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Sialylation in Fc portion of IgG plays a crucial role in the pathogenesis of autoimmune diseases and the working mechanism of intravenous immunoglobulin (IVIG). We aim to test whether IgG-Fc sialylation is a biomarker of disease activity for chronic inflammatory demyelinating polyneuropathy (CIDP).By using specific lectins for sialylation, galactosylation and agalactosylation, lectin-enzyme assay and lectin blotting with pretreatment of IgG degradating enzyme of Streptococcus pyogenes were performed to compare the glycosylation levels of serum IgG-Fc (1) between patients of untreated CIDP (n=107) and normal control subjects (n=27), (2) among patients with untreated CIDP of different clinical severities and (3) before and after IVIG treatment of patients with CIDP (n=12).Sialylation and galactosylation of IgG-Fc were significantly reduced in patients with CIDP than normal control subjects (p=0.003 and 0.033, respectively), whereas agalactosylation was increased in CIDP (p=0.21). Ratios of sialylated/agalactosylated IgG-Fc levels were significantly reduced in CIDP (p0.001) and inversely related to disease severity (p=0.044). After IVIG treatment, levels of sialylated IgG-Fc significantly increased (p=0.003).Sialylation of IgG-Fc is reduced in CIDP. Its level correlated with clinical severity and increased after IVIG treatment. Sialylated as well as ratio of sialylated/agalactosylated IgG-Fc could be new measures to monitor the disease severity and treatment status in CIDP.

The clinical effectiveness and relative ease of administering intravenous immunoglobulin (IVIG) make it the preferred treatment option for several immune mediated conditions including chronic inflammatory demyelinating polyneuropathy (CIDP). Timing and dosage of IVIG vary considerably in CIDP between patients. The cost implications for establishing sensitive and reliable biomarkers, which accurately predict IVIG dosing regimens and avoid overtreatment are therefore considerable and warrant investigation. In this issue, Kuitwaard and colleagues examine the variability of serum IgG levels in patients receiving IVIG for treatment of CIDP.1 They demonstrate …

Background Whether or not antiganglioside antibodies are related to axonal or demyelinating Guillain–Barre syndrome (GBS) is still a matter of controversy, as detailed in previous studies conducted in Western and Asian countries. Objective To clarify whether antiganglioside antibodies are associated with axonal dysfunction in Japanese and Italian GBS patient cohorts. Methods Clinical and electrophysiological profiles were reviewed for 156 GBS patients collected from Japan (n=103) and Italy (n=53). Serum IgG antibodies against GM1, GM1b, GD1a and GalNAc-GD1a were measured by ELISA in the same laboratory. Electrodiagnostic criteria and results of serial electrophysiological studies were used for classification of GBS subtypes: acute inflammatory demyelinating polyneuropathy (AIDP) and acute motor axonal neuropathy (AMAN). Results In both Japanese and Italian cohorts, any of the antibodies were positive in 36% of the patients, and antibody positivity had a significant association with the AMAN electrodiagnosis. Approximately 30% of Japanese and Italian antiganglioside positive patients showed the AIDP pattern at the first examination whereas sequential studies showed that most finally showed the AMAN pattern. Clinically, seropositive patients more frequently had preceding diarrhoea and pure motor neuropathy in both Japanese and Italian cohorts; vibratory sensation was normal in 97% of Japanese and in 94% of Italian seropositive patients. Conclusions In GBS, clinical and electrophysiological features appear to be determined by antiganglioside antibodies, and the antibodies are associated with motor axonal GBS in both Japan and Italy. Classification of the GBS subtypes as a disease entity should be made, combining the results of antiganglioside assays and serial electrodiagnostic studies.

Background Ataxic Guillain–Barre syndrome is characterised by profound ataxia with negative Romberg sign and no ophthalmoplegia. Its nosological relationship to acute sensory ataxic neuropathy has yet to be discussed. Methods Medical records were reviewed of patients suffering acute ataxia and reduced muscle stretch reflexes but without external ophthalmoplegia. Clinical features and laboratory findings were analysed. Rat muscle spindles were immunostained by anti-GQ1b and -GD1b antibodies. Results The Romberg sign was negative in 37 (69%) of 54 patients with acute ataxic neuropathy without ophthalmoplegia, but positive in the other 17 (31%). The negative and positive subgroups had similar features; preceding infectious symptoms (86% vs 83%), distal paraesthesias (70% vs 88%), superficial sense impairment (27% vs 24%), IgG antibodies to GQ1b (65% vs 18%) and GD1b (46% vs 47%) and cerebrospinal fluid albuminocytological dissociation (30% vs 39%). Findings did not differ between the subgroups of 466 patients with Fisher syndrome with and without sensory ataxia. Acute ataxic neuropathy patients more often had anti-GD1b (46% vs 26%) and less often anti-GQ1b (50% vs 83%) antibodies than Fisher syndrome. Anti-GQ1b and -GD1b antibodies strongly stained parvalbumin-positive nerves in rat muscle spindles, indicative that proprioceptive nerves highly express GQ1b and GD1b. Conclusion Clinical and laboratory features suggest that ataxic Guillain–Barre syndrome and acute sensory ataxic neuropathy form a continuous spectrum. The two conditions could be comprehensively referred to as ‘acute ataxic neuropathy (without ophthalmoplegia)’ to avoid nosological confusion because Fisher syndrome is not classified by the absence or presence of sensory ataxia. That is, acute ataxic neuropathy can be positioned as an incomplete form of Fisher syndrome.

During a mass vaccination campaign in the USA in 1976, there was a statistically significant increased risk of developing Guillain–Barre syndrome (GBS) following receipt of the A/NJ/1976/H1N1 ‘swine flu’ vaccine.1 Because the currently circulating pandemic A (H1N1) flu virus is partially of swine origin, there has been concern about a similar association of GBS with the novel flu A (H1N1) vaccine. Preliminary analysis showed an elevated, statistically significant association between 2009 H1N1 vaccination and GBS.2 If confirmed, the increased risk of GBS associated with 2009 H1N1 vaccine of 0.8 cases per 1 million vaccinations would be comparable with the risk described previously for some trivalent seasonal flu vaccine formulations. GBS is divided into two major subtypes, acute inflammatory demyelinating polyradiculoneuropathy (AIDP) and acute motor axonal neuropathy (AMAN).3 AMAN, but not AIDP, is significantly associated with IgG antibodies against GM1, GM1b, GD1a, GalNAc-GD1a and GD1b. It is not known if the 1976 flu vaccine was associated with AIDP or AMAN. A recent report, however, demonstrated that the 1976 swine flu vaccines, seasonal flu vaccines from 1991–1992 and 2004–2005, and recombinant haemagglutinin proteins derived from high pathogenic avian H5N1 viruses A/HK/156/97 and A/Vietnam/1203/04 induced IgM and IgG anti-GM1 antibodies in mice.4 Here, we report our assessment of the pandemic 2009 A (H1N1) and H5N1 vaccines' ability to induce antiganglioside antibodies in mice and humans, providing information as to the possible risk of developing AMAN following these vaccinations. Inactivated A/H1N1pdm split vaccines (without adjuvant) used during the Japan 2009–2010 …

Background Previous studies have shown that anti-GQ1b antibodies induce massive neuromuscular blocking. If anti-GM1 and -GD1a antibodies have similar effects on the neuromuscular junction (NMJ) in human limb muscles, this may explain selective motor involvement in axonal Guillain–Barre syndrome (GBS). Methods Axonal-stimulating single-fibre electromyography was performed in the extensor digitorum communis muscle of 23 patients with GBS, including 13 with the axonal form whose sera had a high titre of serum IgG anti-GM1 or -GD1a antibodies. Results All patients with axonal or demyelinating GBS showed normal or near-normal jitter, and no blocking. Conclusion In both axonal and demyelinating GBS, neuromuscular transmission is not impaired. Our results failed to support the hypothesis that anti-GM1 or -GD1a antibody affects the NMJ. In GBS, impulse transmission is presumably impaired in the motor nerve terminal axons proximal to the NMJ.

Background The pathogenesis of multifocal motor neuropathy (MMN) has yet to be established. MMN patients often carry anti-GM1 IgM antibodies, suggesting an autoimmune process involving complement. Intravenous immunoglobulin (IVIG) is the first line treatment, but its action mechanism is unknown. Objective To test whether anti-GM1 IgM antibodies in MMN sera activate complement, inducing and propagating the disease and whether IVIG inhibits complement activation, resulting in clinical improvement. Methods Sera with anti-GM1 IgM but not IgG or IgA reactivity were obtained from 13 patients with MMN. We tested whether their anti-GM1 IgM antibodies produced complement component deposits on GM1-coated microtiter plates and whether IVIG blocks such deposition. Results C1q, C4b, C3b and C5b-9 were deposited on GM1-coated wells. Their depositions were highly correlated with anti-GM1 IgM antibody titre. IVIG reduced the deposition of these complement components dose-dependently. Conclusions Anti-GM1 IgM antibodies bound to GM1 and activated complement in vitro. The results together with earlier data from our group suggest that IgM-induced, complement-mediated injury occurs at the nodes of Ranvier in peripheral motor nerves and generates conduction block and muscle weakness. In vitro IVIG inhibited this type of complement activation, suggesting that in vivo, the resulting reduction in membrane attack complex-mediated damage leads to improved muscle strength.

Background Clinical severity of Guillain–Barre syndrome (GBS) is highly variable, but the immunopathological reason is unknown. Objective The study was designed to show which antibody parameters are associated with disease severity in GBS patients with serum anti-GM1 IgG antibodies. Methods Thirty-four GBS patients with anti-GM 1 IgG antibodies were grouped into two categories according to disease severity at nadir: mild (grades 1–3 by Hughes functional scale, n=13) and severe (grades 4 and 5, n=21). Titre, affinity, fine specificity and cell binding of anti-GM 1 antibodies were obtained and compared between the two groups. Results No differences in antibody titre (GM 1 -ELISA) or affinity were found between the two patient groups. In contrast, the severe group showed a significantly higher frequency (95%, vs 46% in the mild group, p=0.002) of specific (not cross-reacting with GD 1b ) anti-GM 1 antibodies. In addition, the severe group also exhibited a higher antibody binding titre to cellular GM 1 . Conclusions Differences in fine specificity of antibodies are strong indications that different regions of the GM 1 -oligosaccharide are involved in antibody binding. High titres of specific anti-GM 1 antibody binding to cellular GM 1 can be explained by antigen exposure, that is, GM 1 exposes or forms mainly epitopes recognised by specific antibodies, and ‘hides’ those involved in binding of cross-reacting antibodies. Thus, the fine specificity of anti-GM 1 antibodies may influence disease severity by affecting antibody binding to cellular targets. Additionally, since antibody specificity studies are relatively easy to implement, fine specificity could be considered a useful predictor of disease severity.

Background: Some patients with Fisher syndrome (FS) developed subsequent descending tetraparesis (Fisher/Guillain–Barre overlapping syndrome: FS/GBS). The assumption is that such descending progression may frequently lead to respiratory failure. Objective: To investigate whether patients with FS/GBS more often require artificial ventilation than those with typical GBS and which clinical and serological findings are useful predictors. Methods: Medical records were reviewed of patients who had acute ophthalmoplegia, ataxia and areflexia, as well as subsequent tetraparesis with monophasic course. Forty-five patients fulfilled the FS/GBS criteria. Clinical and serological features were analysed, and clinical predictors of mechanical ventilation were investigated. Results: FS/GBS patients more frequently required mechanical ventilation than did GBS patients (24% vs 10%, p = 0.04). The former also needed artificial ventilation earlier than the latter (p = 0.03), but none of the FS patients required it. As the initial symptom, ventilated FS/GBS patients more frequently showed titubation than non-ventilated patients (55% vs 18%, p = 0.04). During the course of the illness, descending tetraparesis was more common in 11 ventilated FS/GBS patients than in the other 34 non-ventilated patients (64% vs 21%, p = 0.02). The need for artificial ventilation was not associated with anti-GQ1b IgG antibodies, monospecific anti-GT1a IgG antibodies or IgG antibodies to various ganglioside complexes. Conclusions: FS/GBS patients significantly needed mechanical ventilation more often. Such patients showing titubation and descending tetraparesis need to be carefully monitored as the illness progresses because those clinical features are helpful predictors of respiratory failure.

Background: Haemophilus influenzae is considered a causative agent of Guillain-Barre syndrome (GBS) and Fisher syndrome, but the frequency of this infection in GBS is controversial. Objective: To determine whether isolation of H influenzae indicates it is a causative agent in GBS and Fisher syndrome. Results: Four (15%) of 27 patients with GBS and Fisher syndrome in whom H influenzae was isolated were also seropositive for Campylobacter jejuni . Antiganglioside IgG antibodies in these four patients did not cross react with their H influenzae lipo-oligosaccharides, whereas antiganglioside antibodies in the four patients with positive serology for H influenzae did. Conclusions: The findings suggest that H influenzae isolation is not always indicative of the causative agent in these syndromes and that tests for other infections should be made, even in cases of positive culture.

Objective: To investigate the presence of serum anti-GT1a IgG in Guillain-Barre syndrome (GBS) and its relation to clinical manifestations. Background: Several patients with GBS and bulbar palsy have been reported to have serum anti-GT1a IgG. Most, however, also have anti-GQ1b IgG. A previous study failed to detect GT1a in human cranial nerves, but GQ1b was abundant in human ocular motor nerves. Whether anti-GT1a IgG itself determines the clinical manifestations is not yet clear. Methods: The association of clinical manifestations with the presence of anti-GT1a IgG and with its cross reactivity was investigated. An immunochemical study was performed to determine whether GT1a is present in human cranial nerves. Results: Anti-GT1a and anti-GQ1b IgG were positive in 10% and 9% respectively of 220 consecutive patients with GBS. Patients with anti-GT1a IgG often had cranial nerve palsy (ophthalmoparesis, 57%; facial palsy, 57%; bulbar palsy, 70%), and 39% needed artificial ventilation. These features were also seen in patients with anti-GQ1b IgG. There was no significant difference between the two groups with respect to the frequency of clinical findings. An enzyme-linked immunosorbent assay showed that anti-GT1a IgG cross reacted with GQ1b in 75% of the patients, GD1a in 30%, GM1 in 20%, and GD1b in 20%. All five patients who carried anti-GT1a IgG that did not cross react with GQ1b had bulbar palsy, neck weakness, absence of sensory disturbance, and positive Campylobacter jejuni serology. Thin-layer chromatography with immunostaining showed that GT1a is present in human oculomotor and lower cranial nerves. Conclusions: These findings provide further evidence that anti-GT1a IgG itself can determine clinical manifestations. The distinctive clinical features of patients with anti-GT1a IgG without anti-GQ1b activity distinguish a specific subgroup within GBS.

The cross reactivity of anti-GM1 IgG antibody with various gangliosides and asialo-GM1 in serum samples from 27 patients with Guillain-Barré syndrome was investigated. An enzyme linked immunosorbent assay (ELISA) absorption study showed that anti-GM1 IgG antibody cross reacted with asialo-GM1 in 52% of the patients, GM1b in 41%, GD1b in 22%, and GalNAc-GD1a in 19%, and that it did not cross react with GM2, GT1b, or GQ1b. The antibody that cross reacted with GD1b was associated with a high frequency of cranial nerve involvement and negative Campylobacter jejuni serology. Anti-GM1 IgG antibody has a broad range of cross reactivity which may contribute to various clinical variations of Guillain-Barré syndrome.

OBJECTIVES—To investigate the pathophysiology of selective absence of F waves and its relation with antiganglioside antibodies in Guillain-Barré syndrome (GBS). Some patients with GBS show the absence of F waves as an isolated conduction abnormality, which has been interpreted as demyelination in the proximal nerve segments. METHODS—In 62 consecutive patients with GBS, sequential nerve conduction and F wave studies were reviewed, and antibodies against ganglioside GM1, GM1b, GD1a, GalNAc-GD1a, GD1b, and GQ1b were measured by an enzyme linked immunosorbent assay. RESULTS—In the first electrophysiological studies, isolated absence of F waves was found in 12 (19%) patients. Sequential studies in 10 of these patients showed two electrophysiological sequel patterns; rapid restoration of F waves (six patients), and persistent absence of F waves with distal motor nerve degeneration (acute motor axonal neuropathy, four patients). None of the 10 patients showed evidence of demyelination in the proximal, intermediate, or distal nerve segments throughout the course. Of the 62 patients, IgG antibodies against GM1, GM1b, GalNAc-GD1a, or GD1b were significantly associated with the electrodiagnosis of acute motor axonal neuropathy, and patients with these antibodies more often had isolated absence of F waves than patients without them (11 of 36 (31%) v one of 26 (4%); p

OBJECTIVES—To identify valuable antiganglioside antibodies that support the diagnosis of Guillain-Barre syndrome (GBS) and its variants in patients showing bulbar palsy as an initial symptom. METHODS—Medical records of 602 patients with GBS or its variants were reviewed. Fifteen patients had bulbar palsy as an initial symptom. Serum antibodies against GM1, GM1b, GD1a, GalNAc-GD1a, GT1a, and GQ1b were examined in 13 of them. RESULTS—Serum antiganglioside antibodies were positive in 11 (85%) patients. IgG anti-GT1a (n=8; 62%) and anti-GM1b (n=7; 54%) antibodies were often present, whereas all the patients had low or no anti-GM1 antibody activity. High anti-GD1a and anti-GQ1b IgG antibody titres were also present in some patients, but most had higher IgG antibody titres to GM1b or GT1a. All five patients with high IgG antibody titre to GM1b or GT1a only had had antecedent diarrhoea. Some patients with pharyngeal-cervical-brachial weakness (PCB) had IgG antibody to GT1a which did not cross react with GQ1b. Other patients with PCB had antibody to GT1a which cross reacted with GQ1b or antibody to GM1b, but anti-GM1b and anti-GT1a antibodies were not associated with the presence of bulbar palsy. All the patients who had no IgG antiganglioside antibodies recovered completely. CONCLUSIONS—Measurement of serum IgG anti-GT1a and anti-GM1b antibodies gives helpful support for the diagnosis of GBS and its variants when there is early involvement of the oropharyngeal function independently of other neurological findings which appear as the illness progresses.

OBJECTIVES--Investigation of pathophysiology of F wave disappearance in demyelinating neuropathies. METHODS--The peripheral motor nerve conduction was studied by motor evoked potential (MEP) on transcranial magnetic stimulation as well as conventional nerve conduction studies before and after the treatment in 26 patients with inflammatory demyelinating neuropathies. In addition, serum antiganglioside antibodies in the acute or active stage were examined. RESULTS--The F wave was abolished in 10 patients. Seven of the 10 patients showed motor evoked potentials (MEPs) on transcranial magnetic stimulation that ranged from 1-4 mV. In six of them the F wave reappeared in the recovery stage, but the MEP size did not change. This may be caused by humoral factors, because the F wave reappeared immediately after plasma exchange or intravenous immunoglobulin treatment. A correlation of F wave disappearance with the presence of serum antiganglioside antibodies was found. CONCLUSIONS--The major pathophysiology of F wave disappearance in demyelinating neuropathies is impairment of motor neuron excitability or prolonged refractoriness of the most proximal axon for backfiring. The conventional interpretation that absent F waves suggest a conduction block at the proximal site is often inadequate.