterized by a clinical triad of ophthalmoplegia, ataxia, and areflexia, and is closely associated with serum anti-GQ1b antibody. Although the clinical triad is the cardinal diagnostic clue, a variety of other symptoms and signs beyond the triad have been reported. To elucidate the frequency and characteristics of atypical clinical manifestations of MFS, we recruited 38 patients with MFS and evaluated the symptoms or signs beyond the classic triad. Eleven (29%) of 38 patients had atypical clinical manifestations of MFS such as headache (n = 6), delayed facial palsy (n = 3), divergence insufficiency (n = 2), and taste impairment (n = 2). Headache was localized to the periorbital (n = 3), temporal (n = 2), or whole (n = 1) area. Only one of them showed bilateral papilledema and an elevated opening pressure in cerebrospinal fluid analysis. Delayed facial palsy developed after the other signs have reached nadir (n = 1) or started to improve (n = 2), and did not follow a pattern of descending paralysis with other cranial neuropathies. Two patients showed divergence insufficiency without external ophthalmoplegia, and another two had taste impairment over the entire tongue without the other signs of facial and glossopharyngeal nerve involvements. Our study shows that approximately 30% of MFS patients can have atypical clinical manifestations beyond the classic triad. These results reflect the broad clinical spectrum of MFS, and might be associated with the presence of additional antiganglioside antibodies besides anti-GQ1b in patients with MFS.

Clinical relevance of serum antibodies to GD1b in immune-mediated neuropathies.

Antibodies to the ganglioside GD1b have been reported in various forms of immune-mediated neuropathy, but their clinical relevance for diagnosis and prognosis is unknown. We investigated the prevalence of anti-GD1b antibodies in acute and chronic immune-mediated neuropathies, and the clinical presentation and outcome in Guillain-Barré syndrome (GBS) and Miller Fisher-GBS overlap syndrome (MF-GBS). Anti-GD1b, anti-GM1 and anti-GQ1b antibodies were tested in serum of patients with GBS (N = 165), Miller Fisher syndrome (N = 10), MF-GBS (N = 28), monoclonal gammopathy of unknown significance neuropathy (MGUS; N = 101), chronic inflammatory demyelinating polyneuropathy (N = 29), paraneoplastic syndrome with anti-Hu-associated neuropathy (PNS; N = 11), other auto-immune diseases (AID; N = 60), and healthy controls (HC; N = 60). All samples were tested by enzyme-linked immunosorbent assay according to the Inflammatory Neuropathy Cause and Treatment protocol. IgM anti-GD1b antibodies were found in GBS (N = 4; 2.4%), MGUS (N = 3; 3.0%), and PNS patients (N = 1; 9.1%). IgG anti-GD1b antibodies were found in GBS (N = 20; 12.1%) and MF-GBS (N = 4; 14.3%) patients, but not in the AID and HC group. In the combined group of MF-GBS and GBS patients ((MF-)GBS), 14/36 (38.9%) patients with IgG anti-GD1b antibodies also had IgG anti-GM1 antibodies, and IgG anti-GD1b and IgG anti-GQ1b antibodies were found in 3/29 (10.3%) patients. Patients with (MF-)GBS and anti-GD1b without anti-GM1 antibodies did not differ regarding sensory disturbances or disease severity but recovered faster regarding the ability to walk independently compared with patients without anti-GD1b antibodies (P = 0.031) and with patients with both anti-GD1b and anti-GM1 antibodies (P = 0.034). In conclusion, testing for anti-GD1b antibodies may identify a specific group of immune-mediated neuropathies and (MF-)GBS patients with only anti-GD1b antibodies tend to recover faster.

Headache and Ophthalmoparesis: Case Report of an "Atypical" Incomplete Miller-Fisher Syndrome.

OBJECTIVE: To expand the differential diagnosis of headache and ophthalmoparesis by describing a case report in which anti-GQ1b was demonstrated to be the cause. BACKGROUND: Anti-GQ1b antibody syndrome refers to a clinical spectrum of conditions that share common mechanisms and overlapping manifestations, including the Miller-Fisher syndrome, pharyngeal-cervical-brachial weakness, and Bickerstaff brainstem encephalitis. Rare atypical cases presenting as acute ophthalmoparesis (AO) without ataxia or areflexia have been described. Headache is a rare condition in these disorders. METHODS: A 49-year-old woman with no history of headaches began experiencing an acute severe bilateral throbbing headache associated with nausea and photophobia. Five days later, she developed constant binocular horizontal diplopia. RESULTS: Bilateral paresis of both sixth nerves was noted. Her ocular fundi, tendon reflexes, and other findings of the physical exam were normal. In addition, both a brain MRI performed with gadolinium and a lumbar puncture yielded normal results. Serum anti-GQ1b IgG was found to be positive. Her symptoms resolved completely following treatment with immunoglobulins (0.4 g/kg/day for 5 days). CONCLUSIONS: This is the first reported case of AO related to anti-GQ1b antibodies presenting with headache as its initial symptom. The presence of anti-GQ1b antibodies should be determined in patients with headache and AO of unknown origin. Immunoglobulins could hasten the resolution of symptoms in these patients.

Prediction of disease progression in Miller Fisher and overlap syndromes.

Patients with Miller Fisher syndrome (MFS) may have a relatively mild clinical course or progress to Guillain-Barré syndrome (GBS) with limb weakness (MFS-GBS overlap syndrome). Other variants in this spectrum are GBS with ophthalmoparesis and Bickerstaff's Brainstem encephalitis (BBE). To compare the clinical course of MFS and overlap syndromes and to identify predictors of disease progression. In a prospective study of 170 patients with GBS and variant forms, 37 (22%) had a MFS, MFS-GBS overlap syndrome, ophthalmoplegic GBS or BBE. The clinical, serological, and electrophysiological features were compared. Twenty-three patients presented with MFS, of which 10 (43%) developed limb weakness (MFS-GBS overlap syndrome). All these transitions occurred in the first week after onset of symptoms. There were no differences in the clinical, electrophysiological and serological features at entry between MFS and MFS-GBS. Twelve patients had ophthalmoplegic GBS and the disease severity at nadir and outcome was worse than in the patients with a MFS-GBS overlap syndrome. No early predictors for progression from MFS to MFS-GBS overlap syndrome were found. All transitions occurred in the first week. This finding implicates that all patients with MFS need careful monitoring for at least 1 week.

Ca(2+)-dependent anti-GQ1b antibody in GQ1b-seronegative Fisher syndrome and related disorders.

Although serum IgG anti-ganglioside GQ1b antibody is the most specific biomarker for Fisher syndrome and its related disorders (FS-RD), 10%-30% of the patients are still negative in conventional assays ("GQ1b-seronegative") and the relationship between GQ1b-seropositive and -seronegative patients has been unclear. Some molecules require Ca(2+) cations to interact with their ligands (Ca(2+)-dependency). Here we have investigated whether Ca(2+)-dependency is also present in anti-GQ1b antibodies in FS-RD, especially in the GQ1b-seronegative patients and show that IgG antibodies against GQ1b-related antigens (isolated GQ1b and GQ1b-containing complexes) are detected Ca(2+)-dependently in the majority of GQ1b-seronegative patients with FS-RD. The Ca(2+)-dependent antibodies might react specifically with GQ1b-Ca(2+) conformation. This is the first demonstration of disease-related Ca(2+)-dependent antibodies in neurological field. GQ1b-related pathology would be involved in FS-RD more extensively than previously revealed.

Pediatric Miller Fisher Syndrome Complicating an Epstein-Barr Virus Infection.

BACKGROUND: Miller Fisher syndrome, a variant of Guillain-Barré syndrome, is an acute inflammatory demyelinating polyradiculoneuropathy that may occur weeks after a bacterial or viral infection. Campylobacter jejuni and Haemophilus influenzae are frequently reported etiological agents. PATIENT DESCRIPTION: We describe a boy with Miller Fisher syndrome following Epstein-002DBarr virus primary infectious mononucleosis. He presented with bilateral dysfunction of several cranial nerves and hyporeflexia of the limbs but without ataxia. Miller Fisher syndrome was confirmed by the presence of anti-GQ1b antibodies in a blood sample. Epstein-Barr virus was identified by polymerase chain reaction and serology. CONCLUSION: Epstein-Barr virus should be considered as a Miller Fisher syndrome's causative agent. The physiopathology of this condition may involve cross-reactive T-cells against Epstein-Barr virus antigens and gangliosides.

Guillain-Barré and Miller Fisher syndromes in patients with anti-hepatitis E virus antibody: a hospital-based survey in Japan.

There have been reports from several countries that hepatitis E virus (HEV) infection is frequently associated with Guillain-Barré syndrome (GBS). This study aimed to determine the frequency of HEV infection associated with GBS in Japanese patients, and to clarify the clinical characteristics of these patients. Sera obtained from 63 patients with GBS or Miller Fisher syndrome (MFS) and 60 control subjects were examined for both HEV-IgM and HEV-IgG. Of the 63 patients, three were positive for both HEV-IgM and elevated hepatic enzymes: Two had GBS, and one had MFS. No control subjects were positive for HEV-IgM. Our study demonstrated that 4.8 % of patients with GBS or MFS from our institution had associated acute HEV infection. There were no clinical differences between GBS with HEV infection and other GBS cases. To our knowledge, this is the first survey in Japan of HEV-associated GBS or MFS.

Anti-GQ1b antibody syndrome: anti-ganglioside complex reactivity determines clinical spectrum.

BACKGROUND AND PURPOSE: Anti-GQ1b antibodies have been found in patients with Miller Fisher syndrome as well as its related conditions. Our aim was to identify the mechanism by which autoantibodies produce various clinical presentations in 'anti-GQ1b antibody syndrome'. METHODS: Immunoglobulin G antibodies to ganglioside complex (GSC) of GQ1b or GT1a with GM1, GD1a, GD1b or GT1b were tested in sera from patients with anti-GQ1b (n = 708) or anti-GT1a (n = 696) IgG antibodies. Optical densities of the single anti-GQ1b or anti-GT1a antibodies were used as reference (100%), and those of anti-GSC antibodies were expressed in percentages to reference. The relationships between anti-GSC antibody reactivity and the corresponding clinical features were assessed by multivariate logistic regression analysis. RESULTS: Ophthalmoplegia and hypersomnolence were significantly associated with complex-attenuated anti-GQ1b and anti-GT1a antibodies. Ataxia was associated with GD1b- and GT1b-enhanced anti-GQ1b antibodies or GM1-enhanced anti-GT1a antibodies. Bulbar palsy was associated with GT1b-enhanced anti-GQ1b antibodies. Neck weakness was associated with GD1a-enhanced anti-GQ1b antibodies. Arm weakness was associated with GD1b-enhanced anti-GQ1b and GD1a-enhanced anti-GT1a antibodies. Leg weakness was associated with GD1a-enhanced anti-GQ1b and anti-GT1a antibodies. CONCLUSIONS: Differences in fine specificity of anti-GQ1b antibodies are associated with clinical features, possibly due to the different expression of gangliosides in different parts of the nervous system.

False-Positive Serum Botulism Bioassay in Miller-Fisher Syndrome.

We describe a patient with acute progressive weakness and areflexia. Both botulism and Miller-Fisher variant of Guillain-Barré syndrome were initial diagnostic considerations, and she was treated with intravenous immunoglobulin and botulinum antitoxin. A mouse bioassay was positive for botulinum toxin A, although her clinical course, electrodiagnostic studies, and cerebrospinal fluid findings supported Miller-Fisher syndrome. This patient's atypical features offer points of discussion regarding the evaluation of patients with acute neuromuscular weakness and emphasize the limitations of the botulism bioassay.

Autoimmune peripheral neuropathies.

Peripheral nervous system axons and myelin have unique potential protein, proteolipid, and ganglioside antigenic determinants. Despite the existence of a blood-nerve barrier, both humoral and cellular immunity can be directed against peripheral axons and myelin. Molecular mimicry may be triggered at the systemic level, as was best demonstrated in the case of bacterial oligosaccharides. The classification of immune neuropathy has been expanded to take into account specific syndromes that share unique clinical, electrophysiological, prognostic and serological features. Guillain-Barré syndrome encompasses a classical syndrome of acute demyelinating polyradiculoneuropathy and many variants: axonal motor and sensory, axonal motor, Miller-Fisher, autonomic, and sensory. Similarly, chronic immune neuropathy is composed of classic chronic inflammatory demyelinating polyradiculoneuropathy and variants characterized as multifocal (motor or sensorimotor), sensory, distal symmetric, and syndromes associated with monoclonal gammopathy. Among putative biomarkers, myelin associated glycoprotein and several anti-ganglioside autoantibodies have shown statistically significant associations with specific neuropathic syndromes. Currently, the strongest biomarker associations are those linking Miller-Fisher syndrome with anti-GQ1b, multifocal motor neuropathy with anti-GM1, and distal acquired symmetric neuropathy with anti-MAG antibodies. Many other autoantibody associations have been proposed, but presently lack sufficient specificity and sensitivity to qualify as biomarkers. This field of research has contributed to the antigenic characterization of motor and sensory functional systems, as well as helping to define immune neuropathic syndromes with widely different clinical presentation, prognosis and response to therapy. Serologic biomarkers are likely to become even more relevant with the advent of new targeted forms of immunotherapy, such as monoclonal antibodies.