Publications by authors named "Kazuo Fujihara"

226 Publications

Difference in the Source of Anti-AQP4-IgG and Anti-MOG-IgG Antibodies in CSF in Patients With Neuromyelitis Optica Spectrum Disorder.

Neurology 2021 May 12. Epub 2021 May 12.

Department of Neurology, Tohoku Medical and Pharmaceutical University, Sendai, Japan.

Objective: To elucidate the differences in the source and in the level of intrathecal synthesis between anti-aquaporin-4 antibodies (AQP4-IgG) and anti-myelin oligodendrocyte glycoprotein antibodies (MOG-IgG).

Methods: Thirty-eight patients with MOG-IgG-associated disease and 36 with AQP4-IgG-positive neuromyelitis optica spectrum disorders (NMOSD) were studied for the antibody titers in the sera and cerebrospinal fluids (CSF) simultaneously collected in the acute attacks. The quotients between CSF and serum levels of albumin, total IgG, and each disease-specific antibody were calculated. Intrathecal production level in each disease-specific antibody was evaluated by calculating antibody index from these quotients.

Results: Eleven of the 38 patients with MOG-IgG were positive for the antibody only in the CSF, while no patient with AQP4-IgG showed CSF-restricted AQP4-IgG. Blood-brain barrier compromise as shown by raised albumin quotients was seen in 75.0% of MOG-IgG-positive cases and 43.8% of AQP4-IgG-positive cases. Moreover, MOG-IgG quotients were more than 10 times higher than AQP4-IgG quotients (effect size = 0.659, p < 0.0001). Elevated antibody index (>4.0) was confirmed in 12 of 21 with MOG-IgG, whereas it was seen only in one of 16 with AQP4-IgG (φ = 0.528, p < 0.0001). The CSF MOG-IgG titers (rho = +0.519, p = 0.001) and antibody indexes for MOG-IgG (rho = +0.472, p = 0.036) correlated with the CSF cell counts but not with clinical disability.

Conclusions: Intrathecal production of MOG-IgG may occur more frequently than that of AQP4-IgG. This finding implies the different properties of B-cell trafficking and antibody production between MOG-IgG-associated disease and AQP4-IgG-positive NMOSD.
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http://dx.doi.org/10.1212/WNL.0000000000012175DOI Listing
May 2021

Acute retrobulbar optic neuritis with anti-myelin oligodendrocyte glycoprotein antibody-associated disease complicated with microscopic polyangiitis: A case report.

Medicine (Baltimore) 2021 Apr;100(15):e24889

Department of Rheumatology.

Rationale: Anti-myelin oligodendrocyte protein antibody-associated disease (MOGAD) is a new disease entity with various clinical phenotypes. MOGAD often present with recurrent optic neuritis (ON), and it can also develop as a compartment of neuromyelitis optica spectrum disorder (NMOSD). Moreover, multiple autoantibodies such as an anti-myeloperoxidase antineutrophil cytoplasmic antibody (MPO-ANCA) had been reported in the serum of patients with NMOSD.

Patient Concerns: We report an 86-year-old woman with a 2-year history of microscopic polyangiitis (MPA). The patient had a rapid loss of vision in her left eye. No abnormal findings were observed on her left fundus, and she tested negative for MPO-ANCA upon admission. However, anti-MOG antibodies were observed in the patient's serum and cerebrospinal fluid.

Diagnosis: A diagnosis of MOGAD complicated with MPA was made.

Interventions: The patient received twice steroid pulse therapy and oral azathioprine as maintenance therapy.

Outcomes: Her vision rapidly recovered, and no subsequent relapse was observed during the 8-month observation period.

Conclusion: To the best of our knowledge, this is the first case of MOGAD complicated with MPA, and steroid pulse therapy and azathioprine therapy were effective for ON caused by MOGAD.
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http://dx.doi.org/10.1097/MD.0000000000024889DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8052052PMC
April 2021

Staging of astrocytopathy and complement activation in neuromyelitis optica spectrum disorders.

Brain 2021 Mar 12. Epub 2021 Mar 12.

Department of Neurology, Tohoku University Graduate School of Medicine, Sendai, 980-8574, Japan.

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. There were six women and two men, 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 glial fibrillary acidic protein (GFAP): (a) astrocyte lysis: Extensive loss of astrocytes with fragmented and/or dust-like particles; (b) progenitor recruitment: Loss of astrocytes except small nucleated cells with GFAP-positive fibre-forming foot processes; (c) protoplasmic gliosis: Presence of star-shaped astrocytes with abundant GFAP-reactive cytoplasm; and (d) 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.
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http://dx.doi.org/10.1093/brain/awab102DOI Listing
March 2021

Early Treatment Initiation With Oral Prednisolone for Relapse Prevention Alleviates Depression and Fatigue in Aquaporin-4-Positive Spectrum Disorder.

Front Neurol 2021 22;12:608149. Epub 2021 Feb 22.

Department of Neurology, Tohoku Medical and Pharmaceutical University, Sendai, Japan.

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. 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. 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. 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.
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http://dx.doi.org/10.3389/fneur.2021.608149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7938311PMC
February 2021

Eculizumab in Asian patients with anti-aquaporin-IgG-positive neuromyelitis optica spectrum disorder: A subgroup analysis from the randomized phase 3 PREVENT trial and its open-label extension.

Mult Scler Relat Disord 2021 May 20;50:102849. Epub 2021 Feb 20.

Department of Neurology, Tohoku University Graduate School of Medicine, 1-1 Seiryomachi, Aobaku, Sendai, Miyagi 980-8574, Japan; Department of Multiple Sclerosis Therapeutics, Fukushima Medical University School of Medicine, 1 Hikariga-oka, Fukushima City, Fukushima 960-1295, Japan; Multiple Sclerosis and Neuromyelitis Optica Center, Southern TOHOKU Research Institute for Neuroscience (STRINS), Koriyama, 7-115, Yatsuyamada, Koriyama, Fukushima 963-8563, Japan. Electronic address:

Background Eculizumab, a terminal complement inhibitor, significantly reduced the risk of relapse compared with placebo in patients with anti-aquaporin-4 immunoglobulin G-positive (AQP4+) neuromyelitis optica spectrum disorder (NMOSD) in the PREVENT trial. We report efficacy and safety analyses in Asian patients in PREVENT and its open-label extension (OLE). Methods PREVENT was a double-blind, randomized, phase 3 trial. Patients with AQP4+ NMOSD were randomly assigned (2:1) to receive intravenous eculizumab (maintenance dose, 1200 mg/2 weeks) or placebo. Patients who completed PREVENT could receive eculizumab in an OLE. Analyses were performed in a prespecified subgroup of Asian patients. Results Of 143 patients enrolled, 52 (36.4%) were included in the Asian subgroup (eculizumab, n = 37; placebo, n = 15); 45 Asian patients received eculizumab in the OLE. Most Asian patients (86.5%) received concomitant immunosuppressive therapy. During PREVENT, one adjudicated relapse occurred in patients receiving eculizumab and six occurred in patients receiving placebo in the Asian subgroup (hazard ratio, 0.05; 95% confidence interval: 0.01-0.35; p = 0.0002). An estimated 95.2% of Asian patients remained relapse-free after 144 weeks of eculizumab treatment. Upper respiratory tract infections, headache, and nasopharyngitis were the most common adverse events with eculizumab in the Asian subgroup. Conclusion Eculizumab reduces the risk of relapse in Asian patients with AQP4+ NMOSD, with a benefit-risk profile similar to the overall PREVENT population. The benefits of eculizumab were maintained during long-term therapy. Clinical trial registration ClinicalTrials.gov identifiers: NCT01892345 (PREVENT); NCT02003144 (open-label extension).
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http://dx.doi.org/10.1016/j.msard.2021.102849DOI Listing
May 2021

Optic neuritis after ocular trauma in anti-aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder.

Brain Behav 2021 May 16;11(5):e02083. Epub 2021 Feb 16.

Department of Neurology, Tohoku Medical and Pharmaceutical University, Sendai, Japan.

Objective: The aim of this study was to report the possible association between minor trauma to the eyes and the subsequent occurrence of optic neuritis in patients with serum anti-aquaporin-4 (AQP4) antibody-positive neuromyelitis optica spectrum disorder (NMOSD).

Methods: Herein, we present three patients who developed acute optic neuritis with visual disturbances after accidental minor trauma to their eyes, without any fundus abnormality or orbital floor fractures present.

Results: Two of the three patients had a preceding history of neurological disturbances compatible with NMOSD (e.g., myelitis, area postrema syndrome) before the occurrence of trauma. One patient was rapidly treated with steroid pulse therapy and plasmapheresis, and he fully recovered visual acuity. The other two, who were left untreated in the acute phase, had sequelae of severe visual disturbances in the affected eyes.

Conclusions: These cases suggest possible association between minor trauma to the eyes and the subsequent occurrence of optic neuritis in patients with serum anti-AQP4 antibodies. Avoiding ocular trauma and early administration of steroid pulse therapy in response to optic neuritis after trauma are desired in such cases.
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http://dx.doi.org/10.1002/brb3.2083DOI Listing
May 2021

Long-Term Safety and Efficacy of Eculizumab in Aquaporin-4 IgG-Positive NMOSD.

Ann Neurol 2021 Feb 14. Epub 2021 Feb 14.

Mayo Clinic, Rochester, MN.

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.
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http://dx.doi.org/10.1002/ana.26049DOI Listing
February 2021

Sensitivity analysis of the primary endpoint from the N-MOmentum study of inebilizumab in NMOSD.

Mult Scler 2021 Feb 4:1352458521988926. Epub 2021 Feb 4.

Viela Bio, Gaithersburg, MD, USA.

Background: In the N-MOmentum trial, the risk of an adjudicated neuromyelitis optica spectrum disorder (NMOSD) attack was significantly reduced with inebilizumab compared with placebo.

Objective: To demonstrate the robustness of this finding, using pre-specified sensitivity and subgroup analyses.

Methods: N-MOmentum is a prospective, randomized, placebo-controlled, double-masked trial of inebilizumab, an anti-CD19 monoclonal B-cell-depleting antibody, in patients with NMOSD. Pre-planned and analyses were performed to evaluate the primary endpoint across a range of attack definitions and demographic groups, as well as key secondary endpoints.

Results: In the N-MOmentum trial (ClinicalTrials.gov: NCT02200770), 174 participants received inebilizumab and 56 received placebo. Attack risk for inebilizumab versus placebo was consistently and significantly reduced, regardless of attack definition, type of attack, baseline disability, ethnicity, treatment history, or disease course (all with hazard ratios < 0.4 favoring inebilizumab, < 0.05). Analyses of secondary endpoints showed similar trends.

Conclusion: N-MOmentum demonstrated that inebilizumab provides a robust reduction in the risk of NMOSD attacks regardless of attack evaluation method, attack type, patient demographics, or previous therapy.The N-MOmentum study is registered at ClinicalTrials.gov: NCT2200770.
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http://dx.doi.org/10.1177/1352458521988926DOI Listing
February 2021

Optimal management of neuromyelitis optica spectrum disorder with aquaporin-4 antibody by oral prednisolone maintenance therapy.

Mult Scler Relat Disord 2021 Apr 22;49:102750. Epub 2021 Jan 22.

Department of Neurology, Tohoku University Graduate School of Medicine, Sendai, Japan.

Background: Neuromyelitis optica spectrum disorder (NMOSD) is a relapsing neuroinflammatory disease associated with aquaporin-4 antibody. Since disabilities in patients with NMOSD accumulate with attacks, relapse prevention is crucially important for improving long-term outcomes. Corticosteroids are inexpensive and promising drugs for relapse prevention in NMOSD, but few studies have analysed the efficacy of corticosteroids in NMOSD, especially regarding the appropriate dosing and tapering regimens.

Methods: A single-center, retrospective analysis of corticosteroid therapy in aquaporin-4 antibody-positive NMOSD patients fulfilling the 2015 international consensus diagnostic criteria was conducted.

Results: Medical records of a total of 89 Japanese patients with aquaporin-4 antibody-positive NMOSD seen at Department of Neurology, Tohoku University Hospital (2000~2016) were reviewed. At the last follow-up, 66% of the patients were treated with prednisolone (PSL) monotherapy, and the percentage of those receiving PSL monotherapy or a combination of PSL and other immunosuppressants increased from 17.5% in 2000 to 94.1% in 2016. On the other hand, annualised relapse rate (ARR) decreased from 0.78 (13 attacks in 200 person-months) in 2000 to 0.07 (5 attacks in 819 person-months) in 2016. Under PSL treatment, the mean ARR significantly decreased, and disabilities stabilized (PSL treatment vs no-medication; ARR: 0.21 vs 0.98, P < 0.01, Expanded Disability Status Scale score change: +0.02 vs +0.89, P < 0.01, observation periods: 60.1 vs 68.2 months, P=0.26). Using Kaplan-Meier curves, the 10-year relapse-free rate was 46.5% with PSL monotherapy and 7.1% with no medication (hazard ratio: 0.069, 95% confidence interval [CI] 0.024-0.199, P < 0.01). Rapid tapering of PSL (10 mg or less in one year and/or 5 mg or less in two years after clinical attacks) was associated with frequent relapses compared to gradual tapering (more than 10 mg in one year and more than 5 mg in two years after clinical attacks) (rapid vs gradual, 36.7% vs 17.7%, odds ratio 2.69, 95% CI 1.12-6.44, P = 0.02). However, even with PSL of 5 mg/day or less, the relapse rate was low after two years of acute treatment (before vs after, 53.8% vs 13.6%, odds ratio 0.12, 95% CI 0.03-0.50, P < 0.01). Nine patients needed additional immunosuppressants due to insufficient relapse prevention by PSL monotherapy. PSL monotherapy was generally well tolerated, but seven patients had severe adverse events, mainly bone fractures (5 with bone fracture, 1 with femoral capital necrosis and 1 with cerebral infarction).

Conclusion: Our study suggests that PSL monotherapy is effective to prevent relapses in about half of patients with aquaporin-4 antibody-positive NMOSD if the doses are gradually reduced. Although it is important to have a treatment strategy tailored to each patient, this study provides evidence that PSL monotherapy can be an option for relapse prevention in some patients with NMOSD.
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http://dx.doi.org/10.1016/j.msard.2021.102750DOI Listing
April 2021

Patterns of cortical grey matter thickness reduction in multiple sclerosis.

Brain Behav 2021 Apr 27;11(4):e02050. Epub 2021 Jan 27.

Division of Neurology, Tohoku Medical and Pharmaceutical University, Sendai, Japan.

Objective: To examine the patterns of cortical gray matter thickness in multiple sclerosis (MS) patients.

Methods: Seventy-four MS patients-clinically isolated syndrome (4%), relapsing-remitting MS (79%), and progressive MS (17%)-and 21 healthy controls (HCs) underwent 1.5 Tesla T1-weighted 3D MRI examinations to measure brain cortical thickness in a total of 68 regions of interest. Using hierarchical cluster analysis with multivariate cortical thickness data, cortical thickness reduction patterns were cross-sectionally investigated in MS patients.

Results: The MS patients were grouped into three major clusters (Clusters 1, 2, and 3). Most of the regional cortical thickness values were equivalent between the HCs and Cluster 1, but decreased in the order of Clusters 2 and 3. Only the thicknesses of the temporal lobe cortices (the bilateral superior and left middle temporal cortex, as well as the left fusiform cortex) were significantly different among Clusters 1, 2, and 3. In contrast, temporal pole thickness reduction was evident exclusively in Cluster 3, which was also characterized by increased lesion loads in the temporal pole and the adjacent juxtacortical white matter, dilatation of the inferior horn of the lateral ventricle, severe whole-brain volume reduction, and longer disease duration. Although cortical atrophy was significantly more common in the progressive phase, approximately half of the MS patients with the severe cortical atrophy pattern had relapsing-remitting disease.

Conclusion: Cortical thickness reduction patterns in MS are mostly characterized by the degree of temporal lobe cortical atrophy, which may start in the relapsing-remitting phase. Among the temporal lobe cortices, the neurodegenerative change may accelerate in the temporal pole in the progressive phase.
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http://dx.doi.org/10.1002/brb3.2050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8035454PMC
April 2021

CH50 as a putative biomarker of eculizumab treatment in neuromyelitis optica spectrum disorder.

Heliyon 2021 Jan 8;7(1):e05899. Epub 2021 Jan 8.

Department of Neurology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.

Here we report 3 cases of neuromyelitis optica spectrum disorder (NMOSD), who were all treated with eculizumab and could be observed with monitoring serum C3, C4 and 50% hemolytic complement (CH50) before and after the treatment. Serum C3 and C4 were not dramatically changed during the treatment, in contrast serum CH50 level of each patient had diminished and kept under the detection limit after the treatment without clinical worsening, even in the situation of extending dosing. Serum CH50 level is useful to monitor the drug efficacy during eculizumab treatment.
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http://dx.doi.org/10.1016/j.heliyon.2021.e05899DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7809378PMC
January 2021

Impact of comorbid Sjögren syndrome in anti-aquaporin-4 antibody-positive neuromyelitis optica spectrum disorders.

J Neurol 2021 May 8;268(5):1938-1944. Epub 2021 Jan 8.

Department of Neurology, Tohoku Medical and Pharmaceutical University, Sendai, Japan.

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.
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http://dx.doi.org/10.1007/s00415-020-10377-6DOI Listing
May 2021

Progression pattern of neurological disability with respect to clinical attacks in anti-MOG antibody-associated disorders.

J Neuroimmunol 2021 Feb 31;351:577467. Epub 2020 Dec 31.

Department of Neurology, Tohoku Medical and Pharmaceutical University, Sendai, Japan.

The progression pattern of neurological disability among patients with anti-myelin oligodendrocyte glycoprotein antibody-associated disorders (MOGAD) was evaluated. Neurological disability was evaluated annually for 408 person-years in 50 patients. More than 30% of the patients had clinical relapses in the first 5 years. Disability progression independent of relapse activity (PIRA) was not seen, whereas a stepwise disability progression was observed after clinical attacks in some instances. Disability worsening was more frequent after relapses than after the onset episode (p < 0.01). Similar to patients with anti-aquaporin-4 antibodies, attack-related stepwise disability progression without PIRA is typical in MOGAD, suggesting the importance of relapse prevention.
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http://dx.doi.org/10.1016/j.jneuroim.2020.577467DOI Listing
February 2021

Distinctive lesions of brain MRI between MOG-antibody-associated and AQP4-antibody-associated diseases.

J Neurol Neurosurg Psychiatry 2020 Dec 30. Epub 2020 Dec 30.

Department of Neurology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.

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http://dx.doi.org/10.1136/jnnp-2020-324818DOI Listing
December 2020

Benefits of eculizumab in AQP4+ neuromyelitis optica spectrum disorder: Subgroup analyses of the randomized controlled phase 3 PREVENT trial.

Mult Scler Relat Disord 2021 Jan 26;47:102641. Epub 2020 Nov 26.

Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. Electronic address:

Background: Antibodies to the aquaporin-4 (AQP4) water channel in neuromyelitis optica spectrum disorder (NMOSD) are reported to trigger the complement cascade, which is implicated in astrocyte damage and subsequent neuronal injury. The PREVENT study demonstrated that the terminal complement inhibitor eculizumab reduces adjudicated relapse risk in patients with anti-AQP4 immunoglobulin G-positive (AQP4+) NMOSD. The objective of this analysis was to evaluate the efficacy of eculizumab in reducing relapse risk and its safety in AQP4+ NMOSD across clinically relevant subgroups in PREVENT.

Methods: In the randomized, double-blind, time-to-event, phase 3 PREVENT trial, 143 adults received eculizumab (maintenance dose, 1200 mg/2 weeks) or placebo (2:1), with stable-dose concomitant immunosuppressive therapy (IST) permitted (except rituximab and mitoxantrone). Post hoc analyses of relapses and adverse events were performed for prespecified and post hoc subgroups based on concomitant IST and prior rituximab use, demographic and disease characteristics, and autoimmune comorbidity.

Results: The significant reduction in relapse risk observed for eculizumab versus placebo in the overall PREVENT population was consistently maintained across subgroups based on concomitant IST and previous rituximab use, age, sex, region, race, time since clinical onset of NMOSD, historical annualized relapse rate, baseline Expanded Disability Status Scale score, and history of another autoimmune disorder. The serious infection rate was lower with eculizumab than placebo regardless of rituximab use in the previous year, concomitant IST use, or history of another autoimmune disorder.

Conclusion: Across a wide range of clinically relevant AQP4+ NMOSD patient subgroups in PREVENT, eculizumab therapy was consistently effective versus placebo in reducing relapse risk, with no apparent increase in serious infection rate.

Trial Registration: NCT01892345 (ClinicalTrials.gov).
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http://dx.doi.org/10.1016/j.msard.2020.102641DOI Listing
January 2021

New therapies for neuromyelitis optica spectrum disorder.

Lancet Neurol 2021 01 10;20(1):60-67. Epub 2020 Nov 10.

Department of Clinical Neurology, John Radcliffe Hospital and University of Oxford, Oxford, UK.

Background: Neuromyelitis optica spectrum disorder is an autoimmune disease of the CNS that primarily affects the optic nerves and spinal cord. Most patients have serum antibodies targeting the aquaporin-4 water channel expressed on the end-feet of astrocytes. Although the prevalence of neuromyelitis optica spectrum disorder is limited to around 1-2 people per 100 000, severe immune-mediated attacks can quickly lead to blindness and paralysis if undiagnosed and untreated. However, diagnosis is straightforward when the highly specific serum aquaporin-4 antibodies are detected with cell-based assays.

Recent Developments: Four randomised controlled trials have tested the efficacy of three new therapies (eculizumab, satralizumab, and inebilizumab) for patients with neuromyelitis optica spectrum disorder that all showed a benefit in preventing future attacks. These therapies have different targets within the immune pathogenic process, and the four trials have similarities and differences that mean they might change the therapeutic landscape for people with neuromyelitis optica spectrum disorder in different ways. Efficacy, safety, tolerability, and practical considerations, including potential cost, differ for each drug and might affect the rate of use in real-world populations of patients with neuromyelitis optica spectrum disorder. WHERE NEXT?: Despite the rarity of neuromyelitis optica spectrum disorder, a relative abundance of preventive treatment options now exists. In the future, trials should focus on areas of unmet need, including aquaporin-4 seronegative disease, and on development of treatments for acute relapses and for recovery from autoimmune attacks in the CNS.
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http://dx.doi.org/10.1016/S1474-4422(20)30392-6DOI Listing
January 2021

Seasonal variation of onset in patients with anti-aquaporin-4 antibodies and anti-myelin oligodendrocyte glycoprotein antibody.

J Neuroimmunol 2020 12 29;349:577431. Epub 2020 Oct 29.

Department of Neurology, Tohoku Medical and Pharmaceutical University, Sendai, Japan.

This study aimed to determine the seasonal impact on the clinical onset of inflammatory neurological diseases of the central nervous system by analyzing the onset month with information on clinical manifestations in Japanese patients. As a result, patients with anti-aquaporin-4 antibodies (AQP4-IgG)-positive neuromyelitis optica spectrum disorders (NMOSD) showed spring-summer predominance of the clinical onset. Conversely, patients with anti-myelin oligodendrocyte glycoprotein antibody (MOG-IgG)-associated disease showed autumn-winter predominance of the clinical onset. Both seasonal variations were irrespective of the clinical manifestation. Environmental factors with seasonal variation influence the development of neurological conditions related to AQP4-IgG and MOG-IgG.
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http://dx.doi.org/10.1016/j.jneuroim.2020.577431DOI Listing
December 2020

Rapid Administration of High-Dose Intravenous Methylprednisolone Improves Visual Outcomes After Optic Neuritis in Patients With AQP4-IgG-Positive NMOSD.

Front Neurol 2020 2;11:932. Epub 2020 Sep 2.

Department of Neurology, Tohoku Medical and Pharmaceutical University, Sendai, Japan.

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). 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. 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, = 0.0018). The lesion length on orbital MRI was also correlated with the eventual visual prognosis (rho = 0.68, < 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 ( = 0.0004) and a younger age at onset ( = 0.0071) were significantly associated with better visual outcomes. 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.
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http://dx.doi.org/10.3389/fneur.2020.00932DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7505044PMC
September 2020

Interleukin-6 in neuromyelitis optica spectrum disorder pathophysiology.

Neurol Neuroimmunol Neuroinflamm 2020 09 20;7(5). Epub 2020 Aug 20.

From the Department of Multiple Sclerosis Therapeutics (K.F.), Fukushima Medical University School of Medicine; and Multiple Sclerosis and Neuromyelitis Optica Center, Southern TOHOKU Research Institute for Neuroscience, Koriyama, Japan; Departments of Neurology and Ophthalmology (J.L.B.), Programs in Neuroscience and Immunology, School of Medicine, University of Colorado, Aurora; Department of Neurology (J.S.), Hôpital de Hautepierre, Strasbourg Cedex, France; Chugai Pharmaceutical Co. (M.H.), Ltd, Tokyo, Japan; Department of Neurology (I.K.), St. Josef Hospital, Ruhr University Bochum; Marianne-Strauß-Klinik (I.K.), Behandlungszentrum Kempfenhausen für Multiple Sklerose Kranke gGmbH, Berg, Germany; Department of Neurology (B.G.W.), Mayo Clinic, Rochester, MN; ApotheCom (D.K., T.M.), London, UK; and Department of Immunology (T.Y.), National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan.

Neuromyelitis optica spectrum disorder (NMOSD) is a rare autoimmune disorder that preferentially affects the spinal cord and optic nerve. Most patients with NMOSD experience severe relapses that lead to permanent neurologic disability; therefore, limiting frequency and severity of these attacks is the primary goal of disease management. Currently, patients are treated with immunosuppressants. Interleukin-6 (IL-6) is a pleiotropic cytokine that is significantly elevated in the serum and the CSF of patients with NMOSD. IL-6 may have multiple roles in NMOSD pathophysiology by promoting plasmablast survival, stimulating the production of antibodies against aquaporin-4, disrupting blood-brain barrier integrity and functionality, and enhancing proinflammatory T-lymphocyte differentiation and activation. Case series have shown decreased relapse rates following IL-6 receptor (IL-6R) blockade in patients with NMOSD, and 2 recent phase 3 randomized controlled trials confirmed that IL-6R inhibition reduces the risk of relapses in NMOSD. As such, inhibition of IL-6 activity represents a promising emerging therapy for the management of NMOSD manifestations. In this review, we summarize the role of IL-6 in the context of NMOSD.
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http://dx.doi.org/10.1212/NXI.0000000000000841DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7455314PMC
September 2020

Progressive patterns of neurological disability in multiple sclerosis and neuromyelitis optica spectrum disorders.

Sci Rep 2020 08 17;10(1):13890. Epub 2020 Aug 17.

Department of Neurology, Tohoku Medical and Pharmaceutical University, Sendai, Japan.

The progressive patterns of neurological disability in multiple sclerosis (MS) and neuromyelitis optica spectrum disorders (NMOSD) and the significance of clinical relapses to the progressions of neurological disability in these diseases have not been fully elucidated. In this study, to elucidate the impact of relapses to the progression of accumulated neurological disability and to identify the factors to affect the progression of neurological disability in MS and NMOSD, we followed 62 consecutive MS patients and 33 consecutive NMOSD patients for more than 5 years with the clinical symptoms, relapse occurrence, and Expanded Disability Status Scale (EDSS) in the chronic phase. All enrolled MS patients were confirmed to be negative for serum anti-myelin oligodendrocyte glycoprotein antibody. As a result, patients with NMOSD showed significantly severer neurological disability at 5 years from onset than MS patients. Progression in EDSS score was almost exclusively seen after clinical attacks in NMOSD, whereas progression could be observed apart from relapses in MS. Neurological disability did not change without attacks in NMOSD, whereas it sometimes spontaneously improved or deteriorated apart from relapses in MS (p < 0.001). In patients with MS, those with responsible lesions primarily in spinal cord were more likely to show such spontaneous improvement. In conclusion, clinical deterioration in NMOSD patients is irreversible and almost exclusively takes place at the timing of clinical attacks with stepwise accumulation of neurological disability. Meanwhile, changes in EDSS score can be seen apart from relapses in MS patients. Neurological disability in MS patients is partly reversible, and the patients with disease modifying drugs sometimes present spontaneous improvement of the neurological disability.
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http://dx.doi.org/10.1038/s41598-020-70919-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7431838PMC
August 2020

Impact of intrathecal IgG synthesis on neurological disability in patients with multiple sclerosis.

Mult Scler Relat Disord 2020 Oct 7;45:102382. Epub 2020 Jul 7.

Department of Neurology, Tohoku Medical and Pharmaceutical University, Sendai, Japan.

Background: The association between routine laboratory findings, including cerebrospinal fluid biomarkers, and neurological outcomes in patients with multiple sclerosis (MS) has not been fully elucidated. In this study, we evaluated blood and cerebrospinal fluid (CSF) analysis results at diagnosis and before treatment in patients with MS and assessed their correlations with neurological outcomes.

Materials And Methods: In this study, 38 consecutive patients with MS (36 with relapsing-remitting MS and 2 with primary progressive MS) were recruited. Before treatment, all patients underwent routine CSF analysis at the time of diagnosis, including evaluation of albumin and immunoglobulin G (IgG) levels. The association between laboratory data and neurological outcomes was comprehensively evaluated. Subsequent neurological outcome was assessed by using the Expanded Disability Status Scale (EDSS) score at 1 year and 5 years after diagnosis and relapse frequency in the first year and in the first 5 years.

Results: The IgG level in the CSF (rho = 0.46, p = 0.004), oligoclonal band count (rho = 0.61, p = 0.006), ratio of IgG and total protein in CSF (rho = 0.59, p < 0.0001), and ratio of IgG and albumin in CSF (rho = 0.67, p < 0.0001) showed moderate to strong correlations with the subsequent EDSS score 1 year after diagnosis. These variables still showed significant correlations with EDSS 5 years later. Albumin and lactate dehydrogenase levels in CSF did not correlate with the subsequent EDSS score. Relapse frequency did not correlate with any of the studied serum and CSF biomarkers.

Conclusion: IgG levels in CSF at MS diagnosis are significantly correlated with the level of neurological disability independent of the relapse frequency. Markers of intrathecal IgG synthesis, such as the IgG index, are useful in estimating the present and subsequent clinical severity in patients with MS.
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http://dx.doi.org/10.1016/j.msard.2020.102382DOI Listing
October 2020

Epidemiology of Neuromyelitis Optica Spectrum Disorder and Its Prevalence and Incidence Worldwide.

Front Neurol 2020 26;11:501. Epub 2020 Jun 26.

Department of Multiple Sclerosis Therapeutics, Fukushima Medical University School of Medicine, and Multiple Sclerosis and Neuromyelitis Optica Center, Southern TOHOKU Research Institute for Neuroscience, Koriyama, Japan.

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.
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http://dx.doi.org/10.3389/fneur.2020.00501DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7332882PMC
June 2020

Measurements of the corpus callosum index and fractional anisotropy of the corpus callosum and their cutoff values are useful to assess global brain volume loss in multiple sclerosis.

Mult Scler Relat Disord 2020 Oct 8;45:102388. Epub 2020 Jul 8.

Division of Neurology, Tohoku Medical and Pharmaceutical University, Sendai, Japan.

Objectives: Recent studies suggest that parameters of the corpus callosum (CC), such as the CC index (CCI) and fractional anisotropy (FA) of the CC, may be related to the degree of brain volume loss (BVL) in MS patients; however, cutoff values that determine the degree of BVL have not been set.

Methods: Seventy-five MS patients and 21 healthy controls (HCs) underwent volumetric MRI examinations. MS patients were also evaluated for T2 lesion load, the CCI, and FA of the CC. Among the 75 MS patients, 20 had undergone cognitive assessments with the Symbol Digit Modalities Test (SDMT). After 75 MS patients were categorized into mild, moderate, or severe BVL subgroups according to our previous report, we performed receiver operating characteristic analysis to determine the cutoff values of CCI and FA, categorizing the MS patients into the three subgroups.

Results: The volume of the CC was significantly reduced in MS patients compared to that in HCs. The CCI and FA were significantly associated with EDSS, disease duration, clinical phenotype, T2-lesion load, and whole brain volume. The FA was significantly correlated with the SDMT score. We identified optimal cutoff values for the CCI and FA of 0.32 (85% sensitivity, 92% specificity) and 0.39 (100% sensitivity, 92% specificity), respectively, which discriminated the severe BVL group from others, and 0.385 (84% sensitivity, 74% specificity) and 0.45 (81% sensitivity, 89% specificity), respectively, which discriminated the mild BVL group from others.

Conclusion: The CCI and FA cutoff values may be useful for evaluating the degree of MS brain atrophy in clinical practice.
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http://dx.doi.org/10.1016/j.msard.2020.102388DOI Listing
October 2020

Treatment of MOG-IgG-associated disorder with rituximab: An international study of 121 patients.

Mult Scler Relat Disord 2020 Sep 2;44:102251. Epub 2020 Jun 2.

Department of Pediatric Neurology, Children's Hospital Datteln, University Witten/Herdecke, Witten, Germany.

Objective: To assess the effect of anti-CD20 B-cell depletion with rituximab (RTX) on relapse rates in myelin oligodendrocyte glycoprotein antibody-associated disorder (MOGAD).

Methods: Retrospective review of RTX-treated MOGAD patients from 29 centres in 13 countries. The primary outcome measure was change in relapse rate after starting rituximab (Poisson regression model).

Results: Data on 121 patients were analysed, including 30 (24.8%) children. Twenty/121 (16.5%) were treated after one attack, of whom 14/20 (70.0%) remained relapse-free after median (IQR) 11.2 (6.3-14.1) months. The remainder (101/121, 83.5%) were treated after two or more attacks, of whom 53/101 (52.5%) remained relapse-free after median 12.1 (6.3-24.9) months. In this 'relapsing group', relapse rate declined by 37% (95%CI=19-52%, p<0.001) overall, 63% (95%CI=35-79%, p = 0.001) when RTX was used first line (n = 47), and 26% (95%CI=2-44%, p = 0.038) when used after other steroid-sparing immunotherapies (n = 54). Predicted 1-year and 2-year relapse-free survival was 79% and 55% for first-line RTX therapy, and 38% and 18% for second-/third-line therapy. Circulating CD19B-cells were suppressed to <1% of total circulating lymphocyte population at the time of 45/57 (78.9%) relapses.

Conclusion: RTX reduced relapse rates in MOGAD. However, many patients continued to relapse despite apparent B-cell depletion. Prospective controlled studies are needed to validate these results.
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http://dx.doi.org/10.1016/j.msard.2020.102251DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7895306PMC
September 2020

Myelin oligodendrocyte glycoprotein antibody-associated disease: an immunopathological study.

Brain 2020 05;143(5):1431-1446

Department of Neurology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.

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.
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http://dx.doi.org/10.1093/brain/awaa102DOI Listing
May 2020

Neuromyelitis optica spectrum disorders and myelin oligodendrocyte glycoprotein antibody-associated disease: current topics.

Curr Opin Neurol 2020 06;33(3):300-308

University of Utah School of Medicine, Salt Lake City, Utah, USA.

Purpose Of Review: We reviewed present topics on neuromyelitis optica spectrum disorders (NMOSD) and myelin oligodendrocyte glycoprotein (MOG)-antibody-associated disease (MOGAD).

Recent Findings: The number of NMOSD-related publications have increased year by year after the discovery of aquaporin 4 (AQP4)-antibody, and those on MOGAD started to surge since 2012-2013. Recent clinic-epidemiological surveys in NMOSD suggest that some racial differences in the prevalence and the clinical course. At present, experts feel the 2015 diagnostic criteria of AQP4-antibody-seronegative NMOSD should be revised. Randomized controlled trials of monoclonal antibodies in NMOSD have demonstrated a significant risk reduction of relapse, especially in AQP4-antibody-positive cases. Meanwhile, the efficacy in seronegative NMOSD was unclear. MOGAD can show NMO and other clinical phenotypes, but the clinical manifestations and frequencies are different in children and adults. One pathological study has suggested that MOGAD is distinct from AQP4-antibody-positive NMOSD, but may share some features with multiple sclerosis and acute disseminated encephalomyelitis. Immunosuppressive therapy can reduce relapse in MOGAD, but, unlike AQP4-antibody-positive NMOSD, some MOGAD patients treated with rituximab experience relapses despite a complete B-cell depletion.

Summary: Our understanding and therapy of AQP4-antibody-positive NMOSD has made a significant progress, and recent research has identified challenges in seronegative NMOSD and MOGAD.
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http://dx.doi.org/10.1097/WCO.0000000000000828DOI Listing
June 2020

Induction of aquaporin 4-reactive antibodies in Lewis rats immunized with aquaporin 4 mimotopes.

Acta Neuropathol Commun 2020 04 15;8(1):49. Epub 2020 Apr 15.

Department Neuroimmunology, Medical University Vienna, Center for Brain Research, Spitalgasse 4, A-1090, Vienna, Austria.

Most cases of neuromyelitis optica spectrum disorders (NMOSD) harbor pathogenic autoantibodies against the water channel aquaporin 4 (AQP4). Binding of these antibodies to AQP4 on astrocytes initiates damage to these cells, which culminates in the formation of large tissue destructive lesions in the central nervous system (CNS). Consequently, untreated patients may become permanently blind or paralyzed. Studies on the induction and breakage of tolerance to AQP4 could be of great benefit for NMOSD patients. So far, however, all attempts to create suitable animal models by active sensitization have failed. We addressed this challenge and identified peptides, which mimic the conformational AQP4 epitopes recognized by pathogenic antibodies of NMOSD patients. Here we show that these mimotopes can induce the production of AQP4-reactive antibodies in Lewis rats. Hence, our results provide a conceptual framework for the formation of such antibodies in NMOSD patients, and aid to improve immunization strategies for the creation of animal models suitable for tolerance studies in this devastating disease.
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http://dx.doi.org/10.1186/s40478-020-00920-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7160927PMC
April 2020

Risk factors of attacks in neuromyelitis optica spectrum disorders.

J Neuroimmunol 2020 06 7;343:577236. Epub 2020 Apr 7.

Department of Neurology, Tohoku Medical and Pharmaceutical University, Sendai, Japan.

Predisposing factors before the onset of neuromyelitis optica spectrum disorders (NMOSD) have not been systematically evaluated by now. We investigated the detailed pre-onset history in consecutive NMOSD patients. Thirteen of the enrolled 53 NMOSD patients (24.5%) had accompanying autoimmune diseases, such as Sjögren's syndrome. History of malignancy was seen in 8 of the 53 patients (15.1%). Recent history of non-neurological clinical episodes, such as systemic allergic reaction, systemic infection, surgical operation, or traumatic injury, was seen in 23 of the 53 patients (43.4%). NMOSD patients are likely to have pre-onset history of other autoimmune diseases, malignancy, or recent non-neurological systemic conditions, which may predispose or trigger the onset of NMOSD.
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http://dx.doi.org/10.1016/j.jneuroim.2020.577236DOI Listing
June 2020

Number of MRI T1-hypointensity corrected by T2/FLAIR lesion volume indicates clinical severity in patients with multiple sclerosis.

PLoS One 2020 3;15(4):e0231225. Epub 2020 Apr 3.

Department of Neurology, Tohoku Medical and Pharmaceutical University, Sendai, Japan.

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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0231225PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7122737PMC
July 2020

CSF levels of glutamine synthetase and GFAP to explore astrocytic damage in seronegative NMOSD.

J Neurol Neurosurg Psychiatry 2020 06 26;91(6):605-611. Epub 2020 Mar 26.

Institute of Neurology, Neuroimmunology and CSF Laboratory, University College London, London, UK.

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 (r=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.
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http://dx.doi.org/10.1136/jnnp-2019-322286DOI Listing
June 2020