Nationwide Laboratory Surveillance of Progressive Multifocal Leukoencephalopathy in Japan: Fiscal Years 2011-2020.

Progressive multifocal leukoencephalopathy (PML) is a devastating demyelinating disease caused by JC virus (JCV), predominantly affecting patients with impaired cellular immunity. PML is a non-reportable disease with a few exceptions, making national surveillance difficult. In Japan, polymerase chain reaction (PCR) testing for JCV in the cerebrospinal fluid (CSF) is performed at the National Institute of Infectious Diseases to support PML diagnosis. To clarify the overall profile of PML in Japan, patient data provided at the time of CSF-JCV testing over 10 years (FY2011-2020) were analyzed. PCR testing for 1537 new suspected PML cases was conducted, and 288 (18.7%) patients tested positive for CSF-JCV. An analysis of the clinical information on all individuals tested revealed characteristics of PML cases, including the geographic distribution, age and sex patterns, and CSF-JCV-positivity rates among the study subjects for each type of underlying condition. During the last five years of the study period, a surveillance system utilizing ultrasensitive PCR testing and widespread clinical attention to PML led to the detection of CSF-JCV in the earlier stages of the disease. The results of this study will provide valuable information not only for PML diagnosis, but also for the treatment of PML-predisposing conditions.

Real-world application of plasmapheresis for neurological disease: Results from the Japan-Plasmapheresis Outcome and Practice Patterns Study.

INTRODUCTION: Plasmapheresis is a well-recognized treatment for autoimmune neurological diseases in Japan. However, the practice varies depending on the facility, and the actual treatment conditions are unclear. METHODS: To clarify real-world conditions, a prospective observational study was conducted on patients with neurological diseases who were scheduled to receive plasmapheresis. A dataset was analyzed that included 887 treatments from 210 patients with myasthenia gravis (MG), multiple sclerosis (MS), neuromyelitis optica spectrum disorders (NMOSD), and other diseases for 82, 30, 24, and 74 patients, respectively. RESULTS: The types of plasmapheresis performed included immunoadsorption plasmapheresis, plasma exchange, and double filtration plasmapheresis with 620, 213, and 54 treatments, respectively. Approximately, 60% of the treatments were performed using peripheral blood access alone. Non-serious adverse events were observed in 10 patients. CONCLUSIONS: A statistically significant improvement was observed after plasmapheresis in patients with MG, MS, and NMOSD. These were evaluated using the modified Rankin Scale.

[Hilary and Jackie: A Genius Cellist and Multiple Sclerosis].

Hilary and Jackie, is a film about Jacqueline du Pré, a genius cellist, who struggled with the consideration of the significance for being a cellist and a human being after she developed multiple sclerosis (MS). This article describes the clinical course of Jacqueline with MS and the therapeutics that seemed to be the best for Jacqueline, while comparing the medical standards at the time of her diagnosis with MS, with the latest medical treatment strategies for MS.

[Epstein-Barr virus-associated subacute sensorimotor neuropathy with multiple cerebellar microbleeding: a case report].

We report the case of an 82-year-old male with subacute sensorimotor neuropathy associated with Epstein-Barr virus (EBV) infection, who presented with diplopia followed by gait disturbance due to limb weakness. Pathological findings of a biopsied cervical lymph node showed a high frequency of EBV-positive cells. EBV-DNA was detected in blood. A nerve conduction study suggested a mixture of axonal damage and demyelination. Brain MRI showed multiple microbleeds in cerebellar cortices, but cerebrospinal fluid EBV-PCR was negative, suggesting bleeding due to EBV-related vasculitis. Corticosteroid therapy improved the neurological symptoms and the patient was able to walk independently four months later. The main pathogenesis of the neuropathy in this case is likely to be a mixture of vasculitic neuropathy and immune-mediated demyelinating neuropathy, which are considered to be due to EBV reactivation.

Dynamic planar scintigraphy for the rapid kinetic measurement of myocardial 123I-MIBG turnover can identify Lewy body disease.

BACKGROUND: Using two static scans for 123I-meta-iodobenzyl-guanidine (123I-MIBG) myocardial scintigraphy ignores the dynamic response from vesicular trapping in nerve terminals. Moreover, the long pause between scans is impractical for patients with Lewy body diseases (LBDs). Here, we optimized indices that capture norepinephrine kinetics, tested their diagnostic performance, and determined the differences in 123I-MIBG performance among disease groups. METHODS: We developed a new 30-min protocol for 123I-MIBG dynamic planar imaging for suspected LBD patients. Pharmacokinetic modelling of time-activity curves (TACs) was used to calculate three new indices: unidirectional uptake of 123I-MIBG to vesicular trapping (iUp), rate of myocardial 123I-MIBG loss (iLoss), and non-specific fractional distribution of 123I-MIBG in the interstitial space. We compared the performance of the new and existing indices with regard to discrimination of patients with or without LBDs. Subgroup analysis was performed to examine differences in 123I-MIBG turnover between patients in a dementia with Lewy bodies (DLB) group and two Parkinson's disease (PD) groups, one with and the other without REM sleep behaviour disorder (RBD). RESULTS: iLoss was highly discriminative, particularly for patients with low myocardial 123I-MIBG trapping, and the new indices outperformed existing ones. ROC analysis revealed that the AUC of iLoss (0.903) was significantly higher than that of early HMR (0.863), while comparable to that of delayed HMR (0.892). The RBD-positive PD group and the DLB group had higher turnover rates than the RBD-negative PD group, indicating a potential association between prognosis and iLoss. CONCLUSION: 123I-MIBG turnover can be quantified in 30 min using a three-parameter model based on 123I-MIBG TACs. The discriminatory performance of the new model-based indices might help explain the neurotoxicity or neurodegeneration that occurs in LBD patients.

Anti-MOG antibody-associated disorders: differences in clinical profiles and prognosis in Japan and Germany.

BACKGROUND: Neurological disorders with IgG antibodies against myelin-oligodendrocyte glycoprotein (MOG-IgG) have been increasingly recognised as a new type of neuroinflammatory disorder. OBJECTIVE: The study aimed to identify regional and ethnic differences in clinical profiles of MOG-IgG-associated disorders between East Asian (Japanese) and Caucasian (German) patients. METHODS: Demographic, clinical and therapeutic data from 68 MOG-IgG-positive adults were collected (Japanese, n=44; German, n=24). RESULTS: Age 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%). CONCLUSIONS: Among 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.

Clinical and immunological differences between MOG associated disease and anti AQP4 antibody-positive neuromyelitis optica spectrum disorders: Blood-brain barrier breakdown and peripheral plasmablasts.

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSION: 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.

[Anti-myelin oligodendrocyte glycoprotein antibody-positive neurologic disease, manifested as clinical course of classical Devic's disease: A case report].

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.

Tacrolimus is effective for neuromyelitis optica spectrum disorders with or without anti-AQP4 antibody.

BACKGROUND: 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. METHODS: 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. RESULTS: 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% (p < 0.001) 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% (p < 0.05), 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 (p < 0.001). 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 (p < 0.05), which was a clear improvement. CONCLUSION: 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.

The accuracy of flow cytometric cell-based assay to detect anti-myelin oligodendrocyte glycoprotein (MOG) antibodies determining the optimal method for positivity judgement.

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 < .001). In the pattern analysis, all anti-MOG antibody-positive patients but none of the HCs and DCs exhibited the "oblique" pattern. Serial dilution curve analysis fit a quaternary polymodal. FACS-CBA using RPC analysis for anti-MOG antibodies displayed relatively higher specificity, sensitivity, and semiquantitative property, indicating it could become another acceptable test to detect anti-MOG antibodies.

Mean Platelet Volume Is Associated with Early Neurological Deterioration in Patients with Branch Atheromatous Disease: Involvement of Platelet Activation.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Vertebral Artery Stump Syndrome.

Carotid stump syndrome is a well-documented embolic source for ischemic stroke. However, few cases have been reported of a similar condition - termed vertebral artery stump syndrome - which affects the posterior circulation after vertebral artery origin occlusion. We herein report a case of infarction of the right superior cerebellar artery and left posterior inferior cerebellar artery territories due to vertebral artery stump syndrome. In this interesting case, a turbulent flow at the distal side of the vertebral artery occlusion was captured on ultrasonography, and was identified as the probable mechanism of vertebral artery stump syndrome.

A clinical predictive score for postoperative myasthenic crisis.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. INTERPRETATION: A simple scoring system based on 3 preoperative clinical characteristics can predict the possibility of postoperative myasthenic crisis. Ann Neurol 2017;82:841-849.

Immunoadsorption in neurological disorders.

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-Barré 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.

Experimental Neuromyelitis Optica Induces a Type I Interferon Signature in the Spinal Cord.

Neuromyelitis optica (NMO) is an acute inflammatory disease of the central nervous system (CNS) which predominantly affects spinal cord and optic nerves. Most patients harbor pathogenic autoantibodies, the so-called NMO-IgGs, which are directed against the water channel aquaporin 4 (AQP4) on astrocytes. When these antibodies gain access to the CNS, they mediate astrocyte destruction by complement-dependent and by antibody-dependent cellular cytotoxicity. In contrast to multiple sclerosis (MS) patients who benefit from therapies involving type I interferons (I-IFN), NMO patients typically do not profit from such treatments. How is I-IFN involved in NMO pathogenesis? To address this question, we made gene expression profiles of spinal cords from Lewis rat models of experimental neuromyelitis optica (ENMO) and experimental autoimmune encephalomyelitis (EAE). We found an upregulation of I-IFN signature genes in EAE spinal cords, and a further upregulation of these genes in ENMO. To learn whether the local I-IFN signature is harmful or beneficial, we induced ENMO by transfer of CNS antigen-specific T cells and NMO-IgG, and treated the animals with I-IFN at the very onset of clinical symptoms, when the blood-brain barrier was open. With this treatment regimen, we could amplify possible effects of the I-IFN induced genes on the transmigration of infiltrating cells through the blood brain barrier, and on lesion formation and expansion, but could avoid effects of I-IFN on the differentiation of pathogenic T and B cells in the lymph nodes. We observed that I-IFN treated ENMO rats had spinal cord lesions with fewer T cells, macrophages/activated microglia and activated neutrophils, and less astrocyte damage than their vehicle treated counterparts, suggesting beneficial effects of I-IFN.

Quality of life in purely ocular myasthenia in Japan.

BACKGROUND: Since 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. METHODS: We 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. RESULTS: Of 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. CONCLUSION: A treatment strategy designed in accord with a patient's ocular presentation must be considered in order to improve ocular symptoms and the patient's QOL.