Rheumatoid meningitis developed in patient with stable rheumatoid arthritis and myasthenia gravis-detailed analysis of intracranial inflammation using flow cytometry.

BACKGROUND: Rheumatoid meningitis (RM) is a rare disorder that often develops during a remission phase of rheumatoid arthritis (RA). This is the first study to demonstrate differences in regard to immunological disturbance between blood and cerebrospinal fluid (CSF) samples obtained from a patient with RM using flow cytometry. CASE PRESENTATION: A 36-year-old woman with RA and generalized myasthenia gravis (MG) developed RM during a remission phase. Although both RA and MG were stable and well controlled, she noticed fever, headache, and transient sensory disturbance. Blood and CSF examination findings suggested aseptic meningitis, while brain magnetic resonance imaging revealed restricted portions of meningitis and associated cortical lesions, compatible with a diagnosis of RM. The dose of oral prednisolone was increased, which ameliorated the symptoms within 1 week along with improvement in CSF findings. This patient exhibited features of RM that were manifested in a manner independent of the activity of RA. An investigation of cellular immunity using CSF specimens with flow cytometry showed differences in regard to the pathogenesis of inflammation in the CSF as compared to outside of the central nervous system. In contrast to results obtained with paired blood samples, CSF cells at the peak stage of RM showed a marked increase in CCR3+ Th2 cells and marked decrease in CD8+ cells, suggesting an immunoregulatory disturbance in the CSF. Those findings indicated a CSF-specific activation of humoral immunity, resulting in augmentation of meningeal inflammation, as shown by excess synthesis of intrathecal IgG and markedly elevated interleukin-6 level. Results of the present detailed investigation of lymphocyte subsets revealed a discrepancy regarding the process of inflammation in this RM patient between CSF and blood samples. CONCLUSIONS: RM is not a simple reflection of the immune status of RA, as the pathogenesis seems related to, at least in part, CSF-specific immunological dysregulation.

[Diagnosis of multiple sclerosis].

The prevalence of multiple sclerosis (MS) in Japan has been increasing in recent years, and general physicians should be alert for early and correct diagnosis of this disorder. For this purpose, the 2010 revisions to the McDonald criteria are helpful, as they employed simplified parameters for magnetic resonance imaging (MRI) findings to confirm dissemination in space (DIS) as well as dissemination in time (DIT). However, physicians must also carefully consider medical history, combinations of neurological symptoms and signs, and findings obtained from cerebrospinal fluid samples and/or electrophysiological tests for individual diagnoses. Thus, establishment of more specific and sensitive criteria in the near future will help to recruit very early MS patients for disease-modifying therapies, leading to better prognosis.

Systemic cellular immunity and neuroinflammation during acute flare-up in multiple sclerosis and neuromyelitis optica spectrum disorder patients.

Twenty-seven treatment-naïve patients with relapsing-remitting multiple sclerosis (MS) and 13 with neuromyelitis optica spectrum disorder (NMOSD) were enrolled during a time of acute flare-up. Common cerebrospinal fluid (CSF) features were increased CD29- and/or CD45RO-positive helper T cells capable of propagating inflammation in the central nervous system (CNS). B cell activation in the CSF was unique to MS, while an increase in CD4+CD192 (CCR2)+ cells in blood and breakdown of the blood-brain barrier (BBB) characterized NMOSD. Intravenous corticosteroid therapy suppressed neuroinflammation via modulation of cellular immunity in MS, as opposed to restoration of the BBB in NMOSD.

HLA genotype-clinical phenotype correlations in multiple sclerosis and neuromyelitis optica spectrum disorders based on Japan MS/NMOSD Biobank data.

HLA genotype-clinical phenotype correlations are not established for multiple sclerosis (MS) and neuromyelitis optica spectrum disorders (NMOSD). We studied HLA-DRB1/DPB1 genotype-phenotype correlations in 528 MS and 165 NMOSD cases using Japan MS/NMOSD Biobank materials. HLA-DRB1*04:05, DRB1*15:01 and DPB1*03:01 correlated with MS susceptibility and DRB1*01:01, DRB1*09:01, DRB1*13:02 and DPB1*04:01 were protective against MS. HLA-DRB1*15:01 was associated with increased optic neuritis and cerebellar involvement and worsened visual and pyramidal functional scale (FS) scores, resulting in higher progression index values. HLA-DRB1*04:05 was associated with younger onset age, high visual FS scores, and a high tendency to develop optic neuritis. HLA-DPB1*03:01 increased brainstem and cerebellar FS scores. By contrast, HLA-DRB1*01:01 decreased spinal cord involvement and sensory FS scores, HLA-DRB1*09:01 decreased annualized relapse rate, brainstem involvement and bowel and bladder FS scores, and HLA-DRB1*13:02 decreased spinal cord and brainstem involvement. In NMOSD, HLA-DRB1*08:02 and DPB1*05:01 were associated with susceptibility and DRB1*09:01 was protective. Multivariable analysis revealed old onset age, long disease duration, and many relapses as independent disability risks in both MS and NMOSD, and HLA-DRB1*15:01 as an independent risk only in MS. Therefore, both susceptibility and protective alleles can influence the clinical manifestations in MS, while such genotype-phenotype correlations are unclear in NMOSD.

[Anti-NMDA Receptor Antibody-Related Encephalitis].

Recently, the search for diagnostic antibody markers has drawn considerable attention in relation to autoimmune encephalitis. Among the antibody markers, the most frequently detected is the anti-N-methyl-D-aspartate receptor (NMDAR)antibody. Patients with this antibody develop characteristic clinical features. This disease tends to affect young women, and starts with psychiatric symptoms followed by seizures, involuntary movements, autonomic failure, and respiratory failure. Nearly half of these female patients have ovarian teratoma. Some of the patients with anti-NMDAR antibody show atypical clinical features. Approximately 4% show only psychiatric symptoms, which might lead to a diagnosis of malignant catatonia. Other reports describe patients experiencing refractory seizures to have the anti-NMDAR antibody. Some of the antibody-positive patients are associated with demyelinating disorders, and some develop anti-NMDAR encephalitis after recovery from herpes simplex encephalitis. It is important to test the anti-NMDAR antibody in these groups since immunotherapy ameliorates their symptoms. The anti-NMDAR antibody binds to the constitutional epitope at the extracellular domain of GluN1 and disrupts its function. Early introduction of immunotherapy together with tumor resection will results in improvement of neurological symptoms.

Anti-neurofascin antibody in patients with combined central and peripheral demyelination.

OBJECTIVES: We aimed to identify the target antigens for combined central and peripheral demyelination (CCPD). METHODS: We screened target antigens by immunohistochemistry and immunoblotting using peripheral nerve tissues to identify target antigens recognized by serum antibodies from selected CCPD and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) cases. We then measured the level of antibody to the relevant antigen in 7 patients with CCPD, 16 patients with CIDP, 20 patients with multiple sclerosis, 20 patients with Guillain-Barré syndrome, 21 patients with other neuropathies, and 23 healthy controls (HC) by ELISA and cell-based assays using HEK293 cells. RESULTS: At the initial screening, sera from 2 patients with CCPD showed cross-like binding to sciatic nerve sections at fixed intervals, with nearly perfect colocalization with neurofascin immunostaining at the node and paranode. ELISA with recombinant neurofascin revealed significantly higher mean optical density values in the CCPD group than in other disease groups and HC. Anti-neurofascin antibody positivity rates were 86% in patients with CCPD, 10% in patients with multiple sclerosis, 25% in patients with CIDP, 15% in patients with Guillain-Barré syndrome, and 0% in patients with other neuropathies and HC. The cell-based assay detected serum anti-neurofascin antibody in 5 of 7 patients with CCPD; all others were negative. CSF samples examined from 2 patients with CCPD were both positive. In anti-neurofascin antibody-positive CCPD patients, including those with a limited response to corticosteroids, IV immunoglobulin or plasma exchange alleviated the symptoms. CONCLUSION: Anti-neurofascin antibody is frequently present in patients with CCPD. Recognition of this antibody may be important, because patients with CCPD who are antibody positive respond well to IV immunoglobulin or plasma exchange.

Novel FUS mutation in patients with sporadic amyotrophic lateral sclerosis and corticobasal degeneration.

We report a patient with sporadic amyotrophic lateral sclerosis (ALS) with a novel fusion in malignant liposarcoma (FUS) gene mutation whose neurological signs were conspicuous left-sided rigidity and apraxia. A novel heterozygous guanine (G)-to-thymine (T) transition at position 1392, c.1392G>T, leading to a methionine-to-isoleucine substitution (p.Met464Ile), was found in exon13 of FUS. Re-sequencing of the genes for superoxide dismutase 1 (SOD1) and transactive response-DNA binding protein (TARDBP) revealed no mutations. The present findings suggest that this novel FUS mutation (p.Met464Ile) is related to manifestations of ALS as well as clinical features of corticobasal degeneration.

Phenytoin at optimum doses ameliorates experimental autoimmune encephalomyelitis via modulation of immunoregulatory cells.

We investigated the optimum doses of phenytoin for treatment of myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis (EAE). Oral and intraperitoneal administrations of 0.25 to 1.0mg per mouse (12.5-50mg/kg) 3 times a week improved the clinical course. Intraperitoneal injections of 1.0mg phenytoin were the most effective, as a significant reduction in EAE severity was seen after only 2 administrations with that protocol. Treatment efficacy was associated with amelioration of cellular infiltrates in the CNS, and an increase in CD4(+)Foxp3(+) and CD4(+)CD25(+)CD127(-) regulatory T cells as well as CD8(+) suppressor/cytotoxic T cells in blood.

[Case of anti P/Q type VGCC antibody positive small lung cell carcinoma that occured with subacute cerebellar degeneration, Lambert-Eaton myasthenic syndrome, and brainstem encephalitis].

A 62-year-old man was admitted to our hospital because of rapidly progressive dysarthria, truncal ataxia, and gait disturbance. High titers of the ProGRP and anti-P/Q-type VGCC antibody were detected in the serum. High accumulation of [18F] was detected at the hilus of the left lung on [18F]-FDG-PET scan. A high-frequency repetitive stimulation test of the median nerve yielded an incremental response. On the basis of these findings, a diagnosis of paraneoplastic cerebellar degeneration (PCD) and Lambert-Eaton myasthenic syndrome (LEMS) associated with small cell lung carcinoma (SCLC) was diagnosed. After intravenous immunoglobulin therapy (IVIg), methylprednisolone (m-PSL) pulse therapy, and other multidisciplinary concurrent treatments, a partial regression of the SCLC and a significant improvement in neurological symptoms were observed. However, ataxia relapsed and brainstem encephalitis developed 6 months later. A marginal improvement in neurological symptoms was observed with IVIg, m-PSL pulse therapy, and intravenous cyclophosphamide pulse therapy (IVCY). SCLC also recurred later. We hypothesized that VGCC of the brainstem was damaged by anti-P/Q-type VGCC antibody.