Publications by authors named "Ichiro Nakashima"

190 Publications

A 23-year follow-up report of juvenile-onset Sandhoff disease presenting with a motor neuron disease phenotype and a novel variant.

Brain Dev 2021 Jun 30. Epub 2021 Jun 30.

Department of Pediatric Neurology, Miyagi Children's Hospital, Sendai 989-3126, Japan; Department of Pediatric Neurology, Takuto Rehabilitation Center for Children, Sendai, Japan. Electronic address:

Background: The clinical severity of Sandhoff disease is known to vary widely. Furthermore, long-term follow-up report is very limited in the literature.

Case Presentation: We present a long-term follow-up report of a patient with juvenile-onset Sandhoff disease with a motor neuron disease phenotype. The patient had compound heterozygous variants of HEXB (p.Trp460Arg, p. Arg533His); the Trp460Arg was a novel variant. Long-term follow-up revealed no intellectual deterioration, swallowing dysfunction, or respiratory muscle dysfunction despite progressive weakness of the extremities and sensory disturbances.

Conclusion: We need to be aware of Sandhoff disease in patients with juvenile-onset motor neuron disease.
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http://dx.doi.org/10.1016/j.braindev.2021.06.007DOI Listing
June 2021

Asian and African/Caribbean AQP4-NMOSD patient outcomes according to self-identified race and place of residence.

Mult Scler Relat Disord 2021 Jun 15;53:103080. Epub 2021 Jun 15.

Nuffield Department of Clinical Neurosciences, West Wing, John Radcliffe Hospital, Oxford University Hospitals, Oxford OX3 9DU, United Kingdom. Electronic address:

Background: Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune astrocytopathy characterized by aquaporin-4 antibodies, whose prognosis is influenced by onset age, race, environmental exposures and immunosuppression. Distinguishing the contribution of environment from genetics is challenging. We aimed to compare neuromyelitis optica spectrum disorder (NMOSD) patient outcomes according to self-identified racial group and place of residence.

Methods: This retrospective analysis of prospectively collected data included non-white anti-aquaporin-4 antibody positive NMOSD patients under follow-up from 15 centers [United Kingdom, France, Germany, Denmark, Martinique, United States of America, Japan, South Korea, Singapore, Thailand, China (including Hong Kong) and India]. Racial groups were designated: African/Caribbean; South Asian; East Asian (including Southeast Asia). Patients from these racial groups residing outside Africa/Caribbean or Asia were compared with those living in the Caribbean or the Asian areas. Kaplan-Meier survival curves and Cox models were generated using time to sustained Expanded Disability Status Scale≥6.0 or death; time to sustained Kurtzke Visual Function Score≥3.0 or a composite endpoint of all three.

Results: Among 821 patients, African/Caribbean patients (n = 206) had the shortest time to immunosuppression and higher visual disability at onset. South Asian patients (n = 65) were younger, had lower visual disability at onset and higher mortality rate. East Asians (n = 550) had the lowest relapse rate and lowest accrued motor disability. Survival analysis of African/Caribbean outside Africa/Caribbean vs those in the Caribbean showed a significant difference in the composite endpoint (p = 0.024,log-rank test), not apparently related to treatment differences. No significant differences between native and those residing outside Asia were found for other racial groups.

Conclusion: This NMOSD study reports the effects of place of residence on the outcomes in different races. Place of residence may not be a significant driver of disability among Asian patients, while it may influence African/Caribbean patient outcomes. Validating these findings could help distinguish between genetic causes and potentially modifiable environmental factors.
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http://dx.doi.org/10.1016/j.msard.2021.103080DOI Listing
June 2021

Serum neurofilament light is a sensitive biomarker that reflects grey matter volume in Japanese patients with multiple sclerosis.

J Neurol Sci 2021 Jun 2;427:117528. Epub 2021 Jun 2.

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

Objective: To evaluate the degree of neuroaxonal injury in Japanese multiple sclerosis (MS) patients using serum neurofilament light (sNfL) and to investigate the relationship of sNFL with the degree of brain volume.

Methods: sNfL levels in 82 consecutive Japanese MS patients in remission were cross-sectionally evaluated using a single molecule array assay. Within this sample, cross-sectional volumetric brain MRI data was evaluated in 80 patients, and longitudinal data was evaluated in 63 patients.

Results: MS patients (female/male = 61/21), including those with relapsing-remitting MS (82%), secondary progressive MS (17%), and primary progressive MS (1%), were studied. The mean age of the patients was 41.2 ± 8.7 years, and 77 of the MS patients (94%) were treated with disease-modifying therapy (DMT). Their median sNfL level was 7.985 (IQR, 5.959-10.9), and their sNfL levels were significantly correlated with their grey matter volume and their age. A standard least squares regression model revealed that approximately 57% of the variation in grey matter volume could be explained by a regression equation using three explanatory variables: sNfL concentration, age, and sex. Moreover, the sNfL level multiplied by disease duration was significantly correlated with the Expanded Disability Status Scale (EDSS) scores and whole and grey matter volumes.

Conclusion: Although neuroaxonal injury appeared to be mild in our Japanese MS patients, their sNfL levels significantly reflected grey matter volume. Moreover, when multiplied by the disease duration, sNfL can reflect disability and brain volume.
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http://dx.doi.org/10.1016/j.jns.2021.117528DOI Listing
June 2021

[Anti-Myelin Oligodendrocyte Glycoprotein Antibody Associated Disease].

Brain Nerve 2021 May;73(5):483-488

Division of Neurology, Tohoku Medical and Pharmaceutical University.

Anti-myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease belongs to a new spectrum of disease entities that cause acute inflammatory demyelinating lesions in the central nervous system. MOG antibody-associated disease presents with several phenotypes including optic neuritis, myelitis, neuromyelitis optica spectrum disorder, brain stem encephalitis, acute disseminated encephalitis, and cortical encephalitis. For the diagnosis, brain magnetic resonance imaging (MRI) and cerebrospinal fluid studies are required to prove inflammatory demyelination apart from the identification of anti-MOG antibodies using cell-based assays. Immunotherapy is an effective treatment strategy to prevent relapse.
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http://dx.doi.org/10.11477/mf.1416201789DOI Listing
May 2021

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

Neurology 2021 07 12;97(1):e1-e12. Epub 2021 May 12.

From the Department of Neurology (T.A., T.T., T.M., K.K., Y.T., S.N., R.O., M.A.), Tohoku University Graduate School of Medicine; Department of Education and Support for Regional Medicine (T.A., T.I.), Tohoku University Hospital, Sendai; Department of Neurology (T.T.), National Hospital Organization Yonezawa National Hospital; Department of Neurology (J.F., I.N.), Tohoku Medical and Pharmaceutical University, Sendai; and Department of Multiple Sclerosis Therapeutics (K.F.), Fukushima Medical University, 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 CSF simultaneously collected in the acute attacks. The quotients between CSF and serum levels of albumin, total immunoglobulin G, and each disease-specific antibody were calculated. Intrathecal production level in each disease-specific antibody was evaluated by calculating the 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 >10 times higher than AQP4-IgG quotients (effect size = 0.659, < 0.0001). Elevated antibody index (>4.0) was confirmed in 12 of 21 with MOG-IgG, whereas it was seen only in 1 of 16 with AQP4-IgG (φ = 0.528, < 0.0001). The CSF MOG-IgG titers (ρ = 0.519, = 0.001) and antibody indexes for MOG-IgG (ρ = 0.472, = 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
July 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

A nation-wide survey of Japanese pediatric MOG antibody-associated diseases.

Brain Dev 2021 Jun 18;43(6):705-713. Epub 2021 Feb 18.

Department of Pediatrics, Osaka Medical College, Osaka, Japan.

Objective: To elucidate the clinical characteristics of Japanese pediatric patients with acquired demyelinating diseases (ADS), positive for myelin oligodendrocyte glycoprotein antibody (MOG-IgG), we conducted a nation-wide survey.

Methods: Information about pediatric patients under 18 years old with ADS was solicited with surveys sent to 323 facilities. In an initial survey, we asked whether the center had any patients with ADS, and the MOG-IgG serostatus of the patients. In a follow-up survey, we requested more precise information on patients with ADS.

Results: Initial survey: 263 replies providing information on 175 patients were received. MOG-IgG were examined in 78 patients and 54 of those (69%) were positive for MOG-IgG. Follow-up survey: The characteristic involvement was optic neuritis, with visual disturbance and optic pain as characteristic symptoms. The relapse rate was 44% in patients positive for MOG-IgG, which was higher than that in seronegative patients (38%). For acute phase treatments, corticosteroid (CS), plasma exchange, and intravenous immunoglobulin (IVIG) were useful. To prevent relapse, CS, intermittent IVIG, immunosuppressants, and monoclonal antibodies were useful, but the efficacies of disease modifying drugs were uncertain. Sequelae such as visual disturbance, cognitive impairment, motor dysfunction, and epilepsy were observed in 11% of patients with MOG-IgG.

Conclusions: MOG antibody-associated diseases were found to be common among pediatric ADS patients. Since a variety of sequelae were observed in these patients, it is important to identify the appropriate treatment to ensure the best outcome. The presence of the MOG autoantibody should be taken into consideration as part of the diagnostic criteria for pediatric ADS.
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http://dx.doi.org/10.1016/j.braindev.2021.01.008DOI Listing
June 2021

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

Brain Behav 2021 05 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
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8119803PMC
May 2021

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

Ann Neurol 2021 06 27;89(6):1088-1098. Epub 2021 Feb 27.

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;89:1088-1098.
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http://dx.doi.org/10.1002/ana.26049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248139PMC
June 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 04 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

Clinical and Radiological Features of Adult Onset Bilateral Medial Frontal Cerebral Cortical Encephalitis With Anti-myelin Oligodendrocyte Glycoprotein Antibody.

Front Neurol 2020 16;11:600169. Epub 2020 Dec 16.

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

To clarify the clinical and radiological features of adult onset anti-myelin oligodendrocyte glycoprotein (MOG) antibody-associated bilateral medial frontal cerebral cortical encephalitis (BFCCE). 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. 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). 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.
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http://dx.doi.org/10.3389/fneur.2020.600169DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7772389PMC
December 2020

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

J Neuroimmunol 2021 02 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

Anti-NMDAR encephalitis may develop concurrently with anti-MOG antibody-associated bilateral medial frontal cerebral cortical encephalitis and relapse with elevated CSF IL-6 and CXCL13.

Mult Scler Relat Disord 2021 Jan 2;47:102611. Epub 2020 Nov 2.

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

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis may develop concurrently with or separate from episodes of demyelinating disorders. Previously, we reported a patient with relapsing anti-NMDAR encephalitis who had presented with bilateral medial frontal cerebral cortical lesions at onset. Recently, we assessed CSF anti-myelin oligodendrocyte glycoprotein (MOG) antibody for the first time in this case and found that the patient had been double positive for anti-NMDAR and anti-MOG antibodies from onset. The two antibody titres, CSF cells, IL-6 and CXCL13 were all elevated at onset. Anti-NMDAR encephalitis may develop concurrently with anti-MOG antibody-associated cortical encephalitis and relapse with elevated levels of CSF cytokines.
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http://dx.doi.org/10.1016/j.msard.2020.102611DOI 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

Myelin oligodendrocyte glycoprotein-IgG-positive, steroid-responsive combined central and peripheral demyelination with recurrent peripheral neuropathy.

Neurol Sci 2021 Mar 19;42(3):1135-1138. Epub 2020 Oct 19.

Department of Neurology, National Hospital Organization Sendai Medical Center, Sendai, Miyagi, Japan.

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.
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http://dx.doi.org/10.1007/s10072-020-04822-7DOI Listing
March 2021

[Treatment of Multiple Sclerosis, Neuromyelitis Optica Spectrum Disorder and Myasthenia Gravis during the COVID-19 Pandemic].

Brain Nerve 2020 Oct;72(10):1079-1083

Division of Neurology, Department of Medicine, Tohoku Medical and Pharmaceutical University.

Coronavirus disease (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 has become a global pandemic. Neuroimmunological diseases, such as multiple sclerosis, neuromyelitis optica spectrum disorders, and myasthenia gravis, require long-term immunotherapies having the potential to increase the risk of infection. However, there are no evidence-based guidelines for the management of these disease during the pandemic, despite increasing concerns in patients and neurologists. Currently, there is no evidence of an elevated risk of morbidity and aggravation of COVID-19 in patients with these diseases, irrespective of whether they receive treatment. To prevent relapse or aggravation of the underlying diseases due to COVID-19, all patients should perform general preventive measures, such as social distancing, frequent hand washing, and respiratory hygiene. In patients undergoing immunotherapy, current treatment should be continued to prevent exacerbation of symptoms; however, exceptions to this include high-risk patients for COVID-19, such as the elderly, those with comorbidities including cardiac and respiratory diseases, those taking therapy with immunosuppressive agents, and those with deteriorating symptoms of COVID-19.
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http://dx.doi.org/10.11477/mf.1416201652DOI Listing
October 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

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

Unilateral chronic pulsatile headache as the single manifestation of anti-MOG antibody-associated unilateral cerebral cortical encephalitis.

J Neuroimmunol 2020 Jul 11;346:577322. Epub 2020 Jul 11.

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

Unilateral cerebral cortical encephalitis (UCCE) with myelin oligodendrocyte glycoprotein (MOG)-antibody comprises a new spectrum of disease entities generally presenting seizures. Here, we report a case of a young adult with anti-MOG antibody-associated UCCE who only presented persistent left pulsatile headache. Neurological examination revealed no deficits. Brain MRI showed a fluid-attenuated inversion recovery hyperintense lesion along the swollen left cerebral cortex. The patient was positive for anti-MOG antibodies. We diagnosed him with anti-MOG antibody-associated UCCE. Immediately after the administration of high-dose IV methylprednisolone, the headache diminished. Anti-MOG antibody-associated UCCE is a new differential diagnosis in patients with unilateral chronic pulsatile headache.
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http://dx.doi.org/10.1016/j.jneuroim.2020.577322DOI Listing
July 2020

Differences in Clinical Features of Myelin Oligodendrocyte Glycoprotein Antibody-Associated Optic Neuritis in White and Asian Race.

Am J Ophthalmol 2020 11 15;219:332-340. Epub 2020 Jul 15.

Department of Ophthalmology, Stanford University, Palo Alto, California, USA; Department of Neurology and Neurological Sciences, Stanford University, Palo Alto, California, USA. Electronic address:

Purpose: To determine whether clinical features and visual outcomes of myelin oligodendrocyte glycoprotein antibody-associated optic neuritis (MOG-ON) differ between White and Asian subjects.

Design: Multicenter retrospective cohort.

Methods: This was a multicenter study of 153 subjects who were White or Asian with a history of adult-onset (age 18 years or older) optic neuritis (ON) and positive MOG-IgG serology by cell-based assay. Subjects were enrolled from 2 unpublished cohorts (January 2017-November 2019) and 9 published cohorts with case-level data available (2012-2018). Subjects with alternative etiologies of demyelinating disease and positive or lack of aquaporin-4-IgG serology result were excluded. The main outcome measurements were clinical features and final visual outcomes.

Results: Of the 153 subjects who were White (n = 80) or Asian (n = 73) included in the study, 93 (61%) were women, mean age of onset was 40.8 ± 14.9 years, and median follow-up was 35.2 months (range: 1-432 months); all of these characteristics were similar between White and Asian subjects. White subjects were more likely to have recurrent ON (57 [71%] vs 20 [27%]; P = .001) and extra-optic nerve manifestations (35 [44%] vs 8 [11%]; P = .001). Optic disc swelling, neuroimaging findings, presenting visual acuity (VA), treatment, and final VA did not differ according to subjects' race. Despite the high prevalence of severe visual loss (<20/200) during nadir, most subjects had good recovery of VA (>20/40) at final examination (51/77 [66%] White subjects vs 52/70 [74%] Asian subjects).

Conclusion: White subjects with MOG-ON were more likely to have recurrent disease and extra-optic nerve manifestations. Visual outcomes were similar between White and Asian subjects.
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http://dx.doi.org/10.1016/j.ajo.2020.07.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7713508PMC
November 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