Anti-GQ1b IgG antibody syndrome: clinical and immunological range

OBJECTIVES: To clarify the nosological relation among Miller Fisher syndrome (MFS), Guillain-Barré syndrome (GBS) with ophthalmoplegia, Bickerstaff's brain stem encephalitis (BBE), and acute ophthalmoparesis without ataxia. Serum samples from patients with each condition often have anti-GQ1b IgG antibody. METHODS: Information on antecedent illness, initial symptoms, neurological signs during the illness, and CSF findings were reviewed in 194 patients with anti-GQ1b IgG. It was determined whether overlapping MFS and GBS (MFS/GBS), as well as overlapping BBE and GBS (BBE/GBS), is explained by the combined action of anti-GQ1b IgG and anti-GM1 or anti-GD1a IgG, serological markers of GBS. RESULTS: Based on the diagnostic criteria, all the patients with acute ophthalmoparesis, MFS, MFS/GBS, BBE/GBS, and BBE had external ophthalmoplegia; all the patients with MFS, MFS/GBS, or GBS had hyporeflexia or areflexia; and all those with MFS and BBE showed ataxia. Tendon reflexes were decreased or absent in 91% of those with BBE/GBS, 67% of those with BBE, and 53% of those with acute ophthalmoparesis. Ataxia was present in 68% of the patients with MFS/GBS and 45% of those with BBE/GBS. Antecedent illness caused by upper respiratory tract infection had occurred in 60% to 80% of these patients, and CSF albuminocytological dissociation in 25% to 75%. Anti-GM1 or anti-GD1a IgG was present in 50% of those with GBS, 35% of those with MFS/GBS, 27% of those with BBE/GBS, 16% of those with MFS, and 8% of those with BBE. CONCLUSIONS: These findings together with the common autoantibody (anti-GQ1b IgG) suggest that a common autoimmune mechanism functions in the pathogenesis of these illnesses. In a larger study, it was confirmed clinically that MFS, GBS, BBE, and acute ophthalmoparesis are closely related, forming a continuous range. This is supported by the immunological findings. The term "anti-GQ1b IgG antibody syndrome" is not intended to be used as a clinical diagnosis, but recognition of this syndrome is useful for understanding the aetiological relation among the various illnesses and for introducing the established treatments of GBS for use with other conditions.     

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.     

Fine specificity of anti-GQ1b IgG and clinical features

Anti-GQ1b IgG frequently is present in sera of patients with Miller Fisher syndrome (MFS), Guillain-Barré syndrome (GBS) with ophthalmoplegia, Bickerstaff's brainstem encephalitis (BBE), and acute ophthalmoparesis (AO) in the acute phase. Why various clinical signs develop under these conditions, however, has yet to be clarified. We investigated the fine specificity of anti-GQ1b IgG and its clinical correlation in sera from 82 patients: 56 with MFS, 11 with GBS, 13 with BBE, and 2 with AO. Anti-GQ1b IgG antibodies were absorbed by GT1a in 80 (98%) of the 82 sera, by GD1b in 11 (13%), and by the other b-series gangliosides GD3, GD2, or GT1b in 24 (29%). The most frequent pattern of fine specificity was the cross-reaction with GT1a alone, seen in 56 (68%) samples. Of the 11 patients with anti-GQ1b IgG, cross-reacting with GD1b, 6 (55%) had impaired deep sense, and the association was significant (p=0.02). This is the first study to show that the fine specificity of anti-GQ1b IgG is heterogeneous and that the difference is correlated with the presence of a particular clinical sign.     

HLA and anti-GQ1b IgG antibody in Miller Fisher syndrome and Guillain-Barré syndrome

We investigated serological human leukocyte antigen (HLA) types in patients with histories of Miller Fisher syndrome (MFS) and Guillain-Barré syndrome (GBS) with ophthalmoplegia, in whom serum anti-GQ1b IgG antibody was present during the acute phase. We examined class I antigens (A, B and C) in 32 patients and class II antigens (DR and DQ) in 30, but found no association. We conclude that particular serologically defined HLA types are not preferred for the immunoresponse of anti-GQ1b IgG antibody in MFS and GBS.     

Anti-GQ1b IgG antibody is associated with ataxia as well as ophthalmoplegia.

Close association between the increase in anti-GQ1b immunoglobulin G (IgG) antibody and ophthalmoplegia in Miller Fisher syndrome (MFS) and Guillain-Barré syndrome (GBS) has been reported. We investigated whether anti-GQ1b IgG antibody also is associated with ataxia, another of the MFS triad. Of 149 patients who had anti-GQ1b IgG antibody without profound weakness, 144 showed ophthalmoplegia (120 showed both ophthalmoplegia and ataxia; 24, ophthalmoplegia without ataxia). In contrast, five showed ataxia without ophthalmoplegia. Some large neurons of the dorsal root ganglia were immunostained with anti-GQ1b monoclonal antibody. Anti-GQ1b IgG antibody may thus be associated with ataxia as well as ophthalmoplegia. Ataxia may be due to its binding to a subset of primary sensory neurons.     

Clinical correlates of serum anti-GT1a IgG antibodies

Patients with the pharyngeal-cervical-brachial variant (PCB) of Guillain-Barré syndrome (GBS) have anti-GT1a IgG with or without GQ1b reactivity, whereas those with Fisher syndrome (FS) or Bickerstaff's brainstem encephalitis (BBE) have anti-GQ1b IgG antibodies which cross-react with GT1a. The nosological relationship between these conditions has yet to be established. To investigate the relationships between each manifestation and between clinical features and the coexistence of anti-GQ1b IgG, we reviewed neurological signs present during illnesses of 140 patients who had anti-GT1a IgG. Based on our criteria, FS was diagnosed for 64 (46%) patients, GBS for 22 (16%), BBE for 14 (10%), and PCB for 6 (4%). Overlapping conditions were diagnosed for some patients: FS and GBS (5%), PCB and FS (5%), BBE and GBS (4%), and PCB and BBE (1%). Patients who initially had bulbar palsy developed not only PCB but FS or BBE. The population of anti-GT1a-positive patients frequently had ophthalmoplegia, ataxia, and areflexia, whereas the subpopulation who had anti-GT1a IgG without GQ1b reactivity frequently had preceding diarrhea as well as oropharyngeal, neck, and limb weakness. Patients with anti-GT1a IgG presented a variety of clinical conditions, indicative of a continuous clinical spectrum. A major part of this clinical variation was due to the coexistence of anti-GQ1b IgG. The presence of a common autoantibody (anti-GT1a IgG) and overlapping illnesses suggests that PCB is closely related not only to GBS but to FS and BBE as well.     

Ophthalmoplegic Guillain-Barré syndrome: An independent entity or a transitional spectrum?

Ophthalmoplegia can occur in both Miller Fisher syndrome (MFS) and Guillain-Barré syndrome (GBS) with typical limb involvement. However, ophthalmoplegic GBS (OGBS) has been poorly defined. We aimed to characterize OGBS and clarify the pathophysiological implications across the overall GBS spectrum. Twenty GBS and seven MFS patients from three university based teaching hospitals in Korea were enrolled and analyzed. Six GBS patients who were classified as OGBS commonly also had facial diplegia (50%) and bulbar palsy (50%), while only a small portion of non-ophthalmoplegic GBS (NOGBS) patients had facial diplegia (21%). None of the patients had bulbar palsy in the NOGBS or MFS groups. The most frequent anti-ganglioside antibody in OGBS was the IgG anti-GT1a antibody (50%). The IgG anti-GM1 antibody was found mainly in NOGBS (57%) with high concordance with the pure motor type classification on electrophysiology. IgG anti-GQ1b antibody was positive uniquely in MFS (100%), although some patients were also positive for anti-GT1a antibody (71%). OGBS had distinct clinical features, including bulbar palsy, as well as ophthalmoplegia and limb weakness for both GBS and MFS. Relevant immunological factors were anti-GT1a antibody. Whether OGBS is an independent entity or a transitional spectrum remains to be established and further study will be needed.     

Bickerstaff's brainstem encephalitis and Fisher syndrome: their relationship and treatment]

The nosological position of Bickerstaff's brainstem encephalitis (BBE) was not eatablished, and its etiology was not clear until 1993. Because anti-GQ1b IgG antibody frequently occurs in patients with Fisher syndrome (FS) and there are clinical similarities between FS and BBE, we investigated anti-ganglioside antibodies in sera from three patients with BBE. High anti-GQ1b IgG antibody titers were present in their sera, but decreased with the clinical course of the illness. The findings that BBE and FS shared common autoantibody suggest that autoimmune mechanism common to FS is likely in BBE, and that both conditions form a continuous spectrum. To clarify the clinical features of BBE, we reviewed detailed clinical profiles and laboratory findings for 62 cases of BBE diagnosed by the strict criteria of progressive, relatively symmetric external ophthalmoplegia and ataxia by 4 weeks, and disturbance of consciousness or hyperreflexia. A striking feature was the association with flaccid symmetric tetraparesis seen in 60%. Limb weakness in the BBE cases studied was considered the result of overlap by the axonal subtype of Guillain-Barré syndrome. These indicates that the two disorders are closely related and form a continuous spectrum, and that treatment for Guillain-Barré syndrome should be applied for BBE.     

Overlapping Guillain–Barré syndrome and Bickerstaff''s brainstem encephalitis associated with anti-GQ1b IgG antibody after herpes simplex virus infection

Herpes simplex virus (HSV) is a rare, antecedent infectious agent in Guillain-Barré syndrome (GBS). We report a patient with overlapping GBS and Bickerstaff's brainstem encephalitis (BBE). The patient had a vesicular lesion on her nose. Antecedent HSV type 1 (HSV-1) infection was confirmed by isolation of the virus and detection of the presence of serum anti-HSV-1 IgM antibody during the acute phase. Her serum IgG had high anti-GQ1b antibody titer. External ophthalmoplegia has been noted in 2 of 4 reported cases of HSV-associated GBS. Herpetic brainstem encephalitis cases of poor prognosis are known, but only 2 cases of benign brainstem encephalitis secondary to HSV infection, in which there was acute ophthalmoplegia and clinical features consistent with those of BBE have been reported.     

Effects of phospholipids on antiganglioside antibody reactivity in GBS

Serum antibody activities to mixtures of a ganglioside and various phospholipids were compared with those to a ganglioside alone in 30 anti-GM1 IgG-positive GBS patients and 30 anti-GQ1b IgG-positive Miller Fisher syndrome (MFS) patients. Anti-GM1-positive sera had higher antibody reactivities against a mixture of GM1 and several phospholipids including PA, PI and PS, than against GM1 alone. In contrast, in case of anti-GQ1b antibody, no phospholipid provided significant enhancement. Sphingomyelin provided decrease of the activity for both anti-GM1 and anti-GQ1b IgG. The effects of phospholipids must be considered to determine the pathogenetic role of antiganglioside antibodies in GBS and MFS.