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Background and Purpose: Slowly expanding lesions (SELs) have been proposed as novel MRI markers of chronic active lesions in multiple sclerosis (MS). However, the mechanism through which SELs affect brain volume loss in patients with MS remains unknown. Additionally, the prevalence and significance of SELs in Asian patients with MS remain unclear. This study aimed to investigate the association between SELs and no evidence of disease activity (NEDA)‐3 status as well as brain volume loss in Japanese patients. Methods: A total of 99 patients with relapse‐onset MS were retrospectively evaluated. SELs were identified on brain MRI based on local deformation when consecutive scans were registered longitudinally. We developed a logistic regression model and generalized linear mixed models (GLMMs) to evaluate the association between the number of SELs and disease activity and changes in brain volume. Results: During the observation period (2.0 ± 0.22 years), 35 patients developed at least one SEL. Multivariable logistic regression analysis showed that ≥2 SELs were associated with 0.2 times the risk of achieving a NEDA‐3 status. GLMMs revealed that the number of SELs was negatively associated with volume changes in the cortex (p =.00169) and subcortical gray matter (p =.00964) after correction for multiple comparisons. Conclusion: SELs were identified in Japanese patients with MS during the 2‐year observation period. The number of SELs is associated with disease activity and brain volume loss, suggesting that the number of SELs could be a biomarker of disease activity in MS. [ABSTRACT FROM AUTHOR]

Introduction: Satralizumab, an anti-interleukin-6 receptor antibody, is approved in Japan for relapse prevention in neuromyelitis optica spectrum disorder (NMOSD) and is undergoing post-marketing surveillance (PMS) of clinical use. We aimed to describe the real-world safety and effectiveness of satralizumab in Japanese patients with NMOSD. Methods: This is an ongoing PMS (planned completion: February 2027). This 6-month interim analysis assessed the safety and effectiveness of satralizumab in Japanese patients with NMOSD using data collected from August 2020 to July 2021. Results: Among 570 patients who participated, 523 (91.75%) were female and the mean ± standard deviation (SD) age was 52.4 ± 14.1 years. At baseline, NMOSD expanded disability status scale mean ± SD was 4.19 ± 2.19; 490 (85.96%) patients used glucocorticoids and 277 (48.59%) patients used immunosuppressants concomitantly. Of 570 satralizumab-treated patients, 85 (14.91%) had discontinued satralizumab treatment at 6 months. For the overall adverse drug reactions (ADRs), 76.22 (66.07–87.48) events/100 person-years occurred in 118 (20.70%) patients, and infections occurred in 28 (4.91%) patients. Serious infections occurred in 18 (3.15%) patients, with an event rate of 9.05 (5.80–13.47) events/100 person-years. Of the 24 events of serious infections, respiratory tract infections (29.17%; 7) and urinary tract infections (25.00%; 6) were the most common serious infection events. One fatal ADR (septic shock) suspected to be related to satralizumab was reported. The mean ± SD glucocorticoid dose reduced from 12.28 ± 10.17 mg/day at the index date to 8.11 ± 7.30 mg/day at 6 months. The Kaplan–Meier cumulative relapse-free rate (95% confidence interval) was 94.59% (92.25–96.23) at 6 months. Conclusion: In this study, satralizumab was found to be safe, well tolerated, and effective in patients with NMOSD in routine clinical practice. The results are consistent with those of previous clinical trials. The safety and effectiveness of satralizumab in Japanese patients with NMOSD will be analyzed over the 6-year surveillance period. Trial Registration: UMIN Clinical Trials Registry, UMIN000041047. [ABSTRACT FROM AUTHOR]

In recent years, there is growing evidence of associations between antibodies against myelin oligodendrocyte glycoprotein (MOG) and several phenotypes of acute inflammatory demyelinating diseases such as acute disseminated encephalomyelitis (ADEM), optic neuritis, brainstem, and cerebral cortical encephalitis, called MOG antibody associated disorders (MOGAD). Monophasic course is known in about half of cases especially in pediatric onset ADEM and optic neuritis, mainly in cases with transient positivity of MOG antibody. Pathological features of MOGAD are considered as acute demyelinating lesions with CD4 dominant cell infiltrations, the deposition of humoral immunity, perivascular inflammation and perivenous demyelination, which is distinct from multiple sclerosis. Now the diagnosis of MOGAD is based on the international panel criteria of MOGAD launched in 2023, which the diagnostic frameworks are three parts, including MOGAD‐specific clinical features, MOG antibody positivity, and the exclusion of other diseases. The prognosis of MOGAD patients is considered relatively mild, but the problem is refractory relapsing cases. For its prevention, there are no approved drugs, but oral tapering corticosteroids, immunosuppressants such as azathioprine and mycophenolic mofetil, rituximab, and the maintenance intravenous immunoglobulin are recommended, and now there are a few clinical trials of promising biological drugs already approved in other neurological disorders. [ABSTRACT FROM AUTHOR]

Aims: We conducted a questionnaire survey on Japanese MS patients to determine the relationship of fatigue, depression, and physical activity limitations with employment status. Materials and methods: The study was conducted to assess the Patient Reported Outcome of MS patients treated with disease-modifying drug ≥6 months by recruiting MS patients from a web-based patient panel. Multiple regression analysis was performed by using items described in the Work Productivity and Activity Impairment Questionnaire-General Health Version 2.0 (WPAI-GH) and Fatigue Severity Scale (FSS), Quick Inventory of Depressive Symptomatology (Self-Report) (QIDS-SR), and Patient Determined Disease Step (PDDS). Results: Employment rates decreased after MS development and were more pronounced in the group with advanced physical disability with PDDS score ≥ 3. Health-related activity limitations were higher with advanced disability. In the analysis of the five subdomains of WPAI-GH by FSS score, the domains "due to health reasons," "disability rates during work," "overall work disability among the employed," and "health-related limitations' all increased with higher FSS scores." In WPAI-GH by QIDS-SR, the work disability rate was higher in the depressed group than in the normal group, and health-related activity limitations increased with greater depression. Limitations: This is a cross-sectional survey and data are based on PRO, hence are subjective and are collected based on patients' overall responses. Some bias could be attributed to memory and literacy rates as this is an online survey. Conclusions: The results suggested that the onset of MS prevented patients from working and forced them to resign from their jobs or give up full-time work. The rate of employment tended to be lower in the group with advanced limitations; suggesting that controlling the progression of limitations may lead to lower turnover, and the rate of health-related activity limitations was correlated with the degree of physical activity limitations, depression, and fatigue, respectively. PLAIN LANGUAGE SUMMARY: There are very few studies on the employment of MS patients in Japan. We conducted a questionnaire survey on Japanese MS patients to know the association between patient's symptoms and employment status. Employment rates decreased after MS development and more disability was associated with health-related activity limitations. Depression was also related to work related disability. The results suggested that the onset of MS prevented patients from working and forced them to resign or give up their full-time work. Employment was lower in the group with more limitations suggesting that controlling the progression of limitations may lead to higher employment rate. [ABSTRACT FROM AUTHOR]

Background: The terminal complement C5 inhibitor eculizumab is approved in Japan for relapse prevention in aquaporin-4 antibody-positive (AQP4+) neuromyelitis optica spectrum disorder (NMOSD) and is undergoing mandatory post-marketing surveillance (PMS) of clinical use. Objectives: The objective of the study is to assess the real-world, long-term safety and effectiveness of eculizumab in Japanese patients with AQP4+ NMOSD. Design: Regulatory-mandated PMS analysis implemented as an all-case surveillance of all patients with AQP4+ NMOSD who have been treated with eculizumab in Japan since its approval in November 2019. Methods: This PMS interim analysis assessed the safety and effectiveness of eculizumab in Japanese patients with AQP4+ NMOSD from November 2019 to April 2022. Results: Of 147 patients treated with eculizumab who consented to publication, 71 had at least one case report form collected and locked at the interim analysis data cut-off, constituting the safety analysis set; three patients from PREVENT (NCT01892345) were excluded from the effectiveness analysis set. Twelve and 10 patients in the safety and effectiveness analysis sets discontinued, respectively. In the safety analysis set, 67/71 patients (94.4%) were female, mean illness duration was 6.8 [standard deviation (SD): 6.2] years, mean age at eculizumab initiation was 50.7 (SD: 13.3) years, and mean eculizumab treatment duration was 44.6 (SD: 23.7) weeks. At diagnosis of NMOSD, 34/71 patients (47.9%) and 35/71 patients (49.3%) in the safety analysis set had symptoms of optic neuritis and transverse myelitis, respectively. In the safety analysis set, 19/71 patients (26.8%) reported adverse events, 10/71 (14.1%) reported adverse drug reactions (ADRs), and 7/71 (9.9%) reported serious ADRs; no meningococcal infections were observed. In the effectiveness analysis set, 64/68 patients (94.1%) were female, mean disease duration was 6.9 (SD: 6.3) years, mean age at eculizumab initiation was 50.6 (SD: 13.2) years, and 27/68 (39.7%) were tested for C5 genetic polymorphism (all negative). In the 2 years before eculizumab, 51/68 patients (75.0%) experienced relapse. Relapse rate was 0.02/patient-year after eculizumab initiation versus 0.74/patient-year in the 2 years before eculizumab. Overall, 37/68 patients (54.4%) were prescribed immunosuppressants in the 6 months before and 19/40 (47.5%) in the 6–12 months after starting eculizumab treatment. The proportion of patients taking >10 mg/day of prednisolone decreased from 45.6% at 24–20 weeks before to 23.1% and 0% at 48–52 and 100–104 weeks after eculizumab, respectively. Conclusion: This article reports interim PMS data for Japanese patients and provides updated real-world evidence for the safety of eculizumab and its effectiveness at preventing relapses in patients with AQP4+ NMOSD. Safety and effectiveness results are consistent with those from PREVENT. [ABSTRACT FROM AUTHOR]

Objective: CHAMPION‐NMOSD (NCT04201262) is a phase 3, open‐label, externally controlled interventional study evaluating the efficacy and safety of the terminal complement inhibitor ravulizumab in adult patients with anti–aquaporin‐4 antibody–positive (AQP4+) neuromyelitis optica spectrum disorder (NMOSD). Ravulizumab binds the same complement component 5 epitope as the approved therapeutic eculizumab but has a longer half‐life, enabling an extended dosing interval (8 vs 2 weeks). Methods: The availability of eculizumab precluded the use of a concurrent placebo control in CHAMPION‐NMOSD; consequently, the placebo group of the eculizumab phase 3 trial PREVENT (n = 47) was used as an external comparator. Patients received weight‐based intravenous ravulizumab on day 1 and maintenance doses on day 15, then once every 8 weeks. The primary endpoint was time to first adjudicated on‐trial relapse. Results: The primary endpoint was met; no patients taking ravulizumab (n = 58) had an adjudicated relapse (during 84.0 patient‐years of treatment) versus 20 patients with adjudicated relapses in the placebo group of PREVENT (during 46.9 patient‐years; relapse risk reduction = 98.6%, 95% confidence interval = 89.7%–100.0%, p < 0.0001). Median (range) study period follow‐up time was 73.5 (11.0–117.7) weeks for ravulizumab. Most treatment‐emergent adverse events were mild/moderate; no deaths were reported. Two patients taking ravulizumab experienced meningococcal infections. Both recovered with no sequelae; one continued ravulizumab treatment. Interpretation: Ravulizumab significantly reduced relapse risk in patients with AQP4+ NMOSD, with a safety profile consistent with those of eculizumab and ravulizumab across all approved indications. ANN NEUROL 2023;93:1053–1068 [ABSTRACT FROM AUTHOR]

White blood cell (WBC) count profiles in anti-aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder (AQP4-NMOSD) and anti-myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) are still unknown. This study evaluated the total WBC count, differential WBC counts, monocyte-to-lymphocyte ratio (MLR), and neutrophil-to-lymphocyte ratio (NLR) in patients with these diseases within three months from an attack before acute treatment or relapse prevention and compared the profiles with those in matched volunteers or in multiple sclerosis (MS) patients. AQP4-NMOSD patients (n = 13) had a higher neutrophil count (p = 0.0247), monocyte count (p = 0.0359), MLR (p = 0.0004), and NLR (p = 0.0037) and lower eosinophil (p = 0.0111) and basophil (p = 0.0283) counts than those of AQP4-NMOSD-matched volunteers (n = 65). Moreover, patients with MOGAD (n = 26) had a higher overall WBC count (p = 0.0001), neutrophil count (p < 0.0001), monocyte count (p = 0.0191), MLR (p = 0.0320), and NLR (p = 0.0002) than those of MOGAD-matched volunteers (n = 130). The three demyelinating diseases showed similar levels of the total and differential WBC counts; however, MOGAD and MS showed different structures in the hierarchical clustering and distributions on a two-dimensional canonical plot using differential WBC counts from the other three groups. WBC count profiles were similar in patients with MOGAD and MS but differed from profiles in matched volunteers or patients with AQP4-NMOSD. [ABSTRACT FROM AUTHOR]

Background: To our knowledge, no nationwide epidemiological study of myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) has been conducted. Objective: We examined the epidemiology and clinical features of MOGAD in Japan. Methods: We distributed questionnaires on the clinical characteristics of patients with MOGAD to neurology, pediatric-neurology, and neuro-ophthalmology facilities throughout Japan. Results: In total, 887 patients were identified. The estimated number of total and newly diagnosed MOGAD patients was 1,695 [95% confidence interval (CI): 1483–1907] and 487 (95% CI: 414–560), respectively. The estimated prevalence and incidence were 1.34/100,000 (95% CI: 1.18–1.51) and 0.39/100,000 (95% CI: 0.32–0.44), respectively. The median age at onset was 28 years (range: 0–84 years). At onset, optic neuritis was present in approximately 40% of patients, irrespective of the onset age. Acute disseminated encephalomyelitis was more frequent in younger patients, whereas brainstem encephalitis, encephalitis, and myelitis were more frequent in elderly patients. Immunotherapy was highly effective. Conclusion: The prevalence and incidence rates of MOGAD in Japan are similar to those in other countries. Notable characteristics such as the preferential occurrence of acute disseminated encephalomyelitis in children exist; however, general characteristics including symptoms and treatment response are common irrespective of the onset age. [ABSTRACT FROM AUTHOR]

Effect modifiers are study design or patient characteristics that influence the efficacy of the treatment, resulting in different relative treatment effect estimates, e.g., different hazard ratios (HRs) for relapse. Neuromyelitis optica spectrum disorder, Randomized controlled trial, Matching-adjusted indirect comparison, Eculizumab, Inebilizumab, Satralizumab, Aquaporin-4 immunoglobulin G-positive, Bayesian network meta-analysis Keywords: Neuromyelitis optica spectrum disorder; Aquaporin-4 immunoglobulin G-positive; Randomized controlled trial; Bayesian network meta-analysis; Matching-adjusted indirect comparison; Eculizumab; Inebilizumab; Satralizumab EN Neuromyelitis optica spectrum disorder Aquaporin-4 immunoglobulin G-positive Randomized controlled trial Bayesian network meta-analysis Matching-adjusted indirect comparison Eculizumab Inebilizumab Satralizumab 1445 1449 5 08/02/22 20220901 NES 220901 Dear Editor, We read with interest the comments from Cree et al. [[1]] on our recently published study describing a network meta-analysis (NMA) comparing the efficacies of eculizumab, satralizumab, and inebilizumab for neuromyelitis optica spectrum disorder (NMOSD) [[2]]. [Extracted from the article]

Calculating the crude or adjusted annualized relapse rate (ARR) and its confidence interval (CI) is often required in clinical studies to evaluate chronic relapsing diseases, such as multiple sclerosis and neuromyelitis optica spectrum disorders. However, accurately calculating ARR and estimating the 95% CI requires careful application of statistical approaches and basic familiarity with the exponential family of distributions. When the relapse rate can be regarded as constant over time or by individuals, the crude ARR can be calculated using the person-years method, which divides the number of all observed relapses among all participants by the total follow-up period of the study cohort. If the number of relapses can be modeled by the Poisson distribution, the 95% CI of ARR can be obtained by finding the 2.5% upper and lower critical values of the parameter λ as the mean. Basic familiarity with F-statistics is also required when comparing the ARR between two disease groups. It is necessary to distinguish the observed relapse rate ratio (RR) between two sample groups (sample RR) from the unobserved RR between their originating populations (population RR). The ratio of population RR to sample RR roughly follows the F distribution, with degrees of freedom obtained by doubling the number of observed relapses in the two sample groups. Based on this, a 95% CI of the population RR can be estimated. When the count data of the response variable is overdispersed, the negative binomial distribution would be a better fit than the Poisson. Adjusted ARR and the 95% CI can be obtained by using the generalized linear regression models after selecting appropriate error structures (e.g., Poisson, negative binomial, zero-inflated Poisson, and zero-inflated negative binomial) according to the overdispersion and zero-inflation in the response variable. [ABSTRACT FROM AUTHOR]

Objective: The patterns of relapse and relapse-prevention strategies for anti-myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) are not completely investigated. We compared the patterns of relapse in later stages of MOGAD with those of anti-aquaporin-4 antibody (AQP4-Ab)-positive neuromyelitis optica spectrum disorder (NMOSD). Methods: In this observational, comparative cohort study, 66 patients with MOGAD and 90 with AQP4-Ab-positive NMOSD were enrolled. We compared the patterns of relapse and annualized relapse rates (ARRs) in the first 10 years from disease onset, stratified by relapse-prevention treatments. Results: Approximately 50% of the patients with MOGAD experienced relapses in the first 10 years. Among those not undergoing relapse-prevention treatments, ARRs in the first 5 years were slightly lower in MOGAD patients than in AQP4-Ab-positive NMOSD patients (MOGAD vs. AQP4-Ab NMOSD: 0.19 vs. 0.30; p = 0.0753). After 5 years, the ARR decreased in MOGAD patients (MOGAD vs. AQP4-Ab NMOSD: 0.05 vs. 0.34; p = 0.0001), with a 72% reduction from the first 5 years (p = 0.0090). Eight (61.5%) of the 13 MOGAD patients with more than 10-year follow-up from disease onset showed relapse 10 years after onset. Clustering in the timing and phenotype of attacks was observed in both disease patients. The effectiveness of long-term low-dose oral PSL for relapse prevention in patients with MOGAD has not been determined. Conclusions: The relapse risk in patients with MOGAD is generally lower than that in patients with AQP4-Ab-positive NMOSD, especially 5 years after onset. Meanwhile, relapses later than 10 years from onset are not rare in both diseases. [ABSTRACT FROM AUTHOR]

Introduction: Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune disease defined by attacks on the central nervous system that cause irreversible damage. Recent approval of NMOSD therapies warrants investigations of comparative efficacy to inform treatment decisions. Methods: A network meta-analysis (NMA) of all U.S. Food and Drug Administration-approved therapies (eculizumab, inebilizumab, and satralizumab) for adults with aquaporin-4 immunoglobulin G-positive (AQP4+) NMOSD was conducted via a systematic literature review (SLR) using data from randomized controlled trials (RCTs). Database searches of MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were executed for the SLR. A fixed-effects proportional hazards Bayesian NMA was used to estimate relative treatment effects based on data extracted from RCTs identified during the SLR (search end date: 11 September 2020). Four unique RCTs (N-MOmentum, PREVENT, SAkuraSky, and SAkuraStar) were identified, and data from 29 publications were extracted for analysis. Network scenarios describing the most comparable patient population groups (such as by treatment settings) were evaluated in our analyses. Relative treatment effects were evaluated based on time-to-first relapse and were expressed as hazard ratios (HRs) with 95% credible intervals (CrIs). Results: In patients treated with a monoclonal antibody only, eculizumab was associated with a lower risk of relapse compared with satralizumab (HR 0.10, 95% CrI 0.01, 0.65) and inebilizumab (HR 0.11, 95% CrI 0.02, 0.68). In patients treated with monoclonal antibody with or without background immunosuppressive therapy (IST), patients treated with eculizumab ± IST were also less likely to relapse than patients treated with satralizumab ± IST (HR 0.24, 95% CrI 0.06, 0.98). Conclusion: The NMA results suggest that complement component 5 (C5) inhibition prevents NMOSD relapses more effectively than broader mechanisms of action. Plain Language Summary: Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune disease characterized by inflammation that damages the brain and spinal cord. Many patients with NMOSD produce antibodies against a protein called aquaporin-4 (AQP4+). In the past two years, three drugs (eculizumab, inebilizumab, and satralizumab) have been approved by the U.S. Food and Drug Administration for the treatment of adults with AQP4+ NMOSD. Comparing the efficacy of these three drugs would help physicians make treatment decisions for their patients. In the absence of clinical trials directly comparing these three drugs, we conducted a Bayesian network meta-analysis in order to allow for simultaneous comparisons of these three drugs and estimate relative treatment effects between any pair of interventions in a connected network. With a Bayesian methodology, it is also possible to estimate the probability of being the best treatment out of all other interventions in a connected network. While all three drugs are safe and shown to prevent relapses in placebo-controlled trials, the results of our analysis suggests that eculizumab was the most efficacious in preventing relapses when compared with inebilizumab or satralizumab. These findings may help to inform physicians and their patients when determining the best treatment option for preventing the occurrence of relapses in adults with AQP4+ NMOSD. [ABSTRACT FROM AUTHOR]

During PREVENT (a phase 3, randomized, double-blind, placebo-controlled, time-to-event study) and its open-label extension (interim analysis), 33 adults with aquaporin-4 immunoglobulin G-positive neuromyelitis optica spectrum disorder (AQP4-IgG + NMOSD) received eculizumab monotherapy for a median of 2.8 years (range, 14 weeks–5.2 years). At 192 weeks (~4 years), 96% of these patients were free from adjudicated relapses (Kaplan–Meier analysis; 95% confidence interval, 75.7–99.4). During PREVENT, 95% (20/21) of patients receiving eculizumab monotherapy had no disability worsening. Eculizumab monotherapy provides effective long-term relapse prevention, relieving the chronic immunosuppression burden in patients with AQP4-IgG + NMOSD. ClinicalTrials.gov; PREVENT: NCT01892345; open-label extension: NCT02003144. [ABSTRACT FROM AUTHOR]

Background: Two-dimensional (2D) measures have been proposed as potential proxies for whole-brain volume in multiple sclerosis (MS). Objective: To verify whether 2D measurements by routine MRI are useful in predicting brain volume or disability in MS. Methods: In this cross-sectional analysis, eighty-five consecutive Japanese MS patients—relapsing-remitting MS (81%) and progressive MS (19%)—underwent 1.5 Tesla T1-weighted 3D MRI examinations to measure whole-brain and grey matter volume. 2D measurements, namely, third ventricle width, lateral ventricle width (LVW), brain width, bicaudate ratio, and corpus callosum index (CCI), were obtained from each scan. Correlations between 2D measurements and 3D measurements, the Expanded Disability Status Scale (EDSS), or processing speed were analysed. Results: The third and lateral ventricle widths were well-correlated with the whole-brain volume (p < 0.0001), grey matter volume (p < 0.0001), and EDSS scores (p = 0.0001, p =.0004, respectively).The least squares regression model revealed that 78% of the variation in whole-brain volume could be explained using five explanatory variables, namely, LVW, CCI, age, sex, and disease duration. By contrast, the partial correlation coefficient excluding the effect of age showed that the CCI was significantly correlated with the EDSS and processing speed (p < 0.0001). Conclusion: Ventricle width correlated well with brain volumes, while the CCI correlated well with age-independent (i.e. disease-induced) disability. [ABSTRACT FROM AUTHOR]

Introduction: We aimed to determine whether in vivo tau deposits and monoamine oxidase B (MAO-B) detection using 18F-THK5351 positron emission tomography (PET) can assist in the differential distribution in patients with corticobasal syndrome (CBS), progressive supranuclear palsy (PSP), and Alzheimer's disease (AD) and whether 18F-THK5351 retention of lesion sites in CBS and PSP can correlate with clinical parameters. Methods: 18F-THK5351 PET was performed in 35 participants, including 7, 9, and 10 patients with CBS, PSP, and AD, respectively, and 9 age-matched normal controls. In CBS and PSP, cognitive and motor functions were assessed using the Montreal Cognitive Assessment, Addenbrooke's Cognitive Examination–Revised, and Frontal Assessment Battery, Unified Parkinson's Disease Rating Scale Motor Score, and PSP Rating Scale. Results: 18F-THK5351 retention was observed in sites susceptible to disease-related pathologies in CBS, PSP, and AD. 18F-THK5351 uptake in the precentral gyrus clearly differentiated patients with CBS from those with PSP and AD. Furthermore, 18F-THK5351 uptake in the inferior temporal gyrus clearly differentiated patients with AD from those with CBS and PSP. Regional 18F-THK5351 retention was associated with the cognitive function in CBS and PSP. Conclusion: Measurement of the tau deposits and MAO-B density in the brain using 18F-THK5351 may be helpful for the differential diagnosis of tauopathies and for understanding disease stages. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is a major demyelinating disease of the central nervous system; however, its exact mechanism is unknown. This study aimed to elucidate the profile of white blood cells (WBCs) in the acute phase of an MS attack. Sixty-four patients with MS at the time of diagnosis and 2492 age- and sex-adjusted healthy controls (HCs) were enrolled. Data regarding the blood cell counts were compared between the groups. The total WBC (p < 0.0001), monocyte (p < 0.0001), basophil (p = 0.0027), and neutrophil (p < 0.0001) counts were higher in the MS group than in the HC group, whereas the lymphocyte and eosinophil counts did not differ. Adjustments for the smoking status and body mass index yielded the same results. The total and differential WBC counts of the patients with MS did not correlate with the counts of T2 hyperintense brain lesions or the levels of neurological disturbance. In summary, patients with MS showed elevated counts of total WBCs, monocytes, basophils, and neutrophils at the time of diagnosis. However, the clinical relevance of these biomarkers in the context of the development and progression of MS remains unclear. [ABSTRACT FROM AUTHOR]

Background: Neuro‐Behçet's disease (NBD) is typically characterized by inflammatory lesions with vasculitis in the brainstem and basal ganglia. Subcortical white matter lesions and linear lesions along the intramedullary trigeminal nerve are rare, and these lesions make NBD difficult to differentiate from other demyelinating diseases, such as multiple sclerosis. Case presentation: A 48‐year‐old woman with an 11‐year history of intestinal Behçet's disease was referred to Department of Neurology, Tohoku Medical and Pharmaceutical University Hospital, Sendai, Japan owing to numbness on the left side of her face and oral cavity for 12 days. Neurological examination revealed left facial hypoesthesia. Brain magnetic resonance imaging showed a linearly shaped T2/fluid‐attenuated inversion recovery hyperintense magnetic resonance imaging lesion in the left pons, which corresponded neuroanatomically with the intramedullary trigeminal root. Based on the presumptive diagnosis of NBD, a course of high‐dose intravenous methylprednisolone was administered on the 14th hospital day. Thereafter, the patient's neurological symptoms improved. However, on the 18th hospital day, the patient developed a linear subcortical white matter lesion with vasogenic edema in the right hemisphere that resolved after the re‐administration of high‐dose intravenous methylprednisolone. Conclusion: The case of a patient with NBD presenting with atypical brain lesions is reported. The NBD in this case might have a pathogenetic mechanism that is different from that of typical NBD. [ABSTRACT FROM AUTHOR]

Aquaporin 4 (AQP4)-IgG-positive neuromyelitis optica spectrum disorder (AQP4-IgG+NMOSD) is an autoimmune astrocytopathic disease pathologically characterized by the massive destruction and regeneration of astrocytes with diverse types of tissue injury with or without complement deposition. However, it is unknown whether this diversity is derived from differences in pathological processes or temporal changes. Furthermore, unlike for the demyelinating lesions in multiple sclerosis, there has been no staging of astrocytopathy in AQP4-IgG+NMOSD based on astrocyte morphology. Therefore, we classified astrocytopathy of the disease by comparing the characteristic features, such as AQP4 loss, inflammatory cell infiltration, complement deposition and demyelination activity, with the clinical phase. We performed histopathological analyses in eight autopsied cases of AQP4-IgG+NMOSD. Cases comprised six females and two males, with a median age of 56.5 years (range, 46-71 years) and a median disease duration of 62.5 months (range, 0.6-252 months). Astrocytopathy in AQP4-IgG+NMOSD was classified into the following four stages defined by the astrocyte morphology and immunoreactivity for GFAP: (i) astrocyte lysis: extensive loss of astrocytes with fragmented and/or dust-like particles; (ii) progenitor recruitment: loss of astrocytes except small nucleated cells with GFAP-positive fibre-forming foot processes; (iii) protoplasmic gliosis: presence of star-shaped astrocytes with abundant GFAP-reactive cytoplasm; and (iv) fibrous gliosis: lesions composed of densely packed mature astrocytes. The astrocyte lysis and progenitor recruitment stages dominated in clinically acute cases (within 2 months after the last recurrence). Findings common to both stages were the loss of AQP4, a decreased number of oligodendrocytes, the selective loss of myelin-associated glycoprotein and active demyelination with phagocytic macrophages. The infiltration of polymorphonuclear cells and T cells (CD4-dominant) and the deposition of activated complement (C9neo), which reflects the membrane attack complex, a hallmark of acute NMOSD lesions, were selectively observed in the astrocyte lysis stage (98.4% in astrocyte lysis, 1.6% in progenitor recruitment, and 0% in protoplasmic gliosis and fibrous gliosis). Although most of the protoplasmic gliosis and fibrous gliosis lesions were accompanied by inactive demyelinated lesions with a low amount of inflammatory cell infiltration, the deposition of complement degradation product (C3d) was observed in all four stages, even in fibrous gliosis lesions, suggesting the past or chronic occurrence of complement activation, which is a useful finding to distinguish chronic lesions in NMOSD from those in multiple sclerosis. Our staging of astrocytopathy is expected to be useful for understanding the unique temporal pathology of AQP4-IgG+NMOSD. [ABSTRACT FROM AUTHOR]

Objective: During PREVENT (NCT01892345), eculizumab significantly reduced relapse risk versus placebo in patients with aquaporin-4 immunoglobulin G-positive neuromyelitis optica spectrum disorder (AQP4-IgG+ NMOSD). We report an interim analysis of PREVENT's ongoing open-label extension (OLE; NCT02003144) evaluating eculizumab's long-term safety and efficacy.Methods: Patients who completed PREVENT could enroll in the OLE to receive eculizumab (maintenance dose = 1,200 mg/2 weeks, after a blinded induction phase). Safety and efficacy data from PREVENT and its OLE (interim data cut, July 31, 2019) were combined for this analysis.Results: Across PREVENT and the OLE, 137 patients received eculizumab and were monitored for a median (range) of 133.3 weeks (5.1-276.9 weeks), for a combined total of 362.3 patient-years (PY). Treatment-related adverse event (AE) and serious adverse event (SAE) rates were 183.5 in 100 PY and 8.6 in 100 PY, respectively. Serious infection rates were 10.2 in 100 PY in eculizumab-treated patients versus 15.1 in 100 PY in the PREVENT placebo group. No patient developed a meningococcal infection. At 192 weeks (3.7 years), 94.4% (95% confidence interval [CI], 88.6-97.3) of patients remained adjudicated relapse-free. The adjudicated annualized relapse rate was 0.025 (95% CI = 0.013-0.048) in all eculizumab-treated patients versus 0.350 (95% CI = 0.199-0.616) in the PREVENT placebo group. During the OLE, 37% of patients (44 of 119 patients) stopped or decreased background immunosuppressive therapy use.Interpretation: This analysis demonstrates that eculizumab's long-term safety profile in NMOSD is consistent with its established profile across other indications. This analysis also demonstrated the sustained ability of long-term eculizumab treatment to reduce relapse risk in patients with AQP4-IgG+ NMOSD. ANN NEUROL 2021;89:1088-1098. [ABSTRACT FROM AUTHOR]

Background: Neuromyelitis optica spectrum disorders (NMOSD) are autoimmune neurological diseases of the central nervous system, which are characterized by the presence of serum anti-aquaporin-4 autoantibodies (AQP4-IgG). An association between Sjögren syndrome (SjS) and AQP4-IgG-positive NMOSD has been proposed, but the rate of coexistence has not been determined. Methods: In this study, 4,447 patients suspected of having NMOSD with acute neurological episodes were evaluated for the positivity of serum AQP4-IgG, serum SS-A/Ro antibody, and the presence of SjS-related symptoms (dry eye, dry mouth). Results: Of the 4,447 patients, 1,651 were positive for serum AQP4-IgG, and the remaining 2,796 were negative. A significantly higher proportion of AQP4-IgG-positive patients were positive for serum anti-SSA/Ro antibody (26.3 vs. 4.5%; p < 0.0001) and anti-SSB/La antibody (7.2 vs. 1.2%; p < 0.0001) and had dry eye (9.1 vs.4.9%; p < 0.0001) and dry mouth symptoms (8.9 vs. 3.7%; p < 0.0001). More than 80% of the patients with SjS with acute neurological events such as myelitis or optic neuritis were AQP4-IgG positive. AQ4-IgG-positive patients with comorbid SjS showed a higher female rate (97.1 vs. 89.0%; p = 0.0062), a higher positivity rate for oligoclonal bands (15.4 vs. 7.5%; p = 0.029), and a higher relapse frequency (p = 0.027) than AQP4-IgG-positive patients without comorbid SjS. Conclusions: The prevalence of SjS is higher among AQP4-IgG-positive than AQP4-IgG-negative patients, with the potential prevalence of 10–20% at the diagnosis of AQP4-IgG-positive NMOSD. Comorbid SjS is more prevalent in females, and it has a higher relapse frequency among AQP4-IgG-positive patients. [ABSTRACT FROM AUTHOR]

Objectives: A recent Asian study proposed a phenotype of "pure spinal multiple sclerosis." Thus, we tried to identify cases of myelitis that can fulfil the 2017 McDonald criteria with minimum or no brain lesions. Methods: In our consecutive cases, we explored patients who presented with recurrent or monophasic short‐segment partial myelitis, positive cerebrospinal fluid oligoclonal bands and no more than a single asymptomatic periventricular lesion <10 mm on brain magnetic resonance imaging. Results: A total of six patients (1 men and 5 women) were identified. All six patients could fulfil the 2017 McDonald criteria. The patients primarily presented disturbance of superficial sensation, whereas fewer presented motor symptoms or disturbance in deep sensation. No pathological brain atrophy or brainstem, cerebellar, or optic nerve lesions were observed. The sequelae were mild, and no patients showed a progressive disease course. Conclusions: The identified phenotype of multiple sclerosis seems to be female dominant and presents a relatively mild clinical course without pathological brain atrophy. [ABSTRACT FROM AUTHOR]

Myelin oligodendrocyte glycoprotein (MOG)-IgG detected by the cell-based assay is associated with demyelinating diseases of the central nervous system, such as optic neuritis, myelitis, and acute disseminated encephalomyelitis, but rarely with peripheral neuropathy. Here, we describe the case of a 32-year-old MOG-IgG+ woman who developed central and peripheral demyelinating lesions. In contrast to previous similar cases, she uniquely presented with repeated subsequent relapses in the peripheral nerve, mimicking chronic inflammatory demyelinating polyneuropathy. Possible pathogenic implications of MOG-IgG in combined central and peripheral nervous system diseases are considered. [ABSTRACT FROM AUTHOR]

Background: Neuromyelitis optica spectrum disorder (NMOSD) is a relapsing autoimmune-related neurological disorder of the central nervous system. Most patients with NMOSD have serum anti-aquaporin-4 immunoglobulin G antibodies (AQP4-IgG). In addition to optic neuritis and myelitis, other insidious symptoms such as depressive state and chronic fatigue in NMOSD are gradually being recognized. Methods: To elucidate the impact of low- to medium-dose oral prednisolone (PSL) as a relapse prevention therapy for psychiatric disturbances and chronic fatigue in NMOSD, we evaluated clinical data from 39 patients with AQP4-IgG-positive NMOSD, along with the details of present and cumulative oral PSL dosage. Results: Thirty-six of the 39 patients were treated with low- to medium-dose oral PSL, and the mean and standard deviation of the present daily dose of oral PSL were 7.9 ± 4.0 mg/day. None of the patients were treated with a daily PSL dose of >15 mg. As a result, the disease duration and the untreated period before starting oral PSL showed weak to moderate correlations with the subsequent severities of psychiatric disturbance and fatigue level. Meanwhile, none of the other treatment-related variables evaluated, such as the present oral PSL daily dose, cumulative PSL dose, months of oral PSL administration, previous courses of steroid pulse therapy, and coadministered immunosuppressants, were correlated with these insidious symptoms. Conclusion: Our results suggest that the use of long-term low- to medium-dose oral PSL ≤15 mg daily for relapse prevention in AQP4-IgG-positive NMOSD would not aggravate the psychiatric and fatigue conditions. On the contrary, early initiation of oral PSL for relapse prevention, together with significantly decreased relapse rate, alleviated the subsequent depressive state and fatigue from the disease. [ABSTRACT FROM AUTHOR]

Objective: To clarify the clinical and radiological features of adult onset anti-myelin oligodendrocyte glycoprotein (MOG) antibody-associated bilateral medial frontal cerebral cortical encephalitis (BFCCE). Methods: We systematically reviewed the literature for patients with anti-MOG antibody-associated BFCCE. Patients who were also positive for other encephalitis-related autoantibodies were excluded from the study. The frequency of several characteristic neurological symptoms and lesion distributions were analyzed. Results: We identified six patients with anti-MOG antibody-associated BFCCE. Among them, 6/6 had headache, 4/6 had fever, 3/6 had seizure, 2/6 had paraparesis, 2/6 had lethargy, and 2/6 had memory disturbance. CSF pleocytosis was observed in 5/6 patients, while CSF myelin basic protein was not elevated in any of the six patients. On brain MRI, 6/6 had bilateral medial frontal cortical lesions, 3/6 had corpus callosum lesions, and 3/6 had leptomeningeal enhancements. Most of the lesions were distributed in the territory of the anterior cerebral artery (ACA). Conclusion: Our results indicate that anti-MOG antibody-associated BFCCE presents with characteristic clinical symptoms and MRI findings, which might reflect lesion formation in the ACA territory. [ABSTRACT FROM AUTHOR]

Objective: The purpose of this study was to elucidate the rapid impact of high-dose intravenous methylprednisolone pulse therapy (1,000 mg/day for 3 days) on the eventual visual prognosis in patients with serum anti-aquaporin-4 immunoglobulin G (AQP4-IgG)–positive neuromyelitis optica spectrum disorders (NMOSDs) who had an attack of optic neuritis (ON). Methods: Data from 32 consecutive NMOSD patients (1 male and 31 female) with at least one ON attack, involving a total of 36 ON-involved eyes, were evaluated. The following variables at ON onset were evaluated: sex, age at the first ON episode, visual acuity at nadir, visual acuity after 1 year, duration from ON onset to treatment for an acute ON attack, cycles of high-dose intravenous methylprednisolone pulse therapy for the ON attack, and cycles of plasmapheresis for the ON attack. Among the 36 ON-involved eyes, 27 eyes were studied using orbital MRI with a short-T1 inversion recovery sequence and gadolinium-enhanced fat-suppressed T1 imaging before starting treatment in the acute phase. Results: In univariate analyses, a shorter duration from ON onset to the initiation of high-dose intravenous methylprednisolone pulse therapy favorably affected the eventual visual prognosis 1 year later (Spearman's rho = 0.50, p = 0.0018). The lesion length on orbital MRI was also correlated with the eventual visual prognosis (rho = 0.68, p < 0.0001). Meanwhile, the days to steroid pulse therapy and lesion length on orbital MRI did not show a significant correlation. These findings suggest that the rapidness of steroid pulse therapy administration affects the eventual visual prognosis independent of the severity of ON. In multivariate analysis, a shorter time from ON onset to the start of acute treatment (p = 0.0004) and a younger age at onset (p = 0.0071) were significantly associated with better visual outcomes. Conclusions: Rapid initiation of high-dose intravenous methylprednisolone pulse therapy is essential to preserve the eventual visual acuity in patients with serum AQP4-IgG-positive NMOSD. Once clinicians suspect acute ON with serum AQP4-IgG, swift administration of steroid pulse therapy before confirming the positivity of serum AQP4-IgG would be beneficial for preserving visual function. [ABSTRACT FROM AUTHOR]

Neuromyelitis optica spectrum disorder (NMOSD) is an uncommon inflammatory disease of the central nervous system, manifesting clinically as optic neuritis, myelitis, and certain brain and brainstem syndromes. Cases clinically diagnosed as NMOSD may include aquaporin 4 (AQP4)-antibody-seropositive autoimmune astrocytopathic disease, myelin oligodendrocyte glycoprotein (MOG)-antibody-seropositive inflammatory demyelinating disease, and double-seronegative disease. AQP4-antibody disease has a high female-to-male ratio (up to 9:1), and its mean age at onset of ~40 years is later than that seen in multiple sclerosis. For MOG-antibody disease, its gender ratio is closer to 1:1, and it is more common in children than in adults. Its clinical phenotypes differ but overlap with those of AQP4-antibody disease and include acute disseminated encephalomyelitis, brainstem and cerebral cortical encephalitis, as well as optic neuritis and myelitis. Double-seronegative disease requires further research and clarification. Population-based studies over the past two decades report the prevalence and incidence of NMOSD in different populations worldwide. One relevant finding is the varying prevalence observed in different racial groups. Consistently, the prevalence of NMOSD among Whites is ~1/100,000 population, with an annual incidence of <1/million population. Among East Asians, the prevalence is higher, at ~3.5/100,000 population, while the prevalence in Blacks may be up to 10/100,000 population. For MOG-antibody disease, hospital-based studies largely do not observe any significant racial preponderance so far. This disorder comprises a significant proportion of NMOSD cases that are AQP4-antibody-seronegative. A recent Dutch nationwide study reported the annual incidence of MOG-antibody disease as 1.6/million population (adult: 1.3/million, children: 3.1/million). Clinical and radiological differences between AQP4-antibody and MOG-antibody associated diseases have led to interest in the revisions of NMOSD definition and expanded stratification based on detection of a specific autoantibody biomarker. More population-based studies in different geographical regions and racial groups will be useful to further inform the prevalence and incidence of NMOSD and their antibody-specific subgroups. Accessibility to AQP4-antibody and MOG-antibody testing, which is limited in many centers, is a challenge to overcome. Environmental and genetic studies will be useful accompaniments to identify other potential pathogenetic factors and specific biomarkers in NMOSD. [ABSTRACT FROM AUTHOR]

Objective: To explore levels of astrocytopathy in neuromyelitis optica spectrum disorder (NMOSD) by measuring levels of the astrocytic enzyme glutamine synthetase (GS) and glial fibrillary acidic protein (GFAP), an established astrocytic biomarker known to be associated with disease activity in multiple sclerosis.Methods: Cerebrospinal fluid concentrations of GS and GFAP were measured by ELISA in patients with NMOSD (n=39, 28 aquaporin-4 (AQP4)-Ab-seropositive, 3 double-Ab-seronegative, 4 myelin oligodendrocyte glycoprotein (MOG)-Ab-seropositive and 4 AQP4-Ab-seronegative with unknown MOG-Ab-serostatus), multiple sclerosis (MS) (n=69), optic neuritis (n=5) and non-neurological controls (n=37).Results: GFAP and GS concentrations differed significantly across groups (both p<0.001), showing a similar pattern of elevation in patients with AQP4-Ab-seropositive NMOSD. GS and GFAP were significantly correlated, particularly in patients with AQP4-Ab-seropositive NMOSD (rs=0.70, p<0.001). Interestingly, GFAP levels in some patients with double-Ab-seronegative NMOSD were markedly increased.Conclusions: Our data indicate astrocytic injury occurs in some patients with double-Ab-seronegative NMOSD, which hints at the possible existence of yet undiscovered astrocytic autoimmune targets. We hypothesise that elevated GS and GFAP levels could identify those double-Ab-seronegative patients suitable to undergo in-depth autoimmune screening for astrocytic antibodies. [ABSTRACT FROM AUTHOR]

Amantadine intoxication occurred despite moderate renal dysfunction. This may have been affected by the use of donepezil, and we require careful attention to these combinations. [ABSTRACT FROM AUTHOR]

Conformation-sensitive antibodies against myelin oligodendrocyte glycoprotein (MOG) are detectable in patients with optic neuritis, myelitis, opticomyelitis, acute or multiphasic disseminated encephalomyelitis (ADEM/MDEM) and brainstem/cerebral cortical encephalitis, but are rarely detected in patients with prototypic multiple sclerosis. So far, there has been no systematic study on the pathological relationship between demyelinating lesions and cellular/humoral immunity in MOG antibody-associated disease. Furthermore, it is unclear whether the pathomechanisms of MOG antibody-mediated demyelination are similar to the demyelination patterns of multiple sclerosis, neuromyelitis optica spectrum disorders (NMOSD) with AQP4 antibody, or ADEM. In this study, we immunohistochemically analysed biopsied brain tissues from 11 patients with MOG antibody-associated disease and other inflammatory demyelinating diseases. Patient median onset age was 29 years (range 9-64), and the median interval from attack to biopsy was 1 month (range 0.5-96). The clinical diagnoses were ADEM (n = 2), MDEM (n = 1), multiple brain lesions without encephalopathy (n = 3), leukoencephalopathy (n = 3) and cortical encephalitis (n = 2). All these cases had multiple/extensive lesions on MRI and were oligoclonal IgG band-negative. Most demyelinating lesions in 10 of 11 cases showed a perivenous demyelinating pattern previously reported in ADEM (153/167 lesions) and a fusion pattern (11/167 lesions) mainly in the cortico-medullary junctions and white matter, and only three lesions in two cases showed confluent demyelinated plaques. In addition, 60 of 167 demyelinating lesions (mainly in the early phase) showed MOG-dominant myelin loss, but relatively preserved oligodendrocytes, which were distinct from those of AQP4 antibody-positive NMOSD exhibiting myelin-associated glycoprotein-dominant oligodendrogliopathy. In MOG antibody-associated diseases, MOG-laden macrophages were found in the perivascular spaces and demyelinating lesions, and infiltrated cells were abundant surrounding multiple blood vessels in and around the demyelinating lesions, mainly consisting of macrophages (CD68; 1814 ± 1188 cells/mm2), B cells (CD20; 468 ± 817 cells/mm2), and T cells (CD3; 2286 ± 1951 cells/mm2), with CD4-dominance (CD4+ versus CD8+; 1281 ± 1196 cells/mm2 versus 851 ± 762 cells/mm2, P < 0.01). Humoral immunity, evidenced by perivascular deposits of activated complements and immunoglobulins, was occasionally observed in some MOG antibody-associated demyelinating lesions, and the frequency was much lower than that in AQP4 antibody-positive NMOSD. Subpial lesions with perivenous demyelination were observed in both ADEM and cortical encephalitis. Our study suggests that ADEM-like perivenous inflammatory demyelination with MOG-dominant myelin loss is a characteristic finding of MOG antibody-associated disease regardless of whether the diagnostic criteria of ADEM are met. These pathological features are clearly different from those of multiple sclerosis and AQP4 antibody-positive NMOSD, suggesting an independent autoimmune demyelinating disease entity. [ABSTRACT FROM AUTHOR]

Background: Myelin oligodendrocyte glycoprotein antibody (MOG‐IgG) has been identified in demyelinating diseases of the central nervous system, including neuromyelitis optica spectrum disorders (NMOSD) without the presence of anti‐aquaporin‐4 antibody. Patients with MOG‐IgG present with clinical symptoms distinct from those of multiple sclerosis or NMOSD, so MOG‐IgG‐associated encephalomyelitis (MOG‐EM) is regarded as an entity distinct from multiple sclerosis and NMOSD. In contrast to NMOSD with anti‐aquaporin‐4 antibody, MOG‐EM has been reported to respond well to steroid therapy, and the functional prognosis of this disease is good. However, here we report a patient with MOG‐EM and lumbosacral radiculitis who showed little response to various immune therapies. Case presentation: A 40‐year‐old man presented with acute paraplegia and sensory disturbance in the lower body. MOG‐IgG was positive both in serum and cerebrospinal fluid. Steroid pulse therapy, plasma exchange, intravenous immunoglobulin and cyclophosphamide pulse therapy were ineffective. In nerve conduction studies, compound muscle action potentials and F‐waves were not evoked in bilateral lower limb nerves, suggesting severe damage of peripheral nerves and lower motor neurons. Gadolinium enhancement was observed in the cauda equina. Conclusions: The mechanisms of peripheral nerve system involvement in MOG‐EM are unknown, but the present case suggests that MOG‐EM might occasionally combine with peripheral nerve system disturbance. Lumbosacral radiculitis combined with MOG‐IgG can be refractory, and serious sequela might be observed. [ABSTRACT FROM AUTHOR]

Background: Anti‐myelin oligodendrocyte glycoprotein (MOG) antibody‐associated encephalitis is a new spectrum of disease entities that includes acute disseminated encephalomyelitis, brainstem encephalitis and cortical encephalitis. Recently, we encountered a case of anti‐MOG antibody‐associated encephalitis in which the patient presented with a linearly shaped lesion at the trigeminal root entry zone, which is one of the well‐known characteristic magnetic resonance imaging (MRI) findings in patients with multiple sclerosis. Here, we report this case, as several studies suggested that the reactivation of Herpes simplex viruses contribute to the formation of the linear pontine trigeminal root lesions in multiple sclerosis. Case presentation: A 39‐year‐old woman was referred to our department because she developed numbness of the left side of her face. She had experienced convulsive seizures of unknown cause 2 years prior. Neurological examination showed left facial hypesthesia (ophthalmic and maxillary divisions). Brain MRI showed a linearly shaped T2/fluid‐attenuated inversion recovery hyperintense MRI lesion in the pons, which corresponded neuroanatomically with the intramedullary trigeminal root. A live cell‐based assay showed that the patient was positive for serum anti‐MOG antibodies. We diagnosed her with anti‐MOG antibody‐associated encephalitis. Two courses of high‐dose i.v. methylprednisolone were administered. Thereafter, the patient's neurological symptoms and MRI findings improved. Conclusions: A linear pontine trigeminal root lesion was observed in a patient with anti‐MOG antibody‐associated encephalitis. The association of herpesviruses requires more attention in the pathogenesis of anti‐MOG antibody‐associated encephalitis. [ABSTRACT FROM AUTHOR]

Introduction: Progressive brain atrophy, development of T1-hypointense areas, and T2-fluid-attenuated inversion recovery (FLAIR)-hyperintense lesion formation in multiple sclerosis (MS) are popular volumetric data that are often utilized as clinical outcomes. However, the exact clinical interpretation of these volumetric data has not yet been fully established. Methods: We enrolled 42 consecutive patients with MS who fulfilled the revised McDonald criteria of 2010. They were followed-up for more than 3 years from onset, and cross-sectional brain volumetry was performed. Patients with no brain lesions were excluded in advance from this study. For the brain volumetric data, we evaluated several parameters including age-adjusted gray-matter volume atrophy, age-adjusted white-matter volume atrophy, and T2-FLAIR lesion volume. The numbers of T1-hypointense and T2-FLAIR-hyperintense areas were also measured along the same timeline. The clinical data pertaining to disease duration, expanded disability status scale (EDSS), and MS severity score (MSSS) at the timing of volumetry were collected. Results: Among the 42 patients with MS and brain lesions, the number of T1-hypointensity (rho = 0.51, p<0.001), gray-matter atrophy (rho = 0.40, p<0.01) and white-matter atrophy (rho = 0.49, p<0.001) correlated with the EDSS. T1-hypointensity count divided by FLAIR lesion volume correlated with the MSSS (rho = 0.60, p<0.001). Meanwhile, counts or volumes of FLAIR-hyperintense lesions were associated only with the times of past relapses, and did not correlate with present neurological disability level or ongoing disease activity. These findings were consistent regardless of the presence of spinal cord lesions. Conclusion: Numbers of T1-hypointensities and brain atrophy equally indicated the current neurological disability in MS. The number of T1-hypointensities divided by FLAIR lesion volume represented the clinical severity. The size or number of FLAIR lesions reflected earlier relapses but was not a good indicator of neurological disability or clinical severity. [ABSTRACT FROM AUTHOR]

Myelin oligodendrocyte glycoprotein (MOG) is a minor myelin protein localized at the outermost layer of the myelin sheath. Cell‐based assays to detect conformation‐sensitive MOG‐immunoglobulin G (IgG) have identified a unique group of patients with optic neuritis, acute/multiphasic disseminated encephalomyelitis, encephalitides (brainstem and cerebral cortical), myelitis and aquaporin‐4 IgG‐negative neuromyelitis optica spectrum disorders. MOG‐IgG‐associated disease affects both children and adults, and the female : male ratio is almost 1:1. Cerebrospinal fluid (CSF) examination shows pleocytosis of mononuclear or polymorphonuclear cells during acute exacerbation, but oligoclonal IgG bands are usually negative. CSF‐myelin basic protein levels are high, but CSF‐glial fibrillary acidic protein is not elevated, suggesting demyelination. CSF‐cytokines related to T helper cell‐17, B cells and neutrophils are remarkably upregulated, which is similar to aquaporin‐4 IgG‐positive neuromyelitis optica spectrum disorders, but distinct from multiple sclerosis. As for treatment of MOG‐IgG‐associated disease, high‐dose intravenous methylprednisolone is commonly used in the acute phase, but it has not been established which patients require long‐term immunosuppression and which drugs should be chosen to prevent relapse. There have been some recent studies to support the pathogenicity of MOG‐IgG in vitro and in vivo. Taken together, MOG‐IgG‐associated disease seems to be a unique inflammatory demyelinating disease of the central nervous system, but further research is required to clarify the clinical and epidemiological features, treatment strategy, and the underlying pathology. [ABSTRACT FROM AUTHOR]

By the discovery of an antibody to aquaporin 4 (AQP4), the clinical and radiological findings of neuromyelitis optica (NMO) such as diffuse cerebral or longitudinally extended spinal cord lesions had been clarified as distinct features from multiple sclerosis (MS). Pathological studies in NMO demonstrated loss of immunoreactivity to AQP4 and glial fibrillary acidic protein but a relative preservation of myelin basic protein, especially at the lesions with perivascular deposition of immunoglobulins and complements, suggesting autoimmune disease against astrocytes. In recent years, the antibody against myelin oligodendrocyte glycoprotein (MOG) has been studied for its association with acute demyelinating diseases such as acute or multiphasic disseminated encephalomyelitis (ADEM/MDEM), optic neuritis, AQP4 antibody–negative NMOSD, and brainstem or cerebral cortical encephalomyelitis. We could identify the dominance of perivenous inflammatory demyelination like ADEM in our biopsied case series with MOG antibody. In recent brain‐biopsied cases with MOG antibody, the deposition of humoral immunity, perivascular inflammation, and perivenous demyelination were observed especially in atypical cases including cortical encephalitis or disseminated encephalitis. In this review, we focus on MOG antibody–related diseases, which we considered it as a differentiated disease from MS by means of the disease‐specific autoantibody and the distinct pathophysiology. [ABSTRACT FROM AUTHOR]

Objectives: Although whole and individual regional brain volume loss have been separately reported to correlate with disability in multiple sclerosis (MS), hierarchical cluster analyses of the whole and regional brain to find their pattern in MS are few. Methods: We cross-sectionally conducted high-resolution, T1-weighted volumetric MRI examinations in 75 MS patients and 21 healthy controls (HCs) to measure the volumes of whole brain and a total of 56 brain regions of interest. Using a hierarchical cluster analysis with multivariate imaging data, we classified the patients into clusters according to their brain-volume patterns. Principal component analysis was also applied. Clinical features and brain volumes were then compared among the MS clusters. Results: The MS patients were categorized into three major clusters (Clusters 1, 2, and 3) with increasing disability in that order. Principal component analysis also identified Clusters 1, 2 and 3. Whole brain volume and supratentorial regional brain volumes, including thalamus and corpus callosum, decreased severely in Cluster 3 and moderately in Cluster 2, while equally preserved in Cluster 1 and the HCs. Only the volumes of the ventral diencephalon and T1 white matter hypointensities significantly differed in Clusters 1, 2 and 3 and HCs. In contrast, the volumes of the cerebellar cortex and brainstem were significantly different between Clusters 3 and 1, whereas there were no significant differences between Clusters 1 and 2 and Clusters 2 and 3. Conclusion: We identified brain regions that exhibit different degree of atrophy in a background of global brain atrophy in MS. [ABSTRACT FROM AUTHOR]

Background: Several types of physical examinations are used in the diagnosis of meningitis, including nuchal rigidity, jolt accentuation, Kernig's sign, and Brudzinski's sign. Jolt accentuation was reported to have sensitivity of nearly 100% and to be highly efficient for excluding meningitis, but more recent studies showed that a number of patients with meningitis may present negative in this test. Methods: We systematically reviewed studies on the above‐mentioned physical examination tests and performed meta‐analysis of their diagnostic characteristics to evaluate the clinical usefulness. Nine studies, comprising a total of 599 patients with pleocytosis in the cerebrospinal fluid (CSF) and 1216 patients without CSF pleocytosis, were enrolled in the analysis. Results: Jolt accentuation showed a decent level of odds ratio (3.62; 99% confidence interval (CI): 1.13‐11.60, P = 0.004) comparable to that in nuchal rigidity (2.52; 1.21‐5.27, P = 0.001) for the correct prediction of CSF pleocytosis among subjects with suspected meningitis. The estimated sensitivity was relatively high (40%‐60%) in nuchal rigidity or jolt accentuation tests. On the other hand, Kernig's and Brudzinski's signs exhibited relatively low sensitivity (20%‐30%). The estimated specificity was higher in Kernig's and Brudzinski's signs (85%‐95%) than in nuchal rigidity or jolt accentuation tests (65%‐75%). Conclusion: Approximately half of the patients with meningitis may not present typical meningeal signs upon physical examination. Combining several examinations for the detection of meningeal signs may decrease the risk of misdiagnosis. [ABSTRACT FROM AUTHOR]

Pathogenic antibodies targeting the aquaporin-4 water channel on astrocytes are associated with relapsing inflammatory neuromyelitis optica spectrum disorders. The clinical phenotype is characterized by recurrent episodes of optic neuritis, longitudinally extensive transverse myelitis, area postrema attacks and less common brainstem and cerebral events. Patients often develop major residual disability from these attacks, so early diagnosis and initiation of attackpreventing medications is important. Accurate prediction of relapse would assist physicians in counselling patients, planning treatment and designing clinical trials. We used a large multicentre dataset of 441 patients from the UK, USA, Japan and Martinique who collectively experienced 1976 attacks, and applied sophisticated mathematical modelling to predict likelihood of relapse and disability at different time points. We found that Japanese patients had a lower risk of subsequent attacks except for brainstem and cerebral events, with an overall relative relapse risk of 0.681 (P = 0.001) compared to Caucasians and African patients, who had a higher likelihood of cerebral attacks, with a relative relapse risk of 3.309 (P = 0.009) compared to Caucasians. Female patients had a higher chance of relapse than male patients (P = 0.009), and patients with younger age of onset were more likely to have optic neuritis relapses (P < 0.001). Immunosuppressant drugs reduced and multiple sclerosis disease-modifying agents increased the likelihood of relapse (P < 0.001). Patients with optic neuritis at onset were more likely to develop blindness (P < 0.001), and those with older age of onset were more likely to develop ambulatory disability. Only 25% of long-term disability was related to initial onset attack, indicating the importance of early attack prevention. With respect to selection of patients for clinical trial design, there would be no gain in power by selecting recent onset patients and only a small gain by selecting patients with recent high disease activity. We provide risk estimates of relapse and disability for patients diagnosed and treated with immunosuppressive treatments over the subsequent 2, 3, 5 and 10 years according to type of attack at onset or the first 2-year course, ethnicity, sex and onset age. This study supports significant effects of onset age, onset phenotype and ethnicity on neuromyelitis optica spectrum disorders outcomes. Our results suggest that powering clinical treatment trials based upon relapse activity in the preceding 2 years may offer little benefit in the way of attack risk yet severely hamper clinical trial success. [ABSTRACT FROM AUTHOR]

In this report, we present the successful treatment of five consecutive cases of premenopausal women suffering from severe menstrual migraine with tokishakuyakusan (TSS). Two patients were complicated by tension‐type headache (TTH), and another patient was by medication overuse headache (MOH). The effects of triptans were limited in all of them. After starting TSS, they showed dramatic improvement in the severity and frequency of their attacks. The patients with TTH and MOH also showed dramatic improvement in their symptoms. TSS could be a promising alternative choice for patients with intractable menstruation–related headaches that are refractory to conventional treatments, including triptans. [ABSTRACT FROM AUTHOR]

Rheumatoid meningitis (RM) is a rare central nervous system manifestation of rheumatoid arthritis (RA). A meningeal biopsy is useful for diagnosis but is invasive and not very sensitive. We report about a patient with RM who was diagnosed using indices of anti‐cyclic citrullinated peptide (CCP) antibody and anti‐galactose‐deficient IgG antibody (carbohydrate in rheumatoid factor [CARF]) and who had refused to undergo biopsy. The patient's antibody titer indices of anti‐CCP antibody and CARF were 21.01 and 4.44, respectively. The patient's symptoms and abnormalities on brain magnetic resonance imaging improved after steroid therapy. Antibody titer indices of the anti‐CCP antibody and CARF can be used to diagnose RM in cases where biopsy is unavailable. [ABSTRACT FROM AUTHOR]

Overshunting‐associated myelopathy (OSAM) is a rare complication of ventriculoperitoneal (VP) shunts. Here, we report the case of a 52‐year‐old man who presented with OSAM without positional headache 27 years after the placement of a VP shunt. The patient recovered after shunt ligation and transection. Although rare, chronic cerebrospinal fluid overdrainage can lead to cervical myelopathy due to spinal cord compression by the dilated vertebral veins/epidural venous plexus. Thus, reversible OSAM needs to be differentiated during the diagnosis of cervical myelopathy. [ABSTRACT FROM AUTHOR]

It is well established that the binding of pathogenic aquaporin-4 (AQP4)-specific autoantibodies to astrocytes may initiate a cascade of events culminating in the destruction of these cells and in the formation of large tissue-destructive lesions typical for patients with neuromyelitis optica spectrum disorders (NMOSD). To date, not a single experimental study has shown that the systemic presence of the antibody alone can induce any damage to the central nervous system (CNS), while pathological studies on brains of NMOSD patients suggested that there might be ways for antibody entry and subsequent tissue damage. Here, we systemically applied a highly pathogenic, monoclonal antibody with high affinity to AQP4 over prolonged period of time to rats, and show that AQP4-abs can enter the CNS on their own, via circumventricular organs and meningeal or parenchymal blood vessels, that these antibodies initiate the formation of radically different lesions with AQP4 loss, depending on their mode and site of entry, and that lesion formation is much more efficient in the presence of encephalitogenic T-cell responses. We further demonstrate that the established tissue-destructive lesions trigger the formation of additional lesions by short and far reaching effects on blood vessels and their branches, and that AQP4-abs have profound effects on the AQP4 expression in peripheral tissues which counter-act possible titer loss by antibody absorption outside the CNS. Cumulatively, these data indicate that directly induced pathological changes caused by AQP4-abs inside and outside the CNS are efficient drivers of disease evolution in seropositive organisms. [ABSTRACT FROM AUTHOR]

A multicenter, randomized, double‐blind, placebo‐controlled, efficacy and safety study of BG00012 in participants from the Asia–Pacific region and other countries with relapsing–remitting multiple sclerosis (APEX), including Japan, established the efficacy of dimethyl fumarate (DMF) in preventing relapses and disease progression in patients with multiple sclerosis (MS). Consequently, in December 2016, DMF was approved as the second oral disease‐modifying drug for MS in Japan. However, the new Japanese guidelines for MS and neuromyelitis optica published in 2017 did not include DMF. Later, after the committee discussed a guideline for DMF, a supplement of the new guidelines for MS and neuromyelitis optica, which included DMF, was published in June 2018; this supplement comprised the following four clinical questions: (i) is DMF effective in preventing relapses in patients with MS?; (ii) is DMF effective in preventing disease progression in patients with MS?; (iii) how to use DMF?; and (iv) what adverse events does DMF possibly cause? Furthermore, the supplement comprised answers to the questions and comments. Overall, this supplement is anticipated to contribute toward the treatment of Japanese MS patients with DMF. In December 2016, dimethyl fumarate (DMF) was approved as the second oral disease‐modifying drug for multiple sclerosis (MS) in Japan. After the committee discussed a guideline for DMF, a supplement of the new guidelines for MS and neuromyelitis optica, which included DMF, was published in June 2018. Overall, this supplement is anticipated to contribute toward the treatment of Japanese patients with MS with DMF. [ABSTRACT FROM AUTHOR]

Objective: To evaluate cerebrospinal fluid (CSF) cytokine profiles in myelin oligodendrocyte glycoprotein IgG-positive (MOG-IgG+) disease in adult and paediatric patients.Methods: In this cross-sectional study, we measured 27 cytokines in the CSF of MOG-IgG+ disease in acute phase before treatment (n=29). The data were directly compared with those in aquaporin-4 antibody-positive (AQP4-IgG+) neuromyelitis optica spectrum disorder (NMOSD) (n=20), multiple sclerosis (MS) (n=20) and non-inflammatory controls (n=14).Results: In MOG-IgG+ disease, there was no female preponderance and the ages were younger (mean 18 years, range 3-68; 15 were below 18 years) relative to AQP4-IgG+ NMOSD (41, 15-77) and MS (34, 17-48). CSF cell counts were higher and oligoclonal IgG bands were mostly negative in MOG-IgG+ disease and AQP4-IgG+ NMOSD compared with MS. MOG-IgG+ disease had significantly elevated levels of interleukin (IL)-6, IL-8, granulocyte-colony stimulating factor and granulocyte macrophage-colony stimulating factor, interferon-γ, IL-10, IL-1 receptor antagonist, monocyte chemotactic protein-1 and macrophage inflammatory protein-1α as compared with MS. No cytokine in MOG-IgG+ disease was significantly different from AQP4-IgG+ NMOSD. Moreover many elevated cytokines were correlated with each other in MOG-IgG+ disease and AQP4-IgG+ NMOSD but not in MS. No difference in the data was seen between adult and paediatric MOG-IgG+ cases.Conclusions: The CSF cytokine profile in the acute phase of MOG-IgG+ disease is characterised by coordinated upregulation of T helper 17 (Th17) and other cytokines including some Th1-related and regulatory T cells-related ones in adults and children, which is similar to AQP4-IgG+ NMOSD but clearly different from MS. The results suggest that as with AQP4-IgG+ NMOSD, some disease-modifying drugs for MS may be ineffective in MOG-IgG+ disease while they may provide potential therapeutic targets. [ABSTRACT FROM AUTHOR]

Abstract: Background: Anti‐myelin oligodendrocyte glycoprotein antibodies (MOG‐Ab) are positive in some patients with neuromyelitis optica/neuromyelitis optica spectrum disorders; however, their clinical diversity remains unclear. Case presentation: We encountered three anti‐MOG‐Ab‐positive Japanese adult patients with brain lesions, but lacking optic neuritis and myelitis. Magnetic resonance imaging detected lesions in the cerebral gray and white matter, brainstem, and cerebellum, and 18‐fluorodeoxyglucose positron emission tomography imaging showed normal or decreased uptake in acute lesions. Conclusions: Patients with anti‐MOG‐Ab might present with brain lesions only, and lack optic neuritis and myelitis. The anti‐MOG‐Ab titer needs to be measured in inflammatory diseases that affect the central nervous system, including atypical multiple sclerosis and autoimmune meningoencephalitis. [ABSTRACT FROM AUTHOR]