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ObjectiveApproximately 15%–20% of patients with Guillain-Barré syndrome (GBS) are unable to walk independently at 6 months from the onset of neurological symptom. The modified Erasmus GBS outcome score (mEGOS) has been reported as a prognostic tool.Herein we investigated the association between a poor outcome, inability to walk independently at 6 months and presence of antiganglioside antibodies.MethodsThe clinical and serological data of 177 patients with GBS were retrospectively collected in Japan to assess the associations between a poor outcome and serum IgG antibodies against each ganglioside (GM1, GD1a, GalNAc-GD1a, GQ1b and GT1a). In addition, we investigated whether the combination of mEGOS and serum IgG antibodies against gangliosides is useful in predicting a poor outcome.ResultsThe patients with IgG anti-GD1a antibodies more frequently showed poor outcomes than those without these antibodies (9 (36%) of 25 vs 8 (6%) of 127 patients, pConclusionsThe combination of serum IgG anti-GD1a antibodies and a high mEGOS could help in making a more accurate prognosis of patients than mEGOS alone, especially for predicting poor outcomes.

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.

Most of the diseases for which apheresis therapy is indicated are intractable and rare, and each patient has a different background and treatment course prior to apheresis therapy initiation. Therefore, it is difficult to conduct large-scale randomized controlled trials to secure high-quality evidence. Under such circumstances, the American Society for Apheresis (ASFA) issued its guidelines in 2007, which were repeatedly revised until the latest edition in 2019. The ASFA guidelines are comprehensive. However, in the United States, a centrifugal separation method is mainly used for apheresis, whereas the mainstream procedure in Japan is the membrane separation method. The target diseases and their backgrounds are different from those in Japan. Due to these differences, the direct adoption of the ASFA guidelines in Japanese practice creates various problems. One of the features of apheresis in Japan is the development of treatment methods using hollow-fiber devices such as double filtration plasmapheresis (DFPP) and selective plasma exchange and adsorption-type devices such as polymyxin B-immobilized endotoxin adsorption columns. Specialists in emergency medicine, hematology, collagen diseases/rheumatology, respiratory medicine, cardiovascular medicine, gastroenterology, neurology, nephrology, and dermatology who are familiar with apheresis therapy gathered for this guideline, which covers 86 diseases. In addition, since apheresis therapy involves not only physicians but also clinical engineers, nurses, dieticians, and many other medical professionals, this guideline was prepared in the form of a worksheet so that it can be easily understood at the bedside. Moreover, to the clinical purposes, this guideline is designed to summarize apheresis therapy in Japan and to disseminate and further develop Japanese apheresis technology to the world. As diagnostic and therapeutic techniques are constantly advancing, the guidelines need to be revised every few years. In order to ensure the high quality of apheresis therapy in Japan, both the Japanese Society for Apheresis Registry and the guidelines will be inseparable.

INTRODUCTION/AIMS Predicting when a patient will require invasive mechanical ventilation (IMV) is a major challenge in routine care for some neuromuscular diseases. In this study, we prospectively investigated whether phrenic nerve conduction studies (PNCS) can predict when IMV will be required in patients with amyotrophic lateral sclerosis (ALS), Guillain-Barre syndrome (GBS), chronic inflammatory demyelinating polyneuropathy (CIDP), and myotonic dystrophy (DM). METHODS PNCS amplitude (avAMP) and latency (avLAT) were compared between patients who required IMV (IMV group) and those who did not (non-IMV group). PNCS were performed in 62 healthy controls and in patients with four different diseases that may require IMV: ALS (n = 56), GBS (n = 72), CIDP (n = 38), and DM (n = 24). RESULTS The IMV group consisted of 12 patients with ALS, 14 with GBS, 2 with CIDP, and 4 with DM. avAMP was significantly lower in the IMV group with ALS than in the non-IMV group (P

Although intravascular large B-cell lymphoma (IVLBCL) is an extranodal lymphoma characterized by the selective growth of lymphoma cells within the lumina of small vessels, we here report three autopsy cases of IVLBCL characterized by the proliferation within large blood vessels. These three cases were diagnosed as IVLBCL of the bone marrow or skin biopsy. Two cases died suddenly before treatment, whereas the other died during treatment. Autopsies showed a large embolus of dense lymphoma cells extending from the truncus pulmonalis to the pulmonary arteries in Case 1, emboli of lymphoma cells in the aorta and carotis in Case 2, and a mass of lymphoma cells blocking the lumen of the aortic arch in Case 3. This is the first report of IVLBCL involving large blood vessels, and it is essential to note that this type of IVLBCL might cause sudden death because of tumor emboli within large blood vessels.

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.

BackgroundNeurological disorders with IgG antibodies against myelin-oligodendrocyte glycoprotein (MOG-IgG) have been increasingly recognised as a new type of neuroinflammatory disorder.ObjectiveThe study aimed to identify regional and ethnic differences in clinical profiles of MOG-IgG–associated disorders between East Asian (Japanese) and Caucasian (German) patients.MethodsDemographic, clinical and therapeutic data from 68 MOG-IgG–positive adults were collected (Japanese, n=44; German, n=24).ResultsAge and sex were similar between cohorts, with optic neuritis occurring most frequently at onset (Japanese: 61%; German: 58%). However, Japanese patients had a lower annualised relapse rate (0.4 vs 0.8, p=0.019; no relapse, 64% vs 25%, p=0.002) and lower Expanded Disability Status Scale score at the last visit (1.0 vs 2.0; p=0.008), despite similar follow-up periods (mean, 73.9 months vs 73.4 months), than those of German patients, respectively. Cerebral syndromes were more common (27% vs 4%; p=0.021) and myelitis less common (21% vs 50%; p=0.012) in Japanese than in German patients, respectively. Japanese patients were more commonly treated with long-term corticosteroids (73%), whereas German patients were more commonly treated with rituximab or other immunosuppressants (63%).ConclusionsAmong patients with MOG-IgG, Japanese tended to have a monophasic milder disease, whereas the majority of German patients had a relapsing course and more frequent myelitis, findings compatible with neuromyelitis optica spectrum disorder. Although the attack-prevention treatment regimens were considerably different, genetic and environmental factors may be important to determine clinical phenotypes and disease activity.

The most attentive clinical problem in patients with branch atheromatous disease (BAD) is early neurological deterioration (END). Although the platelet activation (PA) is involved in pathogenesis, the relationship between PA and END has remained unclear. We investigated clinical data including mean platelet volume (MPV, fL) as a marker for PA to identify clinically useful biomarkers for END.A total of 64 patients with BAD were investigated retrospectively, and divided into 2 groups based on whether neurologic symptoms deteriorated or not: BAD with and without END (END and non-END). The END was defined as patients with point increase of 1 or greater in the National Institutes of Health Stroke Scale (NIHSS); non-END was defined as those without such increase. Clinical features such as NIHSS, modified Rankin scale (mRS), laboratory data including MPV, lesion size (LS, mm) on admission, and treatments were compared between the 2 groups.Of 64 patients, 17 cases had an END. The median values of NIHSS, mRS, MPV, and LS on admission were significantly greater in END than in non-END (P .05, respectively). There was no correlation of MPV with NIHSS, mRS and LS, respectively. The median values of MPV were significantly higher in END than in non-END and control (P .05, respectively). A receiver operating characteristic curve indicated a value of 10.1 as cutoff level for MPV to discriminate between END and non-END.High MPV values on admission may be an independent biomarker for END. Physicians should pay more careful attention to END in BAD showing MPV values higher than 10.1 on admission.

Summary Background No treatment has consistently shown efficacy in slowing disability progression in patients with secondary progressive multiple sclerosis (SPMS). We assessed the effect of siponimod, a selective sphingosine 1-phosphate (S1P) receptor 1,5 modulator, on disability progression in patients with SPMS. Methods This event-driven and exposure-driven, double-blind, phase 3 trial was done at 292 hospital clinics and specialised multiple sclerosis centres in 31 countries. Using interactive response technology to assign numbers linked to treatment arms, patients (age 18–60 years) with SPMS and an Expanded Disability Status Scale score of 3·0–6·5 were randomly assigned (2:1) to once daily oral siponimod 2 mg or placebo for up to 3 years or until the occurrence of a prespecified number of confirmed disability progression (CDP) events. The primary endpoint was time to 3-month CDP. Efficacy was assessed for the full analysis set (ie, all randomly assigned and treated patients); safety was assessed for the safety set. This trial is registered with ClinicalTrials.gov, number NCT01665144. Findings 1651 patients were randomly assigned between Feb 5, 2013, and June 2, 2015 (1105 to the siponimod group, and 546 to the placebo group). One patient did not sign the consent form, and five patients did not receive study drug, all of whom were in the siponimod group. 1645 patients were included in the analyses (1099 in the siponimod group and 546 in the placebo). At baseline, the mean time since first multiple sclerosis symptoms was 16·8 years (SD 8·3), and the mean time since conversion to SPMS was 3·8 years (SD 3·5); 1055 (64%) patients had not relapsed in the previous 2 years, and 918 (56%) of 1651 needed walking assistance. 903 (82%) patients receiving siponimod and 424 (78%) patients receiving placebo completed the study. 288 (26%) of 1096 patients receiving siponimod and 173 (32%) of 545 patients receiving placebo had 3-month CDP (hazard ratio 0·79, 95% CI 0·65–0·95; relative risk reduction 21%; p=0·013). Adverse events occurred in 975 (89%) of 1099 patients receiving siponimod versus 445 (82%) of 546 patients receiving placebo; serious adverse events were reported for 197 (18%) patients in the siponimod group versus 83 (15%) patients in the placebo group. Lymphopenia, increased liver transaminase concentration, bradycardia and bradyarrhythmia at treatment initiation, macular oedema, hypertension, varicella zoster reactivation, and convulsions occurred more frequently with siponimod than with placebo. Initial dose titration mitigated cardiac first-dose effects. Frequencies of infections, malignancies, and fatalities did not differ between groups. Interpretation Siponimod reduced the risk of disability progression with a safety profile similar to that of other S1P modulators and is likely to be a useful treatment for SPMS. Funding Novartis Pharma AG.

Objective: Myasthenia gravis (MG) is an autoimmune disease mostly caused by autoantibodies against acetylcholine receptor (AChR) associated with thymus abnormalities. Thymectomy has been proven to be an efficacious treatment for patients with MG, but postoperative myasthenic crisis often occurs and is a major complication. We aimed to develop and validate a simple scoring system based on clinical characteristics in the preoperative status to predict the risk of postoperative myasthenic crisis. Methods: We studied 393 patients with MG who underwent thymectomy at six tertiary centers in Japan (275 patients for derivation and 118 for validation). Clinical characteristics, such as gender, age at onset and operation, body mass index, disease duration, MG subtype, severity, symptoms, preoperative therapy, operative data, and laboratory data, were reviewed retrospectively. A multivariate logistic regression with LASSO penalties was used to determine the factors associated with postoperative myasthenic crisis and score was assigned. Finally, the predictive score was evaluated using bootstrapping technique in the derivation and validation group. Results: Multivariate logistic regression identified three clinical factors for predicting postoperative myasthenic crisis risk: (1) vital capacity

Background Guillain–Barre syndrome (GBS) is an acute inflammatory neuropathy characterized by areflexic quadriparesis. Urinary dysfunction has been known to occur in approximately 25% of GBS patients during the clinical course and usually emerges during peak motor weakness. According to the diagnostic criteria for GBS, bladder dysfunction at onset makes the diagnosis of GBS rather doubtful. We report here a rare case of GBS that initially manifested as motor weakness with urinary dysfunction and hyperreflexia. Case presentation A 66-year-old Japanese man experienced mild weakness in his hands that extended to the entire upper extremities the following day. At the same time, he started experiencing difficulty voiding. On the fourth day after the onset of weakness, he was admitted to Saitama Medical Center, Kawagoe, Japan, because of an inability to stand up without support. Neurological examination revealed moderate generalized weakness, hyperreflexia, and poor urinary volume and flow. Early in hospitalization, his deep tendon reflexes gradually decreased and ultimately he became areflexic. A nerve conduction study indicated the axonal form of GBS. He was treated with immunoadsorption plasmapheresis, followed by two sessions of intravenous immunoglobulin G treatment. The motor weakness and urinary dysfunction gradually ameliorated, and he was discharged and transferred for rehabilitation on hospital day 47. Conclusions The present case suggests that urinary dysfunction in GBS might not necessarily occur during peak motor weakness, but could start at onset. Physicians should consider GBS in differential diagnosis of patients presenting with initial symptoms of motor weakness and urinary dysfunction.

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.

Neuromyelitis optica spectrum disorders (NMOSD) are a group of inflammatory central nervous system disorders characterized by optic neuritis, transverse myelitis, and anti-aquaporin 4 (AQP4) antibody production. However, it has recently been shown that some cases of typical NMOSD can be anti-AQP4 antibody-negative as well. In this study, we retrospectively investigated the disorder relapse-suppressing effect of tacrolimus (TAC) when combined with prednisolone (PSL) in anti-AQP4 antibody-positive and -negative NMOSD cases.Subjects were NMOSD outpatients treated at our hospital in August 2016 who fulfilled the 2015 International Panel for NMO Diagnosis criteria and whose medical history before visiting our department was known; anti-myelin oligodendrocyte glycoprotein antibody-positive cases were excluded. We retrospectively investigated the annualized relapse rate (ARR) before and after combined TAC and PSL treatment in 50 NMOSD cases who had been using TAC with PSL for at least 1 year and whom we were also able to observe.There were 42 anti-AQP4 antibody-positive cases and 8 negative cases. Observation periods of the anti-AQP4 antibody-positive cases were 1.1 years before TAC and 5.1 years after TAC. ARR before TAC was 1.0 and 0.08 after TAC, indicating a relapse-suppression rate of 92% (p0.001) and clear improvement. In the anti-AQP4 antibody-negative group, the observation period was 5.6 years before and 4.1 years after TAC. ARR before TAC was 0.5 and 0.07 after TAC. The relapse-suppression rate was 86% (p0.05), which was obviously as effective as in the anti-AQP4 antibody-positive group. PSL dose in the anti-AQP4 antibody-positive group was 15.0 mg/day at the start of TAC and was reduced to 6.3 mg/day after 2 years (p0.001). The Expanded Disability Status Scale (EDSS) score decreased from 4.5 at the start of TAC to 2.0 after 2 years in the anti-AQP4 antibody-positive group (p0.05), which was a clear improvement.Combined use of TAC with PSL clearly suppressed relapse of both anti-AQP4 antibody-positive and -negative NMOSD. In the anti-AQP4 antibody-positive group, both PSL dose and EDSS score decreased compared with the dose at the start of the study.

Patients with anti-aquaporin-4 (AQP4) water channel antibody-positive neuromyelitis optica spectrum disorders (AQP4-NMOSD) and myelin oligodendrocyte glycoprotein (MOG) associated disease (MOGAD) often present with similar clinical symptoms, and some cases are hard to differentiate at the time of onset. In this study, we compared the clinical characteristics, cerebrospinal fluid (CSF) analysis parameters, and peripheral T/B lymphocyte subsets during the active and chronic phases in AQP4-NMOSD and MOGAD.A total of 17 MOGAD cases and 24 AQP4-NMOSD cases were studied. The clinical characteristics in both groups were summarized, including disease duration, total number of attacks, lesions, prevention of relapse during remission, and CSF analysis results during the active phase. T/B lymphocyte subsets were further investigated in the active and chronic phases.In the comparative study on clinical symptoms, a large proportion of optic neuritis was unilateral in MOGAD. In the comparative study on CSF analysis, protein level was significantly lower in MOGAD compared with AQP4-NMOSD (p = 0.006); myelin basic protein was significantly lower in MOGAD compared with AQP4-NMOSD (p = 0.04); albumin quotient was significantly lower in MOGAD compared with AQP4-NMOSD (p = 0.02); and IgG Quotient was significantly lower in MOGAD compared with AQP4-NMOSD (p = 0.05). In the analysis of T/B lymphocyte subsets, plasmablasts of the B cell subset in the active phase were significantly lower in MOGAD (2.1 ± 2.4) compared to AQP4-NMOSD (7.8 ± 7.2) (p 0.05). In the chronic phase, transitional B cells were significantly higher in MOGAD (2.1 ± 1.8) compared to AQP4-NMOSD (0.6 ± 0.4) (p 0.01).Clinical characteristics of MOGAD were similar to those of AQP4-NMOSD, but increased blood brain barrier permeability was suggested to be less severe in MOGAD compared to AQP4-NMOSD from CSF analysis. Furthermore, the pathogenesis of the two diseases was clearly distinct as plasmablasts in the active phase were not elevated in MOGAD, but were increased in AQP4-NMOSD.

BACKGROUND AND PURPOSE Tapering immunosuppressants is desirable in patients with well-controlled myasthenia gravis (MG). However, the association between tapering of calcineurin inhibitor dosage and reduction-associated exacerbation is not known. The aim of this study was to clarify the frequency of reduction-associated exacerbation when tacrolimus is tapered in stable patients with anti-acetylcholine receptor antibody-positive MG, and to determine the factors that predict exacerbations. METHODS We retrospectively analyzed 115 patients in whom tacrolimus dosage was tapered. The reduction-associated exacerbation was defined as the appearance or worsening of one or more MG symptoms

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.

Although intravascular large B-cell lymphoma (IVLBCL) is an extranodal lymphoma characterized by the selective growth of lymphoma cells within the lumina of small vessels, we here report three autopsy cases of IVLBCL characterized by the proliferation within large blood vessels. These three cases were diagnosed as IVLBCL of the bone marrow or skin biopsy. Two cases died suddenly before treatment, whereas the other died during treatment. Autopsies showed a large embolus of dense lymphoma cells extending from the truncus pulmonalis to the pulmonary arteries in Case 1, emboli of lymphoma cells in the aorta and carotis in Case 2, and a mass of lymphoma cells blocking the lumen of the aortic arch in Case 3. This is the first report of IVLBCL involving large blood vessels, and it is essential to note that this type of IVLBCL might cause sudden death because of tumor emboli within large blood vessels.

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.

In recent years, immunoadsorption has been increasingly recognized as an alternative to therapeutic plasma exchange and used for the treatment of neurological disorders such as Guillain-Barre syndrome, chronic inflammatory demyelinating polyneuropathy, myasthenia gravis, neuromyelitis optica spectrum disorders, and multiple sclerosis, as well as autoimmune encephalitis. Unlike therapeutic plasma exchange, which requires fluid replacement with a blood solution such as fresh frozen plasma or albumin, immunoadsorption is a blood purification technique that enables the selective removal of humoral factors from separated plasma through a high-affinity adsorbent with tryptophan or phenylalanine. Although the mechanisms underlying the therapeutic effects of immunoadsorption treatment remain to be fully elucidated, they are based on the removal of pathogenic humoral factors from circulating blood, such as disease-specific autoantibodies, complement, and inflammatory cytokines. The American Society for Apheresis has published evidence-based guidelines on the use of therapeutic apheresis in clinical practice, with specific instructions on 16 neurological disorders. However, the modality recommended in the guidelines for most of these disorders is therapeutic plasma exchange. This part of our review focuses on the clinical aspects of immunoadsorption. We also describe the efficacy of immunoadsorption and the evidence obtained by previous studies of the treatment of neurological disorders. Immunoadsorption could greatly improve the treatment of patients with autoimmune neurological disorders but further evidence is needed to confirm the efficacy of immunoadsorption in clinical practice.

Guillain-Barré syndrome (GBS) is an acute monophasic neuropathy. Prognostic tools include the modified Erasmus GBS outcome score (mEGOS), Erasmus GBS respiratory insufficiency score (EGRIS), and the increase in serum IgG levels (ΔIgG) 2 weeks after intravenous immunoglobulin (IVIg) treatment. Given that proportions of GBS subtypes differ between Western countries and Japan, the usefulness of these tools in Japan or other countries remains unknown. We enrolled 177 Japanese patients with GBS from 15 university hospitals and retrospectively obtained mEGOS and EGRIS for all and ΔIgG status for 79 of them. High mEGOS scores on admission or on day 7 were significantly associated with poorer outcomes (unable to walk independently at 6 months). High EGRIS scores (≥5 points) were associated with an increased risk for mechanical ventilation. Patients with ΔIgG1,108 mg/dl had significantly poorer outcomes. We suggest that mEGOS, EGRIS, and ΔIgG in GBS are clinically relevant in Japan.

Myasthenia gravis (MG) is an autoimmune disease mostly caused by autoantibodies against acetylcholine receptor associated with thymus abnormalities. Thymectomy has been proven to be an efficacious treatment for patients with MG, but postoperative myasthenic crisis often occurs and is a major complication. We aimed to develop and validate a simple scoring system based on clinical characteristics in the preoperative status to predict the risk of postoperative myasthenic crisis.We studied 393 patients with MG who underwent thymectomy at 6 tertiary centers in Japan (275 patients for derivation and 118 for validation). Clinical characteristics, such as gender, age at onset and operation, body mass index, disease duration, MG subtype, severity, symptoms, preoperative therapy, operative data, and laboratory data, were reviewed retrospectively. A multivariate logistic regression with LASSO penalties was used to determine the factors associated with postoperative myasthenic crisis, and a score was assigned. Finally, the predictive score was evaluated using bootstrapping technique in the derivation and validation groups.Multivariate logistic regression identified 3 clinical factors for predicting postoperative myasthenic crisis risk: (1) vital capacity 80%, (2) disease duration 3 months, and (3) bulbar symptoms immediately before thymectomy. The postoperative myasthenic crisis predictive score, ranging from 0 to 6 points, had areas under the curve of 0.84 (0.66-0.96) in the derivation group and 0.80 (0.62-0.95) in the validation group.A simple scoring system based on 3 preoperative clinical characteristics can predict the possibility of postoperative myasthenic crisis. Ann Neurol 2017;82:841-849.

Anti-aquaporin 4 (AQP4) antibodies (Abs) are essential in neuromyelitis optica spectrum disorders (NMOSD), but the relationship between CNS demyelinating disorders (CNSDD) and other neural Abs remains unclear. Here we screened anti-neural Abs in the sera of 70 Japanese CNSDD patients. While two had only demyelinating events among three anti-N-methyl-d-aspartate receptor (NMDAR) Ab-positive subjects, the other subject who also had anti-AQP4 Abs experienced episodes of anti-NMDAR encephalitis and of NMOSD. Major lesions in the three anti-contactin-associated protein 2 Ab-positive subjects were infratentorial, including one co-carrying anti-AQP4 Abs. Thus, autoantibodies can be clinically silent, but multiple autoantibodies may participate in the pathogenesis.

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.

To illustrate the accuracy of the fluorescence-activated cell sorting cell-based assay (FACS-CBA) and to detect anti-myelin oligodendrocyte glycoprotein (MOG) antibodies and ascertain the optimal method for positivity judgement, referencing the findings of microscopic CBA. We tested serum anti-MOG antibodies in 57 patients with central nervous system inflammatory disorders (CIDs), 30 healthy controls (HCs), and 63 disease controls (DCs) by FACS-CBA. To assess the diagnostic performance of 2 positive judgement methods for FACS-CBA, we evaluated the ratio of positive cells (RPC) and median fluorescence intensity (MFIratio); samples from 57 CIDs and 3 antiaquaporin-4 antibody-positive patients whose anti-MOG antibody levels were relatively high but negative by FACS-CBA were tested by microscopic CBA. Blinded to the RPC and MFIratio results, we classified the acquired dot plot into 3 patterns—“upright,” “broadband,” and “oblique”—as pattern analysis. The sample with the highest RPC in CIDs was subjected to serial dilution analysis. Finally, we analyzed the clinical and laboratory data of anti-MOG antibody-positive patients in the acute phase. Referencing results by microscopic CBA and receiver-operating characteristic curve analysis, the area under the curve, sensitivity, specificity, and cutoff value were 0.952, 92%, 94%, and 1.52 for RPC and 0.931, 79%, 94%, and 6.39 for MFIratio, respectively, suggesting the optimality of RPC for positive judgement. Titers by microscopic CBA analysis significantly correlated with RPC (P = .031). In the validation study, the positive rate of RPC for anti-MOG antibodies was 42.1% in CIDs, but 0% in HCs and DCs (both P

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.

Distal myopathy is a group of heterogeneous disorders affecting predominantly distal muscles usually appearing from young to late adulthood with very rare cardiac complications. We report a 27-year-old man characterized clinically by distal myopathy and dilated cardiomyopathy, pathologically by lipid storage, and genetically by a PNPLA2 mutation. The patient developed weakness in his lower legs and fingers at age 20 years. Physical examination at age 27 years revealed muscle weakness and atrophy predominantly in lower legs and hands, and severe dilated cardiomyopathy. The patient had a homozygous four-base duplication (c.475_478dupCTCC) in exon 4 of PNPLA2.

The treatment of Guillain-Barre syndromé (GBS) was mainly symptomatic until the 1950s, followed by corticosteroid treatment in the 1950s through 1960s. Plasma exchange (PE) was then performed during 1970s through the 1980s, after which intravenous immunoglobulin (IVIg) was performed in 1990s through the 2000s. The effectiveness of IVIg and PE has been established by randomized controlled trial(RCT). Recently, new treatments using biological products have been explored. In this paper, we summarize the development of the treatment of GBS.

Treatment of NMO and NMO spectrum disorders is divided into two objectives: one is to control the inflammatory damage in acute attacks, and other one is a maintenance treatment to avoid relapses. The former is based on high-dose intravenous corticosteroids and plasmapheresis, the latter is based on low-dose corticosteroids and non-specific immunosuppressants; like azathioprine, tacrolimus, cyclosporine, mycophenolate mofetil and mitoxantrone. New therapy strategies using monoclonal antibodies like rituximab: an anti-CD20 monoclonal antibody, and eculizumab: an anti-C5 monoclonal antibody, can also prevent relapse of NMO. On the other hand, interferon-β, natalizumab, and fingolimod, a modifying drug of multiple sclerosis, is not effective in NMO spectrum disorders.