Publications by authors named "Nasrin Asgari"

52 Publications

Frequency of comorbidities in Neuromyelitis Optica spectrum disorder.

Mult Scler Relat Disord 2021 Feb 9;48:102685. Epub 2020 Dec 9.

Department of Neurology, Slagelse Hospital, Institute of Regional Health Research, Denmark; Department of Neurobiology, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark. Electronic address:

Background: Comorbidity may influence clinical aspects of neuromyelitis optica spectrum disorder (NMOSD). We estimated the prevalence of comorbidities to assess their association with outcomes.

Methods: This retrospective study assessed records of NMOSD patients from 2008 to 2019, categorizing comorbidities into three groups: somatic, psychiatric and autoimmune. Severity of disease was evaluated by the Expanded Disability Status Scale, progression index (PI) and annualized relapse rate. The frequency of comorbidities was compared between anti-aquaporin 4 antibody (AQP4-IgG) seropositive and seronegative patients.

Results: A total of 67 NMOSD patients were enrolled. Thirty-five (52.2%) patients reported at least one comorbidity. In total, 44 comorbidities were found, of which 24 occurred prior to NMOSD onset: 29 somatic, 13 psychiatric and 2 autoimmune entities. The most common comorbidities were anxiety disorders 7/67 (10.4%), followed by migraine 6/67 (8.9%) major depression disorder 6/67 (8.9%), iron deficiency anemia 8/54 (14.8%), and non-autoimmune hypothyroidism 4/67 (6.0%). Psychiatric comorbidities associated with PI in unadjusted (OR=0.538, 95% CI=0.141, 0.935, P=0.009) and adjusted models (OR=0.386, 95% CI=0.022, 0.751, P=0.038). A significantly higher frequency of psychiatric comorbidities was observed in the AQP4-IgG positive patients (P=0.031).

Conclusion: Half of the patients had comorbidities, suggesting screening for comorbidity as part of NMOSD care. The psychiatric comorbidities had impact on clinical outcome.
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http://dx.doi.org/10.1016/j.msard.2020.102685DOI Listing
February 2021

Type I interferon-activated microglia are critical for neuromyelitis optica pathology.

Glia 2021 Apr 26;69(4):943-953. Epub 2020 Nov 26.

Department of Neurobiology Research, Institute for Molecular Medicine, University of Southern Denmark, Odense, Denmark.

Neuromyelitis optica (NMO) is an inflammatory disease of the central nervous system (CNS) most frequently mediated by serum autoantibodies against the water channel aquaporin 4, expressed on CNS astrocytes, resulting in primary astrocytopathy. There is no cure for NMO, and treatment with Type I interferon (IFNI)-IFNβ is ineffective or even detrimental. We have previously shown that both NMO lesions and associated microglial activation were reduced in mice lacking the receptor for IFNβ. However, the role of microglia in NMO is not well understood. In this study, we clarify the pathomechanism for IFNI dependence of and the role of microglia in experimental NMO. Transcriptome analysis showed a strong IFNI footprint in affected CNS tissue as well as in microglial subpopulations. Treatment with IFNβ led to exacerbated pathology and further microglial activation as evidenced by expansion of a CD11c subset of microglia. Importantly, depletion of microglia led to suppression of pathology and decrease of IFNI signature genes. Our data show a pro-pathologic role for IFNI-activated microglia in NMO and open new perspectives for microglia-targeted therapies.
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http://dx.doi.org/10.1002/glia.23938DOI Listing
April 2021

Cohort profile: a collaborative multicentre study of retinal optical coherence tomography in 539 patients with neuromyelitis optica spectrum disorders (CROCTINO).

BMJ Open 2020 10 29;10(10):e035397. Epub 2020 Oct 29.

Experimental and Clinical Research Center, Max Delbrück Center for Molecular Medicine and Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany

Purpose: Optical coherence tomography (OCT) captures retinal damage in neuromyelitis optica spectrum disorders (NMOSD). Previous studies investigating OCT in NMOSD have been limited by the rareness and heterogeneity of the disease. The goal of this study was to establish an image repository platform, which will facilitate neuroimaging studies in NMOSD. Here we summarise the profile of the Collaborative OCT in NMOSD repository as the initial effort in establishing this platform. This repository should prove invaluable for studies using OCT to investigate NMOSD.

Participants: The current cohort includes data from 539 patients with NMOSD and 114 healthy controls. These were collected at 22 participating centres from North and South America, Asia and Europe. The dataset consists of demographic details, diagnosis, antibody status, clinical disability, visual function, history of optic neuritis and other NMOSD defining attacks, and OCT source data from three different OCT devices.

Findings To Date: The cohort informs similar demographic and clinical characteristics as those of previously published NMOSD cohorts. The image repository platform and centre network continue to be available for future prospective neuroimaging studies in NMOSD. For the conduct of the study, we have refined OCT image quality criteria and developed a cross-device intraretinal segmentation pipeline.

Future Plans: We are pursuing several scientific projects based on the repository, such as analysing retinal layer thickness measurements, in this cohort in an attempt to identify differences between distinct disease phenotypes, demographics and ethnicities. The dataset will be available for further projects to interested, qualified parties, such as those using specialised image analysis or artificial intelligence applications.
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http://dx.doi.org/10.1136/bmjopen-2019-035397DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7597491PMC
October 2020

Gender issues of antibody-mediated diseases in neurology: (NMOSD/autoimmune encephalitis/MG).

Ther Adv Neurol Disord 2020 25;13:1756286420949808. Epub 2020 Aug 25.

Department of Neurology, St. Josef Hospital Bochum, Ruhr University of Bochum, Gudrunstrasse 56, Bochum, 44791, Germany.

Neuromyelitis optica spectrum disorder (NMOSD), autoimmune encephalitis (AE), myasthenia gravis (MG) and Lambert-Eaton myasthenic syndrome (LEMS) are antibody-mediated neurological diseases. They have mostly female predominance, affecting many women during childbearing age. Interactions between the underlying disease (or necessary treatment) and pregnancy can occur in every of these illnesses. Herein, we present the characteristics of NMOSD, AE, MG and LEMS in general, and review published data regarding the influence of the different diseases on fertility, pregnancy, puerperium, treatment strategy during pregnancy and post-partum period, and menopause but also male factors. We summarise key elements that should be borne in mind when confronted with such cases.
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http://dx.doi.org/10.1177/1756286420949808DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7450460PMC
August 2020

Cerebrospinal fluid findings in patients with myelin oligodendrocyte glycoprotein (MOG) antibodies. Part 1: Results from 163 lumbar punctures in 100 adult patients.

J Neuroinflammation 2020 Sep 3;17(1):261. Epub 2020 Sep 3.

Molecular Neuroimmunology Group, Department of Neurology, University of Heidelberg, Heidelberg, Germany.

Background: New-generation cell-based assays have demonstrated a robust association of serum autoantibodies to full-length human myelin oligodendrocyte glycoprotein (MOG-IgG) with (mostly recurrent) optic neuritis, myelitis, and brainstem encephalitis, as well as with neuromyelitis optica (NMO)-like or acute-disseminated encephalomyelitis (ADEM)-like presentations. However, only limited data are yet available on cerebrospinal fluid (CSF) findings in MOG-IgG-associated encephalomyelitis (MOG-EM; also termed MOG antibody-associated disease, MOGAD).

Objective: To describe systematically the CSF profile in MOG-EM.

Material And Methods: Cytological and biochemical findings (including white cell counts and differentiation; frequency and patterns of oligoclonal bands; IgG/IgM/IgA and albumin concentrations and CSF/serum ratios; intrathecal IgG/IgA/IgM fractions; locally produced IgG/IgM/IgA concentrations; immunoglobulin class patterns; IgG/IgA/IgM reibergrams; Link index; measles/rubella/zoster (MRZ) reaction; other anti-viral and anti-bacterial antibody indices; CSF total protein; CSF L-lactate) from 163 lumbar punctures in 100 adult patients of mainly Caucasian descent with MOG-EM were analyzed retrospectively.

Results: Most strikingly, CSF-restricted oligoclonal IgG bands, a hallmark of multiple sclerosis (MS), were absent in almost 90% of samples (N = 151), and the MRZ reaction, the most specific laboratory marker of MS known so far, in 100% (N = 62). If present, intrathecal IgG (and, more rarely, IgM) synthesis was low, often transient and mostly restricted to acute attacks. CSF WCC was elevated in > 50% of samples (median 31 cells/μl; mostly lymphocytes and monocytes; > 100/μl in 12%). Neutrophils were present in > 40% of samples; activated lymphocytes were found less frequently and eosinophils and/or plasma cells only very rarely (< 4%). Blood-CSF barrier dysfunction (as indicated by an elevated albumin CSF/serum ratio) was present in 48% of all samples and at least once in 55% of all patients (N = 88) tested. The frequency and degree of CSF alterations were significantly higher in patients with acute myelitis than in patients with acute ON and varied strongly depending on attack severity. CSF L-lactate levels correlated significantly with the spinal cord lesion load in patients with acute myelitis (p < 0.0001). Like pleocytosis, blood-CSF barrier dysfunction was present also during remission in a substantial number of patients.

Conclusion: MOG-IgG-positive EM is characterized by CSF features that are distinct from those in MS. Our findings are important for the differential diagnosis of MS and MOG-EM and add to the understanding of the immunopathogenesis of this newly described autoimmune disease.
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http://dx.doi.org/10.1186/s12974-020-01824-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7470615PMC
September 2020

Protective roles for myeloid cells in neuroinflammation.

Scand J Immunol 2020 Nov 7;92(5):e12963. Epub 2020 Oct 7.

Neurobiology Research, Institute of Molecular Medicine, and BRIDGE, Brain Research - Inter-Disciplinary Guided Excellence, University of Southern Denmark, Odense C, Denmark.

Myeloid cells represent the major cellular component of innate immune responses. Myeloid cells include monocytes and macrophages, granulocytes (neutrophils, basophils and eosinophils) and dendritic cells (DC). The role of myeloid cells has been broadly described both in physiological and in pathological conditions. All tissues or organs are equipped with resident myeloid cells, such as parenchymal microglia in the brain, which contribute to maintaining homeostasis. Moreover, in case of infection or tissue damage, other myeloid cells such as monocytes or granulocytes (especially neutrophils) can be recruited from the circulation, at first to promote inflammation and later to participate in repair and regeneration. This review aims to address the regulatory roles of myeloid cells in inflammatory diseases of the central nervous system (CNS), with a particular focus on recent work showing induction of suppressive function via stimulation of innate signalling in multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE).
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http://dx.doi.org/10.1111/sji.12963DOI Listing
November 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

Pre-pregnancy, obstetric and delivery status in women with neuromyelitis optica spectrum disorder.

Mult Scler Relat Disord 2020 Sep 2;44:102252. Epub 2020 Jun 2.

Department of Neurology, Slagelse Hospital, Institute of Regional Health Research, Denmark; Department of Neurobiology, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark. Electronic address:

Background: Neuromyelitis optica spectrum disorder (NMOSD) is a potentially disabling disease which affects predominantly women of reproductive age.

Objectives: To evaluate the pre-pregnancy condition and to investigate the prevalence of obstetrical and neonatal complaints in NMOSD.

Methods: An observational retrospective study of 37 NMOSD patients positive for aquaporin-4-immunoglobulin-IgG. Age at menarche, menstrual cycle, gravidity, type of delivery obstetrical complications and perinatal problems were recorded. We assessed the annualized relapse rate (ARR).

Results: A total of 23 patients (62%) suffered from irregular menstruations and two from infertility after disease onset. 11 patients had 20 informative pregnancies with 14 deliveries (5 cesareans) and six abortions, four spontaneous, and two ectopic pregnancies after the first trimester. Additionally, three patients experienced threatening abortion and one preeclampsia. No stillbirth or premature birth was recorded. None of the patients experienced attacks during pregnancy, but postpartum relapses occurred after 10 deliveries (71,4%) with the highest ARR (0.937; p = 0.037) during the first three months postpartum compared to pre-pregnancy ARR (0.375). Four patients (10.8%) developed the initial symptoms of NMOSD postpartum.

Conclusion: Irregular menstruation in more than half of NMOSD patients may reflect a hormonal imbalance. Pregnancies were associated with obstetrical complications and increased disease activity postpartum.
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http://dx.doi.org/10.1016/j.msard.2020.102252DOI Listing
September 2020

Efficacy and safety of rituximab in patients with refractory neuromyelitis optica spectrum disorders: A prospective observation in Iranian cases.

Caspian J Intern Med 2020 ;11(2):155-162

Multiple Sclerosis Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran.

Background: Rituximab has been used successfully in the recent years for treatment of neuromyelitis optica spectrum disorders (NMOSD). However, a uniform treatment protocol for maintenance therapy and the best interval for evaluation and retreatment have not been postulated. We evaluated the efficacy and safety of rituximab treatment as second line therapy, in Iranian patients with refractory NMOSD, based on annualized relapse rate (ARR) and expanded disability status scale (EDSS).

Methods: In this prospective before-after study, a total of 18 patients were treated with a loading dose of rituximab (375 mg/m weekly in 4 consecutive weeks). Flow cytometric determination of CD19 B cell in peripheral blood sample was carried every 6 weeks and patients were re-treated based on B cell repopulation with a single dose of 375 mg/m. Wilcoxon signed rank test was used to evaluate the ARR and EDSS before and after treatment. A p-value of <0.05 was considered statistically significant.

Results: Of the 18 patients, 10 (55.5%) were relapse-free during the period of follow up. The EDSS scores were reduced in nine (50%) patients and stable in the remaining nine (50%). The mean EDSS score before and after treatment were 4.1±0.4 and 3.7±0.3, respectively, which was statistically significant. There was also a statistically significant reduction in median ARR after treatment (1.48 (range 0.47-5) vs. 0 (range 0-2)). Rituximab administration did not have significant adverse effect in 94% of patients.

Conclusion: Repeated treatment with Rituximab is an effective and well-tolerated treatment in refractory NMOSD.
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http://dx.doi.org/10.22088/cjim.11.2.155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7265520PMC
January 2020

Inflammatory profiles relate to survival in subtypes of amyotrophic lateral sclerosis.

Neurol Neuroimmunol Neuroinflamm 2020 05 2;7(3). Epub 2020 Mar 2.

From the Institutes of Regional Health Research and Molecular Medicine (M.N.O., N.A.), University of Southern Denmark; Departments of Neurology (M.N.O.), Slagelse Hospital & Biochemistry & Immunology, Lillebaelt Hospital, Vejle, Denmark; Department of Pharmacology and Clinical Neuroscience (A.W., K.F., P.M.A.), Umeå University, Sweden; Department of Clinical Immunology (A.C.N., S.T.L.), Odense University Hospital, Denmark; Department of Pathology (M.W.), Odense University Hospital, Denmark; Biochemistry & Immunology (J.S.M., I.B.), Lillebaelt Hospital, Vejle, Denmark; Institute of Regional Health Research (J.S.M., I.B.), University of Southern Denmark, Odense; Department of Neurology (N.A.), Slagelse Hospital; and OPEN, Odense Patient Data Explorative Network (N.A.), Odense University Hospital, Denmark.

Objective: To investigate inflammatory cytokines in patients with motor neuron disease (MND) evaluating the putative contribution of amyotrophic lateral sclerosis (ALS)-causing gene variants.

Methods: This study is a retrospective case series with prospective follow-up (1994-2016) of 248 patients with MND, of whom 164 had ALS who were screened for mutations in the genes for and . Paired CSF and plasma were collected at the diagnostic evaluation before treatment. A panel of cytokines were measured blindly via digital ELISA on the Simoa platform.

Results: Time from disease onset to death was longer for patients with ALS-causing mutations (mSOD1, n = 24) than those with hexanucleotide repeat expansion (C9orf72HRE) ALS (n = 19; = 0.001) and other ALS (OALS) (n = 119; = 0.0008). Patients with OALS had higher CSF tumor necrosis factor alpha (TNF-α) compared with those with C9orf72HRE ALS ( = 0.014). Patients with C9orf72HRE ALS had higher CSF interferon alpha compared with those with OALS and mSOD1 ALS ( = 0.042 and = 0.042). In patients with ALS, the survival was negatively correlated with plasma interleukin (IL) 10 (hazard ratio [HR] 1.17, 95% CI 1.05-1.30). Plasma TNF-α, IL-10, and TNF-related apoptosis-inducing ligand (TRAIL) (HR 1.01 [1.00-1.02], 1.15 [1.02-1.30], and 1.01 [1.00-1.01], respectively) of patients with OALS, plasma IL-1β (HR 5.90 [1.27-27.5]) of patients with C9orf72HRE ALS, and CSF TRAIL (10.5 [1.12-98.6]) of patients with mSOD1 ALS all correlated negatively with survival.

Conclusions: Differences in survival times in ALS subtypes were correlated with cytokine levels, suggesting specific immune responses related to ALS genetic variants.
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http://dx.doi.org/10.1212/NXI.0000000000000697DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7136052PMC
May 2020

Clinically stable disease is associated with a lower risk of both income loss and disability pension for patients with multiple sclerosis.

J Neurol Neurosurg Psychiatry 2020 01 14;91(1):67-74. Epub 2019 Nov 14.

Danish Multiple Sclerosis Center, Department of Neurology, University of Copenhagen, Rigshospitalet Glostrup, Copenhagen, Denmark.

Objective: To assess the risk of losing income from salaries and risk disability pension for multiple sclerosis patients with a clinically stable disease course 3 years after the start of disease-modifying therapy (DMT).

Methods: Data from the Danish Multiple Sclerosis Registry were linked to other Danish nationwide population-based databases. We included patients who started treatment with a DMT between 2001 and 2014. Patients were categorised into a clinically stable group (No Evidence of Disease Activity (NEDA-2)) and a clinically active group (relapse activity or 6-month confirmed Expanded Disability Status Scale worsening). Outcomes were: (1) loss of regular income from salaries and (2) a transfer payment labelled as disability pension. We used a Cox proportional hazards model to estimate confounder-adjusted HRs, and absolute risks were plotted using cumulative incidence curves accounting for competing risks.

Results: We included 2406 patients for the income analyses and 3123 patients for the disability pension analysis. Median follow-up from index date was ~5 years in both analyses. The NEDA-2 group had a 26% reduced rate of losing income (HR 0.74; 95% CI 0.60 to 0.92). HRs were calculated for 5-year intervals in the disability pension analysis: year 0-5: a 57% reduced rate of disability pension for the NEDA-2 group (HR 0.43; 95% CI 0.33 to 0.55) and year 5-10: a 36% reduced rate (HR 0.64; 95% CI 0.40 to 1.01).

Conclusion: Clinically stable disease course (NEDA-2) is associated with a reduced risk of losing income from salaries and a reduced risk of disability pension.
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http://dx.doi.org/10.1136/jnnp-2019-321523DOI Listing
January 2020

Reader response: Nationwide prevalence and incidence study of neuromyelitis optica spectrum disorder in Denmark.

Neurology 2019 10;93(16):722-723

(Rochester, MN).

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http://dx.doi.org/10.1212/WNL.0000000000008325DOI Listing
October 2019

Disability and Therapeutic Response in Paediatric Neuromyelitis Optica Spectrum Disorder: A Case Series from Iran.

Iran J Child Neurol 2019 ;13(3):99-104

Neurology Department; Booalisina Hospital, Mazandaran University of Medical Sciences; Sari, Iran.

Objectives: The characteristics of paediatric neuromyelitis optica spectrum disorder (NMOSD) may indicate the degree of disability and identify factors that predict the response to treatment.

Materials & Methods: Among 114 NMOSD patients in an acquired demyelinating syndromes registry at the Sina Hospital, in Tehran, Iran, 10 paediatric NMOSD patients with longitudinal follow-up from 2005 to 2016 were retrospectively identified. The median time between disease onset and diagnosis was 18 months (range 1-108 months).

Results: All patients had a relapsing course, which resulted in disability in six with severe visual impairment and functional blindness in one and impaired ambulation in five patients during follow-up. Azathioprine (AZA) was first drug of choice for prophylaxis, but in five patients new attacks occurred and therapy was switched to rituximab (RTX) with no further relapses after median two years (range 1-3 y) follow-up.

Conclusion: Paediatric onset of NMOSD was associated with severe attacks and poor response in 50 % of cases to AZA, RTX seemed to decrease the relapse rate.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6586449PMC
January 2019

Angiotensin AT2 receptor-induced interleukin-10 attenuates neuromyelitis optica spectrum disorder-like pathology.

Mult Scler 2020 09 9;26(10):1187-1196. Epub 2019 Jul 9.

Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark.

Background: Neuromyelitis optica spectrum disorder (NMOSD) is a relapsing inflammatory central nervous system (CNS) disease for which there is no cure. Immunoglobulin G autoantibodies specific for the water channel aquaporin-4 are a serum biomarker, believed to induce complement-dependent astrocyte damage with secondary demyelination.

Objective: To investigate the effect of angiotensin AT2 receptor (AT2R) stimulation on NMOSD-like pathology and its underlying mechanism.

Methods: NMOSD-like pathology was induced in mice by intracerebral injection of immunoglobulin-G isolated from NMOSD patient serum, with complement. This mouse model produces the characteristic histological features of NMOSD. A specific AT2R agonist, Compound 21 (C21), was given intracerebrally at day 0 and by intrathecal injection at day 2.

Results: Loss of aquaporin-4 and glial fibrillary acidic protein was attenuated by treatment with C21. Administration of C21 induced mRNA for interleukin-10 in the brain. NMOSD-like pathology was exacerbated in interleukin-10-deficient mice, suggesting a protective role. C21 treatment did not attenuate NMOSD-like pathology in interleukin-10-deficient mice, indicating that the protective effect of AT2R stimulation was dependent on interleukin-10.

Conclusion: Our findings identify AT2R as a novel potential therapeutic target for the treatment of NMOSD. Interleukin-10 signaling is an essential part of the protective mechanism counteracting NMOSD pathology.
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http://dx.doi.org/10.1177/1352458519860327DOI Listing
September 2020

Epidemiology of neuromyelitis optica spectrum disorder in Denmark (1998-2008, 2007-2014).

Brain Behav 2019 07 11;9(7):e01338. Epub 2019 Jun 11.

OPEN (Odense Patient data Explorative Network), Odense University Hospital, Odense, Denmark.

Epidemiological studies of the uncommon disorder neuromyelitis optica spectrum disorder (NMOSD) may be difficult to interpret because of the evolving nature of diagnostic criteria, differences in the definition and accuracy of NMOSD diagnosis, the completeness of case ascertainment, and variability in assays for the disease-specific biomarker aquaporin-4 (AQP4)-IgG. A sub-group of patients with the clinical syndrome NMOSD lack detectable AQP4-IgG and in these cases an accurate diagnosis requires precise diagnostic algorithms and longitudinal follow-up. Consecutive sets of criteria for NMO/NMOSD have been introduced during the two last decades. Such criteria need validation in different populations. Detection of other autoantibodies, such as IgG specific for myelin oligodendrocyte glycoprotein or for glial fibrillary acidic protein in a sub-group of AQP4-IgG-negative NMOSD patients, has improved over the past decade and may lead to overlap of the clinical syndromes/phenotypes. This review begins by summarizing current knowledge on the widening clinical spectrum of NMOSD. Subsequently, we describe two epidemiological studies from Denmark carried out in two different decades (1998-2008 and 2007-2014) and comment on the differences in study design, patient ascertainment, and interpretation of results. These factors may explain some of the observed differences, reflecting the complexity and providing a clear example of this development.
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http://dx.doi.org/10.1002/brb3.1338DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6625475PMC
July 2019

Vocal cord paralysis as primary and secondary results of malignancy. A prospective descriptive study.

Laryngoscope Investig Otolaryngol 2019 Apr 29;4(2):241-245. Epub 2019 Jan 29.

Odense Patient data Explorative Network Odense University Hospital Odense Denmark.

Objective: Vocal cord paralysis (VCP) may be caused by a primary malignancy and associated immune cross-reactivity. We aimed to illuminate underlying causes of VCP and to assess if onconeural antibodies occur in association to VCP as an early predictor of cancer.

Methods: A prospective study was performed in patients with newly diagnosed VCP from 2014 to 2016. All patients underwent fiberoptic laryngoscopy, ultrasound of the neck and computed tomography (CT) of the neck and thorax. Patients with idiopathic VCP underwent neurological examination, positron emission tomography/CT, and serum analysis for onconeural antibodies. All patients were offered a one-year clinical follow-up.

Results: In total 53 patients fulfilled the inclusion criteria. Left VCP occurred in 37 (70%), right in 15 (28%), and bilateral in one patient (2%). The cause of VCP was cancer in 27 (51%) patients, of those 15 (56%) had VCP as the primary symptom, including all cases with laryngeal and esophageal cancer. Median time interval between VCP and cancer was 7 days (range 1-30). In 12 (23%) VCP was a secondary symptom. Lung cancer was the most common etiology, 14 of 27 (52%), 12 patients (86%) with non-small cell lung cancer. Idiopathic VCP was diagnosed in 18 (34%) patients, of those nine patients had a neurological examination and were screened for well-known onconeural antibodies, which were not detected. Reactions against Purkinje cell nuclei were seen in three patients, none showed symptoms or signs of cancer at follow-up.

Conclusions: The causes of VCP were described. VCP was frequently the primary symptom, and also occurred as a secondary symptom of cancer. Exclusion of malignancy is important in patients with VCP.

Level Of Evidence: 1b.
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http://dx.doi.org/10.1002/lio2.251DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6476270PMC
April 2019

Leptomeningeal and Intraparenchymal Blood Barrier Disruption in a MOG-IgG-Positive Patient.

Case Rep Neurol Med 2018 9;2018:1365175. Epub 2018 Dec 9.

Department of Neurology, Slagelse Hospital, Institute of Regional Health Research, Denmark.

Background: Recently, pathogenic serum immunoglobulin G (IgG) autoantibodies to myelin oligodendrocyte glycoprotein (MOG) have been detected in a subgroup of patients with central nervous system (CNS) demyelination, including in patients with myelitis. Relatively little is known so far about leptomeningeal involvement in MOG-IgG-positive myelitis.

Findings: We report the case of a 30-year-old previously healthy woman presenting with longitudinally extensive transverse myelitis and tetraparesis, in whom both the leptomeningeal barrier and the blood-brain barrier (BBB) were altered, as demonstrated by gadolinium-enhanced MRI during relapse. Blood samples taken at onset and four years later were retrospectively found positive for MOG-IgG.

Conclusion: Our findings demonstrate that spinal leptomeningeal enhancement (LME) can occur in MOG-IgG-positive encephalomyelitis (EM) and may accompany intraparenchymal BBB breakdown.
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http://dx.doi.org/10.1155/2018/1365175DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6374805PMC
December 2018

Autoimmune diseases associated with Neuromyelitis Optica Spectrum Disorders: A literature review.

Mult Scler Relat Disord 2019 Jan 16;27:350-363. Epub 2018 Nov 16.

MS Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran. Electronic address:

Introduction: Neuromyelitis Optica (NMO) is an autoimmune inflammatory demyelinating disease of the central nervous system (CNS) which predominantly involves optic nerves and spinal cord. Since the introduction of Neuromyelitis Optica Spectrum Disorders (NMOSD) as a separate entity, there have been many reports on its association with other disorders including systemic and organ-specific autoimmune diseases. Here, we reviewed other immune-mediated diseases associated with NMOSD and tried to categorize them.

Methods: The present review was conducted using the PUBMED database based on papers from 1976 (i.e., since the first NMO comorbidity with SLE was reported) to 2017. We included all articles published in English. The keywords utilized included Neuromyelitis optica, Neuromyelitis Optica Spectrum Disorders, Devic's disease, in combination with comorbidity or comorbidities.

Results: Diseases with immune-based pathogenesis are the most frequently reported co-morbidities associated with NMOSD, most of which are antibody-mediated diseases. According to literature, Sjogren's Syndrome (SS) and Systemic Lupus Erythematosus (SLE) are the most frequently reported diseases associated with NMOSD among systemic autoimmune diseases. Further, myasthenia gravis in neurological and autoimmune thyroid diseases in non-neurological organ-specific autoimmune diseases are the most reported comorbidities associated with NMOSD in the literature.

Conclusions: NMOSD may be associated with a variety of different types of autoimmune diseases. Therefore, systemic or laboratory signs which are not typical for NMOSD should be properly investigated to exclude other associated comorbidities. These comorbidities may affect the treatment strategy and may improve the patients' care and management.
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http://dx.doi.org/10.1016/j.msard.2018.11.008DOI Listing
January 2019

Racial differences in neuromyelitis optica spectrum disorder.

Neurology 2018 11 26;91(22):e2089-e2099. Epub 2018 Oct 26.

From the Department of Neurology (S.-H.K., H.-J.S., J.-W.H., H.J.K.) and Biometric Research Branch (M.H.), Research Institute and Hospital of National Cancer Center, Goyang, South Korea; Department of Neurology (M.A.M., M.L.), Johns Hopkins University School of Medicine, Baltimore, MD; NeuroCure Clinical Research Center (F.S., F.P.) and Department of Neurology (F.S., K.R., F.P.), Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health; Experimental and Clinical Research Center (F.S., F.P.), Max Delbrück Center for Molecular Medicine and Charité-Universitätsmedizin Berlin; Department of Neurology (M.R., O.A., H.-P.H.), Medical Faculty, Heinrich Heine University, Düsseldorf, Germany; Department of Neurology (N.A.), Slagelse Hospital and Institute of Regional Health Research & Molecular Medicine, University of Southern Denmark, Odense; Department of Neurology (J.L.T.-C.), Queen Elizabeth Hospital, Hong Kong, China; Department of Medicine (S.S., N.P.), Siriraj Hospital, Mahidol University, Bangkok, Thailand; and Nuffield Department of Clinical Neurosciences (M.I.L., J.P.), John Radcliffe Hospital, University of Oxford, UK.

Objective: We aimed to evaluate racial differences in the clinical features of neuromyelitis optica spectrum disorder.

Methods: This retrospective review included 603 patients (304 Asian, 207 Caucasian, and 92 Afro-American/Afro-European), who were seropositive for anti-aquaporin-4 antibody, from 6 centers in Denmark, Germany, South Korea, United Kingdom, United States, and Thailand.

Results: Median disease duration at last follow-up was 8 years (range 0.3-38.4 years). Asian and Afro-American/Afro-European patients had a younger onset age than Caucasian patients (mean 36, 33, and 44 years, respectively; < 0.001). During the disease course, Caucasian patients (23%) had a lower incidence of brain/brainstem involvement than Asian (42%) and Afro-American/Afro-European patients (38%) ( < 0.001). Severe attacks (visual acuity ≤0.1 in at least one eye or Expanded Disability Status Scale score ≥6.0 at nadir) at onset occurred more frequently in Afro-American/Afro-European (58%) than in Asian (46%) and Caucasian (38%) patients ( = 0.005). In the multivariable analysis, older age at onset, higher number of attacks before and after immunosuppressive treatment, but not race, were independent predictors of severe motor disabilities at last follow-up.

Conclusion: A review of a large international cohort revealed that race affected the clinical phenotype, age at onset, and severity of attacks, but the overall outcome was most dependent on early and effective immunosuppressive treatment.
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http://dx.doi.org/10.1212/WNL.0000000000006574DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6282238PMC
November 2018

Optical coherence tomography in acute optic neuritis: A population-based study.

Acta Neurol Scand 2018 Dec 14;138(6):566-573. Epub 2018 Aug 14.

Institutes of Regional Health Research and Molecular Medicine, University of Southern Denmark, Odense, Denmark.

Objectives: To measure early structural damage caused by autoimmune inflammatory optic neuritis (ON) by optical coherence tomography (OCT) in a population-based cohort.

Methods: In a prospective population-based study over 24 months in Southern Denmark, patients diagnosed with acute ON and without prior diagnosis of a chronic neuroinflammatory disorder were included and examined with OCT, visual evoked potentials (VEP), visual fields, high contrast visual acuity (HCVA), and low contrast letter acuity (LCLA). Structural and functional outcomes were determined at 6-month follow-up based on interocular differences.

Results: The 50 included patients had on average 16.9 μm peripapillary retinal nerve fiber layer loss, 10.6 μm ganglion cell and inner plexiform layer (GCIP) loss, and an average HCVA decrease of 0.22 dec. Based on a linear regression model, average GCIP loss amounted to -0.2 μm per day and started 8 days after onset. OCT outcomes but not VEP correlated well with all visual function measurements at follow-up. Structural and functional damage in 20 patients (40%) diagnosed de novo with multiple sclerosis (MS) and in 2 patients (4%) with positive myelin oligodendrocyte glycoprotein antibodies (MOG-IgG) test did not differ from patients with idiopathic ON.

Conclusions: Optic neuritis causes substantial retinal damage and vision loss independent of the underlying disease. Our study supports that GCIP damage starts closely to clinical onset. Good structure-function correlations between OCT and vision support the importance of OCT in monitoring acute ON.
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http://dx.doi.org/10.1111/ane.13004DOI Listing
December 2018

Selective localization of IgG from cerebrospinal fluid to brain parenchyma.

J Neuroinflammation 2018 Apr 17;15(1):110. Epub 2018 Apr 17.

Neurobiology, Institute of Molecular Medicine, University of Southern Denmark, JB. Winsloewsvej 25, 5000, Odense, Denmark.

Background: Encounter of autoantibodies with specific antigens can lead to hypersensitivity reactions and pathology. In multiple sclerosis and neuromyelitis optica spectrum disease (NMOSD), immunoglobulin-G (IgG) deposition has been observed in pathological lesions in the central nervous system. The paradigmatic autoantibodies in NMOSD are specific for the water channel aquaporin-4, localized to astrocytic end-feet at the blood-brain barrier and ependymal cells at the cerebrospinal fluid-brain barrier. We have previously observed that IgG antibodies from NMO patients (NMO-IgG) access brain parenchyma from the cerebrospinal fluid and induce subpial and periventricular NMO-like lesions and blood-brain barrier breakdown, in a complement-dependent manner.

Objective: To investigate how IgG trafficking from cerebrospinal fluid to brain parenchyma can be influenced by injury.

Methods: IgG from healthy donors was intrathecally injected into the cerebrospinal fluid via cisterna magna at 1, 2, 4, or 7 days after a distal stereotactic sterile needle insertion to the striatum.

Results: Antibody deposition, detected by staining for human IgG, peaked 1 day after the intrathecal injection and was selectively seen close to the needle insertion. When NMO-IgG was intrathecally injected, we observed complement-dependent NMO-like pathology (loss of aquaporin-4 and glial fibrillary acidic protein) proximal to the insertion site, with similar kinetics. A fluorescent tracer did not show the same distribution indicating IgG-selective localization.

Conclusion: These findings suggest that IgG from cerebrospinal fluid localize selectively in brain parenchyma at the site of injury and pathogenic NMO-IgG induce astrocyte pathology at the same location.
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http://dx.doi.org/10.1186/s12974-018-1159-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5904996PMC
April 2018

Environmental risk factors in neuromyelitis optica spectrum disorder: a case-control study.

Acta Neurol Belg 2018 Jun 2;118(2):277-287. Epub 2018 Mar 2.

MS Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran.

Neuromyelitis optica spectrum disorder (NMOSD) has unknown risk factors. The aim of this study was to identify the environmental risk factors for NMOSD. A case-control study was conducted in Tehran from 2015 to 2016 among 100 patients with NMOSD. Sex-matched healthy controls (n = 400) were selected through random digit dialing (RDD). Logistic regression was used to estimate unadjusted and adjusted ORs (odds ratio) at 95% confidence intervals (CI) via SPSS. Compared with the control population, in NMOSD patients, the adjusted OR for low dairy consumption per week was (OR = 18.09; 95% CI 6.91, 47.37), following low sea food intake (OR = 13.91; 95% CI 6.13, 31.57) and low fruit and vegetable consumption (OR = 6.23; 95% CI 3.07, 12.62). The lower heavy physical activity (OR: 16.11, 95% CI 7.03, 36.91) among patients had risen the risk of NMOSD. A past history of head trauma was considered a risk for NMOSD (OR: 8.39, 95% CI 4.97, 14.16). The association between NMOSD and intentional abortion only among females (OR: 7.42, 95% CI 2.81, 19.55) was detected. This study indicates significant associations between dietary habits, life style, history of head trauma and intentional abortion in female and the later diagnosis of NMOSD.
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http://dx.doi.org/10.1007/s13760-018-0900-5DOI Listing
June 2018

A comparison of pediatric and adult neuromyelitis optica spectrum disorders: A review of clinical manifestation, diagnosis, and treatment.

J Neurol Sci 2018 05 19;388:222-231. Epub 2018 Feb 19.

MS Research Centre, Department of Neurology, Tehran University of Medical Sciences, Neuroscience Institute, Sina Hospital, Hasan Abad Square, Tehran 11367-46911, Iran.

Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune inflammatory disorder of the central nervous system (CNS). Serum immunoglobulin G autoantibodies (NMO-IgG) are identified in the majority of NMOSD patients. The Pediatric form presents before 18 years. Based on the similarity of clinical, neuroimaging, and laboratory characteristics of pediatric NMOSD to those of the adult form, the international panel suggested that adult criteria of NMOSD also are appropriate in pediatric patients. However, the proposed criteria need validation in pediatric patients. This strategy poses challenges to the study design in clinical trials in pediatric NMOSD patients.
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http://dx.doi.org/10.1016/j.jns.2018.02.028DOI Listing
May 2018

Parental ethnicity associated with risk for multiple sclerosis: A population-based incident case-control study in Iran.

Mult Scler Relat Disord 2018 Feb 31;20:100-103. Epub 2018 Jan 31.

Institutes of Regional Health Research and of Molecular Medicine, University of Southern Denmark, Denmark.

Background: The epidemiology of multiple sclerosis (MS) includes a consideration of geography and population ethnicity. To determine whether there is any association between ethnicity and risk of MS in a multiethnic, population-based case-control study.

Methods: We conducted a population-based case-control of 547 incident MS cases and 1057 healthy controls between August 2013 and February 2015, Tehran, a multi-ethnic city. The patients were identified and enrolled through the Iranian MS Society. Case status was confirmed by a panel of MS specialists beside of 2010 McDonald criteria. Controls were selected through random digit dialing. A logistic regression model was applied to estimate the odds ratios (95%CI) adjusted for age, sex, tobacco smoking and socioeconomic status.

Results: The risk of MS for Kurd, Turk and Fars ethnicities was apparently smaller compared to one specific ethnic background (Lor); OR 0.36 (0.15-0.86) for Kurd, OR 0.42 (0.24-0.74) for Turk and OR 0.53 (0.31-0.89) for Fars. Heterogeneity in parental ethnicity of common ethnic groups was significantly associated with increased risk of MS OR 1.61 (1.13-2.29). All associations remained after adjustment for relevant confounders.

Conclusions: MS was unequally distributed in the ethnic groups. Moreover, heterogeneity in parental ethnicity seems to be a risk factor for MS.
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http://dx.doi.org/10.1016/j.msard.2018.01.008DOI Listing
February 2018

Diagnosis and management of Neuromyelitis Optica Spectrum Disorder (NMOSD) in Iran: A consensus guideline and recommendations.

Mult Scler Relat Disord 2017 Nov 25;18:144-151. Epub 2017 Sep 25.

Scientific Committee, Iranian MS Society, Iran.

Neuromyelitis Optica Spectrum Disorder (NMOSD) is a relapsing neuro inflammatory disease of the central nervous system that typically presents with optic neuritis or myelitis and may cause severe disability. The diagnostic criteria have been updated and several immunosuppressive agents have been demonstrated to prevent acute exacerbations. As the disease rarely develops in a progressive course, management of acute attacks and proper prevention of exacerbations may change the long term out-come and prevent future disability. Consensus recommendations and guidelines will help the physicians to improve their practice and unify the treatment approaches in different communities. In order to develop a national consensus and recommendations for the diagnosis and management of NMOSD in Iran, a group of neurologists with long term experience in management of NMOSD were gathered to develop this consensus based on available national and international data. The primary draft was prepared and discussed to suggest the most appropriate treatment for these patients. We propose strategies for early diagnosis and treatment for prevention of relapses and minimizing consequences of attacks as a primary therapeutic goal. Attacks are currently treated with intravenous corticosteroids and, in refractory cases, with plasma exchange. All participants agreed on preventive treatment with currently available immunosuppressive agents such as azothioprin, rituximab and mycofenolate mofetil based on previous positive data in NMOSD in order to reduce attack frequency. The current consensus reviews the previous data and provides the clinicians with practical recommendations and advices for the diagnosis and management of NMOSD based on scientific data and clinical experience.
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http://dx.doi.org/10.1016/j.msard.2017.09.015DOI Listing
November 2017

Comparison of the efficacy of azathioprine and rituximab in neuromyelitis optica spectrum disorder: a randomized clinical trial.

J Neurol 2017 Sep 22;264(9):2003-2009. Epub 2017 Aug 22.

Department of Neurology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.

Neuromyelitis optica spectrum disorder (NMOSD) often follows a relapsing course. As disability in NMOSD is attack-related, effective treatments are needed. We aimed to compare the efficacy of azathioprine (AZA) and rituximab (RIT) as maintenance therapy in NMOSD patients. An open, randomized clinical trial was conducted during September 2015 to December 2016, in Isfahan, Iran. Initially, 100 NMOSD patients were approached, 86 entered the study, and 68 cases completed the trial. All patients had a relapsing-remitting course with expanded disability extended scale (EDSS) ≤7 (median 2.75, range = 0-7). Patients were randomized into two groups, which did not differ according to age, gender distribution, and disease duration. In the AZA group, 35 patients [20 aquaporin-4 (AQP4)-IgG positive] were started on 50 mg/day oral AZA and increased to 2-3 mg/kg/day (with oral prednisolone as adjunctive therapy). In the RIT group, 33 patients (13 aquaporin-4-IgG positive) received 1 g intravenous rituximab and repeated 2 weeks later and then every 6 months. Annualized relapse rate (ARR) was measured as the primary outcome and EDSS as the secondary outcome after 12 months of intervention. The mean ARR [standard deviation (SD)] in the AZA group decreased from 1 (0.38) to 0.51 (0.55) (P value <0.001) and in the RIT group decreased from 1.30 (0.68) to 0.21 (0.42) (P value <0.001). ARR after intervention minus ARR before intervention [mean (SD)] was 1.09 (0.72) in RIT group and 0.49 (0.59) in AZA group (P value <0.001). EDSS after intervention minus EDSS before intervention [mean (SD)] was 0.98 (1.14) in RIT group and 0.44 (0.54) in AZA group (P value <0.001). Nineteen patients (54.3%) in AZA group and 26 patients (78.8%) in RIT group became relapse-free after intervention (P value = 0.033). AZA and RIT can both effectively decrease ARR and EDSS in NMOSD patients. RIT was significantly more effective than AZA treatment. Trial Registration Name of registry: clinicaltrials.gov; ID: NCT03002038; URL: https://clinicaltrials.gov/ct2/show/NCT03002038 .
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http://dx.doi.org/10.1007/s00415-017-8590-0DOI Listing
September 2017

Influence of type I IFN signaling on anti-MOG antibody-mediated demyelination.

J Neuroinflammation 2017 06 24;14(1):127. Epub 2017 Jun 24.

Institute of Molecular Medicine, Neurobiology, University of Southern Denmark, JB. Winsloewsvej 25, 5000, Odense C, Denmark.

Background: Antibodies with specificity for myelin oligodendrocyte glycoprotein (MOG) are implicated in multiple sclerosis and related diseases. The pathogenic importance of anti-MOG antibody in primary demyelinating pathology remains poorly characterized.

Objective: The objective of this study is to investigate whether administration of anti-MOG antibody would be sufficient for demyelination and to determine if type I interferon (IFN) signaling plays a similar role in anti-MOG antibody-mediated pathology, as has been shown for neuromyelitis optica-like pathology.

Methods: Purified IgG2a monoclonal anti-MOG antibody and mouse complement were stereotactically injected into the corpus callosum of wild-type and type I IFN receptor deficient mice (IFNAR1-KO) with and without pre-established experimental autoimmune encephalomyelitis (EAE).

Results: Anti-MOG induced complement-dependent demyelination in the corpus callosum of wild-type mice and did not occur in mice that received control IgG2a. Deposition of activated complement coincided with demyelination, and this was significantly reduced in IFNAR1-KO mice. Co-injection of anti-MOG and complement at onset of symptoms of EAE induced similar levels of callosal demyelination in wild-type and IFNAR1-KO mice.

Conclusions: Anti-MOG antibody and complement was sufficient to induce callosal demyelination, and pathology was dependent on type I IFN. Induction of EAE in IFNAR1-KO mice overcame the dependence on type I IFN for anti-MOG and complement-mediated demyelination.
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http://dx.doi.org/10.1186/s12974-017-0899-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5483301PMC
June 2017

Disruption of the leptomeningeal blood barrier in neuromyelitis optica spectrum disorder.

Neurol Neuroimmunol Neuroinflamm 2017 Jul 21;4(4):e343. Epub 2017 Apr 21.

Department of Neurobiology (N.A.), Institute of Molecular Medicine, University of Southern Denmark; Department of Neurology (E.P.F., S.J.P., B.G.W.), Mayo Clinic, Rochester, MN; Department of Multiple Sclerosis Therapeutics (K.F.), Fukushima Medical University School of Medicine; Multiple Sclerosis and Neuromyelitis Optica Center (K.F.), Southern TOHOKU Research Institute for Neuroscience, Koriyama, Japan; Department of Neurology (H.J.K., S.H.K.), Research Institute and Hospital of National Cancer Center, Goyang, Korea; Department of Radiology (H.P.S.), Aleris-Hamlet Hospital, Copenhagen, Denmark; Medical Image Analysis Center Basel (J.W.); Department of Biomedical Engineering (J.W.), University Basel, Switzerland; NeuroCure Clinical Research Center and Clinical and Experimental Multiple Sclerosis Research Center (J.W., F.P.), Department of Neurology, Charité Universitätsmedizin Berlin; Experimental and Clinical Research Center (J.W., F.P.), Max Delbrueck Center for Molecular Medicine and Charité Universitätsmedizin Berlin, Germany; Department of Neurology (H.K.), Tohoku University Graduate School of Medicine, Sendai, Japan; Department of Neurology (E.M.), Hôpital Pitié-Salpêtrière, APHP, Paris, France; Service de Neurologie A and Eugène Devic EDMUS Foundation against Multiple Sclerosis (R.M.), Observatoire Français de la Sclérose en Plaques (OFSEP), Hôpital Neurologique Pierre Wertheimer, Hospices Civils de Lyon, Bron; and Lyon Neurosciences Research Center (R.M.), FLUID team, Inserm U 1028/CNRS 5292, France.

Objective: To describe leptomeningeal blood-barrier impairment reflected by MRI gadolinium-enhanced lesions in patients with aquaporin-4 immunoglobulin G (AQP4-IgG)-positive neuromyelitis optica spectrum disorder (NMOSD).

Methods: A retrospective case series of 11 AQP4-IgG-positive NMOSD patients with leptomeningeal enhancement (LME) were collected from 5 centers. External neuroradiologists, blinded to the clinical details, evaluated MRIs.

Results: LME was demonstrated on postcontrast T1-weighted and fluid-attenuated inversion recovery images as a sign of leptomeningeal blood-barrier disruption and transient leakage of contrast agent into the subarachnoid space in 11 patients, 6 in the brain and 6 in the spinal cord. The patterns of LME were linear or extensive and were accompanied by periependymal enhancement in 5 cases and intraparenchymal enhancement in all cases. The location of LME in the spinal cord was adjacent to intraparenchymal contrast enhancement with involvement of a median number of 12 (range 5-17) vertebral segments. At the time of LME on MRI, all patients had a clinical attack such as encephalopathy (36%) and/or myelopathy (70%) with median interval between symptom onset and LME of 12 days (range 2-30). LME occurred in association with an initial area postrema attack (44%), signs of systemic infection (33%), or AQP4-IgG in CSF (22%) followed by clinical progression. LME was found at initial clinical presentation in 5 cases and at clinical relapses leading to a diagnosis of NMOSD in 6 cases.

Conclusion: This study suggests that altered leptomeningeal blood barrier may be accompanied by intraparenchymal blood-brain barrier breakdown in patients with AQP4-IgG-positive NMOSD during relapses.
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http://dx.doi.org/10.1212/NXI.0000000000000343DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5400808PMC
July 2017

Aquaporin-4-autoimmunity in patients with systemic lupus erythematosus: A predominantly population-based study.

Mult Scler 2018 03 22;24(3):331-339. Epub 2017 Mar 22.

Department of Rheumatology, Odense University Hospital, Odense, Denmark.

Background: Serum immunoglobulin G targeting the astrocyte water channel aquaporin-4 (AQP4) in the central nervous system (CNS) is a biomarker for neuromyelitis optica spectrum disease (NMOSD). Co-existence of NMOSD with systemic lupus erythematosus (SLE) putatively suggests susceptibility to antibody-mediated autoimmune disease.

Objective: To estimate the prevalence of NMOSD in SLE and investigate the immunogenetic background for an association of NMOSD and SLE.

Methods: The study included a predominantly population-based cohort with clinical and serological investigations of 208 patients with SLE, followed prospectively since 1995. All patients received immunosuppressive treatment. NMOSD was evaluated retrospectively based on the 2015 International Panel for NMOSD Diagnosis (IPND) criteria. Polymorphisms in programmed cell death protein 1 (PDCD-1) PD-1.3 G/A were genotyped. AGP4-IgG and other autoantibodies, including myelin oligodendrocyte glycoprotein (MOG), was determined blinded to clinical diagnosis.

Results: Of 208 patients with SLE, 45(22%) had neuropsychiatric (NP) SLE, and CNS involvement predominated in 30 of 45 (67%) patients. Serum AQP4-IgG was detected in 2 of 30 (6.7%) neuropsychiatric SLE (NPSLE) patients both of whom had myelitis and antiphospholipid syndrome; one patient also had myasthenia gravis. None had MOG-IgG. PD-1.3A allele was not associated with SLE nor with NPSLE.

Conclusion: AQP4-IgG autoimmune syndrome may rarely co-exist with SLE, and such patients have other NMOSD-typical syndromes such as myelitis.
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http://dx.doi.org/10.1177/1352458517699791DOI Listing
March 2018