BACKGROUND AND PURPOSE: Takotsubo cardiomyopathy (TCM) is a serious autonomic complication of Guillain-Barré syndrome (GBS). However, the association between TCM and GBS has not been investigated in detail. We investigated the characteristics of GBS patients with TCM (GBS-TCM). METHODS: Clinical features and anti-ganglioside antibody between the GBS-TCM patients and 62 classical GBS patients without TCM as control patients were compared. RESULTS: Eight GBS-TCM patients were identified, in whom TCM was diagnosed at a mean of 6.5 [range 3-42] days after the onset of GBS. The age at onset of GBS was elder in the GBS-TCM patients than in the control GBS patients (76.5 [56-87] vs. 52 [20-88] years, p < 0.01). Notably, cranial nerve deficits, particularly in the lower cranial nerves, were observed in all GBS-TCM patients (100% vs. 41.9%, p < 0.01). Additionally, the GBS-TCM patients showed a higher GBS disability score at nadir (5 [4-5] vs. 4 [1-5], p < 0.01), and lower Medical Research Council sum scores at admission and nadir (37 [30-44] vs. 48 [12-60] at admission, p < 0.05, and 20 [12-44] vs. 40 [0-60] at nadir, p < 0.05, respectively). Mechanical ventilation was more frequently required in the GBS-TCM patients (62.5% vs. 11.3%, p < 0.01). Three GBS-TCM patients were positive for anti-ganglioside antibodies. CONCLUSIONS: TCM occurred at a relatively early phase of GBS. The characteristics of GBS-TCM were the elder, lower cranial nerve involvements, severe limb weakness, and respiratory failure.

Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS) has recently been attributed to biallelic repeat expansions in RFC1. More recently, the disease entity has expanded to atypical phenotypes, including chronic neuropathy without cerebellar ataxia or vestibular areflexia. Very recently, RFC1 expansions were found in patients with Sjögren syndrome who had neuropathy that did not respond to immunotherapy. In this study RFC1 was examined in 240 patients with acute or chronic neuropathies, including 105 with Guillain-Barré syndrome or Miller Fisher syndrome, 76 with chronic inflammatory demyelinating polyneuropathy, and 59 with other types of chronic neuropathy. Biallelic RFC1 mutations were found in three patients with immune-mediated neuropathies, including Guillain-Barré syndrome, idiopathic sensory ataxic neuropathy, or anti-myelin-associated glycoprotein (MAG) neuropathy, who responded to immunotherapies. In addition, a patient with chronic sensory autonomic neuropathy had biallelic mutations, and subclinical changes in Schwann cells on nerve biopsy. In summary, we found CANVAS-related RFC1 mutations in patients with treatable immune-mediated neuropathy or demyelinating neuropathy.

Anti-glycolipid antibodies have been reported to play pathogenic roles in peripheral inflammatory neuropathies, such as Guillain–Barré syndrome. On the other hand, the role in multiple sclerosis (MS), inflammatory demyelinating disease in the central nervous system (CNS), is largely unknown, although the presence of anti-glycolipid antibodies was reported to differ among MS patients with relapsing-remitting (RR), primary progressive (PP), and secondary progressive (SP) disease courses. We investigated whether the induction of anti-glycolipid antibodies could differ among experimental MS models with distinct clinical courses, depending on induction methods. Using three mouse strains, SJL/J, C57BL/6, and A.SW mice, we induced five distinct experimental autoimmune encephalomyelitis (EAE) models with myelin oligodendrocyte glycoprotein (MOG)35–55, MOG92–106, or myelin proteolipid protein (PLP)139–151, with or without an additional adjuvant curdlan injection. We also induced a viral model of MS, using Theiler’s murine encephalomyelitis virus (TMEV). Each MS model had an RR, SP, PP, hyperacute, or chronic clinical course. Using the sera from the MS models, we quantified antibodies against 11 glycolipids: GM1, GM2, GM3, GM4, GD3, galactocerebroside, GD1a, GD1b, GT1b, GQ1b, and sulfatide. Among the MS models, we detected significant increases in four anti-glycolipid antibodies, GM1, GM3, GM4, and sulfatide, in PLP139–151-induced EAE with an RR disease course. We also tested cellular immune responses to the glycolipids and found CD1d-independent lymphoproliferative responses only to sulfatide with decreased interleukin (IL)-10 production. Although these results implied that anti-glycolipid antibodies might play a role in remissions or relapses in RR-EAE, their functional roles need to be determined by mechanistic experiments, such as injections of monoclonal anti-glycolipid antibodies.

BACKGROUND AND OBJECTIVES: Deposition of myelin-associated glycoprotein (MAG) immunoglobulin M (IgM) antibodies in the sural nerve is a key feature in anti-MAG neuropathy. Whether the blood-nerve barrier (BNB) is disrupted in anti-MAG neuropathy remains elusive.We aimed to evaluate the effect of sera from anti-MAG neuropathy at the molecular level using our in vitro human BNB model and observe the change of BNB endothelial cells in the sural nerve of anti-MAG neuropathy. METHODS: Diluted sera from patients with anti-MAG neuropathy (n = 16), monoclonal gammopathies of undetermined significance (MGUS) neuropathy (n = 7), amyotrophic lateral sclerosis (ALS, n = 10), and healthy controls (HCs, n = 10) incubated with human BNB endothelial cells to identify the key molecule of BNB activation using RNA-seq and a high-content imaging system, and exposed with a BNB coculture model to evaluate small molecule/IgG/IgM/anti-MAG antibody permeability. RESULTS: RNA-seq and the high-content imaging system showed the significant upregulation of tumor necrosis factor (TNF-α) and nuclear factor-kappa B (NF-κB) in BNB endothelial cells after exposure to sera from patients with anti-MAG neuropathy, whereas the serum TNF-α concentration was not changed among the MAG/MGUS/ALS/HC groups. Sera from patients with anti-MAG neuropathy did not increase 10-kDa dextran or IgG permeability but enhanced IgM and anti-MAG antibody permeability. Sural nerve biopsy specimens from patients with anti-MAG neuropathy showed higher TNF-α expression levels in BNB endothelial cells and preservation of the structural integrity of the tight junctions and the presence of more vesicles in BNB endothelial cells. Neutralization of TNF-α reduces IgM/anti-MAG antibody permeability. DISCUSSION: Sera from individuals with anti-MAG neuropathy increased transcellular IgM/anti-MAG antibody permeability via autocrine TNF-α secretion and NF-κB signaling in the BNB.

Complement is involved in the pathogenesis of neuroimmune disease, but the detailed pathological roles of the complement pathway remain incompletely understood. Recently, eculizumab, a humanized anti-C5 monoclonal antibody, has been clinically applied against neuroimmune diseases such as myasthenia gravis and neuromyelitis optica spectrum disorders (NMOSD). Clinical application of eculizumab is also being investigated for another neuroimmune disease, Guillain-Barré syndrome (GBS). However, while the effectiveness of eculizumab for NMOSD is extremely high in many cases, there are some cases of myasthenia gravis and GBS in which eculizumab has little or no efficacy. Development of effective biomarkers that reflect complement activation in these diseases is therefore important. To identify biomarkers that could predict disease status, we retrospectively analyzed serum levels of complement factors in 21 patients with NMOSD and 25 patients with GBS. Ba, an activation marker of the alternative complement pathway, was elevated in the acute phases of both NMOSD and GBS. Meanwhile, sC5b-9, an activation marker generated by the terminal complement pathway, was elevated in NMOSD but not in GBS. Complement factor H (CFH), a complement regulatory factor, was decreased in the acute phase as well as in the remission phase of NMOSD, but not in any phases of GBS. Together, these findings suggest that complement biomarkers, such as Ba, sC5b-9 and CFH in peripheral blood, have potential utility in understanding the pathological status of NMOSD.

Abstract Exploratory factor analysis (EFA) has been developed as a powerful statistical procedure in psychological research. EFA’s purpose is to identify the nature and number of latent constructs (= factors) underlying a set of observed variables. Since the research goal of EFA is to determine what causes the observed responses, EFA is ideal for hypothesis-based studies, such as identifying the number and nature of latent factors (e.g., cause, risk factors, etc.). However, the application of EFA in the biomedical field has been limited. Guillain–Barré syndrome (GBS) is peripheral neuropathy, in which the presence of antibodies to glycolipids has been associated with clinical signs. Although the precise mechanism for the generation of anti-glycolipid antibodies is unclear, we hypothesized that latent factors, such as distinct autoantigens and microbes, could induce different sets of anti-glycolipid antibodies in subsets of GBS patients. Using 55 glycolipid antibody titers from 100 GBS and 30 control sera obtained by glycoarray, we conducted EFA and extracted four factors related to neuroantigens and one potentially suppressive factor, each of which was composed of the distinct set of anti-glycolipid antibodies. The four groups of anti-glycolipid antibodies categorized by unsupervised EFA were consistent with experimental and clinical findings reported previously. Therefore, we proved that unsupervised EFA could be applied to biomedical data to extract latent factors. Applying EFA for other biomedical big data may elucidate latent factors of other diseases with unknown causes or suppressing/exacerbating factors, including COVID-19.

BACKGROUND AND OBJECTIVES: Infections play a key role in the development of Guillain-Barré syndrome (GBS) and have been associated with specific clinical features and disease severity. The clinical variation of GBS across geographical regions has been suggested to be related to differences in the distribution of preceding infections, but this has not been studied on a large scale. METHODS: We analyzed the first 1,000 patients included in the International GBS Outcome Study with available biosamples (n = 768) for the presence of a recent infection with Campylobacter jejuni, hepatitis E virus, Mycoplasma pneumoniae, cytomegalovirus, and Epstein-Barr virus. RESULTS: Serologic evidence of a recent infection with C. jejuni was found in 228 (30%), M. pneumoniae in 77 (10%), hepatitis E virus in 23 (3%), cytomegalovirus in 30 (4%), and Epstein-Barr virus in 7 (1%) patients. Evidence of more than 1 recent infection was found in 49 (6%) of these patients. Symptoms of antecedent infections were reported in 556 patients (72%), and this proportion did not significantly differ between those testing positive or negative for a recent infection. The proportions of infections were similar across continents. The sensorimotor variant and the demyelinating electrophysiologic subtype were most frequent across all infection groups, although proportions were significantly higher in patients with a cytomegalovirus and significantly lower in those with a C. jejuni infection. C. jejuni-positive patients were more severely affected, indicated by a lower Medical Research Council sum score at nadir (p = 0.004) and a longer time to regain the ability to walk independently (p = 0.005). The pure motor variant and axonal electrophysiologic subtype were more frequent in Asian compared with American or European C. jejuni-positive patients (p < 0.001, resp. p = 0.001). Time to nadir was longer in the cytomegalovirus-positive patients (p = 0.004). DISCUSSION: Across geographical regions, the distribution of infections was similar, but the association between infection and clinical phenotype differed. A mismatch between symptom reporting and serologic results and the high frequency of coinfections demonstrate the importance of broad serologic testing in identifying the most likely infectious trigger. The association between infections and outcome indicates their value for future prognostic models.

Ophthalmoplegia is a common neurological finding in Miller Fisher syndrome (MFS), but acute eye movement-retained internal ophthalmoplegia is a rare variant of MFS. In this report, we present three cases of acute eye movement-retained internal ophthalmoplegia; IgG anti-GQ1b antibodies were detected in all patients. We reviewed a total of 13 cases, including 10 previously reported cases, and revealed that IgG anti-GQ1b antibodies were identified in all but one patient. In addition, we investigated the correlation between acute eye movement-retained internal ophthalmoplegia and antibodies against ganglioside complexes. We found that anti-GQ1b antibodies in our patients reacted with GQ1b or GT1a but not GQ1b/GM1 or GQ1b/GD1a complexes, indicating that antibodies against disialosyl residues have a pathogenetic role in acute eye movement-retained internal ophthalmoplegia. This is the first study describing that acute eye movement-retained internal ophthalmoplegia is associated with IgG antibodies specific to GQ1b or GT1a.

We propose the finger drop sign as a new clinical variant of acute motor axonal neuropathy (AMAN) defined by immunological and radiological evidence. We identified eight consecutive patients who had AMAN. All of them developed prominent involvement of the finger extensors. We performed magnetic resonance imaging (MRI) of the extremity muscles and serological assays for antiganglioside antibodies and Campylobacter jejuni. Patients with AMAN showed characteristic and a markedly sustained weakness of the finger extensors with a distinctive pattern of the finger drop sign. Limb MRI revealed unevenly distributed abnormal signals in the muscles mainly innervated by the posterior interosseous nerve. All tested patients showed positivity for immunoglobulin G antibody against ganglioside complex of GM1 and phosphatidic acid. A pathophysiological understanding of this unique syndrome can provide further insight into antiganglioside-antibody-mediated axonal injury in Guillain-Barré syndrome.

OBJECTIVE: Approximately 15%-20% of patients with Guillain-Barré syndrome (GBS) are unable to walk independently at 6 months from the onset of neurological symptom. The modified Erasmus GBS outcome score (mEGOS) has been reported as a prognostic tool.Herein we investigated the association between a poor outcome, inability to walk independently at 6 months and presence of antiganglioside antibodies. METHODS: The clinical and serological data of 177 patients with GBS were retrospectively collected in Japan to assess the associations between a poor outcome and serum IgG antibodies against each ganglioside (GM1, GD1a, GalNAc-GD1a, GQ1b and GT1a). In addition, we investigated whether the combination of mEGOS and serum IgG antibodies against gangliosides is useful in predicting a poor outcome. RESULTS: The patients with IgG anti-GD1a antibodies more frequently showed poor outcomes than those without these antibodies (9 (36%) of 25 vs 8 (6%) of 127 patients, p<0.001). Particularly, 80% showed a poor outcome when they had both serum IgG anti-GD1a antibody and a high mEGOS of ≥10 on day 7 of admission. CONCLUSIONS: The combination of serum IgG anti-GD1a antibodies and a high mEGOS could help in making a more accurate prognosis of patients than mEGOS alone, especially for predicting poor outcomes.

OBJECTIVE: To clarify the differences in clinical characteristics between anti-GQ1b antibody-positive and antibody-negative Bickerstaff brainstem encephalitis (BBE). METHODS: We compared 73 anti-GQ1b antibody-positive BBE cases with 10 antibody-negative cases. Their clinical information and sera were collected from various hospitals throughout Japan between 2014 and 2017. The anti-GQ1b antibody was examined in each serum sample by ELISA. RESULTS: We identified the distinctive findings of anti-GQ1b antibody-positive BBE compared with the antibody-negative cases: (1) upper respiratory infection and sensory disturbance were more common, (2) the cell count or protein concentration was lower in the CSF, (3) the abnormal findings on brain MRI were less, and (4) the consciousness disturbance disappeared earlier. Furthermore, IV immunoglobulin (IVIG) was more frequently administered to the anti-GQ1b antibody-positive cases of BBE compared with the antibody-negative cases. CONCLUSIONS: BBE with anti-GQ1b antibody has homogeneous features. IVIG is the treatment used prevalently for BBE with anti-GQ1b antibody in Japan.

A 41-year-old man noticed numbness of the fingers and toes, and gradually developed limb weakness and sensory impairment. The patient was diagnosed with typical chronic inflammatory demyelinating polyradiculoneuropathy. Over the course of clinical diagnosis, the limb and trunk ataxia, and finger tremor became prominent, and the presence anti-neurofascin-155 antibody was examined and confirmed positive. The effects of corticosteroids, intravenous immunoglobulin, and plasma apheresis were limited, and the disease progressed slowly and noticeably. Therefore, cyclosporine was introduced as treatment, and the patient's weakness and ataxia significantly improved. Rituximab treatment is expected to be effective in patients with the same antibody and immunosuppressant treatment may be useful in intractable cases.

OBJECTIVE: To characterize the CSF cytokine profile in chronic inflammatory demyelinating polyneuropathy (CIDP) patients with IgG4 anti-neurofascin 155 (NF155) antibodies (NF155+ CIDP) or those lacking anti-NF155 antibodies (NF155- CIDP). METHODS: Twenty-eight CSF cytokines/chemokines/growth factors were measured by multiplexed fluorescent immunoassay in 35 patients with NF155+ CIDP, 36 with NF155- CIDP, and 28 with non-inflammatory neurological disease (NIND). RESULTS: CSF CXCL8/IL-8, IL-13, TNF-α, CCL11/eotaxin, CCL2/MCP-1, and IFN-γ were significantly higher, while IL-1β, IL-1ra, and G-CSF were lower, in NF155+ CIDP than in NIND. Compared with NF155- CIDP, CXCL8/IL-8 and IL-13 were significantly higher, and IL-1β, IL-1ra, and IL-6 were lower, in NF155+ CIDP. CXCL8/IL-8, IL-13, CCL11/eotaxin, CXCL10/IP-10, CCL3/MIP-1α, CCL4/MIP-1β, and TNF-α levels were positively correlated with markedly elevated CSF protein, while IL-13, CCL11/eotaxin, and IL-17 levels were positively correlated with increased CSF cell counts. IL-13, CXCL8/IL-8, CCL4/MIP-1β, CCL3/MIP-1α, and CCL5/RANTES were decreased by combined immunotherapies in nine NF155+ CIDP patients examined longitudinally. By contrast, NF155- CIDP had significantly increased IFN-γ compared with NIND, and exhibited positive correlations of IFN-γ, CXCL10/IP-10, and CXCL8/IL-8 with CSF protein. Canonical discriminant analysis of cytokines/chemokines revealed that NF155+ and NF155- CIDP were separable, and that IL-4, IL-10, and IL-13 were the three most significant discriminators. INTERPRETATION: Intrathecal upregulation of type 2 helper T (Th2) cell cytokines is characteristic of IgG4 NF155+ CIDP, while type 1 helper T cell cytokines are increased in CIDP regardless of the presence or absence of anti-NF155 antibodies, suggesting that overproduction of Th2 cell cytokines is unique to NF155+ CIDP.

Intravascular lymphoma (IVL) is a malignant lymphoma that lacks the expression of cell surface adhesion molecules so that cells fluidly migrate within the blood vessels. The patient in the present study had restricted eye movement caused by IVL, mimicking a cavernous sinus tumor. Because the cavernous sinus lumen is divided into multiple compartments by trabeculae and venous channels, IVL tumor cells were trapped in these compartments, thus forming a mass, which subsequently extended into the contralateral cavernous sinus via the anterior and posterior intercavernous sinuses. This is a rare case of IVL forming a mass inside the cavernous sinus.

Objective: We examined the clinical and serologic features of Guillain-Barré syndrome (GBS)-related diseases (GBSRDs), including GBS, Fisher syndrome (FS), and Bickerstaff brainstem encephalitis (BBE), after influenza virus infection (GBSRD-I) to reveal potential underlying autoimmune mechanisms. Methods: We retrospectively investigated the presence of antiglycolipid antibodies against 11 glycolipids and the clinical features of 63 patients with GBSRD-I. Autoantibody profiles and clinical features were compared with those of 82 patients with GBSRDs after Campylobacter jejuni infection (GBSRD-C). Results: The anti-GQ1b seropositivity rate was significantly higher, whereas the GM1 and GD1a seropositivity rates were significantly lower in GBSRD-I compared with GBSRD-C. Anti-GQ1b and anti-GT1a were the most frequently detected antiglycolipid antibodies in GBSRD-I (both 15/63, 24%). Consequently, FS was more frequent in GBSRD-I than GBSRD-C (22% vs 9%, p < 0.05). In addition, as for GBS, cranial nerve deficits, sensory disturbances, and ataxia were more frequent in the cases after influenza infection (GBS-I) than in those after C. jejuni infection (GBS-C) (46% vs 15%, 75% vs 46%, and 29% vs 4%, respectively; all p < 0.01). Nerve conduction studies revealed acute inflammatory demyelinating polyneuropathy (AIDP) in 60% of patients with GBS-I but only 25% of patients with GBS-C (p < 0.01). Conclusions: Anti-GQ1b antibodies are the most frequently detected antibodies in GBSRD-I. Compared with GBS-C, GBS-I is characterized by AIDP predominance and frequent presence of cranial nerve involvement and ataxia.

Complement activation is involved in the pathogenetic mechanism of Guillain-Barré syndrome (GBS). To date, the effectiveness of complement inhibitors for GBS has been shown by in vitro and in vivo studies. A recent Japanese randomized controlled trial with eculizumab, a monoclonal antibody against the complement C5, indicated that eculizumab might improve the outcomes of GBS patients at six months from onset. In future, the prognosis of severe GBS cases may possibly be improved by a novel therapy targeting the complement.

Spastic paraplegia 30 is a recently established autosomal recessive disease characterized by a complex form of spastic paraplegia associated with neuropathy. Homozygous mutations of KIF1A reportedly lead to hereditary spastic paraplegia or hereditary sensory and autonomic neuropathy type 2 (HSAN2), whereas heterozygous mutations can cause nonsyndromic and syndromic intellectual disability (MRD9). Here we report the case of a 37-year-old female who presented with gait disturbance complicated with moyamoya disease. Results: The patient exhibited hypotonia during infancy, after which intellectual disability, epileptic fits, spastic paraplegia, and cerebellar atrophy occurred. Genetic analysis revealed a novel de novo mutation (c.254C > A, p.A85D) in the motor domain of KIF1A.

Objective: To investigate the relationship between antibody reactivities against glycolipid complexes and clinical features in Miller Fisher syndrome (MFS), Bickerstaff brainstem encephalitis (BBE), and Guillain-Barré syndrome with ophthalmoplegia (GBS-OP). Methods: Using glycoarray, antibodies against 10 glycolipid antigens (GM1, GM2, GM4, GD1a, GD1b, GQ1b, galactocerebroside, lactosylceramide, GA1, and sulfatide) and 45 glycolipid complexes consisting 2 of the glycolipids were examined in the sera of 63 patients with GBS-OP, 37 patients with MFS, and 27 patients with BBE. Results: Antibodies to antigens containing GQ1b were identified in 73% of patients with GBS-OP (46/63), 86.5% of patients with MFS (32/37), and 74.1% of patients with BBE (20/27), and GD1b-related antibodies were identified in 49.2% of patients with GBS-OP (31/63), 29.7% of patients with MFS (11/37), and 11.1% of patients with BBE (3/27). Comparing clinical features between patients with GBS-OP with and without both antibodies, the proportion of patients requiring artificial ventilation and presenting moderate or severe muscle weakness was higher in the positive group than in the negative group (p = 0.017 and p = 0.046, respectively). Conclusions: Antibodies binding to antigens containing GD1b and to those containing GQ1b may be involved in the development of limb weakness and respiratory failure in anti-GQ1b antibody-related diseases.

BACKGROUND: Despite the introduction of plasmapheresis and immunoglobulin therapy, many patients with Guillain-Barré syndrome still have an incomplete recovery. Evidence from pathogenesis studies suggests the involvement of complement-mediated peripheral nerve damage. We aimed to investigate the safety and efficacy of eculizumab, a humanised monoclonal antibody against the complement protein C5, in patients with severe Guillain-Barré syndrome. METHODS: This study was a 24 week, multicentre, double-blind, placebo-controlled, randomised phase 2 trial done at 13 hospitals in Japan. Eligible patients with Guillain-Barré syndrome were aged 18 years or older and could not walk independently (Guillain-Barré syndrome functional grade 3-5). Patients were randomly assigned (2:1) to receive 4 weeks of intravenous immunoglobulin plus either eculizumab (900 mg) or placebo; randomisation was done via a computer-generated process and web response system with minimisation for functional grade and age. The study had a parallel non-comparative single-arm outcome measure. The primary outcomes were efficacy (the proportion of patients with restored ability to walk independently [functional grade ≤2] at week 4) in the eculizumab group and safety in the full analysis set. For the efficacy endpoint, we predefined a response rate threshold of the lower 90% CI boundary exceeding 50%. This trial is registered with ClinicalTrials.gov, number, NCT02493725. FINDINGS: Between Aug 10, 2015, and April 21, 2016, 34 patients were assigned to receive either eculizumab (n=23) or placebo (n=11). At week 4, the proportion of the patients able to walk independently (functional grade ≤2) was 61% (90% CI 42-78; n=14) in the eculizumab group, and 45% (20-73; n=5) in the placebo group. Adverse events occurred in all 34 patients. Three patients had serious adverse events: two in the eculizumab group (anaphylaxis in one patient and intracranial haemorrhage and abscess in another patient) and one in the placebo group (depression). The possibility that anaphylaxis and intracranial abscess were related to eculizumab could not be excluded. No deaths or meningococcal infections occurred. INTERPRETATION: The primary outcome measure did not reach the predefined response rate. However, because this is a small study without statistical comparison with the placebo group, the efficacy and safety of eculizumab could be investigated in larger, randomised controlled trials. FUNDING: The Japan Agency for Medical Research and Development, Ministry of Health, Labor and Welfare, and Alexion Pharmaceuticals.

Background. Acute flaccid myelitis (AFM) is an acute flaccid paralysis syndrome with spinal motor neuron involvement of unknown etiology. We investigated the characteristics and prognostic factors of AFM clusters coincident with an enterovirus D68 (EV-D68) outbreak in Japan during autumn 2015. Methods. An AFM case series study was conducted following a nationwide survey from August to December 2015. Radiographic and neurophysiologic data were subjected to centralized review, and virology studies were conducted for available specimens. Results. Fifty-nine AFM cases (58 definite, 1 probable) were identified, including 55 children and 4 adults (median age, 4.4 years). Te AFM epidemic curve showed strong temporal correlation with EV-D68 detection from pathogen surveillance, but not with other pathogens. EV-D68 was detected in 9 patients: 5 in nasopharyngeal, 2 in stool, 1 in cerebrospinal fluid (adult case), and 1 in tracheal aspiration, nasopharyngeal, and serum samples (a pediatric case with preceding steroid usage). Cases exhibited heterogeneous paralysis patterns from 1-to 4-limb involvement, but all definite cases had longitudinal spinal gray matter lesions on magnetic resonance imaging (median, 20 spinal segments). Cerebrospinal fluid pleocytosis was observed in 50 of 59 cases (85%), and 8 of 29 (28%) were positive for antiganglioside antibodies, as frequently observed in Guillain-Barré syndrome. Fifty-two patients showed variable residual weakness at follow-up. Good prognostic factors included a pretreatment manual muscle strength test unit score > 3, normal F-wave persistence, and EV-D68-negative status. Conclusions. EV-D68 may be one of the causative agents for AFM, while host susceptibility factors such as immune response could contribute to AFM development.

Parkinson's disease (PD) is difficult to distinguish from progressive supranuclear palsy (PSP) and multiple system atrophy (MSA); in addition, biomarker studies in PD mostly focused on those found in the cerebrospinal fluid, and there are few reports of simple biomarkers identified by blood analysis. Previously, the DJ-1 gene was identified as a causative gene of familial PD. Oxidized DJ-1 protein (oxDJ-1) levels were reported to increase in the blood of patients with unmedicated PD. Therefore, we determined the levels of oxDJ-1 in the erythrocytes of patients with PD, PSP, and MSA using ELISA. The oxDJ-1 levels were 165±117, 96±78, and 69±40ng/mg protein in the PD, PSP, and MSA groups, respectively. The mean level in disease control group was 66±31, revealing significant differences between the PD and PSP groups, the PD and MSA groups, and the PD and disease control groups. Our results indicated that oxDJ-1 levels in erythrocytes can be used as a marker for the differential diagnosis of PD.

Introduction: Neurofascin155 (NF155) is a target antigen for autoantibodies in a subset of chronic inflammatory demyelinating polyneuropathy (CIDP). Methods: We report the cases of 4 patients with anti-NF155 immunoglobulin G4 (IgG4) antibody-positive CIDP who underwent sural nerve biopsies. Results: All patients were relatively young at onset. Three patients experienced tremors, and 2 patients had severe ataxia. Although the response to intravenous immunoglobulin was poor in all patients, plasma exchange and corticosteroids were at least partially effective. Immunoadsorption plasmapheresis was performed in 1 patient but was ineffective. Electron microscopic examination of sural nerve biopsies revealed loss of paranodal transverse bands in all patients. Discussion: Anti-NF155 IgG4 antibody-positive CIDP shows distinctive clinicopathological features, indicating that the IgG4 antibody is directly associated with the pathogenic mechanisms of anti-NF155 IgG4 antibody-positive CIDP. Muscle Nerve 57: 498–502, 2018.

Mycoplasma pneumoniae infection often causes various neurological complications of both the central nervous system (CNS) and the peripheral nervous system. We retrospectively investigated the IgM and IgG antibodies to nine glycolipids [GM1, GM2, GM3, GD1a, GD1b, GD3, GT1b, GQ1b, and Gal-C (galactocerebroside)] and clinical features in neurological diseases associated with M. pneumoniae infection diagnosed in multiple hospitals throughout Japan between September 2010 and March 2012. Of the 46 patients with neurological diseases associated with M. pneumoniae infection, 27 were diagnosed with Guillain-Barr, syndrome (GBS), 2 with Fisher syndrome (FS), 16 with CNS diseases, and 1 with both GBS and CNS disease. Anti-Gal-C IgM and IgG antibodies were most frequently detected (23/46, 50%). Patients with CNS diseases were younger than patients with GBS or FS, and IgM antibodies to Gal-C were more frequently detected in the patients with CNS diseases (41%) than in those with GBS or FS (13%). Of the nine patients who were positive for anti-Gal-C IgM antibody but lacked IgG antibody, we found the class-switch of anti-Gal-C antibody from IgM to IgG in two patients. The IgG antibodies appeared during their recovery phase, and the IgG belonged to the IgG1 subclass. Anti-Gal-C antibodies are closely associated with neurological diseases after M. pneumoniae infection. Particularly, anti-Gal-C IgM antibody is more frequently detected in younger patients affected with CNS involvement. The class-switch from IgM to IgG sometimes occurs in anti-Gal-C antibodies.

The efficacy of plasma exchange (PE) and intravenous immunoglobulin (IVIg) therapies for Guillain-Barr� syndrome have been established by numerous randomized controlled trials. However, 10-20 % of GBS patients cannot walk without aid after one year from onset of the disease. Thus, new treatment is required for these intractable cases. The Japan GBS outcome study (JGOS) has been conducted to identify clinical or biological markers that predict the prognosis of Japanese GBS patients at an early stage. In the future, we expect to provide intractable patients so predicted with novel therapy, including molecular target drugs.

Whether patients who have GBS with antibodies to galactocerebroside (Gal-C) and gangliosides (Gal-C-GS-GBS) more often have demyelinating or axonal neuropathy remains controversial. We assessed the electrophysiological data from 16 patients with Gal-C-GS-GBS based on the two established criteria to clarify this issue. In this largest cohort of Gal-C-GS-GBS, eight patients had demyelinating neuropathy and none exhibited axonal neuropathy on either criterion. These data indicated that antibodies to Gal-C, a myelin antigen, might predominantly be associated with demyelinating neuropathy, even in the presence of concomitant antibodies to gangliosides. (C) 2016 Elsevier B.V. All rights reserved.

We performed a serological investigation using glycoarray in Guillain-Barre syndrome (GBS), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), and multifocal motor neuropathy (MMN). Antibodies to 10 glycolipids and 45 glycolipid complexes were tested. Anti-GM1/sulfatide and anti-GA1/sulfatide IgG antibodies were common in GBS (20.0% and 19.0%, respectively). Anti-GQ1b/sulfatide IgG antibody was detected in 14.0% of GBS patients. IgG antibodies to antigens containing GQ1b were significantly correlated with ophthalmoplegia in GBS (p < 0.01). IgM antibodies to antigens containing GM1 or GaINAc-GD1a were in 50% and 37.5% of MMN patients, respectively. Glycoarray is efficient for detecting antibodies against numerous glycolipid complexes in immune-mediated neuropathies. (C) 2016 Elsevier B.V. All rights reserved.

Objective: To investigate anti-neurofascin 155 (NF155) antibody-positive chronic inflammatory demyelinating polyneuropathy (CIDP). Methods: Sera from 50 consecutive CIDP patients diagnosed in our clinic, 32 patients with multiple sclerosis, 40 patients with other neuropathies including 26 with Guillain-Barre syndrome (GBS)/Fisher syndrome, and 30 healthy controls were measured for anti-NF antibodies by flow cytometry using HEK293 cell lines stably expressing human NF155 or NF186. Four additional CIDP patients with anti-NF155 antibodies referred from other clinics were enrolled for clinical characterization. Results: The positivity rate for anti-NF155 antibodies in CIDP patients was 18% (9/50), who all showed a predominance of IgG4 subclass. No other subjects were positive, except one GBS patient harboring IgG1 anti-NF155 antibodies. No anti-NF155 antibody carriers had anti-NF186 antibodies. Anti-NF155 antibody-positive CIDP patients had a significantly younger onset age, higher frequency of drop foot, gait disturbance, tremor and distal acquired demyelinating symmetric phenotype, greater cervical root diameter on magnetic resonance imaging neurography, higher cerebrospinal fluid protein levels, and longer distal and F-wave latencies than anti-NF155 antibody-negative patients. Marked symmetric hypertrophy of cervical and lumbosacral roots/plexuses was present in all anti-NF155 antibody-positive CIDP patients examined by neurography. Biopsied sural nerves from two patients with anti-NF155 antibodies demonstrated subperineurial edema and occasional paranodal demyelination, but no vasculitis, inflammatory cell infiltrates, or onion bulbs. Among anti-NF155 antibody-positive patients, treatment responders more frequently had daily oral corticosteroids and/or immunosuppressants in addition to intravenous immunoglobulins than nonresponders did. Interpretation: Anti-NF155 antibodies occur in a subset of CIDP patients with distal-dominant involvement and symmetric nerve hypertrophy.

Anti-myelin-associated-glycoprotein (MAG) neuropathy is an intractable autoimmune polyneuropathy. The antigenic region of MAG is the human natural killer-1 (HNK-1) carbohydrate. We and others previously suggested that the extension of antibody reactivities to HNK-1-bearing proteins other than MAG was associated with treatment resistance, without statistical analyses. In this study, we established an ELISA method with recombinant proteins to test binding specificities of currently available monoclonal antibodies to MAG and another HNK-1-bearing protein, phosphacan. Using this system, we found the distinct binding specificities of anti-MAG antibody in 19 patients with anti-MAG neuropathy. Their clinical relevance was then determined retrospectively with the adjusted 10-points INCAT disability score (0 = normal and 10 = highly disable). The results showed that strong reactivities of anti-MAG antibodies to phosphacan were significantly associated with treatment resistance or progressive clinical courses, indicating a possible clinical relevance of the binding specificities. (C) 2014 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.

Introduction: Guillain-Barre syndrome (GBS) has often been associated with antibodies to glycolipids, such as galactocerebroside (Gal-C), a component of myelin. Whether patients who have GBS with anti-Gal-C antibody (Gal-C-GBS) more often have demyelinating neuropathy or axonal neuropathy remains controversial. Their clinical features have also been unestablished. Methods: We enrolled 47 patients with Gal-C-GBS. Their clinical and electrophysiological data were retrospectively reviewed and compared to 119 patients with CBS without anti-Gal-C antibody (non-Gal-C-GBS). Results: Demyelinating polyneuropathy occurred 4 times more frequently than axonal polyneuropathy in patients with Gal-C-GBS, but without statistical significance compared to patients with non-Gal-C-GBS (2.2:1). Patients with Gal-C-GBS had more frequent sensory deficits, autonomic involvements, and antecedent Mycoplasma pneumoniae (MP) infection than patients with non-Gal-C-GBS. Conclusions: This is the largest study clarifying the clinical and electrophysiological findings that more frequent sensory deficits, autonomic involvements, and antecedent MP infection are associated with Gal-C-GBS. (C) 2013 Elsevier B.V. All rights reserved.

Background LM1 is the predominant glycolipid in human peripheral nerve myelin and antibodies to LM1 and LM1-containing ganglioside complexes are detected in some patients with chronic inflammatory demyelinating polyneuropathy (CIDP). The clinical features of patients with such antibodies have not yet been investigated. Methods Serum antibodies to LM1, a mixture of GM1 and LM1 (GM1/LM1), and that of GD1b and LM1 (GD1b/LM1) were examined in 75 consecutive patients with CIDP. The clinical features of the CIDP patients with such antibodies in the present series and those in the previous reports were investigated and compared with those of antibody-negative patients. Results Of the 75 patients with CIDP, two had antibodies to LM1, three had anti-GM1/LM1 complex antibody, one had anti-GD1b/LM1 complex antibody and two had antibodies to both the GM1/LM1 and GD1b/LM1 complexes. Patients with the LM1-associated antibodies did not have cranial nerve deficits (p<0.05) and exhibited ataxia more frequently than the antibody-negative patients (p<0.01). Conclusion In humans, LM1 is contained more in the dorsal root than in the cranial nerves. The clinical features of CIDP patients with antibodies to LM1 and LM1-containing complexes may be associated with the distribution of the LM1 antigen. LM1-associated antibodies are possible markers for a subclass of CIDP.

慢性炎症性脱髄性多発ニューロパチー(chronic inflammatory demyelinating polyradiculoneuropathy:CIDP)は、難治性の末梢神経に対する自己免疫性疾患であるが、その病態は未解明の部分が多い。本研究では、2010年のEuropean Federation of Neurological Societies/Peripheral Nerve Society(EFNS/PNS)のCIDP診断基準に基づいてprobable以上であった106例を解析した。抗糖脂質抗体の測定と、ファーストラインの治療である免疫グロブリン大量療法(intravenous immunoglobulins:IVIG)、副腎皮質ステロイド療法の反応性を中心にアンケート調査に基づいて、臨床的解析を行った。抗糖脂質抗体陽性率は8.4%であった。IVIGの有効率は86%、副腎皮質ステロイド療法の有効率は69%であった。髄液中総蛋白が高値(>100mg/dl)であった症例はIVIGもしくは副腎皮質ステロイド療法にて反応性が得られていた。また、少数例での検討であったが、抗糖脂質抗体陽性例は感覚障害が優位である例が多かった。(著者抄録)

Anti-N-methyl-d-aspartate receptor (anti-NMDAR) antibody-associated encephalitis is an immunologic disease characterized by a female preponderance. Males are infrequently affected. The clinical symptoms of affected boys as well as girls have been summarized, and they have some clinical features distinct from those of adults. However, the characteristics of men have been described in only a few reports. We describe in detail four men with anti-NMDAR encephalitis who presented with several clinical features that complicated disease management and recovery, including venous thrombosis, bilateral hippocampal involvement, hypersexuality, and joint contracture. We also report the first detailed clinical information about a male patient who died of this disease. In addition, we summarize the clinical characteristics of five patients previously reported by others. © 2012 S. Karger AG, Basel.

Antibodies to a ganglioside complex consisting of GM1 and GalNAc-GD1a (GM1/GalNAc-GD1a) are found in sera from patients with Guillain-Barré syndrome (GBS). To elucidate the clinical significance of anti-GM1/GalNAc-GD1a antibodies in GBS, clinical features of 58 GBS patients with IgG anti-GM1/GalNAc-GD1a antibodies confirmed by enzyme-linked immunosorbent assay and thin layer chromatography immunostaining were analyzed. Compared to GBS patients without anti-GM1/GalNAc-GD1a antibodies, anti-GM1/GalNAc-GD1a-positive patients more frequently had a preceding respiratory infection (n = 38, 66%, p. < 0.01) and were characterized by infrequency of cranial nerve deficits (n = 9, 16%, p. < 0.01) and sensory disturbances (n = 26, 45%, p. < 0.01). Of the 28 anti-GM1/GalNAc-GD1a-positive patients for whom electrophysiological data were available, 14 had conduction blocks (CBs) at intermediate segments of motor nerves, which were not followed by evident remyelination. Eight of 10 bedridden cases were able to walk independently within one month after the nadir. These results show that the presence of anti-GM1/GalNAc-GD1a antibodies correlated with pure motor GBS characterized by antecedent respiratory infection, fewer cranial nerve deficits, and CBs at intermediate sites of motor nerves. The CB may be generated through alteration of the regulatory function of sodium channels in the nodal axolemma. © 2012 Elsevier B.V.

We report a case of IgM paraproteinemic neuropathy associated with anti-sulfated glucuronic paragloboside (SGPG) IgG antibody. An 84-year old man complained of numbness on the left side of the face and in the distal portions of the limbs. Neurological examination showed mild sensory ataxia. The laboratory tests revealed the presence of IgM lambda paraproteinemia and anti-SGPG IgG antibody without anti-myelin-associated glycoprotein (MAG) activity and anti-MAG/SGPG IgM antibody. Results of nerve conduction study showed decreased sensory nerve action potential (SNAP) amplitude, indicating the presence of sensory-dominant axonal polyneuropathy, and the prolongation of distal latency was not observed. Treatment with corticosteroids resulted in a rapid improvement in neurological abnormalities. In IgM paraproteinemic neuropathy associated with anti-MAG/SGPG antibody, distal acquired demyelinating sensory neuropathy and resistance to immunological treatments are the characteristic pathologic and clinical features, respectively. On the other hand our rare case of IgM paraproteinemic neuropathy positive for anti-SGPG IgG antibody presented with axonal sensory polyneuropathy and a good responsiveness to corticosteroids.

We report a case of IgM paraproteinemic neuropathy associated with anti-sulfated glucuronic paragloboside (SGPG) IgG antibody. An 84-year old man complained of numbness on the left side of the face and in the distal portions of the limbs. Neurological examination showed mild sensory ataxia. The laboratory tests revealed the presence of IgM lambda paraproteinemia and anti-SGPG IgG antibody without anti-myelin-associated glycoprotein (MAG) activity and anti-MAG/SGPG IgM antibody. Results of nerve conduction study showed decreased sensory nerve action potential (SNAP) amplitude, indicating the presence of sensory-dominant axonal polyneuropathy, and the prolongation of distal latency was not observed. Treatment with corticosteroids resulted in a rapid improvement in neurological abnormalities. In IgM paraproteinemic neuropathy associated with anti-MAG/SGPG antibody, distal acquired demyelinating sensory neuropathy and resistance to immunological treatments are the characteristic pathologic and clinical features, respectively. On the other hand our rare case of IgM paraproteinemic neuropathy positive for anti-SGPG IgG antibody presented with axonal sensory polyneuropathy and a good responsiveness to corticosteroids.

Acute disseminated encephalomyelitis causes multifocal demyelination in the central nerve system. Although this disease generally responds well to steroid therapy, it is occasionally steroid-resistant, leading to poor outcomes. Serological markers of prognosis are currently unavailable. We measured anti-glycolipid antibodies in 25 consecutive patients with acute disseminated encephalomyelitis, and found that four patients were positive for anti-galactocerebroside antibodies. All four patients had a poor response to steroids. We summarize clinical information on these four patients and three similar patients reported previously. This is the first report to describe concomitant involvement of the central nerve system and peripheral nervous system in anti-galactocerebroside antibody-associated acute disseminated encephalomyelitis, consistent with the location of galactocerebroside, and to document a dramatic response to repeated intravenous immunoglobulin therapy after unsuccessful steroid treatment in one patient. (C) 2012 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.

Background Neuralgic amyotrophy (NA) is a distinct peripheral nervous system disorder characterized by attacks of acute neuropathic pain and rapid multifocal weakness and atrophy unilaterally in the upper limb. The current hypothesis is that the episodes are caused by an immune-mediated response to the brachial plexus, however, therapeutic strategies for NA have not been well established. Methods and Results We retrospectively reviewed 15 case series of NA; 10 of the 15 patients received intravenous immunoglobulin (IVIg) with methylprednisolone pulse therapy (MPPT) and 9 of these10 patients showed clinical improvement of motor impairment. Conclusion Our clinical observations do not contradict the possibility that IVIg with MPPT may be one of the potential therapeutics for NA, however the efficacy remains to be established. Further confirmatory trials are needed in patients with various clinical severities and phases of NA. Further basic research and confirmatory trials should be performed to survey the efficacy of such immunomodulation therapy for NA.

A 36-year-old, previously healthy man presented with Miller Fisher syndrome (MFS) five days after he was diagnosed with an influenza A infection by a rapid antigen test. He had not received any recent vaccinations. He had no loss of consciousness. Bilateral ophthalmoplegia, blepharoptosis, areflexia, and ataxic gait were noted. One week after treatment with intravenous immunoglobulin, his ophthalmoplegia, blepharoptosis, and ataxic gait had gradually improved, and his deep tendon reflexes returned. Anti-GQ1b IgG antibodies were detected in his serum. There has been no previous report of postinfectious MFS following confirmed an influenza A infection in an adult.

LM1 is localized in human peripheral nerve myelin. Antibodies to ganglioside complexes (GSCs) have been reported in Guillain-Barre syndrome (GBS). We investigated IgG antibodies to LM1 and two GSCs (GM1 and LM1, or GD1b and LM1) in the sera of each 40 patients with chronic inflammatory demyelinating polyneuropathy (CIDP) and CBS. using ELISA. We detected anti-LM1 antibody in five with CBS and seven with CIDP; anti-GM1/LM1 antibody in three with CBS and one with CIDP; and anti-GD1b/LM1 antibody in two with CIDP. Antibodies to LM1 and LM1-containing GSCs may be among the targets for autoimmunity in CBS and CIDP. (C) 2011 Elsevier B.V. All rights reserved.

[抄録] Acute oropharyngeal palsy（AOP）は口咽頭筋麻痺を主徴とする比較的稀なGuillain-Barre症候群の亜型である．今回我々は，開鼻声，嚥下障害などの球症状が急速に進行し当初は脳血管障害を疑ったが，抗ガングリオシド抗体の測定により比較的早期に診断，加療し得たAOP の１例を経験したので文献的考察を加え報告する．

遺伝子診断でミトコンドリア遺伝子3243変異をみとめ、脳卒中様症状を伴うミトコンドリア脳筋症(Mitochondrial myopathy、Encephalopathy、Lactic Acidosis、Stroke-like episodes,MELAS)と診断され、脳卒中様発作の再発、軽快を繰り返した症例である。脳波異常が続き、フェニトイン内服を続けていたが、2008年12月再発し、頭部MRIでは右側頭葉などに多発する新たな病変をみとめ、脳波では同期性周期性放電(PSD)をみとめた。経過とともに、脳波でのPSDは改善した。(著者抄録)

本研究は神経疾患の病態における補体の関与について解析し、病態に関与する補体活性を示す新規マーカーを見出し、治療の効果判定や予後を予測できるバイオマーカーを開発することを目的とする。 補体は、ウイルスや細菌などの外敵から生体を守る免疫システムで重要な働きをしているが、その制御が破綻すると疾患の原因となってしまう。神経疾患では重症筋無力症や視神経脊髄炎（NMOSD）は、補体が関与した自己抗体誘導性の病態が想定されている。近年、再発予防治療に補体C5に対する抗体製剤が承認されているが、無効例も存在し、その予測は困難である。補体の活性化経路は、古典経路、レクチン経路、第二経路があるが、これらの神経疾患の病態における補体の詳細な作用機序は明らかにされていない。 今年度は、まずNMOSDの解析から行った。NMOSDは水分子を通すタンパク質であるアクアポリン４に対する自己抗体によって、中枢神経のアストロサイトが破壊され、視神経や脊髄に障害を引き起こす神経疾患である。急性期と安定期のペア血清が保存されている21名のNMOSD患者の補体因子を測定したところ、安定期に比べて急性期でsC5b-9とBaが有意に上昇していた。また補体制御因子CFHは急性期に有意に低下していた。sC5b-9は終末補体経路、Baは補体第二経路の活性化を表すことから、NMOSDでは補体第二経路が活性化しており、制御因子が低下しているため、そのまま終末経路まで補体が活性化し、神経細胞が傷害されることが判明した。 次に、同じく神経免疫疾患であるギラン・バレー症候群でも同様の解析を行った。25名の補体因子を測定したところ、補体第二経路Baは上昇していたが、制御因子CFHが機能しており、その結果、sC5b-9は上昇しておらず終末補体経路は活性化していなかった。 これらの新しい知見は Front Immunol誌に論文発表した。

慢性免疫性ニューロパチーである多巣性運動ニューロパチー（MMN）では、約半数で糖脂質のガングリオシドGM1に対するIgM抗体が陽性となる。また、近年ではミエリンに多く含まれている中性糖脂質のGal-CとGM1の混合抗原（GM1/Gal-C）に対するIgM抗体が高率に検出されることが報告されている。一方、急性免疫性ニューロパチーのギラン・バレー症候群（GBS）では半数以上でガングリオシドに対するIgG抗体が陽性となり、各種のリン脂質をガングリオシド抗原に混合することで抗体活性の増強や減弱がみられ、２種類のガングリオシドを混合した抗原に特異的な抗体が検出されることがある。本研究では免疫性の脱髄性ニューロパチーにおいて混合抗原に対する特異的な自己抗体を見出し、脱髄機序に関連する病態メカニズムを明らかにする。今年度は、MMNにおいてリン脂質であるフォスファチジン酸（PA）とGM1、またはGal-CとGM1の混合した抗原に対するIgM抗体反応について検討した。EFNS/PNSの診断基準でprobable以上のMMN症例を対象として、PA添加GM1およびGM1/Gal-Cに対するIgM抗体活性を調べたところ、MMNではPA添加GM1に対する特異的な抗体反応が新たに検出されたが正常対照ではそのような反応はほとんどみられなかった。一方、GM1/Gal-Cに対する特異的な抗体反応はMMN、正常対照、共にほとんど検出されなかった。GBSと同様にMMNにおけるIgM抗体についても、ガングリオシドの単独抗原だけでなくPA添加抗原を用いることによって抗体の検出感度が向上することが示された。

Autoantibodies in neuroimmunological diseases against complex antigens formed by glycolipids and phospholipids or cholesterol were investigated. IgM antibodies to complex antigens including such myelin antigens as Gal-C and sulfatide were frequently detected in chronic inflammatory demyelinating polyneuropathy. Those antibodies may be involved in the pathogenetic mechanism of demyelination. In multifocal motor neuropathy, the positive rate of IgM anti-GM1 antibodies was increased when phosphatidic acid was added to the GM1 antigen. IgG anti-GD1a antibodies were found to be associated with Guillain-Barre syndrome with poor prognosis. Patients with Bickerstaff brainstem encephalitis having GQ1b-related antibodies showed relatively uniform clinical features.

Serum antibodies to glycolipids and glycolipid complexes in patients with neuroimmunological diseases were investigated comprehensively using glycoarray. Antibody activities to glycolipid complexes containing sulfatide in Guillain-Barré syndrome (GBS) and to those containing GalNAc-GD1a in multifocal motor neuropathy (MMN) were newly found by the present study. It was suggested that those antibodies are involved in the pathogenetic mechanisms of GBS and MMN. Among the patients with anti-GQ1b antibody-associated diseases, antibodies to glycolipid complexes containing GD1b were frequently present in GBS. Patients with such antibodies were frequently affected with severe GBS. Clinical features of neuroimmunological diseases with anti-Gal-C antibodies and those of neuropathy with anti-neurofascin 155 antibodies were revealed.