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Objective: To assess the diagnostic and prognostic potential of serum neurofilament light chain (sNfL) in children with first acquired demyelinating syndrome (ADS). Methods: We selected 129 children with first ADS including 19 children with myelin oligodendrocyte glycoprotein (MOG)-antibody associated disease (MOGAD), 36 MOG/AQP4-seronegative ADS, and 74 with multiple sclerosis (MS) from the BIOMARKER study cohort. All children had a complete set of clinical, radiological, laboratory data and serum for NfL measurement using a highly sensitive digital ELISA (SIMOA). A control group of 35 children with non-inflammatory neurological diseases was included. sNfL levels were compared across patient groups according to clinical, laboratory, neuroradiological features and outcome after 2 years. Results: sNfL levels were significantly increased in MOGAD, seronegative ADS and MS compared to controls (p -value < 0.001), in particular in children with an acute disseminated encephalomyelitis (ADEM)-like magnetic resonance imaging (MRI) pattern (p < 0.001) or longitudinally extensive myelitis (p < 0.01). In pediatric MS, elevated sNfL levels were significantly associated with higher numbers of cerebral (p < 0.001) and presence of spinal (p < 0.05) MRI lesions at baseline and predicted a higher number of relapses (p < 0.05). Conclusion: sNfL levels are significantly elevated in all three studied pediatric ADS subtypes indicating neuroaxonal injury. In pediatric MS high levels of sNfL are associated with risk factors for disease progression. [ABSTRACT FROM AUTHOR]

Background: Myelin oligodendrocyte glycoprotein (MOG) antibody disease (MOG-AD) is recognized as a distinct nosological entity. IgG antibodies against MOG (MOG-Ab) overlap with neuromyelitis optica spectrum disorders (NMOSD) phenotype in adults. However, an increasing number of clinical phenotypes have been reported to be associated with MOG-Ab. Objective: To investigate the seroprevalence of MOG-Ab under consideration of demographics, disease entities and time course in a large cohort of unselected neurological patients. Methods: Blood samples of 2.107 consecutive adult neurologic patients admitted to our department between 2016-2017 were tested for MOG-Ab using a cell-based assay. MOG-Ab persistence was analyzed in follow-up samples. External validation was performed in two independent laboratories. Results: We found MOG-Ab in 25 of 2.107 (1.2%) patients. High antibody ratios were mostly associated with NMOSD and MOG-AD phenotype (5/25). Low ratios occurred in a wide range of neurological diseases, predominantly in other demyelinating CNS diseases (5/25) and stroke (6/25). MOG-Ab persistence over time was not confined to NMOSD and MOG-AD phenotype. Conclusion: The present study demonstrates the occurrence of MOG-Ab in a wide range of neurological diseases. Only high MOG-Ab ratios were associated with a defined clinical phenotype, but low MOG-Ab ratios were not. The diagnostic value of low MOG-Ab is thus highly limited. [ABSTRACT FROM AUTHOR]

Interestingly, no patient in our cohort suffered from a relapse after time of first seroconversion, although fluctuating MOG-IgG titres with increase after a period of low or even negative MOG-IgG titres were reported in selected patients. Likewise, onset serum MOG-IgG titres, despite being important for the diagnosis of MOGAD, do not predict recovery or relapse.[1],[7] In most patients MOG-IgG titres decline with time, but may also remain positive in other patients for years. [Extracted from the article]

In the past few years, acquired demyelinating syndromes of the central nervous system associated with antibodies against myelin oligodendrocyte glycoprotein (MOG) have evolved into a new inflammatory disease entity distinct from neuromyelitis optica spectrum disorders or multiple sclerosis. The meticulous clinical description of patients with MOG IgG antibodies (MOG-IgG) has been achieved by development and use of highly specific cell-based assays. MOG-IgG associated disorders comprise a wide spectrum of syndromes ranging from acute disseminated encephalomyelitis predominantly in children to optic neuritis or myelitis mostly in adults. In recent studies, phenotype of MOG-IgG associated disorders has further broadened with the description of cases of brainstem encephalitis, encephalitis with seizures and overlap syndromes with other types of autoimmune encephalitis. In this review, we provide an overview of current knowledge of MOG-IgG associated disorders, describe the clinical presentations identified, highlight differences from neuromyelitis optica spectrum disorders and multiple sclerosis, summarize clinical outcome and concepts of immune treatment, depict the underlying mechanisms of antibody pathogenicity and provide the methodological essentials of MOG-IgG assays. [ABSTRACT FROM AUTHOR]

Limited data exist on isolated optic neuritis in children. We report the clinical features and treatment of pediatric subjects with monophasic and recurrent idiopathic optic neuritis. This retrospective cohort study of patients with isolated optic neuritis identified 10 monophasic and 7 recurrent optic neuritis cases. Monophasic optic neuritis patients were older (mean 13.3 ± 4.22) than those with recurrent idiopathic optic neuritis (9.86 ± 3.63). Females represented 50% of monophasic and 85.7% of recurrent idiopathic optic neuritis cases. Patients with monophasic optic neuritis were less likely to have a bilateral onset than recurrent idiopathic optic neuritis (40% vs 57.1%). Only 1 case had oligoclonal bands in the cerebrospinal fluid CSF. Most recurrent idiopathic optic neuritis cases had evidence of anti–myelin oligodendrocyte glycoprotein (MOG) antibodies (5/7). Treatment of recurrent idiopathic optic neuritis cases included intravenous pulse glucocorticosteroids and immunotherapy. We observed differences between recurrent and monophasic idiopathic optic neuritis. Immunosuppression appeared to prevent further relapses in recurrent idiopathic optic neuritis patients. Weaning immunotherapies after several years of quiescence in recurrent idiopathic optic neuritis may be possible, but larger studies are needed. [ABSTRACT FROM AUTHOR]

Background: Demyelinating diseases of the central nervous system associated with autoantibodies against aquaporin-4 and myelin-oligodendrocyte-glycoprotein are mediated by different immunopathological mechanisms compared to multiple sclerosis. Objective: The purpose of this study was to evaluate serum and cerebrospinal fluid cytokine/chemokine profiles in patients with autoantibodies against aquaporin-4 or autoantibodies against myelinoligodendrocyte-glycoprotein-associated demyelination compared to multiple sclerosis and autoimmune encephalitis. Methods: Serum and cerebrospinal fluid cytokine/chemokine levels were analysed using Procartaplex Multiplex Immunoassays. First, we analysed a panel of 32 cytokines/chemokines in a discovery group (nine aquaporin-4-antibody seropositive, nine myelin oligodendrocyte glycoprotein-antibody seropositive, eight encephalitis, 10 multiple sclerosis). Significantly dysregulated cytokines/chemokines were validated in a second cohort (11 aquaporin-4-antibody seropositive, 18 myelin oligodendrocyte glycoprotein-antibody seropositive, 18 encephalitis, 33 multiple sclerosis). Results: We found 11 significantly altered cytokines/chemokines in cerebrospinal fluid and serum samples in the discovery group (a proliferation-inducing ligand, fractalkine=CX3CL1, growthregulated oncogene-α, interleukin-1 receptor antagonist, interleukin-6, interleukin-8=CXCL8, interleukin-10, interleukin-21, interferon-Ç-induced protein-10=CXCL10, monokine induced by interferon-Ç=CXCL9, macrophage inflammatory protein-1ß=CCL4). Most of these cytokines/chemokines were up-regulated in autoantibodies against aquaporin-4 or autoantibodies against myelinoligodendrocyte-glycoprotein positive patients compared to multiple sclerosis. We confirmed these results for cerebrospinal fluid interleukin-6 and serum interleukin-8, growth-regulated oncogene-α, a proliferation-inducing ligand and macrophage inflammatory protein-1b in the validation set. Receiveroperating characteristic analysis revealed increased levels of cerebrospinal fluid interleukin-6, serum interleukin-8 and growth-regulated oncogene-α in most patients with autoantibody-associated neurological diseases. Conclusion: This study suggests that distinctive cerebrospinal fluid and serum cytokine/chemokine profiles are associated with autoantibody-mediated demyelination, but not with multiple sclerosis. [ABSTRACT FROM AUTHOR]

Background: Impaired olfactory threshold has been reported in early inflammatory phases of MS, while impaired odor identification was associated with more widespread disability. Objective: To prospectively assess the development of olfactory function and its correlation with relapse and disability progression. Methods: In this prospective, 3-year longitudinal study on 151 MS patients and 30 healthy controls, three different qualities of olfactory function (threshold, discrimination, and identification) were quantified using the Sniffin' Sticks test. The influence of relapses and disability on olfactory function was analyzed at different time points and in a multivariate model. Results: Discrimination and identification capability significantly worsened over 3 years, while threshold did not. Threshold was markedly impaired in patients with relapse activity within 12 months, recovered in the absence of relapse, and was associated with a 2.5-fold increased risk of relapse. Deterioration of discrimination and identification was irreversible and both strongly associated with and predictive of EDSS progression. Conclusion: Olfactory function changes over time in MS. Threshold impairment is transient and predicts inflammatory disease activity, while odor identification and discrimination are associated with disability progression. Olfactory dysfunction might be a useful and easily obtainable parameter to monitor patients with regard to inflammation and neurodegeneration in MS. [ABSTRACT FROM AUTHOR]

Background: Cerebrospinal fluid (CSF) immunoglobulin free light chains (FLC) have been suggested as quantitative alternative to oligoclonal bands (OCB) in the diagnosis of multiple sclerosis (MS). However, little is known on their role in predicting clinical and paraclinical disease progression, particularly in early stages. Objective: To assess the prognostic value of FLC in OCB-positive patients with clinically isolated syndrome (CIS) suggestive of MS and early MS. Methods: We determined FLC kappa (KFLC) and lambda (LFLC) in CSF and serum by nephelometry in 61 patients (CIS (n = 48), relapsing-remitting multiple sclerosis (n = 13)) and 60 non-inflammatory neurological controls. Median clinical follow-up time in CIS was 4.8 years (interquartile range (IQR), 1.5-6.5 years). Patients underwent 3T magnetic resonance imaging (MRI) at baseline and follow-up (median time interval, 2.2 years; IQR, 1.0-3.7 years) to determine T2 lesion load (T2LL) and percent brain volume change (PBVC). Results: CSF FLC were significantly increased in CIS/MS compared to controls (all p < 0.001). A lower KFLC/LFLC CSF ratio was associated with CIS-clinically definite multiple sclerosis (CDMS) conversion (hazard ratio (HR) = 2.89; 95% confidence interval (CI) = 1.17-7.14; p < 0.05). No correlations were found for FLC variables with T2LL or PBVC. Conclusion: Our study confirms increased intrathecal synthesis of FLC in CIS/MS which supports their diagnostic contribution. The KFLC/LFLC CSF ratio appears to have a prognostic value in CIS beyond OCB. [ABSTRACT FROM AUTHOR]

Background: Stable disease course may prompt consideration of disease-modifying treatment (DMT) discontinuation in relapsing–remitting multiple sclerosis (RRMS). Objective: To investigate the clinical outcome after DMT discontinuation and to identify predictive factors supporting decision-making. Methods: We included 221 RRMS patients, who discontinued DMT after ⩾12 months and had documented follow-up ⩾2 years after discontinuation. Hazard ratios (HRs) with 95% confidence intervals (CIs) regarding relapse and disability progression after DMT discontinuation were calculated from Cox regression models. Results: Age >45 years at discontinuation (HR = 0.47, CI = 0.23–0.95, p = 0.038), absence of relapses for ⩾4 years on DMT before discontinuation (HR = 0.29, CI = 0.10–0.82, p = 0.020) and absence of contrast enhancing lesions (HR = 0.46, CI = 0.28–0.78, p = 0.004) were independent predictors of absence of relapse after discontinuation. Age >45 years and absence of relapses ⩾4 years on DMT combined had an HR of 0.06 (CI = 0.01–0.44, p < 0.001). Higher Expanded Disability Status Scale (EDSS) at discontinuation, age >45 years and longer disease duration were significantly associated with disability progression after discontinuation. Conclusion: While freedom from further disease activity is generally unpredictable, there is a subset of patients (age ⩾45 years, DMT intake ⩾4 years without evidence of clinical or radiological disease activity) having a high likelihood of remaining relapse-free after DMT discontinuation. However, close clinical monitoring for recurrent disease activity is mandatory after discontinuing treatment. [ABSTRACT FROM AUTHOR]

Background: Myelin oligodendrocyte glycoprotein (MOG) antibodies have been described in children with acute disseminated encephalomyelitis (ADEM), recurrent optic neuritis, neuromyelitis optica spectrum disorders and more recently in children with multiphasic disseminated encephalomyelitis (MDEM). Objective: To delineate the clinical, cerebrospinal fluid (CSF) and radiological features of paediatric MDEM with MOG antibodies. Methods: Clinical course, serum antibodies, CSF, magnetic resonance imaging (MRI) studies and outcome of paediatric MDEM patients were reviewed. Results: A total of 8 children with two or more episodes of ADEM were identified from a cohort of 295 children with acute demyelinating events. All children had persisting MOG antibodies (median titre: 1:1280). All ADEM episodes included encephalopathy, polyfocal neurological signs and a typical MRI. Apart from ADEM episodes, three children had further clinical attacks without encephalopathy. Median age at initial presentation was 3 years (range: 1–7 years) and median follow-up 4 years (range: 1–8 years). New ADEM episodes were associated with new neurological signs and new MRI lesions. Clinical outcome did range from normal (four of the eight) to mild or moderate impairment (four of the eight). A total of four children received monthly immunoglobulin treatment during the disease course. Conclusion: Children with MDEM and persisting MOG antibodies constitute a distinct entity of relapsing demyelinating events and extend the spectrum of MOG antibody–associated diseases. [ABSTRACT FROM AUTHOR]

Background: Histopathological studies have revealed four different immunopathological patterns of lesion pathology in early multiple sclerosis (MS). Pattern II MS is characterised by immunoglobulin and complement deposition in addition to T-cell and macrophage infiltration and is more likely to respond to plasma exchange therapy, suggesting a contribution of autoantibodies. Objective: To assess the frequency of anti-myelin oligodendrocyte glycoprotein (MOG), anti-M1-aquaporin-4 (AQP4), anti-M23-AQP4, anti-N-methyl-d-aspartate-type glutamate receptors (NMDAR) and 25 other anti-neural antibodies in pattern II MS. Methods: Thirty-nine serum samples from patients with MS who had undergone brain biopsy (n = 24; including 13 from patients with pattern II MS) and from histopathologically non-classified MS patients (n = 15) were tested for anti-MOG, anti-M1-AQP4, anti-M23-AQP4, anti-NMDAR, anti-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor-type glutamate receptors (AMPAR), anti-gamma-aminobutyric acid receptors (GABABR), anti-leucine-rich, glioma-activated protein 1 (LGI1), anti-contactin-associated protein 2 (CASPR2), anti-dipeptidyl-peptidase-like protein-6 (DPPX), anti-Tr/Delta/notch-like epidermal growth factor–related receptor (DNER), anti-Hu, anti-Yo, anti-Ri, anti-Ma1/Ma2, anti-CV2/collapsin response mediator protein 5 (CRMP5), anti-glutamic acid decarboxylase (GAD), anti-amphiphysin, anti-Ca/RhoGTPase-activating protein 26 (ARHGAP26), anti-Sj/inositol-1,4,5-trisphosphate receptor 1 (ITPR1), anti-Homer3, anti-carbonic anhydrase–related protein (CARPVIII), anti-protein kinase gamma (PKCgamma), anti-glutamate receptor delta 2 (GluRdelta2), anti-metabotropic glutamate receptor 1 (mGluR1) and anti-mGluR5, as well as for anti-glial nuclei antibodies (AGNA) and Purkinje cell antibody 2 (PCA2). Results: Antibodies to MOG belonging to the complement-activating immunoglobulin G1 (IgG1) subclass were detected in a patient with pattern II MS. Detailed brain biopsy findings are shown. Conclusion: This is the largest study on established anti-neural antibodies performed in MS so far. MOG-IgG may play a role in a small percentage of patients diagnosed with pattern II MS. [ABSTRACT FROM AUTHOR]

The article presents a study which examines the frequency and implications of antibodies to myelin oligodendrocyte glycoprotein (MOG-ab) and aquaporin 4 antibodies (AQP4-ab) in adult patients with suspected limited forms of neuromyelitis optica (NMO). The study is investigated by cell-based assays, Mann-Whitney U test, and Chi-square test. Results show that MOG-ab is commonly detected in the serum of patients with NMO, longitudinally extensive myelitis (LETM), and optic neuritis (ON).

We have recently demonstrated the safety and tolerability of a novel therapeutic regimen employing autologous blood cells chemically coupled with seven myelin peptides to induce antigen-specific tolerance in MS (ETIMS study). The aim of the current study was an extended safety analysis to assess the effect of the ETIMS approach on antibodies to common autoantigens, the myelin peptides used and common recall antigens. None of the patients showed induction of autoantibody responses. One patient had a measurable myelin peptide-specific response at baseline, which was reduced after treatment. Total immunoglobulins and recall antibody responses showed no significant change. [ABSTRACT FROM AUTHOR]

The article presents a study which describes the cognitive dysfunction in pediatric transverse myelitis (TM) patients. The study also explores the impact of depression, medication, and fatigue on cognitive functioning. The study uses the neuropsychological screening as the method of the study. Results show that a slight higher frequencies of impairment were observed as compared to processing speed and verbal fluency.

Background: A new autoantibody (termed NMO-IgG, or AQP4-Ab) has recently been described in patients with neuromyelitis optica (NMO) and its formes frustes, longitudinally extensive transverse myelitis (LETM) and recurrent optic neuritis (rON). However, AQP4-Ab has been found also in patients with co-existing rheumatic diseases such as systemic lupus erythematosus (SLE) or Sjögren’s syndrome (SS), conditions which are characterized by broad, polyspecific B cell activation.Objectives: In this study, we aimed at evaluating the syndrome specificity and frequency of AQP4-Ab in patients with rheumatic diseases and neurological symptoms.Methods: For this purpose, serum samples from 109 neurological patients with established connective tissue disorders (CTD) (n = 54), possible CTD (n = 42), or vasculitis (n = 13) were analysed for the presence of AQP4-Ab by a cell-based assay employing recombinant human AQP4.Results: AQP4-Ab was detectable in 31/40 (78%) patients with CTD and NMO spectrum disorders (median titre, 1:1000) but in none of the samples obtained from patients with CTD or vasculitis and neurological disorders other than NMO, LETM, or rON (n = 69).Conclusion: The high syndrome specificity of the antibody for neuromyelitis optica spectrum disorders (NMOSDs) in patients with CTD supports the concept of AQP4-Ab being involved in the pathogenesis of these neurological conditions, and argues against AQP4-Ab simply being part of the polyclonal B cell activation generally associated with rheumatic diseases. Moreover, the finding that AQP4-Ab is present in patients with CTD and co-existing NMOSD with approximately the same frequency as in patients without CTD strengthens the case of CTD and AQP4-Ab positive NMOSD representing two co-existing yet distinct entities in the majority of patients. [ABSTRACT FROM AUTHOR]

The article discusses a study on the role of rate CYP27BI gene variants in multiple sclerosis (MS) patients in Austria. It examines the potential role of vitamin D deficiency as a risk factor for MS as well as looks at the cause of vitamin D-dependent rickets type 1. The study suggests that rate CYP27B1 variants have no major role in the etiology of MS.