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.     

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     

Anti-disialosyl antibodies mediate selective neuronal or Schwann cell injury at mouse neuromuscular junctions

The human paralytic neuropathy, Miller Fisher syndrome (MFS) is associated with autoantibodies specific for disialosyl epitopes on gangliosides GQ1b, GT1a, and GD3. Since these gangliosides are enriched in synaptic membranes, anti-ganglioside antibodies may target neuromuscular junctions (NMJs), thereby contributing to disease symptoms. We have shown previously that at murine NMJs, anti-disialosyl antibodies induce an alpha-latrotoxin-like effect, electrophysiologically characterized by transient massive increase of spontaneous neurotransmitter release followed by block of evoked release, resulting in paralysis of the muscle preparation. Morphologically, motor nerve terminal damage, as well as perisynaptic Schwann cell (pSC) death is observed. The relative contributions of neuronal and pSC injury to the paralytic effect and subsequent repair are unknown. In this study, we have examined the ability of subsets of anti-disialosyl antibodies to discriminate between the neuronal and glial elements of the NMJ and thereby induce either neuronal injury or pSC death. Most antibodies reactive with GD3 induced pSC death, whereas antibody reactivity with GT1a correlated with the extent of nerve terminal injury. Motor nerve terminal injury resulted in massive uncontrolled exocytosis with paralysis. However, pSC ablation induced no acute (within 1 h) electrophysiological or morphological changes to the underlying nerve terminal. These data suggest that at mammalian NMJs, acute pSC injury or ablation has no major deleterious influence on synapse function. Our studies provide evidence for highly selective targeting of mammalian NMJ membranes, based on ganglioside composition, that can be exploited for examining axonal-glial interactions both in disease states and in normal NMJ homeostasis.     

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.     

Recent developments in Miller Fisher syndrome and related disorders

PURPOSE OF REVIEW: Miller Fisher syndrome is a localized variant of Guillain-Barré syndrome, characterized by ophthalmoplegia, areflexia and ataxia. Bickerstaff's brainstem encephalitis is a related syndrome in which upper motor neurone features accompany the classic triad. Anti-GQ1b antibodies are uniquely found in both conditions and are believed to be pathogenic. RECENT FINDINGS: Infectious illnesses usually precede Miller Fisher syndrome. The clearest associations have been described with Haemophilus influenzae and Campylobacter jejuni infection. Raised cerebrospinal fluid protein is seen in 60% of patients, but clinical features and anti-GQ1b antibody testing are diagnostically more informative. Experimental studies demonstrating complement-dependent neuromuscular block may be relevant to the clinical pathophysiology of Miller Fisher syndrome. Recent neurophysiological studies suggest abnormal neuromuscular transmission occurs in some cases of Miller Fisher syndrome and Guillain-Barré syndrome. Recent mouse models have demonstrated that presynaptic neuronal membranes and perisynaptic Schwann cells are targets for anti-GQ1b antibody attack. The elimination of antiganglioside antibodies from the circulation through specific immunoadsorption therapy has the potential to ameliorate the course of Miller Fisher syndrome. This condition is typically a benign, self-limiting illness. Both plasmapheresis and intravenous immunoglobulin may be employed as treatment, especially in cases of Bickerstaff's brainstem encephalitis or those with overlapping Guillain-Barré syndrome. SUMMARY: Anti-GQ1b antibody testing has allowed clinicians to develop a greater understanding of the spectrum of Miller Fisher syndromes and to refine clinical diagnoses in patients with unusual presentations. Experimental studies strongly suggest anti-GQ1b antibodies are pathogenic, which in principle should direct treatments towards antibody neutralization or elimination.     

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.     

Anti-GQ1b antibody does not affect neuromuscular transmission in human limb muscle

Anti-ganglioside GQ1b antibody induces neuromuscular blocking on mouse phrenic nerve-diaphragm preparations. Several reports suggest that patients with this antibody show abnormal neuromuscular transmission in the facial or limb muscles, but limb muscle weakness is unusual in Miller Fisher syndrome that is often associated with anti-GQ1b antibody. To determine whether anti-GQ1b sera affect neuromuscular transmission in human limb muscles, axonal-stimulating single fiber electromyography was performed in the forearm muscle of seven patients with anti-GQ1b antibody. All showed normal jitter and no blocking. Anti-GQ1b antibody does not affect neuromuscular transmission in human limb muscles. The different findings in mouse and human may be explained by the extent of expression of GQ1b on the motor nerve terminals in the muscle examined.     

The immunobiology of Guillain-Barré syndromes

This presentation highlights aspects of the immunobiology of the Guillain-Barré syndromes (GBS), the world's leading cause of acute autoimmune neuromuscular paralysis. Understanding the key pathophysiological pathways of GBS and developing rational, specific immunotherapies are essential steps towards improving the clinical outcome of this devastating disorder. Much of the research into GBS over the last decade has focused on the forms mediated by anti-ganglioside antibodies, and we have made substantial progress in our understanding in several related areas. Particular highlights include (a) the emerging correlations between anti-ganglioside antibodies and specific clinical phenotypes, notably between anti-GM1/anti-GD1a antibodies and the acute motor axonal variant and anti-GQ1b/anti-GT1a antibodies and the Miller Fisher syndrome; (b) the identification of molecular mimicry between GBS-associated Campylobacter jejuni oligosaccharides and GM1, GD1a, and GT1a gangliosides as a mechanism for anti-ganglioside antibody induction; (c) the development of rodent models of GBS with sensory ataxic or motor phenotypes induced by immunisation with GD1b or GM1 gangliosides, respectively. Our work has particularly studied the motor nerve terminal as a model site of injury, and through combined active and passive immunisation paradigms, we have developed murine neuropathy phenotypes mediated by anti-ganglioside antibodies. This has been achieved through use of glycosyltransferase and complement regulator knock-out mice, both for cloning anti-ganglioside antibodies and inducing disease. Through such studies, we have proven a neuropathogenic role for murine anti-ganglioside antibodies and human GBS-associated antisera and identified several determinants that influence disease expression including (a) the level of immunological tolerance to microbial glycans that mimic self-gangliosides; (b) the ganglioside density in target tissue; (c) the level of complement activation and the neuroprotective effects of endogenous complement regulators; and (d) the role of calcium influx through complement pores in mediating axonal injury. Such studies provide us with clear information on an antibody-mediated pathogenesis model for GBS and should lead to rational therapeutic testing of agents that are potentially suitable for use in humans.     

Acute ophthalmoparesis in the anti-GQ1b antibody syndrome: electrophysiological evidence of neuromuscular transmission defect in the orbicularis oculi

OBJECTIVE: To prospectively study anti-GQ1b antibody positive cases of acute ophthalmoparesis (AO) clinically and electrophysiologically. METHODS: Nine consecutive cases presenting with predominantly acute ophthalmoplegia were assessed clinically and had stimulated single fibre electromyography (SFEMG) of the orbicularis oculi at presentation. All had magnetic resonance imaging brain scans and anti-GQ1b antibody titres determined. RESULTS: Four cases had elevated anti-GQ1b antibody titres and abnormal SFEMG studies, which improved in tandem with clinical recovery over three months. Five other anti-GQ1b antibody negative cases were diagnosed as diabetic related cranial neuropathy, idiopathic cranial neuropathy, ocular myasthenia gravis, and Tolosa-Hunt syndrome. All five cases showed complete recovery over a three month period. CONCLUSIONS: This study demonstrated electrophysiologically the dynamic improvement of neuromuscular transmission of anti-GQ1b antibody positive cases of AO, in tandem with clinical recovery. SFEMG is of value in differentiating weakness due to neuromuscular transmission defect from neuropathy in these clinical situations.     

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

Abstract 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.     

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.     

Reduced tissue damage and improved recovery of motor function after traumatic brain injury in mice deficient in complement component C4.

Complement component C4 mediates C3-dependent tissue damage after systemic ischemia-reperfusion injury. Activation of C3 also contributes to the pathogenesis of experimental and human traumatic brain injury (TBI); however, few data exist regarding the specific pathways (classic, alternative, and lectin) involved. Using complement knockout mice and a controlled cortical impact (CCI) model, we tested the hypothesis that the classic pathway mediates secondary damage after TBI. After CCI, C4c and C3d immunostaining were detected in cortical vascular endothelial cells in wild-type (WT) mice; however, C4c and C3d immunostaining were also detected in C1q(-/-) mice, and C3d immunostaining was detected in C4(-/-) mice. After CCI, WT and C1q(-/-) mice had similar motor deficits, Morris water maze performance, and brain lesion size. Naive C4(-/-) and WT mice did not differ in baseline motor performance, but C4(-/-) mice had reduced postinjury motor deficits (days 1 to 7, P<0.05) and decreased brain tissue damage (days 14 and 35, P<0.05) versus WT. Reconstitution of C4(-/-) mice with human C4 (hC4) reversed their protection against postinjury motor deficits (P<0.05 versus vehicle), but administration of hC4 did not impair postinjury motor performance (versus vehicle) in WT mice. The protective effects of C4(-/-) were functionally distinct from the classic pathway and terminal complement, as C1q(-/-) and C3(-/-) mice had postinjury tissue damage and motor dysfunction similar to WT. Thus, C4 contributes to motor deficits and brain tissue damage after CCI by mechanism(s) fundamentally different from those involved in experimental systemic ischemia-reperfusion injury.     

Electrodiagnostic findings related to anti-GM1 and anti-GQ1b antibodies in Guillain-Barré syndrome

Antibodies against the gangliosides GM1 and GQ1b may induce conduction failure in mice. To investigate their possible site of action in the Guillain-Barré syndrome (GBS), we studied the relation between serum anti-GM1 and anti-GQ1b antibodies and electromyography in 124 GBS patients. Anti-GM1 antibodies were found in 22 (18%) and anti-GQ1b antibodies in 5 (4%) patients. Anti-GM1 antibodies were associated with low distal compound muscle action potential amplitudes and relatively high compound sensory nerve action potential (CSNAP) amplitudes. In none of the patients with anti-GQ1b antibodies could CSNAPs be detected. Patients with anti-GM1 and anti-GQ1b antibodies were heterogenous with respect to electrodiagnostic features exclusive for demyelination or axonal degeneration, although the anti-GM1 positive patients tended to have more axonal degeneration. In conclusion, electromyographic studies indicate selective and more severe damage of motor nerves in patients with anti-GM1 antibodies, while patients with anti-GQ1b antibodies have more severe damage of sensory nerves. These antibodies may interfere with the electrophysiologic properties of different nerve fibers and thereby contribute to the clinical heterogeneity in GBS. © 1997 John Wiley & Sons, Inc. Muscle Nerve, 20: 446–452, 1997     

Combined pre- and postsynaptic action of IgG antibodies in Miller Fisher syndrome

BACKGROUND: Miller Fisher syndrome (MFS), a variant of the Guillain-Barré syndrome, is associated with the presence of neuromuscular blocking antibodies, some of which may be directed at the ganglioside GQ1b. MATERIALS AND METHODS: The authors investigated the in vitro effects of serum and purified immunoglobulin (Ig) G in a total of 11 patients with typical MFS during active disease, and in three of those patients after recovery. From one patient's serum, we prepared an IgG fraction enriched in anti-GQ1b antibodies by affinity chromatography. For combined pre- and postsynaptic analysis, endplate currents were recorded by a perfused macro-patch clamp electrode. Postsynaptic nicotinic acetylcholine receptor channels were investigated by an outside-out patch clamp technique in cultured mouse myotubes. RESULTS: AllMFS-sera depressed evoked quantal release and reduced the amplitude of postsynaptic currents. Five of the 11 sera were additionally examined by outside-out patch clamp analysis and caused a concentration-dependent and reversible decrease in acetylcholine-induced currents. The time course of activation and desensitization of nicotinic acetylcholine receptor channels was not altered by MFS-IgG. Nine patients (82 %) were positive for anti-GQ1b antibodies in ELISA and dot-blot. The enriched anti-GQ1b antibody fraction had a similar effect as whole serum. After recovery from MFS, blocking activity was lost and sera originally positive for anti-GQ1b antibodies became negative. CONCLUSION: Circulating IgG antibodies induce both pre- and postsynaptic blockade and may play a pathogenic role in acute MFS.     

Complement upregulation and activation on motor neurons and neuromuscular junction in the SOD1 G93A mouse model of familial amyotrophic lateral sclerosis

Complement activation products are elevated in cerebrospinal fluid, spinal cord and motor cortex of patients with amyotrophic lateral sclerosis (ALS) but are untested in models. We determined complement expression and activation in the SOD1 G93A mouse model of familial ALS (fALS). At 126days, C3 mRNA was upregulated in spinal cord and C3 protein accumulated in astrocytes and motor neurons. C3 activation products C3b/iC3b were localized exclusively on motor neurons. At the neuromuscular junction, deposits of C3b/iC3b and C1q were detected at day 47, before the appearance of clinical symptoms, and remained detectable at symptomatic stage (126days). Our findings implicate complement in the denervation of the muscle endplate by day 47 and destruction of the neuromuscular junction and spinal neuron loss by day 126 in the SOD1 G93A mouse model of fALS.     

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.     

Anti-ganglioside antibody and neuropathy: review of our research

Some patients developed Guillain-Barré syndrome (GBS) after the administration of bovine gangliosides. Patients with GBS subsequent to Campylobacter jejuni enteritis frequently have IgG antibody to GM1 ganglioside. Fisher's syndrome (FS), a variant of GBS, is associated with IgG antibody to GQ1b ganglioside. We showed the existence of molecular mimicry between GM1 and lipopolysaccharide (LPS) of C. jejuni isolated from a GBS patient, and that between GQ1b and C. jejuni LPSs from FS patients. Several lines of evidence suggest a pathogenic role for anti-ganglioside antibodies. Some patients developed sensorimotor polyneuropathy after anti-GD2 antibody administration. Anti-GM1 antibody can block motor nerve conduction. The molecular mimicry between infectious agents and gangliosides may function in the production of anti-ganglioside antibodies and the development of GBS and FS. Anti-GQ1b IgG antibody is detected also in Bickerstaff's brainstem encephalitis and acute ophthalmoparesis, which suggests that these conditions are categorized as autoimmune diseases related to FS. Since a tryptophan-immobilized column effectively adsorb anti-GQ1b IgG antibody, immunoadsorption with the column should be considered as an alternative form of plasmapheresis for the anti-GQ1b IgG antibody syndrome.     

Neuro-ophthalmology and the anti-GQ1b antibody syndromes

The discovery of the association of the anti-GQ1b IgG antibody with the postinfectious clinical syndromes of ophthalmoplegia, ataxia, and areflexia helped house the phenotypes of the Miller Fisher syndrome (MFS), atypical MFS, Guillain-Barr’e syndrome with ophthalmoplegia, and Bickerstaff’s brainstem encephalitis under one roof. The neuro-ophthalmologic signs classically predominate and may vary from case to case, but they maintain clinically recognizable patterns that assist with the diagnosis. The identification of a common lipopolysaccharide on the plasma membrane in human cranial and peripheral nerves at the GQ1b epitope and on infectious particles of bacteria and viruses (ie, Campylobacter jejuni) demonstrates molecular mimicry. The high frequency of oculomotor dysfunction is partially explained by the tissue ganglioside concentration and distribution and the attraction of antibody-stimulating complement activation. Current experimental treatment targets antibody removal and neutralization and prevents membrane attack complex formation through deactivation of complement. This article aims to bring together the historically disparate opinions on the origins of these syndromes as either a purely peripheral nervous system or central nervous system dysfunction, highlight the clinical neuro-ophthalmologic signs, discuss some of the biology of the anti-GQ1b antibody, and review imaging abnormalities and treatment of this fascinating disorder.     

Three patients with ophthalmoplegia associated with Campylobacter jejuni

Cranial polyneuropathy is idiopathic in most patients. Idiopathic cranial polyneuropathy is an acute postinfectious syndrome, along with Guillain-Barré syndrome and Miller Fisher syndrome, in which the common preceding pathogen is Campylobacter jejuni. Serum anti-GQ1b antibodies are elevated in Miller Fisher syndrome and Guillain-Barré syndrome with ophthalmoplegia. Three patients with idiopathic cranial polyneuropathy with predominant ocular involvement are presented. C. jejuni isolated from stool specimens belonged to Penner serotypes O:4, O:23, and O:33. Serum anti-GQ1b antibodies were elevated in all patients but demonstrated rapid reduction concomitant with clinical recovery. All patients recovered completely. Because both preceding C. jejuni infection and elevated anti-GQ1b antibodies decreasing with time were seen in all patients, the pathogenesis of idiopathic cranial polyneuropathy with ophthalmoplegia may be similar to that of Miller Fisher syndrome.     

Miller Fisher syndrome with presynaptic neuromuscular transmission disorder

Miller Fisher syndrome is defined by a triad of symptoms, namely areflexia, ataxia, and ophthalmoparesis. The ophthalmoparesis is mostly severe, undulating weakness of eye movements with ptosis and increased fatigability resembling a neuromuscular transmission disorder. We present a 52-year-old man with severe Miller Fisher syndrome with a high level of anti-GQ1b antibodies and a presynaptic type of neuromuscular transmission disorder. The diagnosis was confirmed by stimulated single-fiber electromyography with the use of a concentric needle electrode and various stimulation rates.