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A 33-year-old male was admitted to our hospital due to bilateral optic neuritis (ON) and transverse myelitis (TM), which occurred almost simultaneously. Spinal MRI showed the longitudinally extensive TM, located from C2 to conus. Serum anti-aquaporin 4 antibody was negative. He was tentatively diagnosed as seronegative neuromyelitis optica spectrum disorders (NMOSD). During the clinical course, serum anti-myelin oligodendrocyte glycoprotein (MOG) antibody was detected, and finally he was diagnosed as anti-MOG antibody positive neurologic disease (MOG-ND). Our case highlighted that early detection of MOG antibody should be considered in male cases with clinical manifestation of classical Devic's disease, such as simultaneous disease onset of bilateral ON or ON + TM.

Myotonic dystrophy type 1 (DM1) is an autosomal dominant genetic disease. In DM1, the mutant allele expands during gametogenesis, and an extended CTG repeat sequence is inherited by the offspring. This often results in increased severity of DM1 symptoms in the affected offspring and may cause congenital myotonic dystrophy (CDM). This study aimed to clarify whether CTG repeat number predicts CDM in offspring. This retrospective study examined 14 women with DM1, their pregnancy and labor histories, and their 14 children diagnosed with DM1. There were 12 CDM patients and 2 non-CDM patients. Correlations between CDM onset and CTG repeat numbers of the mother and child were analyzed. Women who bore a child with CDM (infants with detected polyhydramnios during pregnancy, hypotonia, respiratory insufficiency, or suckling failure at birth) had a mean repeat number of 643 (standard deviation [SD] 436). For women who bore a child without CDM, the mean repeat number was 950 (SD 71), and no significant between-group difference was detected. The mean (SD) CTG repeat numbers observed in children with and without CDM were 1,646 (324) and 1,700 (565), respectively. CDM cannot be predicted based on the CTG repeat numbers of mothers or children.

Background and Purpose: High blood pressure increases bleeding risk during treatment with antithrombotic medication. The association between blood pressure levels and the risk of recurrent stroke during long-term secondary stroke prevention with thienopyridines (particularly prasugrel) has not been well studied. Methods: This was a post hoc analysis of the randomized, double-blind, multicenter PRASTRO-I trial (Comparison of Prasugrel and Clopidogrel in Japanese Patients With Ischemic Stroke-I). Patients with noncardioembolic stroke were randomly assigned (1:1) to receive prasugrel 3.75 mg/day or clopidogrel 75 mg/day for 96 to 104 weeks. Risks of any ischemic or hemorrhagic stroke, combined ischemic events, and combined bleeding events were determined based on the mean level and visit-to-visit variability, including successive variation, of systolic blood pressure (SBP) throughout the observational period. These risks were also compared between quartiles of mean SBP level and successive variation of SBP. Results: A total of 3747 patients (age 62.1±8.5 years, 797 women), with a median average SBP level during the observational period of 132.5 mm Hg, were studied. All the risks of any stroke (146 events; hazard ratio, 1.318 [95% CI, 1.094–1.583] per 10-mm Hg increase), ischemic stroke (133 events, 1.219 [1.010–1.466]), hemorrhagic stroke (13 events, 3.247 [1.660–6.296]), ischemic events (142 events, 1.219 [1.020–1.466]), and bleeding events (47 events, 1.629 [1.172–2.261]) correlated with increasing mean SBP overall. Similarly, an increased risk of these events correlated with increasing successive variation of SBP (hazard ratio, 3.078 [95% CI, 2.220–4.225] per 10-mm Hg increase; 3.051 [2.179–4.262]; 3.276 [1.172–9.092]; 2.865 [2.042–4.011]; 2.764 [1.524–5.016], respectively). Event rates did not differ between the clopidogrel and prasugrel groups within each quartile of SBP or successive variation of SBP. Conclusions: Both high mean SBP level and high visit-to-visit variability in SBP were significantly associated with the risk of recurrent stroke during long-term medication with either prasugrel or clopidogrel after stroke. Control of hypertension would be important regardless of the type of antiplatelet drugs. Registration: URL: https://www.clinicaltrials.jp ; Unique identifier: JapicCTI-111582.

Background Levodopa remains the most effective symptomatic treatment for Parkinson’s disease (PD) more than 50 years after its clinical introduction. However, the onset of motor complications can limit pharmacological intervention with levodopa, which can be a challenge when treating PD patients. Clinical data suggest using the lowest possible levodopa dose to balance the risk/benefit. Istradefylline, an adenosine A2A receptor antagonist indicated as an adjunctive treatment to levodopa-containing preparations in PD patients experiencing wearing off, is currently available in Japan and the US. Preclinical and preliminary clinical data suggested that adjunctive istradefylline may provide sustained antiparkinsonian benefits without a levodopa dose increase; however, available data on the impact of istradefylline on levodopa dose titration are limited. The ISTRA ADJUST PD study will evaluate the effect of adjunctive istradefylline on levodopa dosage titration in PD patients. Methods This 37-week, multicenter, randomized, open-label, parallel-group controlled study in PD patients aged 30–84 years who are experiencing the wearing-off phenomenon despite receiving levodopa-containing medications ≥ 3 times daily (daily dose 300–400 mg) began in February 2019 and will continue until February 2022. Enrollment is planned to attain 100 evaluable patients for the efficacy analyses. Patients will receive adjunctive istradefylline (20 mg/day, increasing to 40 mg/day) or the control in a 1:1 ratio, stratified by age, levodopa equivalent dose, and presence/absence of dyskinesia. During the study, the levodopa dose will be increased according to symptom severity. The primary study endpoint is the comparison of the cumulative additional dose of levodopa-containing medications during the treatment period between the adjunctive istradefylline and control groups. Secondary endpoints include changes in efficacy rating scales and safety outcomes. Discussion This study aims to clarify whether adjunctive istradefylline can reduce the cumulative additional dose of levodopa-containing medications in PD patients experiencing the wearing-off phenomenon, and lower the risk of levodopa-associated complications. It is anticipated that data from ISTRA ADJUST PD will help inform future clinical decision-making for patients with PD in the real-world setting. Trial registration Japan Registry of Clinical Trials, jRCTs031180248; registered 12 March 2019.

Background: Patients with Parkinson’s disease (PD) usually experience distress related not only to motor dysfunction, but also to nonmotor symptoms, including gastrointestinal dysfunction. Objective: The purpose of this pilot study was to evaluate the efficacy and safety profile of a traditional Japanese medicine, rikkunshito (RKT), used for the treatment of gastrointestinal symptoms, associated with anorexia and dyspepsia, in patients with PD. Methods: Patients were randomly assigned to either Group A (4-week treatment period with 7.5 g/d RKT followed by a 4-week off-treatment period) or Group B (4-week off-treatment period followed by a 4-week treatment period with 7.5 g/d RKT). Appetite, quality of life for gastrointestinal symptoms, and depression were assessed using a visual analog scale, the Gastrointestinal Symptom Rating Scale and the Self-Rating Depression Scale, respectively. The gastric emptying examination and assay of plasma acylated ghrelin level were performed using the 13C-acetate breath test and commercially available assay kits, respectively. Results: RKT treatment produced a significant increase in the appetite score (1.84 [2.34]; P < 0.05), compared to a decrease in the score over the off-treatment period (−1.36 [2.94]). The mean score for abdominal pain, on the Gastrointestinal Symptom Rating Scale, and for self-reported depression, on the Self-Rating Depression Scale, also decreased significantly with RKT treatment (P < 0.05), compared with the off-treatment period scores. No effect of RKT on plasma acylated ghrelin level and rate of gastric emptying was identified. Conclusions: RKT may improve anorexia in patients with PD. The positive effects of RKT on depression and anorexia may improve the overall quality of life of these patients. The benefits of RKT identified in our pilot study will need to be confirmed in a randomized, double-blind, controlled trial. UMIN Clinical Trial Registry identifier: UMIN000009626.

Objectives We aimed to determine the predictive factors for the ineffectiveness of intravenous methylprednisolone (IVMP) that lead to earlier use of plasmapheresis in patients with relapsing neuromyelitis optica spectrum disorder. Methods A total of 40 patients were investigated retrospectively. The responders were defined as patients who showed IVMP effectiveness within 7 days from IVMP initiation, indicated by an improvement in the Kurtzke Expanded Disability Status Scale (EDSS) ≥0.5, whereas non-responders were defined as those without such an improvement. We analyzed 10 clinical findings and four cerebrospinal fluid (CSF) parameters before IVMP, which included EDSS (baseline before relapse, before IVMP initiation, difference between them: ΔEDSS), CSF-cells, CSF-lactate dehydrogenase, CSF/serum quotient of albumin (Q-ALB) and immunoglobulin G (Q-IgG). Results The 40 patients consisted of 22 responders and 18 non-responders. The levels of ΔEDSS, EDSS before IVMP, CSF-cells, CSF-lactate dehydrogenase, Q-ALB and Q-IgG were significantly higher in non-responders than in responders. Of these, univariate logistic regression analyses showed that the ΔEDSS, EDSS before IVMP, Q-ALB and Q-IgG were significantly related to IVMP ineffectiveness. Because of the significant correlation between ΔEDSS and EDSS before IVMP, and between Q-ALB and Q-IgG, the ΔEDSS and Q-IgG were analyzed as dependent factors for IVMP ineffectiveness in multivariate analysis. The higher Q-IgG level was found to be independently associated with ineffectiveness. The cut-off level for Q-IgG to discriminate non-responders from responders was 4.7 (sensitivity 83, specificity 91%). Conclusions Q-IgG >4.7 before IVMP is a predictive factor for IVMP ineffectiveness. Early use of plasmapheresis should be considered in relapsing neuromyelitis optica spectrum disorder with such high Q-IgG values before IVMP.

Objective Myasthenia gravis (MG) is an autoimmune disorder of unknown cause where neural transmission is blocked at the neuromuscular junction. Although it has been shown that patients with MG show various differences in clinical characteristics depending on the age of onset, differences in pathology remain unclear. Methods In the present study, we divided patients with MG into a late-onset group (n = 26) and an early-onset group (n = 29), and measured T and B lymphocyte subsets using surface markers. Results When T lymphocyte subsets and B lymphocyte subsets (transitional B cells, naive B cells, memory B cells and plasmablasts) were examined, it was found that the percentage of memory B cells was significantly lower in the late-onset group relative to age-matched healthy controls. However, no significant difference was seen between the early-onset group and healthy controls. When the percentage of memory B cells was compared between the late-onset group and the early-onset group, it was found to be significantly lower in the late-onset group. A decrease in circulating memory B cells in patients with late-onset MG was also seen when circulating memory B cells were activated, and proceeded to penetrate and embed in tissue in the lymph nodes and the thymus. It appears that memory B cells that have penetrated and embedded in tissue begin producing autoantibodies after they differentiate from plasmablasts into plasma cells. Conclusions A reduced percentage of memory B cells appears to be a characteristic of late-onset MG observed in circulating T and B lymphocyte subsets.

A 77-year-old woman presented with a 6-month history of slowly progressive cerebellar ataxia. T2-weighted MRI showed high signal intensity in the left upper dorsal pons and bilateral middle cerebellar peduncles. JC virus (JCV) DNA was detected in cerebrospinal fluid (CSF). The patient had no HIV infection, collagen disease, or a history of immunosuppressive treatment, but she was found to have CD4+ lymphocytopenia. We made a diagnosis of cerebellar brainstem form of progressive multifocal leukoencephalopathy (PML) presenting as cerebellar ataxia, which was presumably associated with idiopathic CD4+ lymphocytopenia. Following the treatment with mefloquine, the patient slightly improved clinically and JCV-DNA became negative in CSF.

Objective The aim of the present study was to investigate the association of magnetic resonance imaging (MRI) findings and social activity with cognitive function in Japanese patients with multiple sclerosis (MS). Methods The Brief Repeatable Battery of Neuropsychological tests (BRB-N) was carried out in 184 Japanese patients with MS, and 163 controls matched for age, sex and education. MRI findings of cerebral, brainstem, and cerebellar lesions and social activities of MS patients were further examined. Results MS patients with higher numbers of cerebral lesions on MRI had lower scores in most BRB-N tests. BRB-N scores in the majority of tests were significantly lower in patients with brainstem and cerebellar lesions. Data from an analysis of variance model in which only the main effects of cerebral, brainstem and cerebellar lesions were hypothesized showed an association of cerebral lesions with decreased scores in all BRB-N tests, except symbol digit modalities test (SDMT) and paced auditory serial addition test (PASAT). In contrast, cerebellar lesions were associated with decreased SDMT and PASAT scores. Patients categorized as “unemployed because of MS” had lower BRB-N scores than other social activity groups. Lower SDMT scores had an effect on the “unemployed because of MS” group, whereas the Expanded Disability Status Scale had a significantly greater negative impact on patients in this social category. Conclusions Higher numbers of brain lesions on MRI could have an impact on cognitive function in patients with MS, and impairment of information processing appears significantly associated with cerebellar lesions. Cognitive impairment affects the employment status of patients with MS.

Objectives There has been no large-scale study of methylprednisolone pulse therapy in Asian patients with multiple sclerosis (MS) or neuromyelitis optica (NMO), despite it being widely used for acute relapse. We aimed to clarify treatment response of MS and NMO patients to methylprednisolone pulse therapy and post-pulse oral corticosteroids in real clinical practice in a multicenter study in Japan. Methods Investigators at 28 institutions collected changes in neurological symptoms/signs and Expanded Disability Status Scale (EDSS) scores before and within 1 week of completion of methylprednisolone pulse therapy carried out in 2010, and after post-pulse oral corticosteroids therapy, by retrospective review of medical records. Results In 345 patients (95.1% of all registered patients), 457 series of methylprednisolone pulse therapy were carried out for treatment of acute relapse. EDSS scores improved by 0.8 ± 1.1 (mean ± SD) after the first course. The second and third courses also produced sufficient improvements (by 0.7 and 0.6, respectively), but much smaller improvements were observed thereafter. The target neurological symptoms and signs improved in 79.5% of patients. Improvement rates were 5–20% lower after a course of pulse therapy than after a series of pulse therapy. A half dose (500 mg/day) produced less improvement than a standard dose (1000 mg/day; 65.9 vs 79.5%). During post-pulse oral corticosteroid therapy, EDSS scores decreased by 0.6 ± 0.9. No significant adverse effects were observed. Conclusions Methylprednisolone pulse therapy is beneficial in nearly 80% of Japanese MS and NMO patients, and EDSS score improvements after therapy are compatible with those in Western MS patients.

Objective To compare myelin and astrocyte injury in patients with antibodies against myelin oligodendrocyte glycoprotein (anti-MOG) or aquaporin-4 (anti-AQP4), and multiple sclerosis (MS). Methods Myelin basic protein (MBP) and glial fibrillary acidic protein (GFAP) levels were measured in the cerebral spinal fluid (CSF) from anti-MOG+ or anti-AQP4+ patients tested in both sera and CSF by cell-based assays with live transfected cells. Results In total, 75.6% (68/90) of the patients were positive for either anti-MOG or anti-AQP4 antibodies in both serum and CSF; 74.2% (23/31) were anti-MOG+, and 76.3% (45/59) were anti-AQP4+. No patients were only CSF positive or were positive for both anti-MOG and anti-AQP4 antibodies, and none of the MS patients or controls had these autoantibodies in the serum or CSF. MBP levels were elevated in the anti-MOG+ cases compared to the multiple sclerosis (MS) patients, and the levels found were similar between anti-MOG+ cases and anti-AQP4+ neuromyelitis optica spectrum disorder (NMOSD) cases. Meanwhile, GFAP was only elevated in the anti-AQP4+ NMOSD. Moreover, CSF pleocytosis, high protein levels, and oligoclonal IgG band negativity distinguished the anti-MOG+ cases from MS patients. Conclusions Myelin injury was more severe in the anti-MOG+ cases than in the MS cases, and anti-MOG+ cases have differences in the CSF characteristics compared to MS. GFAP elevation in anti-AQP4+ cases was absent in anti-MOG+ patients (even in cases with NMOSD phenotype), indicating that immune-mediated astrocytopathy is unique to anti-AQP4+ patients. Our study suggests that anti-MOG+ cases are distinct from MS and anti-AQP4+ NMOSD.

A 60-year-old man was admitted to our hospital experiencing difficulty in opening his mouth, and diplopia. Chest computed tomography showed a mass on the right lung. Transbronchial biopsy and scrutiny of the whole body resulted in the diagnosis of small cell lung cancer, cT2N2M1a stage IV. With chemotherapy including carboplatin and etoposide, the primary mass of the right lung shrank, and the patient no longer had diplopia or trouble opening his mouth. After the first-line chemotherapy, itching, ptosis, and dysphagia appeared, accompanied by tumor relapse. These symptoms improved with chemotherapy for lung cancer. After four lines of chemotherapy, the lung cancer was not controlled. The patient died 19 months after the first chemotherapy had started. Difficulty in opening the mouth is a rare symptom for lung cancer patients, but chemotherapy for lung cancer clearly improved this symptom. Therefore, we diagnosed this rare symptom as paraneoplastic neurological syndrome.

A 36-year-old man presented with cognitive impairment and disturbance of short-term memory functions with character change. Cerebrospinal fluid analysis revealed no abnormalities; however, brain MRI revealed high-signal intensity from bilateral hippocampus lesions on fluid attenuated inversion recovery (FLAIR) images and T(2) weighted images. The 18F-fluorodeoxyglucose PET demonstrated high glucose uptake in the bilateral hippocampus lesions. He was diagnosed as limbic encephalitis, and was administered high-dose intravenous methylprednisolone and immune adsorption plasma therapy followed by intravenous immunoglobulin therapy. MRI abnormalities improved after treatment but recent memory disturbance remained. Ma2 antibody, NMDA-receptor antibody, and GluRε2 antibody were positive. Eleven months atter the onset of disease, the tumor was identified in left testicle by ultrasound and removed the tumor. The pathological findings were seminoma. We experienced a case of paraneoplastic limbic encephalitis associated with seminoma with short-term memory disturbance. The occurrence of paraneoplastic limbic encephalitis with antibodies against cell membrane (NMDA-receptor antibody and GluRε2 antibody) and intracellular (Ma2 antibody) is rare even in the literature.

A 78-year-old woman was admitted to our hospital on September 14, 1992, because of systemic myalgia and stiffness, joint pain, and gait disturbance. She had begun to feel headache and pain in the neck and shoulder in the middle of August, 1992. The pain became systemic, and was accompanied by a low-grade fever, which was unresponsive to NSAIDs. On admission, she had no joint swelling or deformities in the extremities. Neurological examination revealed weakness in the right leg, hypoalgesia below the left C4 level, hyperreflexia in the right extremities, and right Babinski's sign. The erythrocyte sedimentation rate was very high (100 mm/h). Levels of other acute phase reactants were also high. Tests for antinuclear antibody and anti-cardiolipin antibody were positive, but a test for rheumatoid factor was negative. Creatine kinase activity was within normal limits. A T1-weighted magnetic resonance image of the cervical spine at 0.5 T showed an intramedullary low signal. A T2-weighted image showed a borderless spindle-like high signal. Four nodules enhanced by Gd DTPA were seen at C1-C4. The age at onset, myalgia, stiffness, and erythrocyte sedimentation rate were considered to be consistent with a diagnosis of polymyalgia rheumatica. Glucocorticoid treatment was therefore started, and a dramatic clinical improvement was evident within a few days. The patient was discharged from hospital on November 30, 1992. To our knowledge, myelopathy complicated by polymyalgia rheumatica has never been reported previously. Recently, some patients with polymyalgia rheumatica have been reported to have anti-cardiolipin antibody in serum. In the present case anti-cardiolipin antibody may have played a role in the formation of microemboli or in angitis of the cervical spine.