Shunya Nakane

Novel immunosuppressive therapy by M2000 in experimental multiple sclerosis

The therapeutic potency of M2000 (β-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.

Health-related quality-of-life and treatment targets in myasthenia gravis.

Introduction: 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). Methods: 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. Results: In a cross‐sectional analysis of 640 MG patients, multivariate regression revealed that disease severity, as evaluated by the MG Composite (P < 0.0001), 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. Conclusions: 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. Muscle Nerve 50: 493–500, 2014

Apathy/depression, but not subjective fatigue, is related with cognitive dysfunction in patients with multiple sclerosis

BackgroundCognitive impairment could affect quality of life for patients with multiple sclerosis (MS), and cognitive function may be correlated with several factors such as depression and fatigue. This study aimed to evaluate cognitive function in Japanese patients with MS and the association between cognitive function and apathy, fatigue, and depression.MethodsThe Brief Repeatable Battery of Neuropsychological tests (BRB-N) was performed in 184 Japanese patients with MS and 163 healthy controls matched for age, gender, and education. The Apathy Scale (AS), Fatigue Questionnaire (FQ), and Beck Depression Inventory Second Edition (BDI-II) were used to evaluate apathy, fatigue, and depression, respectively. Student’s t-test was used to compare MS patients and healthy controls. Correlations between two factors were assessed using the Pearson correlation test, and multiple regression analysis was used to evaluate how much each factor affected the BRB-N score.ResultsIn all BRB-N tests, patients with MS scored significantly lower than controls, and the effect size of symbol digit modalities test was the highest among the 9 tests of the BRB-N. Patients with MS had higher AS (p < 0.001), FQ (p < 0.0001), and BDI-II (p < 0.0001) scores than controls. In patients with MS, scores on most of the BRB-N tests correlated with scores on the AS and BDI-II; however, there was little correlation between scores on the BRB-N tests and those on the FQ.ConclusionsCognitive function was impaired, particularly information-processing speed, and decreased cognitive function was correlated with apathy and depression in Japanese patients with MS. Despite the association between cognitive variables and depression/apathy, cognitive function was impaired beyond the effect of depression and apathy. However, subjective fatigue is not related with cognitive impairment. Taken together, this suggests that different therapeutic approaches are needed to improve subjective fatigue and cognition, and thereby quality of life, in patients with MS.

Clinical Features of Autoimmune Autonomic Ganglionopathy and the Detection of Subunit-Specific Autoantibodies to the Ganglionic Acetylcholine Receptor in Japanese Patients

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.

Effect of Dietary Fatty Acid Composition on Th1/Th2 Polarization in Lymphocytes

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.

Oral corticosteroid therapy and present disease status in myasthenia gravis

Introduction: 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). Methods: 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. Results: 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. Conclusions: 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. Muscle Nerve 51:692–696, 2015

Pathomechanisms of anti–cytosolic 5′-nucleotidase 1A autoantibodies in sporadic inclusion body myositis

Sporadic inclusion body myositis (sIBM), an intractable progressive muscle disease, frequently occurs in older persons. sIBM pathogenesis may involve protein degradation dysfunction and immune abnormalities. Autoantibodies recognizing cytosolic 5′‐nucleotidase 1A (cN1A) were found in plasma and serum from sIBM patients. However, whether anti‐cN1A autoantibodies play a pathogenic role in sIBM is controversial. This study investigated the pathogenic properties of anti‐cN1A autoantibodies in sIBM pathogenesis.

Quality of life in purely ocular myasthenia in Japan

BackgroundSince there has been no conclusive evidence regarding the treatment of ocular myasthenia, treatment guidelines were recently issued by the European Federation of Neurological Societies/European Neurological Society (EFNS/ENS). However, the therapeutic outcomes concerning the quality-of-life (QOL) of patients with ocular myasthenia are not yet fully understood.MethodsWe investigated the therapeutic outcomes of patients with purely ocular myasthenia in a multicenter cross-sectional survey in Japan. To evaluate the severity of ocular symptoms, we used the ocular-quantitative MG (QMG) score advocated by Myasthenia Gravis Foundation of America. We used the Japanese translated version of the MG-QOL15, a self-appraised scoring system.ResultsOf 607 myasthenia gravis (MG) patients with an observation-duration of illness ≥ 2 years, the cases of 123 patients (20%) were limited to ocular muscles (purely ocular myasthenia). During the entire clinical course, 81 patients experienced both ptosis and diplopia, 36 had ptosis alone, and six had diplopia alone. Acetyl-cholinesterase inhibitors and prednisolone were used in 98 and 52 patients, respectively. Treatment improved ocular symptoms, with the mean reduction in ocular-QMG score of 2.3 ± 1.8 points. However, 47 patients (38%) failed to gain minimal manifestation or a better status. Patients with unfavorable outcomes also self-reported severe QOL impairment. Multivariate analyses showed that the pretreatment ocular-QMG score was associated with unfavorable outcomes, but not associated with the patient’s QOL.ConclusionA treatment strategy designed in accord with a patients ocular presentation must be considered in order to improve ocular symptoms and the patients QOL.

Neuroleptic malignant syndrome (parkinsonism-hyperpyrexia syndrome) after deep brain stimulation of the subthalamic nucleus

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.

Structural equation modeling of factors contributing to quality of life in Japanese patients with multiple sclerosis.

BackgroundTo improve quality of life (QOL) in patients with multiple sclerosis (MS), it is important to decrease disability and prevent relapse. The aim of this study was to examine the causal and mutual relationships contributing to QOL in Japanese patients with MS, develop path diagrams, and explore interventions with the potential to improve patient QOL.MethodsData of 163 Japanese MS patients were obtained using the Functional Assessment of MS (FAMS) and Nottingham Adjustment Scale-Japanese version (NAS-J) tests, as well as four additional factors that affect QOL (employment status, change of income, availability of disease information, and communication with medical staff). Data were then used in structural equation modeling to develop path diagrams for factors contributing to QOL.ResultsThe Expanded Disability Status Scale (EDSS) score had a significant effect on the total FAMS score. Although EDSS negatively affected the FAMS symptom score, NAS-J subscale scores of anxiety/depression and acceptance were positively related to the FAMS symptom score. Changes in employment status after MS onset negatively affected all NAS-J scores. Knowledge of disease information improved the total NAS-J score, which in turn improved many FAMS subscale scores. Communication with doctors and nurses directly and positively affected some FAMS subscale scores.ConclusionsDisability and change in employment status decrease patient QOL. However, the present findings suggest that other factors, such as acquiring information on MS and communicating with medical staff, can compensate for the worsening of QOL.