. 2020 Sep 3;17(1):262.

doi: 10.1186/s12974-020-01825-1.

Cerebrospinal fluid findings in patients with myelin oligodendrocyte glycoprotein (MOG) antibodies. Part 2: Results from 108 lumbar punctures in 80 pediatric patients

Sven Jarius¹, Christian Lechner², Eva M Wendel³, Matthias Baumann², Markus Breu⁴, Mareike Schimmel⁵, Michael Karenfort⁶, Adela Della Marina⁷, Andreas Merkenschlager⁸, Charlotte Thiels⁹, Astrid Blaschek¹⁰, Michela Salandin¹¹, Steffen Leiz¹², Frank Leypoldt¹³, Alexander Pschibul¹⁴, Annette Hackenberg¹⁵, Andreas Hahn¹⁶, Steffen Syrbe¹⁷, Jurgis Strautmanis¹⁸, Martin Häusler¹⁹, Peter Krieg²⁰, Astrid Eisenkölbl²¹, Johannes Stoffels²², Matthias Eckenweiler¹⁴, Ilya Ayzenberg²³, Jürgen Haas²⁴, Romana Höftberger²⁵, Ingo Kleiter^{23

26}, Mirjam Korporal-Kuhnke²⁴, Marius Ringelstein^{27

28}, Klemens Ruprecht²⁹, Nadja Siebert^{30

31}, Kathrin Schanda³², Orhan Aktas²², Friedemann Paul^{30

31}, Markus Reindl³², Brigitte Wildemann²⁴, Kevin Rostásy³³; in cooperation with the BIOMARKER study group and the Neuromyelitis optica Study Group (NEMOS)

Affiliations

¹ Molecular Neuroimmunology Group, Department of Neurology, University of Heidelberg, Heidelberg, Germany. sven.jarius@med.uni-heidelberg.de.
² Division of Pediatric Neurology, Department of Pediatrics I, Medical University of Innsbruck, Innsbruck, Austria.
³ Department of Pediatrics, Olgahospital, Klinikum Stuttgart, Stuttgart, Germany.
⁴ Department of Pediatric and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.
⁵ Division of Pediatric Neurology, Children's Hospital, Medical University of Augsburg, Augsburg, Germany.
⁶ Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital, Heinrich-Heine-University, Düsseldorf, Germany.
⁷ Department of Neuropediatrics, Developmental Neurology and Social Pediatrics, Children's Hospital, University of Duisburg-Essen, Duisburg, Germany.
⁸ Division of Pediatric Neurology, University Hospital for Children and Adolescents, Leipzig, Germany.
⁹ Department of Neuropediatrics, University Children's Hospital, Ruhr-University Bochum, Bochum, Germany.
¹⁰ Department of Pediatric Neurology and Developmental Medicine, Dr. von Hauner Children's Hospital, University of Munich, Munich, Germany.
¹¹ Department of Pediatrics, Bozen Hospital, Bozen, Italy.
¹² Department of Pediatrics, Division of Pediatric Neurology, Klinikum Dritter Orden, Munich, Germany.
¹³ Neuroimmunology, Institute of Clinical Chemistry and Department of Neurology, Christian-Albrechts-University Kiel and Medical University Hospital Schleswig-Holstein, Kiel, Germany.
¹⁴ Department of Neuropediatrics and Muscle Disorders, University Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
¹⁵ Division of Pediatric Neurology, University Children's Hospital Zurich, Zurich, Switzerland.
¹⁶ Department of Pediatric Neurology, University Children's Hospital Giessen, Giessen, Germany.
¹⁷ Division of Child Neurology and Inherited Metabolic Diseases, Department of General Pediatrics, Center for Child and Adolescent Medicine, Heidelberg University Hospital, Heidelberg, Germany.
¹⁸ Department of Neurology, Children's Clinical University Hospital, Riga, Latvia.
¹⁹ Department of Pediatrics, Division of Neuropediatrics and Social Pediatrics, Medical University RWTH Aachen, Aachen, Germany.
²⁰ Department of Pediatrics, Städtisches Klinikum Karlsruhe, Karlsruhe, Germany.
²¹ Department of Pediatrics, Women's and Children's Hospital, Linz, Austria.
²² Department of Pediatric Neurology, Children's Hospital Neuburg, Neuburg, Germany.
²³ Department of Neurology, St Josef Hospital, Ruhr-University Bochum, Bochum, Germany.
²⁴ Molecular Neuroimmunology Group, Department of Neurology, University of Heidelberg, Heidelberg, Germany.
²⁵ Institute of Neurology, Medical University of Vienna, Vienna, Austria.
²⁶ Marianne-Strauß-Klinik, Behandlungszentrum Kempfenhausen für Multiple Sklerose Kranke gGmbH, Berg, Germany.
²⁷ Department of Neurology, Medical Faculty, Heinrich Heine University Dusseldorf, Düsseldorf, Germany.
²⁸ Department of Neurology, Center for Neurology and Neuropsychiatry, LVR-Klinikum, Heinrich Heine University Dusseldorf, Düsseldorf, Germany.
²⁹ Department of Neurology, Charité - Universitätsmedizin Berlin, Berlin, Germany.
³⁰ NeuroCure Clinical Research Center, Charité - Universitätsmedizin Berlin, Berlin, Germany.
³¹ Experimental and Clinical Research Center, Max Delbrueck Center for Molecular Medicine, and Charité Universitätsmedizin Berlin, Berlin, Germany.
³² Clinical Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria.
³³ Department of Pediatric Neurology, Children's Hospital Datteln, University Witten/Herdecke, Datteln, Germany. k.rostasy@kinderklinik-datteln.de.

PMID: 32883358
PMCID: PMC7470445
DOI: 10.1186/s12974-020-01825-1

Cerebrospinal fluid findings in patients with myelin oligodendrocyte glycoprotein (MOG) antibodies. Part 2: Results from 108 lumbar punctures in 80 pediatric patients

Sven Jarius et al. J Neuroinflammation. 2020.

. 2020 Sep 3;17(1):262.

doi: 10.1186/s12974-020-01825-1.

Authors

Affiliations

¹ Molecular Neuroimmunology Group, Department of Neurology, University of Heidelberg, Heidelberg, Germany. sven.jarius@med.uni-heidelberg.de.
² Division of Pediatric Neurology, Department of Pediatrics I, Medical University of Innsbruck, Innsbruck, Austria.
³ Department of Pediatrics, Olgahospital, Klinikum Stuttgart, Stuttgart, Germany.
⁴ Department of Pediatric and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.
⁵ Division of Pediatric Neurology, Children's Hospital, Medical University of Augsburg, Augsburg, Germany.
⁶ Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital, Heinrich-Heine-University, Düsseldorf, Germany.
⁷ Department of Neuropediatrics, Developmental Neurology and Social Pediatrics, Children's Hospital, University of Duisburg-Essen, Duisburg, Germany.
⁸ Division of Pediatric Neurology, University Hospital for Children and Adolescents, Leipzig, Germany.
⁹ Department of Neuropediatrics, University Children's Hospital, Ruhr-University Bochum, Bochum, Germany.
¹⁰ Department of Pediatric Neurology and Developmental Medicine, Dr. von Hauner Children's Hospital, University of Munich, Munich, Germany.
¹¹ Department of Pediatrics, Bozen Hospital, Bozen, Italy.
¹² Department of Pediatrics, Division of Pediatric Neurology, Klinikum Dritter Orden, Munich, Germany.
¹³ Neuroimmunology, Institute of Clinical Chemistry and Department of Neurology, Christian-Albrechts-University Kiel and Medical University Hospital Schleswig-Holstein, Kiel, Germany.
¹⁴ Department of Neuropediatrics and Muscle Disorders, University Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
¹⁵ Division of Pediatric Neurology, University Children's Hospital Zurich, Zurich, Switzerland.
¹⁶ Department of Pediatric Neurology, University Children's Hospital Giessen, Giessen, Germany.
¹⁷ Division of Child Neurology and Inherited Metabolic Diseases, Department of General Pediatrics, Center for Child and Adolescent Medicine, Heidelberg University Hospital, Heidelberg, Germany.
¹⁸ Department of Neurology, Children's Clinical University Hospital, Riga, Latvia.
¹⁹ Department of Pediatrics, Division of Neuropediatrics and Social Pediatrics, Medical University RWTH Aachen, Aachen, Germany.
²⁰ Department of Pediatrics, Städtisches Klinikum Karlsruhe, Karlsruhe, Germany.
²¹ Department of Pediatrics, Women's and Children's Hospital, Linz, Austria.
²² Department of Pediatric Neurology, Children's Hospital Neuburg, Neuburg, Germany.
²³ Department of Neurology, St Josef Hospital, Ruhr-University Bochum, Bochum, Germany.
²⁴ Molecular Neuroimmunology Group, Department of Neurology, University of Heidelberg, Heidelberg, Germany.
²⁵ Institute of Neurology, Medical University of Vienna, Vienna, Austria.
²⁶ Marianne-Strauß-Klinik, Behandlungszentrum Kempfenhausen für Multiple Sklerose Kranke gGmbH, Berg, Germany.
²⁷ Department of Neurology, Medical Faculty, Heinrich Heine University Dusseldorf, Düsseldorf, Germany.
²⁸ Department of Neurology, Center for Neurology and Neuropsychiatry, LVR-Klinikum, Heinrich Heine University Dusseldorf, Düsseldorf, Germany.
²⁹ Department of Neurology, Charité - Universitätsmedizin Berlin, Berlin, Germany.
³⁰ NeuroCure Clinical Research Center, Charité - Universitätsmedizin Berlin, Berlin, Germany.
³¹ Experimental and Clinical Research Center, Max Delbrueck Center for Molecular Medicine, and Charité Universitätsmedizin Berlin, Berlin, Germany.
³² Clinical Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria.
³³ Department of Pediatric Neurology, Children's Hospital Datteln, University Witten/Herdecke, Datteln, Germany. k.rostasy@kinderklinik-datteln.de.

PMID: 32883358
PMCID: PMC7470445
DOI: 10.1186/s12974-020-01825-1

Abstract

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 children with MOG-EM.

Material and methods: Cytological and biochemical findings (including white cell counts [WCC] and differentiation; frequency and patterns of oligoclonal bands; IgG/IgM/IgA and albumin concentrations and CSF/serum ratios; intrathecal IgG/IgM/IgA 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 108 lumbar punctures in 80 pediatric 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 89% of samples (N = 96), and the MRZ reaction, the most specific laboratory marker of MS known so far, in 100% (N = 29). If present at all, intrathecal IgG synthesis was low, often transient and mostly restricted to acute attacks. Intrathecal IgM synthesis was present in 21% and exclusively detectable during acute attacks. CSF WCC were elevated in 54% of samples (median 40 cells/μl; range 6-256; mostly lymphocytes and monocytes; > 100/μl in 11%). Neutrophils were present in 71% of samples; eosinophils, activated lymphocytes, and plasma cells were seen only rarely (all < 7%). Blood-CSF barrier dysfunction (as indicated by an elevated albumin CSF/serum ratio) was present in 46% of all samples (N = 79) and at least once in 48% of all patients (N = 67) tested. CSF alterations were significantly more frequent and/or more pronounced in patients with acute spinal cord or brain disease than in patients with acute ON and varied strongly depending on attack severity. CSF L-lactate levels correlated significantly with the spinal cord lesions load (measured in vertebral segments) in patients with acute myelitis (p = 0.0099). An analysis of pooled data from the pediatric and the adult cohort showed a significant relationship of QAlb (p < 0.0005), CST TP (p < 0.0001), and CSF L-lactate (p < 0.0003) during acute attacks with age.

Conclusion: MOG-IgG-associated EM in children is characterized by CSF features that are distinct from those in MS. With regard to most parameters, no marked differences between the pediatric cohort and the adult cohort analyzed in Part 1 were noted. Our findings are important for the differential diagnosis of pediatric MS and MOG-EM and add to the understanding of the immunopathogenesis of this newly described autoimmune disease.

Keywords: Acute disseminated encephalomyelitis (ADEM); Antibodies; Brainstem encephalitis; Cerebrospinal fluid; Children; Encephalomyelitis; Lumbar puncture; MOG antibody-associated disease (MOGAD); Multiple sclerosis (MS); Myelin oligodendrocyte glycoprotein (MOG); NMO spectrum disorders; Neuromyelitis optica (Devic syndrome); Oligoclonal bands; Optic neuritis; Transverse myelitis.

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Conflict of interest statement

S.J. was indirectly supported by research grants from the Dietmar Hopp Stiftung and from Merck Serono to the Department of Neurology, University Hospital Heidelberg, Germany (to B.W.). C.L. reports no conflicts of interest. E.W. reports no conflicts of interest. M.Ba. reports no conflicts of interest. M.Br. reports no conflicts of interest. M.S. reports no conflicts of interest. M.K. reports no conflicts of interest. A.DM. reports no conflicts of interest. A.M. reports no conflicts of interest. C.T. reports no conflicts of interest. A.B. has received travel grands and speakers honoraria from Merck Serono, Genzyme, Sanofi and has served on scientific advisory boards for Novartis. M.S. reports no conflicts of interest. S.L. reports no conflicts of interest. F.L. reports speakers honoraria from Grifols, Teva, Biogen, Bayer, Roche, Novartis, Fresenius, travel funding from Merck, Grifols, and Bayer and serving on advisory boards for Roche, Biogen and Alexion. A.P. reports no conflicts of interest. A.H. reports no conflicts of interest. C.K. reports no conflicts of interest. A.H. reports no conflicts of interest. S.S. reports no conflicts of interest. J.S. reports no conflicts of interest. M.H. reports no conflicts of interest. P.K. reports no conflicts of interest. A.E. reports no conflicts of interest. J.S. reports no conflicts of interest. M.E. reports no conflicts of interest. I.A. has received travel grants from Biogen Idec and the Guthy-Jackson Charitable Foundation, has served on scientific advisory boards for Roche and Alexion and has received research support from Chugai Pharma. J.H. reports no conflicts of interest. I.K. has received travel funding and/or speaker honoraria from Biogen, Merck, Mylan, Novartis, Sanofi, Roche, has consulted for Alexion, Bayer, Chugai, Roche, Shire, has received research support from Chugai and Diamed, and is Associate Editor of BMC Neurology. M.K.K. reports no conflicts of interest. M.Ri. has received speaker honoraria from Novartis, Bayer Vital GmbH and Ipsen, has served on scientific advisory boards for Roche, and received travel reimbursement from Bayer Schering, Biogen Idec, Merz, Genzyme, Teva, Merck and the Guthy-Jackson Charitable Foundation, none related to this study. P.S.R. reports speaker honoraria from Abbvie, Daiichi-Sankyo, Merck, Roche, Biogen, Novartis, Shire; he reports consultancy honoraria from Roche, Merck, Teva, Sandoz/Hexal; and research grants from Biogen, Merck, Roche; none of them resultant in a conflict of interest with regards to the submitted work. K.Ru. has received research support from Novartis, Merck Serono, and the German Federal Ministry of Education and Research; speaker honoraria and travel grants from Bayer, Biogen Idec, Merck Serono, Sanofi-Aventis/Genzyme, Teva, Roche, Novartis, and the Guthy Jackson Charitable Foundation. N.S. has received travel funding from Sanofi-Aventis/Genzyme. O.A. has received grants from the German Research Foundation (DFG) and the German Federal Ministry of Education and Research (BMBF) as part of the ‘German Competence Network Multiple Sclerosis’ (KKNMS; FKZ 01GI1602B); grants from Biogen, Merck Serono, Novartis, Sanofi and Teva; personal fees from Biogen, Merck Serono, Novartis, Sanofi, Roche, and Teva. F.P. has received honoraria and research support from Alexion, Bayer, Biogen, Chugai, MerckSerono, Novartis, Genzyme, MedImmune, Shire, Teva, and serves on scientific advisory boards for Alexion, MedImmune and Novartis; he has received funding from Deutsche Forschungsgemeinschaft (DFG Exc 257), the German Federal Ministry of Education and Research (Competence Network Multiple Sclerosis), the Guthy Jackson Charitable Foundation, the EU Framework Program 7, and the National Multiple Sclerosis Society of the USA. M.R. was supported by research grants from the Austrian Science Funds (FWF), Austrian Science Promotion Agency (FFG) and the Austrian Multiple Sclerosis Research Society. The University Hospital and Medical University of Innsbruck (Austria; M.R. and K.Sch.) receives payments for antibody assays (MOG, AQP4, and other autoantibodies) and for MOG and AQP4 antibody validation experiments organized by Euroimmun (Lübeck, Germany). B.W. has received research grants and/or honoraria from Merck Serono, Biogen, Teva, Novartis, Sanofi Genzyme, and Bayer Healthcare, and research grants from the Dietmar Hopp Foundation, the Klaus Tschira Foundation, the German Federal Ministry of Education and Research (BMBF; FKZ 01GI1602A), and Deutsche Forschungsgemeinschaft (DFG). K.R. has no conflict of interest related to this project.

Figures

**Fig. 1**
CSF white cell counts, IgG, IgA, IgM, and albumin CSF/serum ratios and CSF concentrations, CSF total protein concentrations, and CSF L-lactate concentrations in MOG-IgG-positive EM. A statistically significant difference between the acute MY subgroup and the acute ON subgroup was found regarding all parameters studied. *IgG*/A/M immunoglobulin G/A/M, *QIgG*/A/M CSF/serum IgG/A/M ratios, *QAlb* CSF/serum albumin ratio

**Fig. 2**
CSF white cell counts, IgG, IgA, IgM and albumin CSF/serum ratios, CSF total protein concentrations, and CSF L-lactate concentrations during acute attacks and remission in MOG-IgG-positive EM. *IgG*/A/M immunoglobulin G/A/M, MY myelitis, *QIgG*/A/M CSF/serum IgG/A/M ratios, *QAlb* CSF/serum albumin ratio

**Fig. 3**
Correlation analyses for CSF white cell counts, QAlb and CSF total protein, respectively, and days since attack onset in patients with acute disease. Although the correlations were not statistically significant, a clear trend towards normal values over time is discernible. Given that clear trend and the significant correlations seen in adults, it is likely that the lack of statistical significance is an effect of the lower number of samples in the pediatric cohort. *QAlb* albumin CSF/serum ratio, TP total protein, *WCC* white cell count

**Fig. 4**
Significant correlation of CSF l-lactate (r = 0.549, p < 0.01) and CSF albumin concentrations with the spinal cord lesion load (as measured in vertebral segments) in patients with acute MOG-IgG-positive myelitis. *QAlb* albumin CSF/serum ratio, *QIgG* IgG CSF/serum ratio, TP total protein, *WCC* white cell count

**Fig. 5**
MRZ reaction. Panel a shows the antibody indices for M, R and Z in multiple sclerosis (pooled data from ref. [44, 46]) and in samples from MOG-IgG-positive patients (present study). Groups were compared using the Kruskal–Wallis test with Dunn’s post-test. Note that in those cases in which a negative AI was documented but no exact value was available, the AI was set to 1.5, i.e., just below the cut-off for AI positivity (> 1.5); in consequence, the real differences between MOG-EM and MS may be even more pronounced than shown here. Panel b shows the frequency of a positive MRZ reaction (MR, MZ, RZ, or MRZ) in MOG-EM (present study), in neuromyelitis optica spectrum disorders (NMOSD), and in healthy controls (HC) (data from [44]). AI antibody index, M measles virus AI, R rubella virus AI, Z varicella zoster virus AI

**Fig. 6**
Correlation of CSF l-lactate concentrations with CSF WCC (r = 0.257, p < 0.04) and CSF TP (r = 0.356, p < 0.003). TP total protein, *WCC* white cell count

**Fig. 7**
CSF/serum quotient diagrams for IgG, IgM, and IgA (“reibergrams”). Individual CSF/serum ratios of IgG, IgA, and IgM are plotted against CSF/serum albumin ratios. Values above the upper hyperbolic discrimination line, Q_lim, indicate intrathecal synthesis of the respective immunoglobulin (Ig) class. Individual intrathecal fractions, Ig_IF, can be directly read by interpolation from the percentiles above Q_lim (median values are given in Tables 2 and 3). *IgG*/A/M immunoglobulin G/A/M, *QIgG*/A/M CSF/serum IgG/A/M ratios, *QAlb* CSF/serum albumin ratio

See this image and copyright information in PMC

References

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1. Jarius S, Kleiter I, Ruprecht K, Asgari N, Pitarokoili K, Borisow N, et al. MOG-IgG in NMO and related disorders: a multicenter study of 50 patients. Part 3: Brainstem involvement - frequency, presentation and outcome. J Neuroinflammation. 2016;13:281. - PMC - PubMed
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Cerebrospinal fluid findings in patients with myelin oligodendrocyte glycoprotein (MOG) antibodies. Part 2: Results from 108 lumbar punctures in 80 pediatric patients

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Cerebrospinal fluid findings in patients with myelin oligodendrocyte glycoprotein (MOG) antibodies. Part 2: Results from 108 lumbar punctures in 80 pediatric patients

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