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We describe two cases of myasthenia gravis (MG) with double seropositivity for acetylcholine receptor (AChR) and low-density lipoprotein receptor-related protein 4 (LRP4) antibodies (AChR/LRP4-MG) with invasive thymoma. Both cases showed myasthenic weakness, which was restricted to the ocular muscles for >5 months from onset, and then unprovoked severe clinical deterioration supervened with predominant bulbar symptoms. The patients responded adequately to therapeutic intervention. Serum AChR antibody levels at post-intervention were markedly decreased, whereas LRP4 antibodies were almost unchanged in case 1 and slightly decreased in case 2. Although our results suggest that patients with AChR/LRP4-MG are likely to present with more severe symptoms than those with LRP4-MG, none of the previously reported cases had thymomas. Coexistence of autoantibodies may reflect breakdown of self-tolerance caused by invasive thymomas. The main cause affecting symptoms of MG in our cases was probably AChR antibodies, and anti-LRP4 antibodies might have been an exacerbating factor.

In neuromyelitis optica (NMO), B-cell autoimmunity to aquaporin-4 (AQP4) has been shown to be essential. However, the role of T cells remains ambiguous. Here, we first showed an increase in CD69+ activated T cells in PBMCs during NMO relapses. Next, T-cell responses to AQP4 and myelin peptides were studied in 12 NM0 patients, 10 multiple sclerosis (MS) patients and 10 healthy subjects (HS). Four hours after adding 1 of 28 overlapping AQP4 peptides, a mixture of AQP4 peptides (AQP4-M) or one of six distinct myelin peptides to 2-day cultured PBMC, CD69 expression on CD4+ T cells was examined. Data were analyzed by paired t-test, frequency of samples with 3-fold increase of CD69 on CD4+ cells (fSI3) and mean stimulation index (mSI). The T-cell response to AQP4-M was significantly increased in NMO (fSI3 = 10/12, mSI = 5.50), with AQP4 (11-30) and AQP4 (91-110) representing the two major epitopes (AQP4 (11-30), fSI3 = 11/12, mSI = 16.0 and AQP4 (91-110), fSI3 = 11/12, mSI = 13.0). Significant but less extensive responses to these two epitopes were also observed in MS and HS. Significant reactivities against AQP4 (21-40), AQP4 (61-80), AQP4 (101-120), AQP4 (171-190) and AQP4 (211-230) were exclusively found in NMO. In addition, responses to AQP4 (81-100) were higher and more frequently detected in NMO, without reaching statistical significance. Interestingly, among the six myelin peptides studied, proteolipid protein (95-116) induced a significant T-cell response in NMO (fSI3 = 7/12, mSI = 4.60). Our study suggests that cellular as well as humoral responses to AQP4 are necessary for NMO development and that the immune response to myelin protein may contribute to disease pathogenesis., International Immunology, 23(9), pp.565-573; 2011

Low-density lipoprotein receptor-related protein 4 (LRP4) is crucial membrane protein in the development and function of neuromuscular junctions and motor neurons. And, it is currently known myasthenia gravis (MG) is caused by antibodies to the acetylcholine receptor (AChR), muscle-specific kinase (MuSK), and LRP4. MuSK and LRP4 are coreceptors for agrin in the signaling pathway that causes clustering of AChR. We demonstrated anti-LRP4 antibodies played a key role in MG. LRP4 is essential for maintaining the structural and functional integrity of the neuromuscular junction and that loss of muscle LRP4 in adulthood alone is sufficient to cause myasthenic symptoms. MG with anti-LRP4 antibodies (LRP4-MG) is considered a rare subtype of MG, however, LRP4 autoantibodies have been recently detected in some motor neuron disease (MND) patients, and LRP4 is required for presynaptic and postsynaptic differentiation. We developed the luciferase immunoprecipitation systems for LRP4 autoantibodies detection and with this assay we studied for four years the sera from Japanese patients who had been suspected of MG or other neurological diseases with general myasthenia and/or muscle weakness. The clinical and therapeutic implications of the anti-LRP4 antibody positivity remain to be clarified, and further studies are necessary to elucidate the pathogenic potential of these autoantibodies.

A 78-year-old woman noticed that people's eyes and the right nasal foramens located in her left visual field looked smaller than those observed in the right. The woman reported no change in shape regarding facial outlines or scenic objects. Magnetic resonance imaging revealed an acute infarction of the right side of the splenium of the corpus callosum. Close examination revealed that her metamorphopsia affected the left side of her visual field, especially influencing facial components, particularly the eye. The woman had similar reactions to photographs of several kinds of animals, realistic portraits of humans, and caricatured humans. Meanwhile, presentings caricature human face at a 90° rotation elicited metamorphopsia in eyebrows located on the left side of a picture, but not the eyes. She also reported a change of shape or color tone for geometric objects. The patient's only symptom was metamorphopsia, and she did not show any other neurological defects such as callosal disconnection syndrome. Furthermore, objects that were affected by the patient's metamorphopsia (e.g. facial component especially the eye, and simple geometric figures) may be easy images to use in order to detect this type of distorted vision.

Autoimmune autonomic ganglionopathy (AAG) is a rare acquired channelopathy that is characterized by pandysautonomia, in which autoantibodies to ganglionic nicotinic acetylcholine receptors (gAChR) may play a central role. Radioimmunoprecipitation (RIP) assays have been used for the sensitive detection of autoantibodies to gAChR in the serum of patients with AAG. Here, we developed luciferase immunoprecipitation systems (LIPS) to diagnose AAG based on IgGs to both the α3 and β4 gAChR subunits in patient serum. We reviewed the serological and clinical data of 50 Japanese patients who were diagnosed with AAG. With the LIPS testing, we detected anti-α3 and -β4 gAChR antibodies in 48% (24/50) of the patients. A gradual mode of onset was more common in the seropositive group than in the seronegative group. Patients with AAG frequently have orthostatic hypotension and upper and lower gastrointestinal tract symptoms, with or without anti-gAChR. The occurrence of autonomic symptoms was not significantly different between the seropositive and seronegative group, with the exception of achalasia in three patients from the seropositive group. In addition, we found a significant overrepresentation of autoimmune diseases in the seropositive group and endocrinological abnormalities as an occasional complication of AAG. Our results demonstrated that the LIPS assay was a useful novel tool for detecting autoantibodies against gAChR in patients with AAG., PLOS ONE, 10(3), e0118312; 2015

The therapeutic potency of M2000 (beta-D-mannuronic acid), a novel designed nonsteroidal anti-inflammatory drug with immunosuppressive property in T-cell-mediated autoimmune disease, was tested. The influence of M2000 on myelin basic protein (MBP)-induced experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis, was assessed. M2000 at two doses, 40 and 80 mg/kg/day, was administered intraperitoneally (i.p.) to prevention and treatment groups, respectively. Onset of i.p. injections of M2000 to prophylactic and therapeutic groups was day-1 and day-7 postimmunization. The WEHI-164 cell line was used for assaying the tolerability against M2000. The results of this experiment showed that the treatment of EAE with M2000 could significantly suppress disease development both prophylactically and therapeutically; the onset and symptoms of EAE in Lewis rats could be suppressed following the administration of M2000. Clinical improvement was accompanied by a marked decrease in mean numbers of vessels with perivascular cellular infiltration in M2000-treated rats compared with nontreated control. Disease suppression was associated with a marked suppression of MBP-specific T-cell reactivity in vitro, without any evidence for a generalized impairment of T-cell activity. Moreover, M2000 also showed a very high tolerability compared with certain steroidal and nonsteroidal anti-inflammatory drugs. Collectively, our data suggest that M2000 may provide a novel therapeutic option for T-cell-mediated autoimmune diseases in animal models and possibly in humans.

Autoimmune autonomic ganglionopathy (AAG) is a disorder of isolated autonomic failure associated with antibodies to the nitotinic acetylcholine receptor of the autonomic ganglia resulting in severe autonomic dysfunction. The disorder is associated with and most likely caused by antibodies to gAChR. In this study, we attempted to develop a novel technique to detect antibodies that bind to gAChR. We established a simple in vitro system termed GLIP (gaussia luciferase-reporter immunoprecipitation), which can detect protein-protein interactions with high sensitivity and using no radioisotope. Using this new method, we extensively reviewed the case histories with current clinical and laboratory evaluations that include testing for antibodies to p3 and 34 subunits of gAChR in serum available from the time of symptom onset. Here, we describe 7 patients with gAChR autoantibody and autonomic dysfunction. Our observations also suggest that autoimmune-mediated impairment of autonomic function may be partially reversible. Six of 7 patients improved in response to immunotherapy (e.g. PP, IVMP, IVIg, and immunosuppressant drugs) with symptomatic therapy. We interpreted the improvement in clinical symptoms correlated with the decrease in the levels of anti gAChR antibodies in each case. Some patients with seropositive AAG respond to treatment with IVMP or PP or IVIg, although when used as a single agent, subsequent treatments are required in patients to maintain the improvement.

Autoimmune autonomic ganglionopathy (AAG) is an acquired immune-mediated disorder that leads to autonomic failure. The disorder is associated with autoantibodies (Abs) to the ganglionic nicotinic acetylcholine receptor (gAChR).1 Previously, we developed a luciferase immunoprecipitation systems (LIPS) protocol to aid in the diagnosis of AAG based on serum levels of immunoglobulin G (IgG) to the α3 and β4 gAChR subunits.2 We subsequently observed that AAG is associated with an overrepresentation of autoimmune diseases and endocrine disorders.2 Furthermore, Hayashi et al 3 reviewed 29 Japanese case reports of AAG and pandysautonomia and observed that Japanese patients with AAG tended to exhibit additional coughing episodes/psychiatric symptoms when compared to patients in Western countries. Gibbons et al 4 reported some patients with AAG demonstrated reversible cognitive impairment. The present study aims to elucidate the prevalence of extra-autonomic manifestations including psychiatric symptoms in 80 Japanese patients with AAG who were seropositive for anti-gAChR Abs. ### Ethical approval All participants provided written, informed consent to participate in the study. The Ethics Committee of Nagasaki Kawatana Medical Center approved this study. ### Study population Serum samples from 946 patients with autonomic symptoms were obtained from general and teaching hospitals throughout Japan between January 2012 and April 2016 (mean age: 51±22 years; 488 men and 458 women). Clinical diagnoses were …

Experimental autoimmune encephalomyelitis (EAE) is a major animal model of human multiple sclerosis (MS). CD4+ T cells are thought to play a pivotal role in the patho genesis of EAE and MS. In order to investigate the depletio n of CD4+ T cells from the systemic circulation as an effective strategy for the treatment of MS, we performed extracorporeal CD4+ T cell adsorption, using a filter to which anti-CD4+ antibody is immobilized as a ligand, in adoptively transferred EAE. Rats treated with CD4+ T cell removal filter (C D4RF) exhibited milder clinical signs of EAE and earlier recovery than those receiving sham treatment. Moreover, the thymic cells from EAE rats treated with C D4RF exhibited a suppressed proliferative response and IFN-g production to myelin basic protein. These results suggest that depletion of CD4+ T cells from the systemic circulation by extracorporeal treatment is a potentially useful strategy for treatment of acute phase and relapsing MS.

We compared CNS disease following intracerebral injection of SJL mice with Daniel’s (DA) and BeAn 8386 (BeAn) strains of Theiler’s murine encephalomyelitis virus (TMEV). In tissue culture, DA was more virulent then BeAn. There was a higher incidence of demyelination in the spinal cords of SJL/J mice infected with DA as compared to BeAn. However, the extent of demyelination was similar between virus strains when comparing those mice that developed demyelination. Even though BeAn infection resulted in lower incidence of demyelination in the spinal cord, these mice showed significant brain disease similar to that observed with DA. There was approximately 100 times more virus specific RNA in the CNS of DA infected mice as compared to BeAn infected mice. This was reflected by more virus antigen positive cells (macrophages/microglia and oligodendrocytes) in the spinal cord white matter of DA infected mice as compared to BeAn. There was no difference in the brain infiltrating immune cells of DA or BeAn infected mice. However, BeAn infected mice showed higher titers of TMEV specific antibody. Functional deficits as measured by Rotarod were more severe in DA infected versus BeAn infected mice. These findings indicate that the diseases induced by DA or BeAn are distinct.

The aim of this study was to elucidate the effectiveness of oral prednisolone (PSL) according to dosing regimen in 472 patients with myasthenia gravis (MG).We compared the clinical characteristics and PSL treatment between 226 patients who achieved minimal manifestations (MM) or better and 246 patients who remained improved (I) or worsened, according to the MG Foundation of America postintervention status.Achievement of MM or better at peak PSL dose (odds ratio 12.25, P 0.0001) and combined use of plasma exchange/plasmapheresis (PE/PP) and/or intravenous immunoglobulin (IVIg) (odds ratio 1.92, P = 0.04) were associated positively, and total PSL dose during the past year (odds ratio 0.17, P = 0.03) was associated negatively with present MM or better status.Higher PSL dose and longer PSL treatment do not ensure better outcome. In the absence of a good response, the PSL dose should be decreased by combining with modalities such as PE/PP or IVIg.

Autonomic dysfunction, as well as neuromuscular involvement, is a common manifestation of Lambert-Eaton myasthenic syndrome (LEMS). Dry mouth and impotence have been described as typical features of autonomic dysfunction, but neurogenic bladder is infrequent or subclinical in LEMS. We report a patient with neurogenic bladder secondary to LEMS whose condition responded to 3,4-diaminopyridine (3,4-DAP). In this patient's serum, results of repeated measurement with P/Q-type VGCC antibodies proved positive, but not with N-type VGCC and synaptotagmin antibodies. A review of the literature turned up a few patients with voiding dysfunction related to LEMS, but no urodynamic studies were done on these patients. Ours is the first case in which 3,4-DAP was efficacious in treating LEMS and neurogenic bladder. Responses of 3,4-DAP in urodynamic studies suggest that in this LEMS patient neurogenic bladder was caused by defective neurotransmission both in the autonomic detrusor and skeletal abdominal muscles.

Calcineurin inhibitors (CNIs) and intravenous immunoglobulin (IVIg) are immunomodulatory treatments used to treat patients with myasthenia gravis (MG). The objective of this study was to describe the clinical features of MG treated with CNIs or IVIg. To characterise the clinical features of myasthenic symptoms in MG treated with CNIs compared with MG treated without CNIs. Patients with MG (676 cases) underwent a multidisciplinary clinical examination (quantitative MG score for disease severity (QMG score), MG composite, etc), and we extensively reviewed the case histories with current clinical and laboratory evaluations. We confirmed CNIs were safe and effective in the treatment of MG in association with reduction of corticosteroids. IVIg have efficacy in reducing QMG score in patients with moderate to severe MG.

The Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune disorder of peripheral cholinergic transmission in which autoantibodies decrease the presynaptic release of acetylcholine at the neuromuscular junction and autonomic system. Recent results suggest that the antibodies to P/Q-type calcium channels are the principal pathogenic factors in LEMS. Here, we present our experience with cases of LEMS who are noncarcinomatous. We studied the efficacy of plasmapheresis, analyzing the clinical score, electrophysiological finding, and the titer of anti-P/Q-type voltage-gated calcium channel (P/Q-VGCC) antibody. The first case, a 72-year-old female presenting with leg weakness, was treated by plasma exchange (PE). However, clinical improvement was transient; intravenous immunoglobulin (IVIg) therapy was followed by additional PE. She had a clinical and electromyologic improvement, and her P/Q-VGCC antibody titers decreased. Her clinical status and CMAP amplitude correlated closely with the anti-P/Q-VGCC antibody titers. The second case, a 73-year-old male presenting with leg weakness, was treated by PE and double-filtration plasmapheresis. The P/Q-VGCC antibody titres decreased immediately after these aphereses, but recovered to the pretreatment levels 1 week after them. After the immunosuppressive drugs prednisolone and azathioprine were started, his clinical symptoms improved. His antibody titers decreased gradually after immunosuppressive therapy. It is speculated that no sufficient efficacious improvement could be obtained by apheresis alone because of a high rate of P/Q-VGCC antibody production. Considering our experiences and other literature, we discuss the indication of apheresis treatment of LEMS.

In order to elucidate the underlying mechanisms of a discordant case with HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) in monozygotic twins, we investigated HTLV-I tax sequences of 10 - 18 polymerase chain reaction-based clones each derived from peripheral blood mononuclear cells of the twins as well as their infected mother and an elder brother who also suffered from HAM/TSP. Sequence comparison revealed that three of the infected individuals including a twin with HAM/TSP shared the consensus tax sequence identical to the reference, ATK-1, but that of another healthy twin was different at five nucleotide positions including three nonsynonymous changes from ATK-1. This finding strongly suggested that different HTLV-I strains infected the monozygotic twins and the difference in infected proviral sequences determined the discordant clinical outcomes. Transfection and subsequent reporter assays failed to show a significant difference in transactivation activity on HTLV-I LTR and NF-kappaB elements between the products of the two sequences. Two HAM/TSP patients (a twin and elder brother) among three members infected with the ATK-1 type virus shared a paternal HLA allele which was absent in the healthy individual (mother). Genetic analysis of sequence variation in the tax sequences of the discordant twins showed that the Dn/Ds ratio was high in the healthy twin but low in the twin with HAM/TSP, implying the presence of more intense selection forces in the carrier. Our findings strongly suggested that a particular combination of HTLV-I strains with an HLA genotype would be a risk for HAM/TSP.

We investigated whether matrix metalloproteinase-2 (MMP-2) is induced in peripheral blood T cells after their contact with tumor necrosis factor-alpha (TNF-alpha)-stimulated glioblastoma cell line (T98G), expressing vascular cell adhesion molecule-1 (VCAM-1), in patients with HTLV-I-associated myelopathy (HAM) compared to control patients with other neurological disorders (OND). Gelatin zymography revealed that the incremental ratio of gelatinolytic activity of MMP-2 in culture supernatants derived from T cells cocultured with TNF-alpha-stimulated T98G to that of supernatants derived from cultures of T cells alone was significantly higher in HAM patients than in control patients with OND. Immunoblot analysis of immunoprecipitates of culture supernatant showed that increased gelatinolytic activity of MMP-2 was due to increased production of MMP-2 protein in T cells. Increased gelatinolytic activity of MMP-2 in T cells of HAM patients was blocked by pretreatment of TNF-alpha-stimulated T98G with anti-VCAM-1 antibody before coculture with T cells, indicating that MMP-2 induction was VCAM-1-mediated. Although no significant differences were noted in the percentage of VLA-4-positive cells in cultured T cells between HAM patients and control patients with OND, our results indicate that VCAM-1-mediated MMP-2 induction is up-regulated in T cells of HAM patients.

Object Previously, we reported the efficacy of pentoxifylline (PTX) treatment in human T-lymphotropic virus type I (HTLV-I)-associated myelopathy (HAM). Here, we clarify the relationship between the clinical efficacy of PTX treatment and elevation of T helper type 2 (Th2) cytokine levels in HAM patients. Patients and methods PTX (300mg) was administered daily by the oral route to 12 HAM patients for 4 weeks. We assessed the relationship between the changes in neurological status (motor disability scores, the degree of spasticity on neurological examination, and the time required to walk 10 m) and the changes in serum and cerebrospinal fluid (CSF) levels of interferon-γ (IFN-γ) as a Thl cytokine and interleukin-4 and -10 (IL-4 and -10) as Th2 cytokines measured by an EASIA (enzyme-amplified sensitivity immunoassay) kit. Results PTX treatment induced incremental increases in the levels of IL-4 and IL-10 in both sera and CSF of 6 HAM patients. Clinical improvement was associated with this elevation in IL-4 and IL-10. PTX treatment also induced a decrease in IFN-γ levels in the sera of 6 HAM patients, but this was not correlated with clinical improvement. Conclusion These results suggest that the correction of the immunological imbalance in Thl to Th2 cytokine responses, with upregulation of IL-4 and IL-10, may account for the clinical improvement in HAM patients treated with PTX.(Internal Medicine 38: 717-721, 1999)

We investigated the mRNA expression of inducible nitric oxide synthase (iNOS) and the production of nitric oxide (NO) in human T cell lymphotropic virus type I (HTLV-I) p40 tax -transfected U937 cells, a human monoblast cell line. Transfection of HTLV-I p40 tax U937 cells induced up-regulation of iNOS mRNA expression and subsequent NO production. Furthermore, interferon γ (IFN-γ) stimulation of HTLV-I p40 tax -transfected U937 cells enhanced iNOS mRNA expression and NO production. The kinetics of iNOS mRNA expression and NO production indicated maximal effect at 24 and 48 hours, respectively, after culture with or without IFN-γ. These findings suggest that HTLV-I p40 tax can act as a transactivator of NO production in cells of Mo/Mφ lineage. To what extent this mechanism may be involved in the pathogenesis of HTLV-I -associated diseases warrants further investigation.

Epidemiological studies suggest that an environmental factor (possibly a virus) acquired early in life may trigger multiple sclerosis (MS). The virus may remain dormant in the central nervous system but then becomes activated in adulthood. All existing models of MS are characterized by inflammation or demyelination that follows days after virus infection or antigen inoculation. While investigating the role of CD4+ T cell responses following Theiler's virus infection in mice deficient in STAT4 or STAT6, we discovered a model in which virus infection was followed by demyelination after a very prolonged incubation period. STAT4-/- mice were resistant to demyelination for 180 days after infection, but developed severe demyelination after this time point. Inflammatory cells and up-regulation of Class I and Class II MHC antigens characterized these lesions. Virus antigen was partially controlled during the early chronic phase of the infection even though viral RNA levels remained high throughout infection. Demyelination correlated with the appearance of virus antigen expression. Bone marrow reconstitution experiments indicated that the mechanism of the late onset demyelination was the result of the STAT4-/- immune system. Thus, virus infection of STAT4-/- mice results in a model that may allow for dissection of the immune events predisposing to late-onset demyelination in MS.

Objective Appropriate stimulation of the dorsal column is required in order to achieve optimal control over pain by way of spinal cord stimulation (SCS). In this study, we objectively evaluated changes in somatosensory evoked potentials (SEPs) during a collision test in order to investigate whether paresthetic sensation or amount of pain reduction was correlated with the degree of dorsal column stimulation. Materials and Methods We studied 12 patients with intractable pain who underwent permanent SCS implantation. SEP collision was examined while recording the cortical SEP components elicited by posterior tibial nerve stimulation. A positive collision effect was observed when the SEP amplitude was clearly reduced by the SCS. Results Based on the SEP collision findings, the effects of SCS were classified into four patterns: positive collision with pain reduction (Type 1), positive collision without pain reduction (Type 2), negative collision with pain reduction (Type 3), and negative collision without pain reduction (Type 4). Type 1 was observed for well-known diseases in which SCS was very effective, whereas Type 2 was seen in poor candidates for dorsal column stimulation. Patients with poststroke pain exhibited various patterns including types 1, 2, and 3. One patient showed Type 4 patterning, and we recommended further SCS trials before the abandonment of SCS therapy for this patient. Conclusions We show that SEP collision is useful for evaluating the degree of dorsal column stimulation needed as well as in considering factors related to differences between responders and nonresponders to SCS therapy.

The aim of this study was to determine factors affecting health-related quality of life (HRQOL) and to propose appropriate treatment targets for patients with myasthenia gravis (MG).We evaluated 640 consecutive patients with MG seen at 11 neurological centers. Two-year follow-up data were obtained for 282 patients. Correlations between detailed clinical factors and the Japanese version of the 15-item MG-specific QOL scale score were analyzed.In a cross-sectional analysis of 640 MG patients, multivariate regression revealed that disease severity, as evaluated by the MG Composite (P0.0001), total dose of oral prednisolone during the last year (P=0.002), and Cushingoid appearance index (P=0.0004), showed significant negative effects on HRQOL, but the quantitative MG score and current prednisolone dose did not.Achieving minimal manifestations (MM) status or better with prednisolone ≤ 5 mg/day was found to exert a major positive impact on HRQOL in both the cross-sectional and 2-year follow-up patient samples and can be recommended as a treatment target.

Antibodies against the muscle acetylcholine receptor (AChR) were recognized as the cause of myasthenia gravis in the 1970s'. Since then, other neurological disorders associated with autoantibodies have been identified, each associated with an antibody against a ligand- or voltage-gated ion channel. Autoantibodies against P/Q-type voltage-gated calcium channels (VGCCs) are detected in patients with Lambert-Eaton myasthenic syndrome (LEMS). These antibodies interfere with the calcium-dependent release of acetylcholine from the presynaptic membrane. LEMS is an autoimmune disorder affecting the neuromuscular junction, and is characterized by proximal muscle weakness, reduction of tendon reflex, and autonomic dysfunction. Electrophysiological examinations show small-amplitude compound muscle action potentials and increments on rapid repetitive nerve stimulation. Fifty to sixty percent of LEMS patients present with tumors, mostly small cell lung carcinoma (SCLC), as a paraneoplastic syndrome. SCLC is a neuroendocrine tumor, which expresses neuronal VGCCs. Some patients present cerebellar ataxia, which is always accompanied by SCLC. These patients tend to show higher titers of VGCC antibodies than that by LEMS patients with no ataxia. The diagnosis can be confirmed by finding reduced compound muscle action potential amplitudes at rest that shows increments greater than 100% with repetitive nerve stimulation and antibody detection by using radioimmunoprecipitation assays. The treatment options are generally categorized as anti-tumor, immunomodulating, immunosuppressing, and symptomatic treatments. In cases with SCLC, effective treatment against the tumor can improve LEMS. Plasmapheresis and intravenous administration of high-dose immunoglobulins have a short effect. Prednisone, alone or in combination with immunosuppressants can achieve long-term control of the disorder.

Background/Aims Anti-ganglionic nicotinic acetylcholine receptor (gAChR) antibodies are observed in autoimmune diseases, as well as in patients with autoimmune autonomic ganglionopathy. However, the genetic background of anti-gAChR antibodies is unclear. Here, we investigated HLA alleles in autoimmune hepatitis (AIH) patients with or without anti-gAChR antibodies. Methodology/Principal Findings Genomic DNA from 260 patients with type-1 autoimmune hepatitis (AIH) were genotyped for HLA-A, B, DRB1, and DQB1 loci. Anti-gAChR antibodies in the sera form AIH patients were measured using the luciferase immunoprecipitation system, and examined allelic association in patients with or without anti-gAChR antibodies. Methodology/ Methods We detected anti-α3 or -β4 gAChR antibodies in 11.5% (30/260) of patients with AIH. Among AIH patients there was no significant association between HLA-A, B DQB1 alleles and the positivity for anti-gAChR antibodies. Whereas the HLA-DRB1*0403 allele showed a significantly increased frequency in AIH patients with anti-gAChR antibodies compared with those without anti-gAChR antibodies. Conclusions/Significance The frequency of the HLA-DRB1*0403 allele differed among Japanese patients with AIH according to the presence or absence of anti-gAChR antibodies. Our findings suggest that particular HLA class II molecules might control the development of anti-gAChR antibodies in the autoimmune response to gAChR.

To evaluate health-related quality of life (HRQOL) in Japanese patients with multiple sclerosis (MS) and investigate associations between the results of these QOL assessments and disease severity. One-hundred sixty-three Japanese MS patients completed a questionnaire battery comprising the Functional Assessment of MS (FAMS), the Nottingham Adjustment Scale-Japanese version (NAS-J), and the European QOL scale (EQ-5D). Additional five factors affecting QOL as identified by MS patients in a focus group interview were also investigated: employment status, change of income, availability of disease information, communication with medical staff, and care received. Disease severity was determined using the Expanded Disability Status Scale (EDSS). There was a strong negative correlation of the subscale scores for mobility, symptoms, emotional well-being, thinking and fatigue, and additional concerns on the FAMS with EDSS score. For the NAS-J, only acceptance of the condition was correlated with disease severity. Among the five additional aspects of the condition identified by patients, employment status, income, and disease information were shown to be important for maintaining QOL in patients with MS. Support for finding employment and having increased or maintained household income and readily available information about the disease contribute to improving QOL in Japanese MS patients.

BACKGROUND: It has become increasingly clear that polyunsaturated fatty acids (PUFAs) have immunomodulatory effects. However, the intake of these fatty acids used in animal studies often greatly exceeds dietary human intake. Whether differences in the composition of fatty acids that are consumed in amounts consistent with normal dietary intake can influence immune function remains uncertain. METHODS: We manufactured 3 types of liquid diet, related to modified fatty acid composition (omega-6/omega-3 = 0.25, 2.27 and 42.9), but excluding eicosapentaenoic acid and docosahexaenoic acid, based upon a liquid diet used clinically in humans. We assessed CD3-stimulated cytokine production of splenocytes in female BALB/c mice (n = 4 per group) fed 1 of 3 liquid diets for 4 weeks. We also measured the cytokine production of peripheral blood mononuclear cells stimulated with phorbol myristate acetate and ionomycin in humans at the end of a 4-week period of consumption of 2 different liquid diets (omega-6/omega-3 = 3 and 44). RESULTS: We found that the ratio of interfero omega-gamma (IFN-gamma) / interleukin-4 (IL-4) was significantly higher in mice fed the omega-3 rich diet than in others. In humans, IFN-gamma / IL-4 was significantly higher after the omega-3 versus the omega-6 enhanced diet. CONCLUSIONS: Differences in the composition of omega-3 and omega-6 PUFAs induces a shift in the Th1/Th2 balance in both mouse and human lymphocytes, even when ingested in normal dietary amounts. An omega-3 rich diet containing alpha-linolenic acid modulates immune function., JPEN. Journal of parenteral and enteral nutrition, 33(4), pp.390-396; 2009

Immunological, epidemiological, and genetic data indicate that tissue injury in neuroimmunological disorders results from an abnormal immune response to one or more antigens that develops in genetically susceptible individuals after exposure to an as-yet undefined causal agent. A genetic component in these diseases is indicated by an increased relative risk to siblings compared to the general population, and an increased concordance rate in monozygotic twins. The past few years have seen real progress in defining the genetic basis setting the stage for new approaches for the characterization of the genes involved in susceptibility and pathogenesis. Recent reports suggest a complex genetic etiology, including multiple genes of small to moderate effect and probable genetic heterogeneity. The identification and characterization of susceptibility genes and their correlation with disease phenotypes is likely to define the basic etiology of the disease, improve risk assessment, and influence therapeutics.

Methotrexate (MTX) is a major cause of treatment-related acute neurotoxicity. We report on clinical and imaging findings of reversibly restricted diffusion in a patient with transient encephalopathy after high dose MTX therapy for osteosarcoma. During the chemotherapy, a 19-year-old man was introduced for the evaluation of consciousness disturbance. Neurological examination revealed confusion, inability of speak at the onset On next day, there were still difficulties in swallowing and phonation, and furthermore deep tendon reflexes were hyperactive in bilateral lower limbs with positive Babinski responses bilaterally. By the 6th day, findings at neurological examination were completely normal. Initial imaging on presentation was performed using MRI. Diffusion weighted MRI clearly indicated areas of restricted diffusion within both centrum semiovale. These abnormalities were confirmed by the diffusion tensor (DT) technique (ADC and FA map). The follow-up MRI examinations using same protocol showed resolution of the ADC and FA abnormalities but increasing T2-signal changes. Neither contrast enhancement nor atrophy was encountered. Early detection of MTX white matter injury by DT image has the potential to alert the oncologist and neurologist to this event and provide a technique by which treatment of neurotoxicity can be monitored.

We report a possible case of progressive multifocal leukoencephalopathy (PML) that was attempted to evaluate the pathogenesis by a novel brain MRI techniques. A 72-year-old woman had developed subacute visual disturbance, right hemiparesis and sensory disturbance. Laboratory examinations revealed liver dysfunction and pancytopenia due to liver cirrhosis (type C) and preclinical status of multiple myeloma. Thus, this patient had these two underlying diseases, while anti-HIV antibody was negative. She was suspected with PML by detection of JCV-DNA in cerebrospinal fluid using with PCR. MRI showed multifocal T2-high signals in the bilateral parieto-occipital deep white matter, basal ganglia and right cerebellar hemisphere. No gadolinium enhancement was found. On FLAIR and diffusion weighted images (DWI), the lesion showed hyperintensity. The hyperintense areas on DWI showed various pattern on apparent diffusion coefficient (ADC) and fractional anisotropy (FA). In particular white matter changes, the course of FA reflected the clinical course more than ADC. Proton magnetic resonance spectroscopy (1H-MRS) in deep brain white matter showed ratios of reduced N-acetyl aspartate (NAA) and increased choline (Cho) to creatine. 1H-MRS by chemical shift imaging were undergone three times between 4 and 6 months after the onset. The change of these chemical markers correlated with her clinical course. We conclude that the approach of diffusion tensor imaging (DTI) and 1H-MRS are useful for evaluating neuropathologic observations and clinical course.

A 53-year-old woman was admitted to our hospital because of dropped head. Neurological examination showed no abnormality except for weakness of the neck extensor muscles. Her symptoms worsened in the evening, requiring her to support her head by placing her hand against her chin. Edrophonium and repetitive stimulation tests gave negative results, and anti-acetylcholine receptor antibodies were not detected. She had no thymoma. However, she was found to have a high serum titer of anti-MuSK antibody (37.3 nM). She was diagnosed as having myasthenia gravis (MG) and treatment with pyridostigmine was started. However, this had to be withdrawn because of fasciculation as an adverse effect. She was therefore treated with prednisolone, and this resulted in marked improvement. The initial presenting symptom in this case was dropped head, and there were none of the results of laboratory or electrophysiological examinations that are usually typical of MG. MG was eventually diagnosed by measurement of anti-MuSK antibody. The present case suggests that a patient presenting with dropped head without any obvious cause needs to be studied for the presence of anti-MuSK antibody.

Neuroleptic malignant syndrome (NMS), also called parkinsonism-hyperpyrexia syndrome (PHS), is a severe, general, sometimes fatal, physical reaction, induced by sudden and strong blockade of dopamine receptors. When subthalamic nucleus (STN)-deep brain stimulation (DBS) is used on patients with Parkinson disease (PD), dopaminergic medications are transiently stopped prior to the procedure, and a reduction in the use of drugs is routinely attempted after the procedure. Although a sudden stop or abrupt reduction of dopaminergic medications may set the stage for NMS/PHS, only three cases have been reported after STN-DBS surgery. Here, we describe a 75-year-old woman with PD who experienced delayed onset, yet fatal, PHS after STN-DBS. Although STN-DBS might prevent or suppress PHS, its protective effect is not always complete. We must be aware that fatal PHS can occur when the use of medication for PD is reduced or altered, even when patients are under continuous STN stimulation.

We evaluated the role of gamma interferon (IFN-γ) in protecting neurons from virus-induced injury following central nervous system infection. IFN-γ−/−and IFN-γ+/+mice of the resistant major histocompatibility complex (MHC)H-2bhaplotype and intracerebrally infected with Theiler's murine encephalomyelitis virus (TMEV) cleared virus infection from anterior horn cell neurons. IFN-γ+/+H-2bmice also cleared virus from the spinal cord white matter, whereas IFN-γ−/−H-2bmice developed viral persistence in glial cells of the white matter and exhibited associated spinal cord demyelination. In contrast, infection of IFN-γ−/−mice of the susceptibleH-2qhaplotype resulted in frequent deaths and severe neurologic deficits within 16 days of infection compared to the results obtained for controls. Morphologic analysis demonstrated severe injury to spinal cord neurons in IFN-γ−/−H-2qmice during early infection. More virus RNA was detected in the brain and spinal cord of IFN-γ−/−H-2qmice than in those of control mice at 14 and 21 days after TMEV infection. Virus antigen was localized predominantly to anterior horn cells in infected IFN-γ−/−H-2qmice. IFN-γ deletion did not affect the humoral response directed against the virus. However, the level of expression of CD4, CD8, class I MHC, or class II MHC in the central nervous system of IFN-γ−/−H-2qmice was lower than those in IFN-γ+/+H-2qmice. Finally, in vitro analysis of virus-induced death in NSC34 cells and spinal motor neurons showed that IFN-γ exerted a neuroprotective effect in the absence of other aspects of the immune response. These data support the hypothesis that IFN-γ plays a critical role in protecting spinal cord neurons from persistent infection and death.

International audience; Theiler's virus persists and induces immunemediated demyelination in susceptible mice and serves as a model of multiple sclerosis. Previously, we identified 4 markers-D14Mit54, D14Mit60, D14Mit61, and D14Mit90-in a 40-cM region of chromosome 14 that are associated with demyelination in a cross between susceptible DBA/2 and resistant B10.D2 mice. We generated congenic-inbred mice to examine the contribution of this 40-cM region to disease. DBA Chr.14 B10 mice, containing the chromosomal segment marked by the microsatellite polymorphisms, developed less spinal cord demyelination than did DBA/2 mice. More demyelination was found in the reciprocal congenic mouse B10.D2 Chr.14 D2 than in the B10.D2 strain. Introduction of the DBA/2 chromosomal region onto the B10.D2 genetic background resulted in more severe disease in the striatum and cortex relative to B10.D2 mice. The importance of the marked region of chromosome 14 is indicated by the decrease in neurological performance using the Rotarod test during chronic disease in B10.D2 Chr.14 D2 mice in comparison to B10.D2 mice. Viral replication was increased in B10.D2 Chr.14 D2 mice as determined by quantitative real-time RT-PCR. These results indicate that the 40-cM region on chromosome 14 of DBA/2 mice contributes to viral persistence, subsequent demyelination, and loss of neurological function.

Plasmapheresis not only removes humoral factors, but may also modulate cellular immunity. We investigated whether plasmapheresis influenced T helper type-1/T helper type-2 (Th1/Th2) cytokine-producing-cell balance in 3 patients with neuroimmunological disease. The production of interferon-gamma (IFN-gamma), interleukin-2 (IL-2), and IL-4 in the culture supernatant of peripheral blood mononuclear cells stimulated by anti-CD3 and anti-CD28 was assayed. In 2 of 3 patients, plasmapheresis (immunoadsorption or plasma exchange) reduced Th1/Th2 cytokine ratio. The results may suggest that plasmapheresis induces a shift of Th1/Th2 balance in peripheral blood.

The levels of interleukin-12 (IL-12) (p70 heterodimer), total IL-12 (p70 heterodimer plus p40 chains), interferon-gamma (IFN-gamma) as Th1 cytokine, and those of interleukin-4 (IL-4) and interleukin-10 (IL-10) as Th2 cytokines in sera and cerebrospinal fluid (CSF) from 22 patients with human T lymphotropic virus type I (HTLV-I)-associated myelopathy (HAM) were compared with those of 22 patients with other neurological diseases (OND), including nine anti-HTLV-I-seropositive carriers. Both serum IL-12 (total and p70 heterodimer) and CSF IFN-gamma, measured by the enzyme-linked immunosorbent assay (ELISA), were significantly elevated in patients with HAM as compared to the patients with OND, including the anti-HTLV-I-seropositive carriers. Serum IFN-gamma also was significantly elevated in the HAM patients as compared to the controls. There was no significant difference in the CSF levels of IL-12 (total and p70 heterodimer) between the HAM patients and controls, whereas, for the Th2 cytokines IL-4 was detected in the CSF of four anti-HTLV-I-seropositive carriers of the 13 control patients but not in any of the patients with HAM. No significant difference was found in the serum levels of IL-4 and IL-10, nor in the CSF levels of IL-10 in the patients with HAM and in the controls. These findings indicate that in patients with HAM, the immunological balance of helper T lymphocytes between Th1 and Th2 is toward Th1 in the periphery and that Th1-mediated immunological status in the central nervous system is involved in the pathogenesis of HAM.

Using a 51Cr release assay, we investigated Fas-mediated cytotoxicity of peripheral blood CD4+ T cells of patients with human T-lymphotropic virus type-I (HTLV-I)-associated myelopathy (HAM) against T98G, a glioblastoma cell line which expresses Fas. Cytotoxic activity of CD4+ T cells against T98G was significantly higher in HAM patients than in controls. Moreover, when CD4+ T cells of HAM patients were preincubated with a monoclonal antibody to human Fas ligand (FasL), cytotoxic activity against T98G was significantly suppressed. These results suggest that damage to nervous tissues by the Fas/FasL system is involved in the pathogenesis of HAM.

We compared soluble E-selectin (sE-selectin) and L-selectin (sL- selectin) levels in sera and cerebrospinal fluid (CSF) of 30 patients with human T-lymphotropic virus type I (HTLV-I)-associated myelopathy (HAM), with those of 10 patients with the relapsing-remitting form of multiple sclerosis (MS), and 16 patients with other neurological diseases (OND). Serum levels of both sE-selectin and sL-selectin, as measured by enzyme-linked immunosorbent assay, were significantly elevated in patients with HAM, compared to patients with OND. In addition, serum levels of sL-selectin were significantly elevated in HAM patients compared to MS patients. No significant difference was found in CSF levels of sL-selectin between HAM patients and controls. However, HAM patients who had received blood transfusions had significantly higher CSF levels of sL-selectin than HAM patients without a past history of transfusions, suggesting that HAM patients with past history of transfusion have a more active immunological state in the central nervous system. sE-selectin was not detected in CSF of HAM patients and controls. This finding might be based on exaggerated inflammatory conditions following increased attachment of lymphocytes to activated endothelial cells in HAM patients.