Autoantibody responses to nodal and paranodal antigens in chronic inflammatory neuropathies.

Autoantibodies to nodal/paranodal proteins have been reported in patients with chronic inflammatory demyelinating polyneuropathy (CIDP) and multifocal motor neuropathy (MMN). To determine the frequency of anti-paranodal antibodies in our cohort of CIDP patients and to validate the presence anti-nodal antibodies in MMN, sera were screened for IgG against human neurofascin 155, contactin-1, neurofascin 186 and gliomedin using ELISA. In CIDP patients, 7% were anti-NF155 IgG4 positive and 7% were anti-CNTN1 IgG4 positive. Positive results were confirmed using cell based assays and indirect immunofluorescence on teased nerve fibres. We did not detect IgG autoantibodies against these nodal/paranodal antigens in MMN patients.

Clinical classification of 103 Japanese patients with Guillain-Barré syndrome.

Guillain-Barré syndrome (GBS) is the commonest cause of flaccid paralysis worldwide. Miller Fisher syndrome (MFS) is a variant of GBS characterized by ophthalmoplegia and ataxia. Together GBS and MFS form a continuum of discrete and overlapping subtypes, the frequency of which remains unknown. We retrospectively analysed the clinical features (antecedent symptoms, pattern of neurological weakness or ataxia, presence of hypersomnolence) of 103 patients at a single hospital in Japan. Patients were then classified according to new diagnostic criteria (Wakerley et al., 2014). Laboratory data (neurophysiology and anti-ganglioside antibody profiles) were also analysed. According to the new diagnostic criteria, the 103 patients could be classified as follows: classic GBS 73 (71%), pharyngeal-cervical-brachial weakness 2 (2%), acute pharyngeal weakness 0 (0%), paraparetic GBS 1 (1%), bifacial weakness with paraesthesias 1 (1%), polyneuritis cranialis 0 (0%), classic MFS 18 (17%), acute ophthalmoparesis 1 (1%), acute ptosis 0 (0%), acute mydriasis 0 (0%), acute ataxic neuropathy 1 (1%), Bickerstaff brainstem encephalitis 3 (3%), acute ataxic hypersomnolence 0 (0%), GBS and MFS overlap 1 (1%), GBS and Bickerstaff brainstem encephalitis overlap 1 (1%), MFS and pharyngeal-cervical-brachial weakness overlap 1 (1%). Application of the new clinical diagnostic criteria allowed accurate retrospective diagnosis and classification of GBS and MFS subtypes.

How often and when Fisher syndrome is overlapped by Guillain-Barré syndrome or Bickerstaff brainstem encephalitis?

BACKGROUND AND PURPOSE: Fisher syndrome (FS) may overlap with Guillain-Barré syndrome (GBS), in particular the pharyngeal-cervical-brachial variant form (PCB-GBS), or Bickerstaff brainstem encephalitis (BBE). Our aim was to elucidate the frequency of this overlap and the patterns of clinical progression in patients with FS. METHODS: Sixty consecutive patients with FS were studied. FS/PCB-GBS was diagnosed when the patients developed pharyngeal, cervical and/or brachial weakness. Patients with flaccid tetraparesis were diagnosed as having FS/conventional GBS. FS/BBE was defined as the development of consciousness disturbances. RESULTS: All 60 patients initially developed the FS clinical triad alone (pure FS). Of these, 30 (50%) patients had pure FS throughout their course, whereas the remaining 50% of patients showed an overlap: PCB-GBS in 14 (23%) patients, conventional GBS in nine (15%) patients and BBE in seven (12%) patients. The median (range) durations from FS onset to progression to FS/PCB-GBS, FS/GBS or FS/BBE were 5 (1-7), 3 (1-4) and 3 (1-5) days, respectively. Patients with overlap syndromes more frequently received immune-modulating treatment, and the outcomes were generally favourable. The frequencies of positivity for anti-GQ1b, GT1a, GD1a, GD1b, GalNAc-GD1a and GM1 antibodies were not significantly different amongst the four groups. CONCLUSIONS: Of the patients with pure FS, 50% later developed an overlap with PCB-GBS, conventional GBS or BBE. The overlap occurred within 7 days of FS onset; thus, physicians should pay attention to the possible development of this overlap during the first week after FS onset.

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.

Treatment of pressure ulcers in patients with declining renal function using arginine, glutamine and ß-hydroxy-ß-methylbutyrate.

The aim of this study is to examine the efficacy on healing pressure ulcers (PU) of using a supplement combination containing arginine, glutamine and ß-hydroxy-ß-methylbutyrate, which was given to two elderly patients with renal dysfunction. The PU was surgically opened, decompressed and treated by drugs. A half quantity of the defined dose of the supplement combination, with an enteral nutrition product, was administered to the patients twice a day. This combination improved the PUs, with no effect on renal function. This novel finding may provide a nutritional rationale of arginine, glutamine and ß-hydroxy-ß-methylbutyrate for PUs associated with renal dysfunction.

The value of comparing mortality of Guillain-Barré syndrome across different regions.

OBJECTIVE: To study the clinical profile of Guillain-Barré syndrome (GBS) patients who died in 4 Asian countries in order to understand factors underlying any variation in mortality. METHODS: Retrospectively reviewed medical records of GBS patients who died in 7 hospitals from 4 Asian countries between 2001 and 2012. Baseline characteristics, timing and causes of death were recorded. RESULTS: A total of 16 out of 261 GBS patients died. The overall mortality rate was 6%, with a range of 0 to 13%. The leading causes of death were respiratory infections, followed by myocardial infarction. The median age of our patients was 77 years. Half of the patients required mechanical ventilation and almost all had significant concomitant illnesses. A disproportionate number of patients in the Hong Kong cohort died (13%). Patients with advanced age, fewer antecedent respiratory infections and need for mechanical ventilation were at most risk. Most deaths occurred during the plateau phase of GBS and on the general ward after having initially received intensive care. CONCLUSIONS: There is considerable variability in mortality of GBS among different Asian cohorts. Although the risks factors for mortality were similar to Western cohorts, the timing and site of death differed. This allows specific measures to be implemented to improve GBS care in countries with higher mortality.

Neuromuscular transmission is not impaired in axonal Guillain--Barré syndrome.

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--Barré 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.

Protective effect of Lactobacillus casei strain Shirota against lethal infection with multi-drug resistant Salmonella enterica serovar Typhimurium DT104 in mice.

AIMS: The anti-infectious activity of lactobacilli against multi-drug resistant Salmonella enterica serovar Typhimurium DT104 (DT104) was examined in a murine model of an opportunistic antibiotic-induced infection. METHODS AND RESULTS: Explosive intestinal growth and subsequent lethal extra-intestinal translocation after oral infection with DT104 during fosfomycin (FOM) administration was significantly inhibited by continuous oral administration of Lactobacillus casei strain Shirota (LcS), which is naturally resistant to FOM, at a dose of 10(8) colony-forming units per mouse daily to mice. Comparison of the anti-Salmonella activity of several Lactobacillus type strains with natural resistance to FOM revealed that Lactobacillus brevis ATCC 14869(T) , Lactobacillus plantarum ATCC 14917(T) , Lactobacillus reuteri JCM 1112(T) , Lactobacillus rhamnosus ATCC 7469(T) and Lactobacillus salivarius ATCC 11741(T) conferred no activity even when they obtained the high population levels almost similar to those of the effective strains such as LcS, Lact. casei ATCC 334(T) and Lactobacillus zeae ATCC 15820(T) . The increase in concentration of organic acids and maintenance of the lower pH in the intestine because of Lactobacillus colonization were correlated with the anti-infectious activity. Moreover, heat-killed LcS was not protective against the infection, suggesting that the metabolic activity of lactobacilli is important for the anti-infectious activity. CONCLUSION: These results suggest that certain lactobacilli in combination with antibiotics may be useful for prophylaxis against opportunistic intestinal infections by multi-drug resistant pathogens, such as DT104. SIGNIFICANCE AND IMPACT OF THE STUDY: Antibiotics such as FOM disrupt the metabolic activity of the intestinal microbiota that produce organic acids, and that only probiotic strains that are metabolically active in vivo should be selected to prevent intestinal infection when used clinically in combination with certain antibiotics.

IVIG blocks complement deposition mediated by anti-GM1 antibodies in multifocal motor neuropathy.

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.

Multifocal motor neuropathy: association of anti-GM1 IgM antibodies with clinical features.

OBJECTIVE: To determine the prevalence and specificity of antibodies against single gangliosides and ganglioside complexes in serum from 88 patients with multifocal motor neuropathy (MMN) and to study the association with clinical features. METHODS: ELISA was used to detect immunoglobulin (Ig)M, IgG, and IgA antibodies against GM1, GM2, GD1a, GD1b, GM1b, GT1a, GT1b, GQ1b, GalNAc-GD1a, and the glycolipid SGPG; absorption studies were performed to study cross-reactivity. Presence of antibodies against ganglioside complexes consisting of any of combinations of GM1, GM2, GD1a, GD1b, GT1b, and GQ1b was also tested. RESULTS: Anti-GM1 IgM, IgG, and IgA antibodies were detected in serum from 43%, 1%, and 5% of patients with MMN. Anti-GM2 IgM antibodies were detected in 6% and anti-GD1b IgM antibodies in 9% of patients. Patients with MMN with anti-GM1 IgM antibodies had more severe weakness (p < 0.01), more disability (p < 0.01), and more axon loss (p = 0.05) than patients without anti-GM1 IgM antibodies. Anti-GM1 IgM antibody titers correlated with Medical Research Council scores (correlation coefficient = 0.43; p < 0.0001). Anti-GD1b IgM antibody activity was associated with reduced vibration sense (p < 0.01). Absorption studies showed that anti-GD1b and anti-GM2 IgM antibodies cross-reacted with GM1. Antibodies against ganglioside complexes were not detected. Complexes containing GD1a, GD1b, GT1b, or GQ1b with GM1 lowered antibody activity against GM1. CONCLUSION: Anti-ganglioside IgM antibodies in MMN display limited specificity and are associated with severity and clinical characteristics. Results of this study suggest that anti-GM1 IgM antibodies may play a role in MMN pathogenesis.

Hepatic Toll-Like Receptor 3 expression in chronic hepatitis C genotype 1 correlates with treatment response to peginterferon plus ribavirin.

Recent studies have shown that enhanced hepatic expression of several innate immune genes predicts non-response to 48 weeks of peginterferon plus ribavirin in chronic hepatitis C genotype 1. This study aimed to further address how gene expression of TLR3/RIG-I signalling correlates with the outcome of the 72-week extended treatment regimen. Relative hepatic mRNA expression and copy numbers of positive- and negative-strand hepatitis C virus (HCV) RNA were determined by real-time PCR in 49 patients. Then, a 48-week peginterferon-alpha2b plus ribavirin treatment was commenced and extended to 72 weeks in cases of HCV RNA clearance after week 12. High rate of sustained virologic response was seen both in patients with early HCV clearance (85% [11/13]) and slow virologic responders (85% [11/13]) (per protocol analysis). The response was associated with low TLR3 expression (median, 0.9; range, 0-4.2 vs median, 1.9; range, 0.4-4.9; P = 0.004) but had no relation to the expression of TRIF (P = 0.315), RIG-I (P = 0.953), IPS-1 (P = 0.425), IRF3 (P = 0.329) and interferon-beta (P = 0.584). ROC curve analysis identified TLR3 expression of <1.5 as the best cut-off for predicting response (positive and negative predictive values, 89% [16/18] and 70% [14/20], respectively). The expression was not affected by HCV replication but was higher in female patients (P = 0.043). Multivariate analysis showed TLR3 to be a single baseline predictor (odds ratio 18.5 [95% CI 3.2-111], P = 0.001). Low hepatic TLR3 expression is a novel predictor of response to peginterferon plus ribavirin in genotype 1 patients.

6th International Immunoglobulin Symposium: poster presentations.

The posters presented at the 6th International Immunoglobulin Symposium covered a wide range of fields and included both basic science and clinical research. From the abstracts accepted for poster presentation, 12 abstracts were selected for oral presentations in three parallel sessions on immunodeficiencies, autoimmunity and basic research. The immunodeficiency presentations dealt with novel, rare class-switch recombination (CSR) deficiencies, attenuation of adverse events following IVIg treatment, association of immunoglobulin (Ig)G trough levels and protection against acute infection in patients with X-linked agammaglobulinaemia (XLA) and common variable immunodeficiency (CVID), and the reduction of class-switched memory B cells in patients with specific antibody deficiency (SAD). The impact of intravenous immunoglobulin on fetal alloimmune thrombocytopenia, pregnancy and postpartum-related relapses in multiple sclerosis and refractory myositis, as well as experiences with subcutaneous immunoglobulin in patients with multi-focal motor neuropathy, were the topics presented in the autoimmunity session. The interaction of dendritic cell (DC)-SIGN and alpha2,6-sialylated IgG Fc and its impact on human DCs, the enrichment of sialylated IgG in plasma-derived IgG, as wells as prion surveillance and monitoring of anti-measles titres in immunoglobulin products, were covered in the basic science session. In summary, the presentations illustrated the breadth of immunoglobulin therapy usage and highlighted the progress that is being made in diverse areas of basic and clinical research, extending our understanding of the mechanisms of immunoglobulin action and contributing to improved patient care.

Clinical predictors of mechanical ventilation in Fisher/Guillain-Barré overlap syndrome.

BACKGROUND: Some patients with Fisher syndrome (FS) developed subsequent descending tetraparesis (Fisher/Guillain-Barré 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.

Bickerstaff's brainstem encephalitis and Fisher syndrome form a continuous spectrum: clinical analysis of 581 cases.

Whether Bickerstaff's brainstem encephalitis (BBE) is a distinct disease or a subtype of Fisher syndrome (FS) is unclear as there have been no clinical studies with sufficiently large numbers of patients with FS or BBE. Our aim was to clarify the nosological relationship. Medical records of patients suffering acute ophthalmoplegia and ataxia within four weeks of onset were reviewed. BBE was the diagnosis for patients with impaired consciousness, FS for those with clear consciousness and areflexia. Clinical features, neuroimages, and laboratory findings were analyzed. Patients were grouped as having BBE (n = 53), FS (n = 466), or as unclassified (n = 62). The BBE and FS groups had similar features; positive serum anti-GQ1b IgG antibody (68 % versus 83 %), antecedent Campylobacter jejuni infection (23 % versus 21 %), CSF albuminocytological dissociation (46 % versus 76 %), brain MRI abnormality (11 % versus 2 %), and abnormal EEG findings (57 % versus 25 %). BBE (n = 4) and FS (n = 28) subgroups underwent detailed electrophysiological testing. Both groups frequently showed absent soleus H-reflexes, but normal sensory nerve conduction (75 % versus 74 %) and a 1-Hz power spectrum peak on postural body sway analysis (67 % versus 72 %). Common autoantibodies, antecedent infections, and MRI and neurophysiological results found in this large study offer conclusive evidence that Bickerstaff's brainstem encephalitis and Fisher syndrome form a continuous spectrum with variable CNS and PNS involvement.

Treatment for Fisher syndrome, Bickerstaff's brainstem encephalitis and related disorders.

BACKGROUND: Fisher syndrome is one of the regional variants of Guillain-Barré syndrome, characterised by impairment of eye movements (ophthalmoplegia), incoordination (ataxia) and loss of tendon reflexes (areflexia). It can occur in more limited forms, and may overlap with Guillain-Barré syndrome. A further variant is associated with upper motor neuron signs and disturbance of consciousness (Bickerstaff's brainstem encephalitis). All of these variants are associated with anti-GQ1b IgG antibodies. Intravenous immunoglobulin (IVIg) and plasma exchange are often used as treatments in this patient group. This review was undertaken to systematically assess any available randomised controlled data on acute immunomodulatory therapies in Fisher Syndrome or its variants. OBJECTIVES: To provide the best available evidence from randomised controlled trials on the role of acute immunomodulatory therapy in the treatment of Fisher Syndrome and related disorders. SEARCH STRATEGY: We searched the Cochrane Neuromuscular Disease Trials register (March 2004), MEDLINE (from January 1966 to November 2004), EMBASE (from January 1980 to November 2004), CINAHL (from January 1982 to November 2004) and LILACS (from January 1982 to November 2004) for randomised controlled trials, quasi-randomised trials, historically controlled studies and trials with concurrent controls. We adapted this strategy to search MEDLINE from 1966 and EMBASE from 1980 for comparative cohort studies, case-control studies and case series. SELECTION CRITERIA: All randomised and quasi-randomised controlled clinical trials (in which allocation was not random but was intended to be unbiased, e.g. alternate allocation, and non-randomised controlled studies were to have been selected. Since no such clinical trials were discovered, all retrospective case series containing five or more patients were assessed and summarised in the discussion section. DATA COLLECTION AND ANALYSIS: All studies of Fisher Syndrome and its clinical variants were scrutinised for data on patients treated with any form of acute immunotherapy. Information on the outcome was then collated and summarised. MAIN RESULTS: We found no randomised or non-randomised prospective controlled trials of immunotherapy in Fisher Syndrome or related disorders. We summarised the results of retrospective series containing five or more patients in the discussion section. AUTHORS' CONCLUSIONS: There are no randomised controlled trials of immunomodulatory therapy in Fisher Syndrome or related disorders on which to base practice.