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.     

Acute onset of a bilateral areflexical mydriasis in Miller-Fisher syndrome: a rare neuro-ophthalmologic disease.

Miller-Fisher syndrome (MFS) is characterized by variable ophthalmoplegia, ataxia, and tendon areflexia. It seems to be a variant of Guillain-Barré syndrome (GBS), but unlike in GBS, there is a primitive involvement of the ocular motor nerves, and in some cases there is brainstem or cerebellum direct damage. The unusual case of MFS in the current study started with a bilateral areflexical mydriasis and a slight failure of accommodative-convergence. Ocular-movement abnormalities developed progressively with a palsy of the upward gaze and a bilateral internuclear ophthalmoplegia to a complete ophthalmoplegia. In the serum of this patient, high titers of an IgG anti-GQ1b ganglioside and IgG anti-cerebellum. anti-Purkinje cells in particular, were found. The former autoantibody has been connected to cases of MFS, of GBS with associated ophthalmoplegia, and with other acute ocular nerve palsies. The anti-cerebellum autoantibody could explain central nervous system involvement in MFS. The role of these findings and clinical implications in MFS and in other neuro-ophthalmologic diseases are discussed.     

Clinical and immunological spectrum of the Miller Fisher syndrome

The Miller Fisher syndrome (MFS), characterized by ataxia, areflexia, and ophthalmoplegia, was first recognized as a distinct clinical entity in 1956. MFS is mostly an acute, self-limiting condition, but there is anecdotal evidence of benefit with immunotherapy. Pathological data remain scarce. MFS can be associated with infectious, autoimmune, and neoplastic disorders. Radiological findings have suggested both central and peripheral involvement. The anti-GQ1b IgG antibody titer is most commonly elevated in MFS, but may also be increased in Guillain-Barré syndrome (GBS) and Bickerstaff's brainstem encephalitis (BBE). Molecular mimicry, particularly in relation to antecedent Campylobacter jejuni and Hemophilus influenzae infections, is likely the predominant pathogenic mechanism, but the roles of other biological factors remain to be established. Recent studies have demonstrated the presence of neuromuscular transmission defects in association with anti-GQ1b IgG antibody, both in vitro and in vivo. Collective findings from clinical, radiological, immunological, and electrophysiological techniques have helped to define MFS, GBS, and BBE as major disorders within the proposed spectrum of anti-GQ1b IgG antibody syndrome.     

Bilateral internal ophthalmoplegia as an initial sole manifestation of Miller Fisher syndrome

Although there have been reports regarding the frequent involvement of the pupils in Miller Fisher syndrome (MFS) and related syndromes, internal ophthalmoplegia has not been described as the initial sole manifestation of typical MFS. Recently, we encountered a woman with MFS whose initial manifestation was blurred vision because of bilateral tonic pupils. Investigations, including brain imaging, cerebrospinal fluid examination and nerve conduction studies were normal except for elevated serum levels of immunoglobulin G anti-GQ1b antibody. During the disease, she subsequently developed bilateral sixth and seventh nerve palsies, gait ataxia, and areflexia. We treated her with intravenous immunoglobulin and she showed a stepwise recovery from her illness. This case suggests that bilateral internal ophthalmoplegia can be a preceding sole manifestation of typical MFS.     

Concanavalin A inhibits pathophysiological effects of anti-ganglioside GQ1b antibodies at the mouse neuromuscular synapse

Anti-GQ1b antibodies are present in the Miller Fisher syndrome (MFS), a monophasic neuropathy characterized by ataxia, areflexia, ophthalmoplegia, and sometimes cranial muscle weakness. We have previously shown, at the mouse neuromuscular junction (NMJ) ex vivo, that anti-GQ1b antibodies, through complement classic pathway activation, block synaptic transmission in a way that resembles the effect of the pore-forming alpha-latrotoxin (alphaLTx). In order to clarify the mechanism of these alphaLTx-like effects, including possible involvement of the alternative and mannose-binding protein complement pathways, we studied the effects of concanavalin A (ConA), a lectin known to block the action of alphaLTx, immunoglobulins, and early complement components. With electrophysiological, immunohistological, and bioassay experiments, we showed that the alphaLTx-like effects of anti-GQ1b antibody and complement were inhibited by pre- and coincubation with ConA. However, ConA was not able to inhibit evolution of alphaLTx-like effects when coincubated upon addition of complement at NMJs that had already bound anti-GQ1b antibody. Our data suggest that the mannose-binding protein pathway is not involved in the alphaLTx-like effect and that the inhibiting effect of ConA principally arises through interference with presynaptic binding of anti-GQ1b antibody. In control experiments, ConA prevented the neuroexocytotic effects of alphaLTx, indicating that alphaLTx receptors were inhibited under these conditions. We conclude that, although the physiological effects at the NMJ of anti-GQ1b antibody and alphaLTx are very similar, the activity of anti-GQ1b antibody is not mediated through activation of alphaLTx receptors, but rather is caused by direct presynaptic membrane damage through classic complement pathway activation.     

Total ocular akinesis: Miller Fisher or Guillain-Barré syndrome?

Total, bilateral ophthalmoplegia is very rare. More than 50% of cases are Miller Fisher (MFS) and Guillain-Barré (GBS) syndromes. There is a correlation of MFS with anti-GQ1b antibodies. High levels of GQ1b gangliosides are found in myelin sheathes of cranial nerves supplying the extraocular muscles. This may explain the association of anti-GQ1b antibodies with ophthalmoplegia. Anti-GQ1b were also found in cases of GBS accompanied by ophthalmoplegia, atypical MFS (MFS without ataxia), MFS/GBS overlap syndromes and Bickerstaff brainstem encephalitis. This has led some authors to classify them as 'anti-GQ1b syndromes'. In this article we describe a diagnostically difficult case of a patient with a very rare, total bilateral paralysis of all ocular muscles, accompanied by bilateral ptosis, diminished tendon reflexes of upper extremities, paresis and hypoesthesia of the left upper extremity.     

Anti-GQ1b antibodies and evoked acetylcholine release at mouse motor endplates

Miller Fisher syndrome (MFS) is clinically characterized by ataxia, areflexia, and ophthalmoplegia, and is associated with serum anti-GQ1b-ganglioside antibodies. We have previously shown that anti-GQ1b antibodies induce complement-dependent, alpha-latrotoxin-like effects at mouse neuromuscular junctions (NMJs) in vitro. This effect comprises a massive increase in spontaneous quantal acetylcholine (ACh) release, accompanied by block of evoked release and muscle paralysis. This mechanism may contribute to the motor features of MFS. Whether the block of evoked ACh release is a primary effect of anti-GQ1b antibodies or occurs secondary to massive complement-dependent spontaneous release is unknown. Using conventional micro-electrode methods, we measured in detail ACh release evoked with low- and high-rate nerve stimulation, and studied the effect on it of a purified MFS IgG and a mouse monoclonal anti-GQ1b IgM (without added complement). We found that evoked transmitter release was unaffected. Control experiments proved binding of anti-GQ1b antibody at the NMJ. We conclude that the block of nerve-evoked ACh release at the NMJ is not a primary effect of anti-GQ1b antibodies, but is dependent on antibody-mediated complement activation. It remains to be determined whether the block of nerve-evoked ACh release is the consequence of massive spontaneous ACh release or occurs as a concomitant event.     

Acute isolated ophthalmoplegia with anti-GQ1b antibodies

Ophthalmoplegia without ataxia, areflexia or both has been designated as atypical Miller Fisher syndrome (MFS) or acute ophthalmoplegia (AO). This entity, first reported by Chiba et al. is associated with anti-GQ1b IgG antibodies.We report a patient with isolated acute ophthalmoplegia with high titer of anti-GQ1b IgG antibody activity in the acute phase in whom treatment with intravenous immunoglobulin (IVIg) led to the clinical recovery and the decrease in antibody titer.     

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.     

Acute ophthalmoplegia with pupillary areflexia associated with anti-GQ1b antibody.

Raised anti-GQ1b antibody is associated with Miller Fisher syndrome, Guillain-Barre syndrome (GBS) with ophthalmoplegia, Bickerstaff's brain stem encephalitis, acute ophthalmoparesis without ataxia and ataxic GBS without opthalmoplegia. We report a rare case of acute ophthalmoplegia associated with anti-GQ1b antibody that also had pupillary areflexia. A 35-year-old Chinese lady presented with external ophthalmoplegia, pupillary areflexia and no other abnormalities of cranial nerves, muscle tone, deep tendon reflexes, limb power or cerebellar dysfunction. Anti-GQ1b IgG antibody titre was significantly elevated, while neuroimaging of brain and orbital structures, nerve conduction study and cerebral spinal fluid examination were normal. Pupillary areflexia should be recognized as another feature that may be present in conditions associated with raised anti-GQ1b antibody.     

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.     

Detection and prevalence of alpha-latrotoxin-like effects of serum from patients with Guillain-Barré syndrome

Anti-GQ1b antibodies are associated with the Miller Fisher syndrome (MFS), a variant of the Guillain-Barré syndrome (GBS). In the ex vivo mouse diaphragm, anti-GQ1b-positive MFS serum induces muscle fiber twitching, a temporary dramatic increase of spontaneous quantal acetylcholine release, and transmission blockade at neuromuscular junctions (NMJs). These effects resemble those of alpha-latrotoxin (alpha-LTx) and are induced by antibody-mediated activation of complement. We developed an assay for detection of the alpha-LTx-like effect, using muscle fiber twitching as indicator. We tested 89 serum samples from GBS, MFS, and control subjects, and studied correlations with clinical signs, anti-ganglioside antibodies, micro-electrode physiology, and complement deposition at NMJs. Twitching was observed with 76% of the MFS and 10% of the GBS samples. It was associated with ophthalmoplegia and anti-GQ1b antibodies in patients, and with increased spontaneous acetylcholine release and C3c-deposition at mouse NMJs. This study strongly suggests that antibodies to GQ1b (with cross-reactivity to related gangliosides) are responsible for the alpha-LTx-like activity. The twitching assay is an efficient test for detection of this effect, and allows for screening of large numbers of samples and modifying drugs.     

Miller Fisher anti-GQ1b antibodies: α-Latrotoxin–like effects on motor end plates

In the Miller Fisher syndrome (MFS) variant of the Guillain-Barré syndrome, weakness is restricted to extraocular muscles and occasionally other craniobulbar muscles. Most MFS patients have serum antibodies against ganglioside type GQ1b of which the pathophysiological relevance is unclear. We examined the in vitro effects of MFS sera, MFS IgG, and a human monoclonal anti-GQ1b IgM antibody on mouse neuromuscular junctions (NMJs). It was found that anti-GQ1b antibodies bind at NMJs where they induce massive quantal release of acetylcholine from nerve terminals and eventually block neuromuscular transmission. This effect closely resembled the effect of the paralytic neurotoxin α-latrotoxin at the mouse NMJs, implying possible involvement of α-latrotoxin receptors or associated downstream pathways. By using complement-deficient sera, the effect of anti-GQ1b antibodies on NMJs was shown to be entirely dependent on activation of complement components. However, neither classical pathway activation nor the formation of membrane attack complex was required, indicating the effects could be due to involvement of the alternative pathway and intermediate complement cascade products. Our findings strongly suggest that anti-GQ1b antibodies in conjunction with activated complement components are the principal pathophysiological mediators of motor symptoms in MFS and that the NMJ is an important site of their action. Ann Neurol 1999;45:189–199     

Miller fisher syndrome: a hospital-based retrospective study

Miller Fisher syndrome (MFS), characterized as ataxia, areflexia and ophthalmoplegia, is generally considered as a variant of Guillain-Barré syndrome (GBS). However, some investigators believed that the syndrome could be explained by a central origin. To obtain more information about MFS for comparison with GBS, we conducted a retrospective study by analyzing the clinical data of MFS patients admitted to our hospital over a period of 11 years. The calibrated male/female ratio was 1.65. A seasonal clustering in winter was noted. The percentage of MFS among GBS was especially high (18%, 11/60) in Taiwan when compared with other series. Involvement of limb muscle strength, autonomic function and cranial nerves, except ocular motor nerves, was rarely found in our patients. When MFS is accompanied by limb weakness, it might represent a transitional form between MFS and GBS. Bulbar palsy and dysautonomia might predict a relatively poor prognosis. To obtain more reliable information, lumbar puncture should be done 1 week after disease onset, and electrophysiological tests should be done serially in every MFS patient. Eighty percent (80%, 4/5) of our patients were positive for IgG anti-GQ(1b) antibody activity. In our study, there is more evidence indicating that MFS is a peripheral nervous system disorder; however, no definite conclusion could be made as to whether MFS is exclusively a peripheral or central nervous system disorder. We think MFS is an immune-mediated clinical entity which mainly involves the peripheral nervous system with rare involvement of other parts of the central nervous system.     

Bickerstaff brainstem encephalitis associated with Mycoplasma pneumoniae infection

Bickerstaff brainstem encephalitis is a clinical syndrome of ophthalmoplegia, cerebellar ataxia, and central nervous system signs and is associated with the presence of anti-GQ1b antibodies. There is a clinical continuum between Bickerstaff brainstem encephalitis and Miller Fisher syndrome. We describe the case of an 11-year-old boy with encephalopathy, external ophthalmoplegia, brainstem signs, and ataxia with raised titers of anti-GQ1b antibodies. He presented following a respiratory illness and had laboratory evidence of recent infection with Mycoplasma pneumoniae. M pneumoniae infection has been associated with both Bickerstaff brainstem encephalitis and Miller Fisher syndrome. This is only the second case in the literature of Bickerstaff brainstem encephalitis with raised titers of anti-GQ1b antibodies described in association with M pneumoniae infection. The patient responded to intravenous immunoglobulin administration.     

IgG anti-GQ1b positive acute ataxia without ophthalmoplegia

IgG anti-GQ1b antibody was present in a patient with acute ataxia and areflexia without ophthalmoplegia or elementary sensory loss. Sensory nerve conduction studies and somatosensory evoked potentials were normal, but postural body sway analysis showed dysfunction of the proprioceptive afferent system. The clinical presentation and laboratory results for this patient resemble those of Miller Fisher syndrome, except for the lack of ophthalmoplegia. This case may represent part of an IgG anti-GQ1b syndrome.     

Miller Fisher syndrome: brief overview and update with a focus on electrophysiological findings

Miller Fisher syndrome (MFS), a variant of the Guillain–Barré syndrome (GBS), is characterized by ophthalmoplegia, ataxia, and areflexia. The annual incidence is around one patient per one million population. The antiganglioside anti‐GQ1b IgG antibody has a role in the pathogenesis of the syndrome, especially of ophthalmoplegia. The presence of this antibody in the serum can be identified in over 80% of the patients, peaking in the first week, whereas albuminocytological dissociation in the cerebrospinal fluid (CSF) appears later. The most consistent electrophysiological findings in MFS are reduced sensory nerve action potentials and absent H reflexes. More variability is seen with F waves and various investigations involving cranial structures. Although there are usually no abnormalities in MFS by routine neuroimaging, in a few cases, contrast enhancement of nerve roots and signs of central nervous system involvement were described supporting the hypothesis of an anti‐GQ1b‐syndrome, a continuum involving GBS, MFS, and Bickerstaff’s brainstem encephalitis. Owing to the lack of randomized trials, treatments used for GBS (intravenous immunoglobulin and plasmapheresis) are usually applied, although from retrospective analyses, the outcome was similar between treated and untreated subjects. The outcome of MFS is usually good with case fatality of < 5%. In the few autopsy cases, macroscopic abnormalities were generally not seen in the nervous system. Microscopic examination of the peripheral nervous system (including cranial nerves) showed segmental demyelination with minimal perivascular infiltration with normal spinal cord and brain stem.     

Miller Fisher syndrome with transient coma: comparison with Bickerstaff brainstem encephalitis

We herein report a 4-year-old boy with Miller Fisher syndrome (MFS) who presented with transient coma in addition to the typical triad of internal and external ophthalmoplegia, cerebellar ataxia and areflexia after an influenza type B infection. The electroencephalogram findings revealed intermittently generalized slow wave bursts. The cerebrospinal fluid revealed high protein and a lack of any cellular response. The serum anti-GQ1b IgG antibody was elevated in the acute phase and disappeared in the convalescent phase. The transient coma with the triad of MFS in this patient indicated an extended brainstem lesion including a reticular formation, which is also the responsible lesion of Bickerstaff brainstem encephalitis (BBE), but the magnetic resonance imaging repeatedly showed no abnormal finding. Our patient suggested the involvement of central nervous system in addition to the peripheral nerve injury in MFS. He also suggested that MFS and BBE may belong to the same group of disorders as syndrome of ophthalmoplegia, ataxia and areflexia (SOAA).     

Acute bilateral mydriasis associated with anti-GQ1b antibody

Miller Fisher syndrome (MFS) is an autoimmune neuropathy characterized by external ophthalmoplegia, ataxia and areflexia. Mydriasis is present in 35% of typical MFS. We report five patients with acute bilateral mydriasis, either isolated or associated with external ophthalmoplegia for which the presumed diagnosis of “atypical MFS” was confirmed by the positivity of anti-GQ1b antibodies. Acute bilateral mydriasis raises important differential diagnoses in clinical practice. This report demonstrates that acute mydriasis can be autoimmune mediated and that anti-GQ1b antibodies are useful to confirm the diagnosis in unexplained cases.