Publications by authors named "Makbule Senel"

31 Publications

Varicella zoster virus-induced neurological disease after COVID-19 vaccination: a retrospective monocentric study.

J Neurol 2021 Nov 1. Epub 2021 Nov 1.

Department of Neurology, University of Ulm, Ulm, Germany.

The description of every possible adverse effect or event related to vaccines is mandatory during the ongoing worldwide COVID-19 vaccination program. Although cases of cutaneous varicella zoster virus (VZV) reactivation after COVID-19 vaccination have been increasingly reported in literature and database sets, a description of VZV-induced neurological disease (VZV-ND) is still lacking. In the present study, we retrospectively evaluated patients admitted to our clinic and diagnosed with VZV-ND during the COVID-19 vaccination campaign (January-April 2021) and in the same months in the previous two years. We identified three patients with VZV-ND after COVID-19 vaccination and 19 unvaccinated VZV-ND cases as controls. In the case-control analysis, the two groups showed no difference in clinical features, results of diagnostic investigations, and outcome. Thus, VZV reactivation with neurological involvement might be a possible event triggered by COVID-19 vaccination, but the benefit following COVID-19 vaccination overcomes significantly the potential risk associated with a VZV reactivation.
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http://dx.doi.org/10.1007/s00415-021-10849-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8558363PMC
November 2021

CSF Findings in Acute NMDAR and LGI1 Antibody-Associated Autoimmune Encephalitis.

Neurol Neuroimmunol Neuroinflamm 2021 11 25;8(6). Epub 2021 Oct 25.

From the Department of Neurology (M.D., M.S., J.D., H.T., J.L.), Ulm University; Department of Neurosurgery (M.D.), University Hospital Tübingen; Neuroimmunology (G.N., K.-P.W., F.L.), Institute of Clinical Chemistry, University Hospital Schleswig-Holstein Kiel/Lübeck; Department of Neurology (K.-W.S., P.S.), Hannover Medical School; Department of Neurology (C.G.), University Hospital Jena; Department of Neurology (M.R., H.-P.H., N.M.), Medical Faculty, Heinrich Heine University Düsseldorf; Department of Neurology (M.R.), Center for Neurology and Neuropsychiatry, LVR-Klinikum Düsseldorf, Düsseldorf; Institute of Neuroimmunology and Multiple Sclerosis (M.A.F., M.K.), University Medical Center Hamburg-Eppendorf; Department of Neurology (M.P.M., M.M.), University of Cologne, Faculty of Medicine and University Hospital; Institute of Clinical Neuroimmunology (F.S.T., T.K.), University Hospital and Biomedical Center, Ludwig-Maximilians University Munich; Department of Pediatrics (M.G.H.), University Hospital RWTH Aachen; Technische Universität Dresden (H.S.), and Department of Neurology, University Hospital Augsburg; Department of Neurology (F.T.B.), University Hospital Leipzig; Department of Neurology (C.K.), Klinikum Osnabrück; Department of Neurology (U.K.Z.), Section for Neuroimmunology, University Hospital Rostock; Department of Neurology with Institute of Translational Neurology (N.M., C.C.G.), University Hospital Münster; Department of Neurology (P.L.), University Hospital Göttingen; Institute of Epidemiology and Medical Biometry, Ulm University; and Department of Neurology (F.L.), University Hospital Schleswig-Holstein and Kiel University, Germany.

Background And Objectives: CSF in antibody-defined autoimmune encephalitis (AE) subtypes shows subtype-dependent degrees of inflammation ranging from rare and often mild to frequent and often robust. AEs with NMDA receptor antibodies (NMDAR-E) and leucine-rich glioma-inactivated protein 1 antibodies (LGI1-E) represent opposite ends of this spectrum: NMDAR-E with typically frequent/robust and LGI1-E with rare/mild CSF inflammation. For a more in-depth analysis, we characterized CSF findings in acute, therapy-naive NMDAR-E and LGI1-E in a multicentric, retrospective, cross-sectional setting.

Methods: Eighty-two patients with NMDAR-E and 36 patients with LGI1-E from the GErman NEtwork for Research of AuToimmune Encephalitis (GENERATE) with lumbar puncture within 90 days of onset and before immunotherapy were included. CSF parameters comprised leukocytes, oligoclonal bands (OCBs), and CSF/serum ratios for albumin, immunoglobulin G (IgG), A (IgA), and M (IgM), the latter 3 converted to Z scores according to Reiber formulas. The MRZ reaction was tested in 14 patients with NMDAR-E and 6 patients with LGI1-E, respectively.

Results: CSF was abnormal in 94% of NMDAR-E but only in 36% of LGI1-E patients. Robust quantitative intrathecal immunoglobulin synthesis (IIS, IgG > IgM >> IgA) was characteristic for NMDAR-E, but absent in LGI-E. In NMDAR-E, CSF leukocytes were higher when IIS was present or more pronounced. In addition, in NMDAR-E, CSF leukocytes were lower and IIS occurred less often and if so to a lesser degree at older age. Patients with NMDAR-E with severe functional impairment more often had positive OCBs. In CSF obtained later than 3 weeks of onset, leukocytes were lower. In parallel, the correlation of leukocytes with IIS disappeared as IIS was partially independent of disease duration. The MRZ reaction was positive in 5 (36%) patients with NMDAR-E. All these associations were completely absent in LGI1-E. Here, younger patients showed more blood-CSF barrier dysfunction. In LGI1-E, but not in NMDAR-E, the blood-CSF barrier was more dysfunctional when CSF leukocytes were higher.

Discussion: NMDAR-E and LGI-E differ in their typical extent of CSF inflammation. In addition, the patterns formed by the different inflammatory CSF parameters and their relationship with disease severity, age, and disease duration are subtype-characteristic. Moreover, signs for multiple sclerosis-like chronic inflammation are present in a subgroup of patients with NMDAR-E. These CSF patterns might be markers for the different immunopathogeneses of LGI1-E and NMDAR-E.
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http://dx.doi.org/10.1212/NXI.0000000000001086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8546742PMC
November 2021

Associations between multiple sclerosis and incidence of heart diseases: Systematic review and meta-analysis of observational studies.

Mult Scler Relat Disord 2021 Sep 26;56:103279. Epub 2021 Sep 26.

Department of Neurology, University of Ulm, Oberer Eselsberg 45, 89081 Ulm, Germany. Electronic address:

Background: Observational studies have described associations between multiple sclerosis (MS) and heart diseases, but the results were mixed.

Methods: Medline, Embase, and Cochrane CENTRAL were searched up to 5 October 2020 according to a protocol (PROSPERO registration number CRD42020184493). We included longitudinal non-randomized studies of exposure comparing the incidence of acquired heart diseases between people with multiple sclerosis (pwMS) and people without multiple sclerosis. We used ROBINS-E and the GRADE approach to assess risk of bias and the certainty of evidence, respectively. Data were pooled using random-effect models.

Results: Of 5,159 studies, nine studies met the inclusion criteria. MS was associated with an increased risk for myocardial infarction (HR 1.6, 95% CI 1.2 to 2.0, I2 86%, n = 1,209,079) and heart failure (HR 1.7, 95% CI 1.3 to 2.2, I2 49%, n = 489,814). The associations were more pronounced among women and younger people in subgroup analyses. We found no difference for ischemic heart disease (HR 1.0, 95% CI 0.8 to 1.4, I2 86%, n = 679,378) and bradycardia (HR 1.5, 95% CI 0.4 to 5.0, I2 50%, n = 187,810). The risk of atrial fibrillation was lower in pwMS (HR 0.7, 95% CI 0.6 to 0.8, I2 0%, n = 354,070), but the risk of bias was high, and the certainty of evidence was rated as very low. One study found more cases of infectious endocarditis among pwMS (HR 1.2, 95% CI 1.0 to 1.4, n = 83,712).

Conclusions: Myocardial infarction and heart failure should be considered in people with multiple sclerosis during follow-up examinations.
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http://dx.doi.org/10.1016/j.msard.2021.103279DOI Listing
September 2021

Differentiation of viral and autoimmune central nervous system inflammation by kynurenine pathway.

Ann Clin Transl Neurol 2021 Oct 8. Epub 2021 Oct 8.

Clinical Neuroimmunology and Neurochemistry, Department of Neurology, Hannover Medical School, Hannover, Germany.

Objective: To determine whether the metabolites of Kynurenine pathway (KP) could serve as biomarkers for distinguishing between viral CNS infections and autoimmune neuroinflammatory diseases, especially anti-N-methyl-D-aspartate receptor encephalitis (NMDARE) and herpes virus encephalitis (HSE).

Methods: This study enrolled CSF samples from 76 patients with viral CNS infections, autoimmune neuroinflammatory, and non-inflammatory neurological diseases. We measured cerebrospinal fluid (CSF) concentrations of tryptophan (Trp) and kynurenine (Kyn) by ELISA.

Results: Kyn concentrations and Kyn/Trp ratios were highly increased (p < 0.001, viral vs. autoimmune) in viral CNS infections, whereas patients with autoimmune neuroinflammatory and non-inflammatory diseases exhibited low concentrations. Furthermore, Kyn concentrations and Kyn/Trp ratio turned out to be excellent biomarkers to distinguish between herpes simplex encephalitis (HSE) and NMDARE (AUC 0.920 and AUC 0.906), whereas Trp concentrations were similar in all three groups.

Interpretation: The results suggest that elevated CSF Kyn concentrations and Kyn/Trp ratio may serve as biomarkers for distinguishing viral CNS infections from autoimmune neuroinflammatory diseases. In particular, the distinction between HSE and NMDARE is of great clinical relevance. Further studies are warranted to investigate the potential of CSF Kyn levels and Kyn/Trp ratio as routine parameters in patients with CNS diseases.
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http://dx.doi.org/10.1002/acn3.51383DOI Listing
October 2021

Pain, Depression, and Quality of Life in Neuromyelitis Optica Spectrum Disorder: A Cross-Sectional Study of 166 AQP4 Antibody-Seropositive Patients.

Neurol Neuroimmunol Neuroinflamm 2021 05 20;8(3). Epub 2021 Apr 20.

From the Department of Neurology (I.A., D.R., E.H., K.H., R.G., I.K.), St. Josef-Hospital, Ruhr-University Bochum, Germany; Department of Neurology (I.A.), Sechenov First Moscow State Medical University, Russia; NeuroCure Clinical Research Center (S.A., F.P.), Charité Universitätsmedizin Berlin, Berlin Institute of Health, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Germany; Department of Neurology (C.T., M.W.H.), Hannover Medical School, Germany; Institute of Clinical Neuroimmunology (J.H., T.K., H.L.P.), University Hospital and Biomedical Center, Ludwig-Maximilians University Munich, Germany; Department of Neurology (M.R., O.A.), Medical Faculty, Heinrich Heine University Düsseldorf, Germany; Department of Neurology (M.R.), Center for Neurology and Neuropsychiatry, LVR-Klinikum Düsseldorf, Germany; Molecular Neuroimmunology Group (B.W., S.J.), Department of Neurology, University of Heidelberg, Germany; Institut für Neuroimmunologie und Multiple Sklerose (INIMS) (V.H., J.-P.S.), Zentrum für Molekulare Neurobiologie, Hamburg, Germany; Klinik und Poliklinik für Neurologie (V.H., J.-P.S.), Universitätsklinikum Hamburg-Eppendorf, Germany; APHM (J.-P.S.), Hopital de la Timone, CEMEREM, Marseille, France; Aix Marseille Université (J.-P.S.), CRMBM, CNRS UMR 7339, Marseille, France; Department of Neurology (M.S.), University of Ulm, Germany; Münster Department of Neurology with Institute of Translational Neurology (L.K., M.P.), University Hospital Münster, Germany; Department of Neurology (H.L.P., M.S.W.), University Medical Center, Göttingen, Germany; Department of Neurology (M.P.), Otto-von-Guericke University, Magdeburg, Germany; Department of Neurology (P.S.R.), Medical University of Vienna, Austria; Neuroimmunology Section (P.S.R.), Department of Neurology, University of Rostock, Germany; Department of Neurology (A.B.), School of Medicine, Technical University of Munich, Germany; Charité-Universitätsmedizin Berlin, CRO SOSTANA GmbH Berlin (K.-D.W.), Germany; and Marianne-Strauß-Klinik (I.K.), Behandlungszentrum Kempfenhausen für Multiple Sklerose Kranke gGmbH, Berg, Germany.

Objectives: To evaluate prevalence, clinical characteristics, and predictors of pain, depression, and their impact on the quality of life (QoL) in a large neuromyelitis optica spectrum disorder (NMOSD) cohort.

Methods: We included 166 patients with aquaporin-4-seropositive NMOSD from 13 tertiary referral centers. Patients received questionnaires on demographic and clinical characteristics, PainDetect, short form of Brief Pain Inventory, Beck Depression Inventory-II, and Short Form 36 Health Survey.

Results: One hundred twenty-five (75.3%) patients suffered from chronic NMOSD-associated pain. Of these, 65.9% had neuropathic pain, 68.8% reported spasticity-associated pain and 26.4% painful tonic spasms. Number of previous myelitis attacks (OR = 1.27, = 0.018) and involved upper thoracic segments (OR = 1.31, = 0.018) were the only predictive factors for chronic pain. The latter was specifically associated with spasticity-associated pain (OR = 1.36, = 0.002). More than a third (39.8%) suffered from depression, which was moderate to severe in 51.5%. Pain severity (OR = 1.81, < 0.001) and especially neuropathic character (OR = 3.44, < 0.001) were associated with depression. Pain severity and walking impairment explained 53.9% of the physical QoL variability, while depression and walking impairment 39.7% of the mental QoL variability. No specific medication was given to 70.6% of patients with moderate or severe depression and 42.5% of those with neuropathic pain. Two-thirds (64.2%) of patients with symptomatic treatment still reported moderate to severe pain.

Conclusions: Myelitis episodes involving upper thoracic segments are main drivers of pain in NMOSD. Although pain intensity was lower than in previous studies, pain and depression remain undertreated and strongly affect QoL. Interventional studies on targeted treatment strategies for pain are urgently needed in NMOSD.
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http://dx.doi.org/10.1212/NXI.0000000000000985DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8058953PMC
May 2021

Diagnostic biomarkers in tear fluid: from sampling to preanalytical processing.

Sci Rep 2021 05 12;11(1):10064. Epub 2021 May 12.

Department of Neurology, University Hospital Ulm, Ulm, Germany.

Tear fluid is receiving growing attention as a source for novel diagnostic biomarkers. Multiple techniques are available for its collection and impact the composition of acquired samples. We sought to provide a direct comparison of two collection methods with regard to implementation, acceptance, and impact on sample composition. Tear fluid was collected from fifteen healthy volunteers with capillary tubes and Schirmer strips and analyzed for total protein and IgG concentrations. Sampling parameters and perception by test persons were compared. The use of capillary tubes was more convenient for the participants while causing more effort for the collector. Tear flow rates as well as the relative and absolute amount of IgG were higher when Schirmer strips were used. Consecutive collections with Schirmer strips significantly influenced tear flow rates, IgG, and protein concentrations. A moderate correlation was observed between tear flow rates and IgG concentrations for both methods. Samples collected with both methods can be analyzed by isoelectric focusing, a potential diagnostic application in the field of neurology. The specific advantages and limitations of tear fluid sampling with either capillary tubes or Schirmer strips demonstrate the need for a thorough investigation of collection methods with regard to the application of interest.
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http://dx.doi.org/10.1038/s41598-021-89514-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8114924PMC
May 2021

Phelan McDermid Syndrome: Multiple Sclerosis as a Rare but Treatable Cause for Regression-A Case Report.

Int J Mol Sci 2021 Feb 25;22(5). Epub 2021 Feb 25.

Department of Neurology, Ulm University, 89081 Ulm, Germany.

Phelan McDermid syndrome (PMcD) is a neurogenetic disease associated with haploinsufficiency of the gene due to a spectrum of anomalies in the terminal region of the long arm of chromosome 22. is the abbreviation for SH3 domain and ankyrin repeat-containing protein, a gene that encodes for proteins of the postsynaptic density (PSD) of excitatory synapses. This PSD is relevant for the induction and plasticity of spine and synapse formation as a basis for learning processes and long-term potentiation. Individuals with PMcD present with intellectual disability, muscular hypotonia, and severely delayed or absent speech. Further neuropsychiatric manifestations cover symptoms of the autism spectrum, epilepsy, bipolar disorders, schizophrenia, and regression. Regression is one of the most feared syndromes by relatives of PMcD patients. Current scientific evidence indicates that the onset of regression is variable and affects language, motor skills, activities of daily living and cognition. In the case of regression, patients normally undergo further diagnostics to exclude treatable reasons such as complex-focal seizures or psychiatric comorbidities. Here, we report, for the first time, the case of a young female who developed progressive symptoms of regression and a dystonic-spastic hemiparesis that could be traced back to a comorbid multiple sclerosis and that improved after treatment with methylprednisolone.
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http://dx.doi.org/10.3390/ijms22052311DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7956287PMC
February 2021

Tick-Borne Encephalitis: A Differential Pattern of Intrathecal Humoral Immune Response and Inflammatory Cell Composition Compared with Other Viral CNS Infections.

Cells 2020 09 25;9(10). Epub 2020 Sep 25.

Department of Neurology, University of Ulm, 89081 Ulm, Germany.

To investigate whether and how cerebrospinal fluid (CSF) findings can contribute to distinguish tick-borne encephalitis (TBE) from herpes simplex virus (HSV) and varicella zoster virus (VZV) induced central nervous system (CNS) infections (HSV-I, VZV-I). Chart review and identification of TBE, HSV- I, and VZV-I was carried out, fulfilling the following criteria: (1) clinical signs of encephalitis and/or meningitis, (2) complete CSF analysis and confirmed viral etiology by either PCR or antibody testing in CSF, (3) hospitalized patients, and (4) available brain magnetic resonance imaging (MRI). Fifty-nine patients with 118 CSF/serum pairs were included. These comprised 21 with TBE (35 CSF/serum pairs), 20 (40 CSF/serum pairs) with HSV-I, and 18 (43 CSF/serum pairs) with VZV-I. In contrast to HSV-I and VZV-I, CSF cell differentiation in TBE showed more often an increased (>20%) proportion of granulocytes ( < 0.01) and a more frequent quantitative intrathecal IgM synthesis ( = 0.001 and < 0.01, respectively), while the second was even more pronounced when follow-up CSF analyses were included ( < 0.001). CSF findings help to distinguish TBE from other viral infections. In cases with CSF pleocytosis and a positive history for a stay in or near an endemic area, TBE antibodies in CSF and serum should be determined, especially if granulocytes in CSF cell differentiation and/or an intrathecal IgM synthesis is present.
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http://dx.doi.org/10.3390/cells9102169DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7599799PMC
September 2020

Serum neurofilament light chain: No clear relation to cognition and neuropsychiatric symptoms in stable MS.

Neurol Neuroimmunol Neuroinflamm 2020 11 24;7(6). Epub 2020 Sep 24.

From the Department of Neurology (O.A., M.G., K.L., N.G., J.G., H.-P.H., P.A., I.-K.P.), Medical Faculty, University Düsseldorf, Germany; Cogito Center for Applied Neurocognition and Neuropsychological Research (A.R., M.F., S.B., N.S., I.-K.P.), Düsseldorf, Germany; Department of Neurology (A.H., M.S., M.O., H.T.), University Hospital Ulm, Germany; Department of Neurology (C.E., D.P.), Research Unit for Neuronal Plasticity and Repair, Medical University of Graz, Austria; Division of Neuroradiology, Vascular and Interventional Radiology (C.E.), Department of Radiology, Medical University of Graz, Austria; Department of Diagnostic and Interventional Radiology (G.A., B.T.), Medical Faculty, University Düsseldorf, Germany; and Department of Neurology (H.T.), Dietenbronn, Germany.

Objective: To explore the hypothesis that serum neurofilament light chain (sNfL) indicative of neuroaxonal damage may improve precise disease profiling with regard to cognition and neuropsychiatric symptoms, we analyzed potential associations of sNfL levels with cognitive test scores, fatigue, depression, and anxiety.

Methods: Patients with relapsing-remitting and secondary progressive MS (SPMS) underwent an elaborated assessment including MRI, various cognitive tests, and patient-reported outcomes. We determined sNfL levels by single molecule array (Simoa) assay. Relationships between sNfL, cognition, neuropsychiatric symptoms, and demographical data were analyzed using correlations, group comparisons, and regressions.

Results: In 45 clinically stable patients with MS (Expanded Disability Status Scale = 2.73 ± 1.12, disease duration = 10.03 ± 7.49 years), 40.0% were cognitively impaired. Mean sNfL levels were 16.02 ± 10.39 pg/mL, with higher levels in the SPMS subgroup ( = 0.038). sNfL levels did reliably link neither with the investigated cognitive and affective parameters nor with fatigue levels. The only relationship found in a small subgroup of patients with SPMS (n = 7) with visuospatial learning ( = -0.950, = 0.001) and memory ( = -0.813; = 0.026) disappeared when further controlling for age, educational level, and sex.

Conclusions: In patients with stable MS at less advanced disease stages, sNfL did not convincingly relate to cognitive performance, fatigue, depression, or anxiety and thus may not serve as a surrogate biomarker for neuropsychological status in such populations.
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http://dx.doi.org/10.1212/NXI.0000000000000885DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7673283PMC
November 2020

Safety and Tolerability of Plasma Exchange and Immunoadsorption in Neuroinflammatory Diseases.

J Clin Med 2020 Sep 5;9(9). Epub 2020 Sep 5.

Department of Neurology, University of Ulm, 89081 Ulm, Germany.

Plasma exchange (PE) and immunoadsorption (IA) are frequently used for treatment of various autoimmune-mediated neurological diseases, including multiple sclerosis (MS), chronic inflammatory demyelinating polyneuropathy (CIDP), and Guillain-Barré syndrome (GBS). Although both methods are generally regarded as well-tolerated treatment options, evidence for safety and tolerability is low for most indications and largely relies on small case series. In this study, we retrospectively analysed adverse events (AEs) and laboratory changes in 284 patients with various neurological indications who received either PE ( = 65, 113 cycles) or IA ( = 219, 435 cycles) between 2013 and 2020 in our Neurology department. One standard treatment cycle for PE as well as IA consisted of five treatments on five consecutive days. During every treatment, the 2.0-2.5-fold individual plasma volume (PV) was treated in IA, while in PE, the 0.7-fold individual PV was replaced by human albumin solution. Overall, both methods showed an excellent safety profile; no deaths of life-threatening adverse events were recorded. Severe AEs (corresponding to grade 3 on the Common Terminology Criteria for Adverse Events grading scale v5.0) including three patients with sepsis, one pneumonia, and one pneumothorax were present in 5/435 IA cycles (1.1%); in the PE group, no severe AEs were recorded. Furthermore, although advantageous tolerability is generally considered the main advantage of IA over PE, we found that overall frequency of AEs (including grades 1 and 2) was higher in IA (67.1% of all cycles) compared to PE (35.4%; < 0.001). The low incidence of AEs in PE might be caused by the lower PV exchanged during each treatment (0.7-fold) compared to previous studies which predominantly exchanged the 1.0-1.5-fold PV. In order to verify this hypothesis as well as confirming the efficacy of this lower-dosed scheme, prospective studies comparing different treatment regimens are needed.
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http://dx.doi.org/10.3390/jcm9092874DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7565027PMC
September 2020

Longitudinal Serum Neurofilament Levels of Multiple Sclerosis Patients Before and After Treatment with First-Line Immunomodulatory Therapies.

Biomedicines 2020 Aug 28;8(9). Epub 2020 Aug 28.

Department of Neurology, University Hospital of Ulm, Oberer Eselsberg 45, 89081 Ulm, Germany.

Serum neurofilament light chain (NfL) has been shown to correlate with neuroaxonal damage in multiple sclerosis (MS) and various other neurological diseases. While serum NfL is now regularly reported in clinical approval studies, there is a lack of longitudinal data from patients treated with established basic immunotherapies outside of study conditions. In total, 34 patients with early relapsing-remitting MS (RRMS) were included. The follow-up period was 24 months with regular follow-up visits after 3, 6, 9, 12 and 18 months. Therapy with glatiramer acetate was initiated in 20 patients and with interferon-beta in 12 patients. The disease course was monitored by the events of relapses, Expanded Disability Status Scale (EDSS) score and MRI parameters. Overall, serum NfL levels were higher at time points with a current relapse event than at time points without relapse (12.8 pg/mL vs. 9.7 pg/mL, = 0.011). At follow-up, relapse-free patients showed significantly reduced serum NfL levels starting from 9 months compared to baseline ( < 0.05) and reduced levels after 12 months compared to baseline ( = 0.013) in patients without EDSS progression for 12 months. In this explorative observational study, our data suggest that the longitudinal measurement of serum NfL may be useful in addition to MRI to monitor disease activity and therapy response.
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http://dx.doi.org/10.3390/biomedicines8090312DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7555392PMC
August 2020

A Score Based on NfL and Glial Markers May Differentiate Between Relapsing-Remitting and Progressive MS Course.

Front Neurol 2020 16;11:608. Epub 2020 Jul 16.

Department of Neurology, University Hospital of Ulm, Ulm, Germany.

The diagnostic use of biomarkers in body fluids of multiple sclerosis (MS) patients allows the monitoring of different pathophysiological aspects of the disease. We previously reported elevated cerebrospinal fluid (CSF) and serum levels of glial fibrillary acidic protein (GFAP) but not neurofilament light chain (NfL) in progressive (PMS) compared to relapsing-remitting MS (RRMS) patients. We analyzed the glial marker chitinase-3-like protein 1 (CHI3L1) in the CSF and serum of PMS and RRMS patients. To capture the extent of glial processes in relation to axonal damage in each individual patient, we established a score based on CHI3L1, GFAP, and NfL and compared this score between RRMS and PMS patients and its association with the extended disability status scale (EDSS). For this retrospective study, we included 86 MS patients (47 RRMS and 39 PMS) and 20 patients with other non-inflammatory neurological diseases (OND) as controls. NfL and GFAP levels were determined by the single-molecule array (Simoa). CHI3L1 levels were measured with classical enzyme-linked immunosorbent assay. A score was calculated based on glial to axonal markers (CHI3L1GFAP/NfL, referred to as "Glia score"). CHI3L1 showed higher CSF levels in PMS vs. RRMS and controls ( < 0.001 and < 0.0001, respectively), RMS vs. controls ( < 0.01), and higher serum levels for PMS vs. RRMS ( < 0.05). The Glia score was higher in the CSF of PMS compared to RRMS patients ( < 0.0001) and in the serum of PMS patients compared to RRMS ( < 0.01). Furthermore, the Glia score and CHI3L1 in serum but not in CSF correlated with the disability as determined by EDSS in the PMS group but not in the RRMS group (Spearman ρ = 0.46 and 0.45, = 0.003 and 0.004, respectively). Our data indicate the involvement of glial mechanisms during the pathogenesis of PMS. Moreover, a calculated score may help to differentiate between PMS and RMS in the CSF and monitor disease progression in the serum of PMS patients.
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http://dx.doi.org/10.3389/fneur.2020.00608DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7378743PMC
July 2020

Immunoadsorption and Plasma Exchange in Seropositive and Seronegative Immune-Mediated Neuropathies.

J Clin Med 2020 Jun 27;9(7). Epub 2020 Jun 27.

Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford OX3 9DU, UK.

The inflammatory neuropathies are disabling conditions with diverse immunological mechanisms. In some, a pathogenic role for immunoglobulin G (IgG)-class autoantibodies is increasingly appreciated, and immunoadsorption (IA) may therefore be a useful therapeutic option. We reviewed the use of and response to IA or plasma exchange (PLEx) in a cohort of 41 patients with nodal/paranodal antibodies identified from a total of 573 individuals with suspected inflammatory neuropathies during the course of routine diagnostic testing (PNAb cohort). 20 patients had been treated with PLEx and 4 with IA. Following a global but subjective evaluation by their treating clinicians, none of these patients were judged to have had a good response to either of these treatment modalities. Sequential serology of one PNAb+ case suggests prolonged suppression of antibody levels with frequent apheresis cycles or adjuvant therapies, may be required for effective treatment. We further retrospectively evaluated the serological status of 40 patients with either Guillain-Barré syndrome (GBS) or chronic inflammatory demyelinating polyneuropathy (CIDP), and a control group of 20 patients with clinically-isolated syndrome/multiple sclerosis (CIS/MS), who had all been treated with IgG-depleting IA (IA cohort). 32 of these patients (8/20 with CIDP, 13/20 with GBS, 11/20 with MS) were judged responsive to apheresis despite none of the serum samples from this cohort testing positive for IgG antibodies against glycolipids or nodal/paranodal cell-adhesion molecules. Although negative on antigen specific assays, three patients' pre-treatment sera and eluates were reactive against different components of myelinating co-cultures. In summary, preliminary evidence suggests that GBS/CIDP patients without detectable IgG antibodies on routine diagnostic tests may nevertheless benefit from IA, and that an unbiased screening approach using myelinating co-cultures may assist in the detection of further autoantibodies which remain to be identified in such patients.
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http://dx.doi.org/10.3390/jcm9072025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7409112PMC
June 2020

Stress cardiomyopathy associated with the first manifestation of multiple sclerosis: a case report.

BMC Neurol 2020 Jun 4;20(1):227. Epub 2020 Jun 4.

Department of Neurology, University of Ulm, Oberer Eselsberg 45, 89081, Ulm, Germany.

Background: We present a case with a close temporal association of the first diagnosis of multiple sclerosis and stress cardiomyopathy.

Case Presentation: A 19-year-old man experienced severe dyspnoea. The cardiac biomarkers troponin T and NT-proBNP were elevated, and transthoracic echocardiography showed basal hypokinesia. The man was diagnosed with stress cardiomyopathy after main differential diagnoses such as acute coronary syndrome, myocarditis, and pheochromocytoma were excluded. Furthermore, the patient reported vertigo and paraesthesia. Brain and spinal MRI revealed T2-hyperintense lesions with a prominent acute lesion in the pontomedullary area. Cerebrospinal fluid findings revealed a lymphocytic pleocytosis and intrathecal IgG synthesis. Serum neurofilaments were elevated. The patient was diagnosed with MS, and treatment with intravenous Methylprednisolone was initiated. The brainstem lesion due to multiple sclerosis was assumed to be the cause of stress cardiomyopathy. The patient fully recovered.

Conclusion: Stress cardiomyopathy may be linked with the first manifestation of multiple sclerosis in the presented case since pontomedullary lesions could affect the sympathetic nervous system. This case highlights the importance of neurological history and examination in young patients with unexplained acute cardiac complaints.
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http://dx.doi.org/10.1186/s12883-020-01757-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7271507PMC
June 2020

Explorative study of emerging blood biomarkers in progressive multiple sclerosis (EmBioProMS): Design of a prospective observational multicentre pilot study.

Contemp Clin Trials Commun 2020 Jun 19;18:100574. Epub 2020 May 19.

Department of Neurology, University Hospital of Ulm, Ulm, Germany.

Background: Defining clinical and subclinical progression in multiple sclerosis (MS) is challenging. Patient history, expanded disability status scale (EDSS), and magnetic resonance imaging (MRI) all have shortcomings and may underestimate disease dynamics. Emerging serum biomarkers such as glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) proved useful in many cross-sectional studies. However, longitudinal data on patients with progressive MS is scarce.

Objectives: To assess whether the serum biomarkers GFAP and NfL might differentiate between patients with progressive vs. non-progressive disease stages and predict the disease course according to the Lublin criteria.

Methods: EmBioProMS is a pilot, observational, prospective, multicentric study funded by the German Multiple Sclerosis Society (DMSG). 200 patients with MS according to the 2017 McDonald criteria and history of relapse-independent progression at any time (progressive MS, PMS), younger than 65 years, and with EDSS ≤ 6.5 will be recruited in 6 centres in Germany. At baseline, month 6, and 18, medical history, EDSS, Nine-Hole-Peg-Test (9-HPT), Timed-25-Foot-Walk-Test (T-25FW), Symbol-Digit-Modalities-Test (SDMT), serum GFAP, and NfL, MRI (at least baseline and month 18) and optional optical coherence tomography (OCT) will be performed. Disease progression before and during the study is defined by confirmed EDSS progression, increase by ≥ 20% in 9-HPT or T-25FW time.

Conclusions: This longitudinal multicentre study will reveal to what extent the prediction of disease progression in patients with PMS will be improved by the analysis of serum biomarkers in conjunction with routine clinical data and neuroimaging measures.
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http://dx.doi.org/10.1016/j.conctc.2020.100574DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7251538PMC
June 2020

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

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

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

Objective: To explore levels of astrocytopathy in neuromyelitis optica spectrum disorder (NMOSD) by measuring levels of the astrocytic enzyme glutamine synthetase (GS) and glial fibrillary acidic protein (GFAP), an established astrocytic biomarker known to be associated with disease activity in multiple sclerosis.

Methods: Cerebrospinal fluid concentrations of GS and GFAP were measured by ELISA in patients with NMOSD (n=39, 28 aquaporin-4 (AQP4)-Ab-seropositive, 3 double-Ab-seronegative, 4 myelin oligodendrocyte glycoprotein (MOG)-Ab-seropositive and 4 AQP4-Ab-seronegative with unknown MOG-Ab-serostatus), multiple sclerosis (MS) (n=69), optic neuritis (n=5) and non-neurological controls (n=37).

Results: GFAP and GS concentrations differed significantly across groups (both p<0.001), showing a similar pattern of elevation in patients with AQP4-Ab-seropositive NMOSD. GS and GFAP were significantly correlated, particularly in patients with AQP4-Ab-seropositive NMOSD (r=0.70, p<0.001). Interestingly, GFAP levels in some patients with double-Ab-seronegative NMOSD were markedly increased.

Conclusions: Our data indicate astrocytic injury occurs in some patients with double-Ab-seronegative NMOSD, which hints at the possible existence of yet undiscovered astrocytic autoimmune targets. We hypothesise that elevated GS and GFAP levels could identify those double-Ab-seronegative patients suitable to undergo in-depth autoimmune screening for astrocytic antibodies.
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http://dx.doi.org/10.1136/jnnp-2019-322286DOI Listing
June 2020

Drug-induced liver injury associated with the biosimilar glatiramer acetate (Clift®).

Mult Scler Relat Disord 2020 May 13;40:101948. Epub 2020 Jan 13.

Department of Neurology, University of Ulm, Oberer Eselsberg 45, 89081 Ulm, Germany. Electronic address:

A 23-year old female was diagnosed with relapsing-remitting multiple sclerosis with two symptomatic attacks. Immunomodulatory treatment with Clift® (Glatiramer Acetate biosimilar) was initiated. Shortly after administration, an asymptomatic increase in liver enzymes was noticed, and therapy was paused. However, we observed an enormous increase in liver enzymes within a few days. Histological work up of a liver biopsy showed microfocal liver necrosis accompanied with increased numbers of CD38-positive lymphocytes as shown by immunohistology, indicating a drug-induced liver injury. Subsequently, under oral prednisolone treatment, liver enzymes normalized. This case highlights the importance of tight monitoring of liver function in the initial phase of a new immunotherapy to unravel asymptomatic hepatotoxicity in time and prevent further damage.
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http://dx.doi.org/10.1016/j.msard.2020.101948DOI Listing
May 2020

Safety and efficacy of immunoadsorption versus plasma exchange in steroid-refractory relapse of multiple sclerosis and clinically isolated syndrome: A randomised, parallel-group, controlled trial.

EClinicalMedicine 2019 Nov 14;16:98-106. Epub 2019 Nov 14.

Department of Neurology, University of Ulm, Oberer Eselsberg 45, D-89081 Ulm, Germany.

Background: Plasma exchange (PE) constitutes the standard therapy for steroid-refractory relapse in multiple sclerosis and clinically isolated syndrome. Immunoadsorption (IA) is an alternative method of apheresis which selectively removes immunoglobulines (Ig) while preserving other plasma proteins. Although IA is regarded as a well-tolerated, low-risk procedure, high-level evidence for its efficacy is lacking. Therefore, we sought to investigate whether IA is superior to PE in patients with acute relapse of multiple sclerosis or clinically isolated syndrome who had insufficiently responded to high-dose intravenous methylprednisolone (MP).

Methods: Patients with acute relapse of multiple sclerosis or clinically isolated syndrome and without complete clinical remission of symptoms after at least one cycle of high-dose intravenous MP therapy were enrolled to our randomised, controlled, parallel-group, monocentric trial. Eligible patients were aged at least 12 years and had no clinical or laboratory signs of systemic infection. Eligible patients were randomly assigned (1:1) to receive either IA or PE. Patients in both groups received 5 treatments on 5 consecutive days. In the IA group, the 2.0-fold individual total plasma volume was processed on day 1, and the 2.5-fold on days 2-5. In the PE group, 2 liters of plasma (corresponding to the 0.69 ± 0.12-fold individual total plasma volume) were removed each day and substituted by 5% human albumin solution. Patients were followed up directly after last apheresis as well as 2 and 4 weeks after last treatment. The primary endpoint was change of the Multiple Sclerosis Functional Composite (MSFC) after 4 weeks compared to baseline. Analyses of primary outcome and safety measures were done in all patients who received at least one treatment (intention-to-treat-population). The trial is registered with ClinicalTrials.gov, number NCT02671682.

Findings: Between January 21, 2016, and October 26, 2018, 63 patients were screened for eligibility, and 61 patients were randomly assigned to receive IA ( = 31) or PE ( = 30). All randomised patients were included in the intention-to-treat-analysis. For the primary outcome, the median improvement of MSFC after 4 weeks compared to baseline was 0.385 (IQR 0.200-0.675;  < 0.001) in the IA group and 0.265 (IQR 0.100-0.408;  < 0.001) in the PE group. Improvement in the IA group was significantly larger ( = 0.034) compared to PE. Response rates after 4 weeks were 86.7% in the IA group and 76.7% in the PE group. One deep venous thrombosis occurred in each group.

Interpretation: Both IA and PE were safe in patients with steroid-refractory relapse and resulted in significant improvements of the primary outcome MSFC after 4 weeks compared to baseline. IA patients showed significantly larger improvements of MSFC compared to PE patients after 4 weeks. The results indicate a potential superiority of IA compared to PE in treatment of steroid-refractory relapse in multiple sclerosis and clinically isolated syndrome, which has to be confirmed by future studies.

Funding: Fresenius Medical Care Deutschland GmbH, Bad Homburg, Germany.
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http://dx.doi.org/10.1016/j.eclinm.2019.10.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6890948PMC
November 2019

Association of cerebrospinal fluid kappa free light chains with the intrathecal polyspecific antiviral immune response in multiple sclerosis.

Clin Chim Acta 2019 Nov 19;498:148-153. Epub 2019 Aug 19.

Department of Neurology, University of Ulm, Ulm, Germany. Electronic address:

The polyspecific B-lymphocyte response to neurotropic viruses such as measles (M), rubella (R) and varicella zoster (Z), known as MRZ reaction, is to-date the most specific neurochemical marker for multiple sclerosis (MS). The aim of this study was to investigate a possible association of immunoglobulin (Ig) kappa (κ-) and lambda (λ-) free light chains (FLC) with the presence of the MRZ reaction in multiple sclerosis. Immunoglobulin κ- and λ-FLC, MRZ reaction, oligoclonal IgG bands (OCB), and cerebrospinal fluid (CSF) routine parameters were measured in 65 MS patients. OCB were detected in 97% of MS patients, intrathecal IgG synthesis according to Reiber was detectable in 57%, an elevated IgG index (>0.7) in 66% and the MRZR was positive in 45%. All investigated κ-values (CSF κFLC, CSF-serum ratio of κFLCs (QκFLC), and κFLC index (κFLC/QAlbumin)) were significantly higher in patients with positive MRZ reaction as compared to MRZ negative MS patients. In contrast, λ-values showed no significant differences. Additionally to the putative diagnostic sensitivity and prognostic value of κFLC, the association of κFLC with a highly specific neurochemical marker for MS - the MRZ reaction, especially the determination of κFLCs is an informative tool to assess the B-cell response and determine its extent in MS patients.
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http://dx.doi.org/10.1016/j.cca.2019.08.016DOI Listing
November 2019

Free light chains in the cerebrospinal fluid. Comparison of different methods to determine intrathecal synthesis.

Clin Chem Lab Med 2019 Sep;57(10):1574-1586

Department of Neurology, Wilhelminenspital, Montleartstrasse 37, 1160 Vienna, Austria.

Background Free light chains (FLC) have been proposed as diagnostic biomarkers in the cerebrospinal fluid (CSF) of patients with inflammatory central nervous system (CNS) diseases. However, which method to use for determining an intrathecal FLC synthesis has not yet been clarified. The objective of this study was to compare the diagnostic performance of CSF FLC concentration, FLC quotient (QFLC), FLC index and FLC intrathecal fraction (FLCIF). Methods κ- and λ-FLC were measured by nephelometry under blinded conditions in CSF and serum sample pairs of patients with clinically isolated syndrome (CIS; n = 60), multiple sclerosis (MS; n = 60) and other neurological diseases (n = 60) from four different MS centers. QFLC was calculated as the ratio of CSF/serum FLC concentration, the FLC index as QFLC/albumin quotient and the percentage FLCIF by comparing QFLC to a previously empirically determined, albumin quotient-dependent reference limit. Results CSF FLC concentration, QFLC, FLC index and FLCIF of both the κ- and λ-isotype were significantly higher in patients with CIS and MS than in the control group, as well as in oligoclonal bands (OCB) positive than in OCB negative patients. Each parameter was able to identify MS/CIS patients and OCB positivity, however, diagnostic performance determined by receiver operating characteristic (ROC) analyses differed and revealed superiority of FLC index and FLCIF. Conclusions These findings support the diagnostic value of FLC measures that correct for serum FLC levels and albumin quotient, i.e. blood-CSF barrier function.
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http://dx.doi.org/10.1515/cclm-2018-1300DOI Listing
September 2019

CSF Free Light Chains as a Marker of Intrathecal Immunoglobulin Synthesis in Multiple Sclerosis: A Blood-CSF Barrier Related Evaluation in a Large Cohort.

Front Immunol 2019 29;10:641. Epub 2019 Mar 29.

Department of Neurology, University of Ulm, Ulm, Germany.

The importance of immunoglobulin G (IgG) oligoclonal bands (OCB) in the diagnosis of multiple sclerosis (MS) was reaffirmed again in the recently revised MS diagnostic criteria. Since OCB testing is based on non-quantitative techniques and demands considerable methodological experience, measurement of CSF immunoglobulin free light chains (FLC) has been suggested as quantitative alternative to OCB. We aimed to establish reference values for FLC measures and evaluate their diagnostic accuracy with regard to the diagnosis of MS. Immunoglobulin kappa (KFLC) and lambda (LFLC) free light chains were prospectively measured by nephelometry in CSF and serum sample pairs in 1,224 patients. The analyzed cohort included patients with MS, other autoimmune or infectious inflammatory diseases of the nervous system as well as 989 patients without signs for nervous system inflammation. Regarding diagnosis of MS, the diagnostic sensitivity and specificity of intrathecal KFLC ratio were 93.3 and 93.7% using the CSF-serum albumin ratio-dependent reference values, 92.0 and 95.9% for intrathecal KFLC ratio applying the ROC-curve determined cut-off levels, 62.7 and 98.3% for IgG index, 64.0 and 98.8% for intrathecal IgG synthesis according to Reiber diagrams, and 94.7 and 93.3% for OCB. Diagnostic sensitivity and specificity of intrathecal LFLC were clearly lower than KFLC. Intrathecal KFLC and OCB showed the highest diagnostic sensitivities for MS. However, specificity was slightly lower compared to other quantitative IgG parameters. Consequently, CSF FLC may not replace OCB, but it may support diagnosis in MS as a quantitative parameter.
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http://dx.doi.org/10.3389/fimmu.2019.00641DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6449445PMC
August 2020

Short-term and long-term effects of immunoadsorption in refractory chronic inflammatory demyelinating polyneuropathy: a prospective study in 17 patients.

J Neurol 2018 Dec 6;265(12):2906-2915. Epub 2018 Oct 6.

Universitätsklinik Ulm, RKU, Oberer Eselsberg 45, 89081, Ulm, Germany.

Objective: Chronic inflammatory demyelinating polyneuropathy (CIDP) is a rare, autoimmune-inflammatory disease of the peripheral nervous system. Recently, various immunoglobulin G4 (IgG4) type auto-antibodies have been described in patients with CIDP which can effectively be removed by immunoadsorption (IA). Therefore, we prospectively evaluated the therapeutic effect of IA in 17 patients with progressive CIDP not responding to other treatment.

Methods: We prospectively evaluated the course of disease of 17 patients with CIDP who had insufficiently responded to steroids and/or IVIg previously and who received at least one cycle of IA. As clinical outcome parameter, we used a combined CIDP score of three validated scales comprising disability, motor score, and sensitivity. Seven patients received repeated treatments in regular intervals over a prolonged period up to 46 months.

Results: We observed a small, but significant improvement of the overall score after 2 weeks that mainly reflected an improvement of muscle strength. The median value of the combined CIDP score was 308.0 (266.0-374.5) points before IA and 330.0 (290.0-393.5) points 2 weeks after IA (p = 0.019). More importantly, all but one of seven progressive patients who received long-term immunoadsorption in regular intervals stabilized almost completely. Before IA, these patients lost 6.7 (3.0-13.1) points of combined CIDP score per month. During IA, they lost - 0.1 (0.0-0.8) points per month (p < 0.0001).

Interpretation: Our results suggest that IA might constitute a promising and well-tolerated therapeutic alternative in CIDP for short-term and long-term treatment. We showed that long-term treatment with IA in regular intervals can stabilize the course of disease at least in a subgroup of patients.
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http://dx.doi.org/10.1007/s00415-018-9082-6DOI Listing
December 2018

Intrathecal immunoglobulin M production: A promising high-risk marker in clinically isolated syndrome patients.

Ann Neurol 2018 05 11;83(5):1032-1036. Epub 2018 May 11.

Department of Neurology, University Hospital Ulm, Ulm.

Markers predicting the course of patients with clinically isolated syndrome (CIS) toward multiple sclerosis (MS) are urgently needed. We evaluated the predictive values of intrathecal immunoglobulin (Ig) G and IgM production with different methods for conversion to definite MS according to revised McDonald 2010 criteria in a cohort of 126 CIS patients. Intrathecal IgM production showed the highest likelihood ratio for the conversion of CIS patients to definite MS at 6.3, whereas it was 1.4 for oligoclonal IgG bands. We conclude that the determination of intrathecal IgM is a valuable tool to predict the disease course of patients with CIS. Ann Neurol 2018;83:1032-1036.
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http://dx.doi.org/10.1002/ana.25237DOI Listing
May 2018

Distinct oligoclonal band antibodies in multiple sclerosis recognize ubiquitous self-proteins.

Proc Natl Acad Sci U S A 2016 07 20;113(28):7864-9. Epub 2016 Jun 20.

Institute of Clinical Neuroimmunology, Ludwig-Maximilians-University, 81377 Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), Ludwig-Maximilians-University, 81377 Munich, Germany

Oligoclonal Ig bands (OCBs) of the cerebrospinal fluid are a hallmark of multiple sclerosis (MS), a disabling inflammatory disease of the central nervous system (CNS). OCBs are locally produced by clonally expanded antigen-experienced B cells and therefore are believed to hold an important clue to the pathogenesis. However, their target antigens have remained unknown, mainly because it was thus far not possible to isolate distinct OCBs against a background of polyclonal antibodies. To overcome this obstacle, we copurified disulfide-linked Ig heavy and light chains from distinct OCBs for concurrent analysis by mass spectrometry and aligned patient-specific peptides to corresponding transcriptome databases. This method revealed the full-length sequences of matching chains from distinct OCBs, allowing for antigen searches using recombinant OCB antibodies. As validation, we demonstrate that an OCB antibody from a patient with an infectious CNS disorder, neuroborreliosis, recognized a Borrelia protein. Next, we produced six recombinant antibodies from four MS patients and identified three different autoantigens. All of them are conformational epitopes of ubiquitous intracellular proteins not specific to brain tissue. Our findings indicate that the B-cell response in MS is heterogeneous and partly directed against intracellular autoantigens released during tissue destruction. In addition to helping elucidate the role of B cells in MS, our approach allows the identification of target antigens of OCB antibodies in other neuroinflammatory diseases and the production of therapeutic antibodies in infectious CNS diseases.
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http://dx.doi.org/10.1073/pnas.1522730113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4948369PMC
July 2016

Validation of kappa free light chains as a diagnostic biomarker in multiple sclerosis and clinically isolated syndrome: A multicenter study.

Mult Scler 2016 Apr 21;22(4):502-10. Epub 2015 Jul 21.

Department of Neurology, Innsbruck Medical University, Austria

Background: Kappa free light chains (KFLCs) have been proposed as a diagnostic biomarker in patients with clinically isolated syndrome (CIS) and multiple sclerosis (MS).

Objective: The objective of this paper is to validate the diagnostic accuracy of intrathecal KFLC synthesis in a multicenter study.

Methods: KFLCs were measured by nephelometry under blinded conditions in cerebrospinal fluid (CSF) and serum sample pairs of patients with CIS (n = 60), MS (n = 60) and other neurological diseases (n = 60) from four different MS centers. The upper normal limit for intrathecal KFLC concentrations depending on blood-CSF barrier function was previously calculated in a cohort of 420 control patients.

Results: Diagnostic sensitivity of intrathecal KFLC synthesis, IgG synthesis according to Reiber, IgG index and oligoclonal bands (OCBs) was 95%, 72%, 73% and 93% in patients with MS and 82%, 47%, 43% and 72% in patients with CIS. Specificity of intrathecal KFLC synthesis was 95% and 98% for all other measures.

Conclusion: These findings further support the diagnostic value of intrathecal KFLC synthesis in CIS and MS patients and demonstrate a valid, easier and rater-independent alternative to OCB detection.
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http://dx.doi.org/10.1177/1352458515594044DOI Listing
April 2016

Intrathecal somatic hypermutation of IgM in multiple sclerosis and neuroinflammation.

Brain 2014 Oct 23;137(Pt 10):2703-14. Epub 2014 Jul 23.

1 Institute of Clinical Neuroimmunology, University Hospital Grosshadern, LMU Munich, D-81377 Munich, Germany 7 Munich Cluster for Systems Neurology (SyNergy), Adolf-Butenandt-Institut, Ludwig-Maximilians-Universität München, 80336 München, Germany

Intrathecal oligoclonal bands of the cerebrospinal fluid are considered the most important immunological biomarkers of multiple sclerosis. They typically consist of clonally expanded IgG antibodies that underwent affinity maturation during sustained stimulation by largely unknown antigens. In addition, ∼40% of patients with multiple sclerosis have oligoclonal bands that consist of expanded IgM antibodies. We investigated the molecular composition of IgM- and IgG-chains from cerebrospinal fluid of 12 patients with multiple sclerosis, seven patients with other neurological diseases, and eight healthy control subjects by high-throughput deep-sequencing and single-cell PCR. Further, we studied the expression of activation-induced cytidine deaminase, the key enzyme for affinity maturation of antibodies, in cerebrospinal fluid samples of 16 patients. From the cerebrospinal fluid of two multiple sclerosis patients we isolated single B cells and investigated the co-expression of antibody chains with activation-induced cytidine deaminase. In striking contrast to IgM-chains from peripheral blood, IgM-chains from cerebrospinal fluid of patients with multiple sclerosis or neuroborreliosis showed a high degree of somatic hypermutation. We found a high content of mutations that caused amino acid exchanges as compared to silent mutations. In addition, more mutations were found in the complementarity determining regions of the IgM-chains, which interact with yet unknown antigens, as compared to framework regions. Both observations provide evidence for antigen-driven affinity maturation. Furthermore, single B cells from the cerebrospinal fluid of patients with multiple sclerosis co-expressed somatically hypermutated IgM-chains and activation-induced cytidine deaminase, an enzyme that is crucial for somatic hypermutation and class switch recombination of antibodies and is normally expressed during activation of B cells in germinal centres. Clonal tracking of particular IgM(+) B cells allowed us to relate unmutated ancestor clones in blood to hypermutated offspring clones in CSF. Unexpectedly, however, we found no evidence for intrathecal isotype switching from IgM to IgG. Our data suggest that the intrathecal milieu sustains a germinal centre-like reaction with clonal expansion and extensive accumulation of somatic hypermutation in IgM-producing B cells.
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http://dx.doi.org/10.1093/brain/awu205DOI Listing
October 2014

Cerebrospinal fluid immunoglobulin kappa light chain in clinically isolated syndrome and multiple sclerosis.

PLoS One 2014 2;9(4):e88680. Epub 2014 Apr 2.

Department of Neurology, University of Ulm, Ulm, Germany.

Background: Oligoclonal bands (OCB) are the most widely used CSF test to support the diagnosis of MS and to predict conversion of clinically isolated syndrome (CIS) to multiple sclerosis (MS). Since OCB tests are based on non-quantitative and difficult to standardise techniques, measurement of immunoglobulin kappa free light chains (KFLC) may represent an easier to use quantitative test.

Methods: KFLC were measured in CSF and serum of 211 patients using ELISA. These include patients without any inflammatory central nervous system reaction (NIND, n = 77), MS (n = 20), viral CNS infections (V-CNS-I, n = 10), neuroborreliosis (NB, n = 17) and other bacterial CNS infections (B-CNS-I, n = 10). Furthermore a cohort of 77 patients with CIS, including 39 patients that remained CIS over follow-up of two years (CIS-CIS) and 38 patients that developed MS over the same follow-up time (CIS-MS).

Results: CSF-serum ratio of KFLC (Q KFLC) was elevated in all patients with MS, 86.8% of patients with CIS-MS and 61.5% of patients with CIS-CIS. It was significantly elevated in CIS with presence of OCB (p<0.001). Q KFLC significantly correlated with other CSF variables such as CSF leukocyte count (p<0.001, R = 0.46), CSF CXCL13 levels (p<0.001, R = 0.64) and also intrathecal IgG synthesis (p<0.001, R = 0.74) as determined by nephelometry and quotient diagram. OCB were detected in 66.7% of CIS-CIS and in 92.1% of CIS-MS.

Conclusions: Although the measurement of CSF KFLC is a rapid and quantitative easy to standardize tool, it is almost equal but not superior to OCB with regard to diagnostic sensitivity and specificity in patients with early MS.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0088680PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3973621PMC
February 2015

Patterns of TH1/TH2 cytokines predict clinical response in multiple sclerosis patients treated with glatiramer acetate.

Eur Neurol 2011 3;65(3):164-9. Epub 2011 Mar 3.

Department of Neurology, University of Ulm, Oberer Eselsberg 45, Ulm, Germany.

The patterns of Th1/Th2 cytokines in relapsing-remitting multiple sclerosis were analyzed to evaluate their relevance as biomarkers of therapy response to glatiramer acetate (GA). Serum interferon-γ (IFN-γ), osteopontin and interleukin (IL)-2, IL-4, and IL-10 were measured in 19 relapsing-remitting multiple sclerosis patients treated with GA in a prospective study over 3 years. The quotient (IL-2 + IFN-γ)/(IL-4 + IL-10) was elevated in patients with relapses as compared to relapse-free patients after 12 (p = 0.04), 24 (p = 0.02) and 36 months (p = 0.04). Our study indicates that specific patterns of Th1/Th2 cytokines predict the response to GA therapy.
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http://dx.doi.org/10.1159/000324035DOI Listing
August 2011

The chemokine CXCL13 is a prognostic marker in clinically isolated syndrome (CIS).

PLoS One 2010 Aug 5;5(8):e11986. Epub 2010 Aug 5.

Department of Neurology, University of Ulm, Ulm, Germany.

Background: There is increasing recognition of the importance of B lymphocytes in the immunopathogenesis of multiple sclerosis (MS), encouraging the evaluation of B cell-associated biomarkers in the cerebrospinal fluid (CSF). We aimed to evaluate the relevance of the B cell chemoattractant CXCL13 as a prognostic marker in patients with clinically isolated syndrome (CIS) regarding conversion to MS, and to compare it to Barkhof criteria in magnetic resonance imaging (MRI), oligoclonal bands (OCB) and the polyspecific intrathecal B cell response against measles, rubella and varicella zoster virus (MRZR).

Methodology/principal Findings: CXCL13 was determined in a prospective study over 2 years including 46 patients that remained CIS over follow-up (CIS-CIS), 45 patients that developed MS (CIS-RRMS), and 30 controls using ELISA. CSF CXCL13 was significantly elevated in CIS-RRMS as compared to CIS-CIS and controls (p<0.001). It was significantly elevated in CIS with OCB (p<0.001), positive MRZR (p=0.04), and gadolinium enhancement in MRI (p=0.02) and showed a significant correlation with CSF leukocyte count (p<0.001) and QIgG (p<0.001). CXCL13 showed the best positive predictive value (PPV) of all parameters investigated (70%, 95%-CI: 53-84%), which could be further increased by combination with Barkhof criteria in MRI (80%).

Conclusions/significance: Our data indicate the relevance of CXCL13 in CIS to predict conversion to MS. It furthermore shows CXCL13 to be an important mediator in the inflammatory cascade associated with the polyspecific intrathecal B cell response that manifests itself in OCB and MRZR.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0011986PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2916843PMC
August 2010
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