Publications by authors named "Orhan Aktas"

183 Publications

Sensitivity analysis of the primary endpoint from the N-MOmentum study of inebilizumab in NMOSD.

Mult Scler 2021 Feb 4:1352458521988926. Epub 2021 Feb 4.

Viela Bio, Gaithersburg, MD, USA.

Background: In the N-MOmentum trial, the risk of an adjudicated neuromyelitis optica spectrum disorder (NMOSD) attack was significantly reduced with inebilizumab compared with placebo.

Objective: To demonstrate the robustness of this finding, using pre-specified sensitivity and subgroup analyses.

Methods: N-MOmentum is a prospective, randomized, placebo-controlled, double-masked trial of inebilizumab, an anti-CD19 monoclonal B-cell-depleting antibody, in patients with NMOSD. Pre-planned and analyses were performed to evaluate the primary endpoint across a range of attack definitions and demographic groups, as well as key secondary endpoints.

Results: In the N-MOmentum trial (ClinicalTrials.gov: NCT02200770), 174 participants received inebilizumab and 56 received placebo. Attack risk for inebilizumab versus placebo was consistently and significantly reduced, regardless of attack definition, type of attack, baseline disability, ethnicity, treatment history, or disease course (all with hazard ratios < 0.4 favoring inebilizumab, < 0.05). Analyses of secondary endpoints showed similar trends.

Conclusion: N-MOmentum demonstrated that inebilizumab provides a robust reduction in the risk of NMOSD attacks regardless of attack evaluation method, attack type, patient demographics, or previous therapy.The N-MOmentum study is registered at ClinicalTrials.gov: NCT2200770.
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http://dx.doi.org/10.1177/1352458521988926DOI Listing
February 2021

Pain, depression, and quality of life in adults with MOG-antibody-associated disease.

Eur J Neurol 2021 Jan 10. Epub 2021 Jan 10.

Department of Neurology, St. Josef-Hospital, Ruhr-University Bochum, Bochum, Germany.

Background And Purpose: Myelin oligodendrocyte glycoprotein-antibody-associated disease (MOGAD) is an inflammatory autoimmune condition of the central nervous system. However, data on pain and depression have remained scarce. The aim of this study was to assess features of chronic pain and depression as well as their impact on health-related quality of life (hr-QoL) in MOGAD.

Methods: Patients with MOGAD were identified in the Neuromyelitis Optica Study Group registry. Data were acquired by a questionnaire, including clinical, demographic, pain (PainDetect, Brief Pain Inventory-Short Form, McGill Pain Questionnaire-Short Form), depression (Beck Depression Inventory-II), and hr-QoL (Short Form-36 Health Survey) items.

Results: Twenty-two of 43 patients suffered from MOGAD-related pain (11 nociceptive, eight definite neuropathic, three possible neuropathic) and 18 from depression. Patients with neuropathic pain had the highest pain intensity and most profound activities of daily living (ADL) impairment. Fifteen patients reported spasticity-associated pain, including four with short-lasting painful tonic spasms. Later disease onset, profound physical impairment, and depression were associated with chronic pain. Physical QoL was more affected in pain sufferers (p < 0.001) than in pain-free patients, being most severely reduced by neuropathic pain (p = 0.016). Pain severity, visual impairment, and gait impairment independently predicted lower physical QoL. Depression was the only factor reducing mental QoL. Twelve patients still suffering from moderate pain (pain severity 4.6 ± 2.3) received pain medication. Only four out of 10 patients with moderate to severe depression took antidepressants.

Conclusions: Being highly prevalent, pain and depression strongly affect QoL and ADL in MOGAD. Both conditions remain insufficiently controlled in real-life clinical practice.
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http://dx.doi.org/10.1111/ene.14729DOI Listing
January 2021

Targeting B cells to modify MS, NMOSD, and MOGAD: Part 2.

Neurol Neuroimmunol Neuroinflamm 2021 01 16;8(1). Epub 2020 Dec 16.

From the Department of Neurology (J.G., O.A., P.A., H.-P.H.), University Hospital, Medical Faculty Heinrich Heine University, Düsseldorf, Germany; Department of Neurology (J.M.), Palacky University, Olomouc, Czech Republic; Department of Neurology, Brain and Mind Centre (M.B., H.-P.H.), Department of Neurology, University of Sydney, New South Wales, Australia; and Department of Neurology (S.S.Z.), UCSF Weill Institute of Neurosciences, University of California at San Francisco.

Ocrelizumab, rituximab, ofatumumab, ublituximab, inebilizumab, and evobrutinib are immunotherapies that target various B cell-related proteins. Most of these treatments have proven efficacy in relapsing and progressive forms of MS and neuromyelitis optica spectrum disease (NMOSD) or are in advanced stages of clinical development. Currently, ocrelizumab and inebilizumab are licensed for treatment of MS and NMOSD, respectively. This part of the review focuses on monoclonal antibody B cell-depleting strategies in NMOSD and the emerging related myelin oligodendrocyte glycoprotein (MOG) immunoglobulin G-associated disease (MOGAD). Case series and phase 2/3 studies in these inflammatory disorders are assessed. The safety profile of long-term B-cell depletion in MS, NMOSD, and MOGAD will be highlighted. Finally implications of the current coronavirus disease 2019 pandemic on the management of patients with these disorders and the use of B cell-depleting agents will be discussed.
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http://dx.doi.org/10.1212/NXI.0000000000000919DOI Listing
January 2021

Targeting B Cells to Modify MS, NMOSD, and MOGAD: Part 1.

Neurol Neuroimmunol Neuroinflamm 2021 01 16;8(1). Epub 2020 Dec 16.

From the Department of Neurology (J.G., O.A., P.A., H.-P.H.), University Hospital, Medical Faculty Heinrich-Heine-University, Düsseldorf, Germany; Department of Neurology (J.M.), Palacky University, Olomouc, Czech Republic; Department of Neurology (M.B., H.-P.H.), Brain and Mind Centre, Department of Neurology, University of Sydney, New South Wales, Australia; and UCSF Weill Institute of Neurosciences (S.S.Z.), Department of Neurology, University of California at San Francisco.

Ocrelizumab, rituximab, ofatumumab, ublituximab, inebilizumab, and evobrutinib are immunotherapies that target various B cell-related proteins. Most of these treatments have proven efficacy in relapsing and progressive forms of MS and neuromyelitis optica spectrum disease (NMOSD), or are in advanced stages of clinical development. Currently, ocrelizumab, ofatumumab, and inebilizumab are licensed for treatment of MS and NMOSD, respectively. This review focuses on the current state of knowledge about the role of B lymphocytes in immune-mediated pathophysiology and its implications for the mode of action. To understand the significance of this breakthrough in the context of the current MS therapeutic armamentarium, this review more closely examines the clinical development of CD20 depletion and the pioneering contribution of rituximab. Phase 3 and the recently published postmarketing studies will be highlighted to better understand the relevant efficacy data and safety aspects of long-term B-cell depletion.
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http://dx.doi.org/10.1212/NXI.0000000000000918DOI Listing
January 2021

Anti-CD20 therapies and pregnancy in neuroimmunologic disorders: A cohort study from Germany.

Neurol Neuroimmunol Neuroinflamm 2021 01 17;8(1). Epub 2020 Dec 17.

From the Institute of Clinical Neuroimmunology (T.K., I.M.), Biomedical Center and University Hospital, Ludwig-Maximilians Universitaet München, Munich; Department of Neurology (S.T., A.I.C., I.A., K.H.), Katholisches Klinikum, St. Josef Hospital, Ruhr University Bochum; Institute of Clinical Pharmacy and Pharmacotherapy (A.I.C.), Heinrich Heine University Düsseldorf; Department of Neurology (A.B.), University Hospital of Augsburg; Klinik für Neurologie (F.H.), Krankenhaus Martha-Maria Halle-Dölau gGmbH, Halle (Saale); Klinik für Neurologie (U.H.-v.O.), Knappschaftskrankenhaus Dortmund Klinikum Westfalen, Dortmund; Marianne-Strauß-Klinik (M.-M.H.), Berg; Department of Neurology (J.K.), Klinikum der Stadt Ludwigshafen gGmbH, Ludwigshafen; Department of Neurology (M.R., O.A.), Medical Faculty, Heinrich Heine University Düsseldorf; Department of Neurology (M.R.), Center for Neurology and Neuropsychiatry, LVR-Klinikum Düsseldorf; Department of Neurology (M.S.), University of Leipzig; Sektion Neuroimmunologie (A.W.), Klinik für Neurologie, Klinikum Herford; Institute of Neuropathology and Department of Neurology (M.S.W.), University Medical Center, Georg August University Göttingen, Germany.

Objective: To report pregnancy outcomes and disease activity (DA) in women with MS, neuromyelitis optica spectrum disorders (NMOSDs), and other neuroimmunologic diseases (ONID) after treatment with rituximab (RTX)/ocrelizumab (OCR) 12 months before or during pregnancy.

Methods: Data were collected in the German MS and pregnancy registry and centers from the Neuromyelitis Optica Study Group. Sixty-eight known outcomes of 88 pregnancies from 81 women (64 MS, 10 NMOSD, and 7 ONID) were included and stratified in 3 exposure groups: >6M-group = RTX/OCR >6 but ≤12 months before the last menstrual period (LMP) (n = 8); <6M group = RTX/OCR <6 months before the LMP (n = 47); preg group = RTX/OCR after the LMP (n = 13).

Results: Pregnancy outcomes were similar between groups, but significantly more preterm births (9.8% vs 45%) occurred after exposure during pregnancy. Overall, 2 major congenital abnormalities (3.3%), both in the preg group, were observed. Three women had severe infections during pregnancy. All women with MS (35) and 12/13 women with NMOSD, RTX/OCR exposure before the LMP and known pregnancy outcomes after gestational week 22 were relapse free during pregnancy. Five of 29 (17.2%) women with relapsing-remitting MS (RRMS) and 1 of 12 (8.3%) with NMOSD and at least 6 months postpartum follow-up experienced a relapse postpartum. Duration of RTX/OCR and early retreatment but not detection of B-cells were possible predictors for postpartum relapses in patients with RRMS/NMOSD.

Conclusions: Although RTX/OCR might be an interesting option for women with RRMS/NMOSD who plan to become pregnant to control DA, more data on pregnancy outcomes and rare risks are needed.
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http://dx.doi.org/10.1212/NXI.0000000000000913DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7757754PMC
January 2021

Worldwide Incidence and Prevalence of Neuromyelitis Optica: A Systematic Review.

Neurology 2021 01 11;96(2):59-77. Epub 2020 Dec 11.

From the Department of Neurology (V.P., Z.I.), Odense University Hospital; Danish Multiple Sclerosis Center (M.M.), Copenhagen University Hospital, Rigshospitalet, Denmark; Department of Neurology (O.A.), Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany; Department of Neurology (T.B.), Medical University of Vienna, Austria; Menzies Health Institute Queensland (S.A.B.), Griffith University, Gold Coast; Department of Neurology (S.A.B.), Gold Coast University Hospital, Australia; Department of Neurology (P.C.), Fort-de-France University Hospital Center, Pierre Zobda Quitman Hospital, Fort-de-France, Martinique, France; Department of Neurology (A.J.), The Walton Centre, Liverpool, UK; Cleveland Clinic (A.J.), Abu Dhabi, United Arab Emirates; Departments of Neurology (J.K., J.P.), Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Nuffield Department of Clinical Neurosciences (M.I.L., J.P.), John Radcliffe Hospital, University of Oxford, UK; Service de Neurologie (R.M.), Sclérose en Plaques, Pathologies de la Myéline et Neuro-Inflammation, et Centre de Référence des Maladies Inflammatoires Rares du Cerveau et de la Moelle (MIRCEM), Hôpital Neurologique Pierre Wertheimer, Hospices Civils de Lyon, Bron, France; Department of Neurology (K.M.), Kindai University Graduate School of Medicine, Osaka, Japan; Center of Neuroimmunology (A.S., M.S.), Service of Neurology, Hospital Clínic of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, Spain; Department of Neurology (O.S.), Karolinska University Hospital and Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Institute of Clinical Research (Z.I.), University of Southern Denmark, Odense, Denmark; and Institute of Molecular Medicine (Z.I.), University of Southern Denmark, Odense.

Objective: Since the last epidemiologic review of neuromyelitis optica/neuromyelitis optica spectrum disorder (NMO/NMOSD), 22 additional studies have been conducted. We systematically review the worldwide prevalence, incidence, and basic demographic characteristics of NMOSD and provide a critical overview of studies.

Methods: PubMed, Ovid MEDLINE, and Embase using Medical Subject Headings and keyword search terms and reference lists of retrieved articles were searched from 1999 until August 2019. We collected data on the country; region; methods of case assessment and aquaporin-4 antibody (AQP4-Ab) test; study period; limitations; incidence (per 100,000 person-years); prevalence (per 100,000 persons); and age-, sex-, and ethnic group-specific incidence or prevalence.

Results: We identified 33 relevant articles. The results indicated the highest estimates of incidence and prevalence of NMOSD in Afro-Caribbean region (0.73/100 000 person-years [95% CI: 0.45-1.01] and 10/100 000 persons [95% CI: 6.8-13.2]). The lowest incidence and prevalence of NMOSD were found in Australia and New Zealand (0.037/100 000 person-years [95% CI: 0.036-0.038] and 0.7/100,000 persons [95% CI: 0.66-0.74]). There was prominent female predominance in adults and the AQP4-Ab-seropositive subpopulation. The incidence and prevalence peaked in middle-aged adults. African ethnicity had the highest incidence and prevalence of NMOSD, whereas White ethnicity had the lowest. No remarkable trend of incidence was described over time.

Conclusion: NMOSD is a rare disease worldwide. Variations in prevalence and incidence have been described among different geographic areas and ethnicities. These are only partially explained by different study methods and NMO/NMOSD definitions, highlighting the need for specifically designed epidemiologic studies to identify genetic effects and etiologic factors.
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http://dx.doi.org/10.1212/WNL.0000000000011153DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905781PMC
January 2021

Long-term adherence and response to botulinum toxin in different indications.

Ann Clin Transl Neurol 2021 01 1;8(1):15-28. Epub 2020 Dec 1.

Department of Neurology, Medical Faculty, Heinrich Heine University Düsseldorf, Moorenstrasse 5, Düsseldorf, D-40225, Germany.

Objective: The objective of the study was the analysis of adherence and self-perceived treatment response to long-term botulinum neurotoxin type A (BoNT-A) treatment in different neurological indications.

Methods: In this retrospective, monocentric, observational study, cross-sectional and longitudinal data of 1351 patients documenting 20705 injection appointments at the BoNT outpatient clinic of Heinrich Heine University Duesseldorf between 1989 and 2014 were retrospectively analyzed. Patients had been treated with BoNT for neurological conditions, including cervical dystonia (CD), blepharospasm (BSP), other dystonia (ODT), hemifacial spasm (HFS), and spasticity (SPAS). The parameters longitudinally analyzed for the entire cohort were therapy duration as well as the mean and cumulative BoNT-A dose. Cross-sectionally, for subgroups of at least 721, patients' global self-perceived quality of health and life, global self-perceived reduction of symptoms by BoNT-A treatment as well as the clinical global impression were evaluated. Furthermore, mouse hemidiaphragm assay antibodies (MHDA-ABs) were analyzed in a subgroup.

Results: The mean treatment duration was 4.58 years (95% CI 4.32-4.84), and 678 (50.2%) therapy dropouts of 1351 patients occurred within the first 8 years. Therapy adherence and self-perceived symptom reduction in long-term BoNT-A treatment over the years were significantly longer in BSP, HFS, and CD patients than in ODT and SPAS patients.

Interpretation: The treatment indication determines long-term adherence and self-perceived symptom reduction in BoNT-A therapy, which are better in BSP, HFS, and CD patients than in ODT and SPAS patients. MHDA-ABs had a significant impact on global self-perceived symptom reduction, but with only a limited degree.
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http://dx.doi.org/10.1002/acn3.51225DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7818277PMC
January 2021

Occipital repetitive transcranial magnetic stimulation does not affect multifocal visual evoked potentials.

BMC Neurosci 2020 11 23;21(1):48. Epub 2020 Nov 23.

Department of Neurology, Medical Faculty, Heinrich-Heine University, Moorenstraße 5, 40225, Düsseldorf, Germany.

Background: To identify mechanisms of cortical plasticity of the visual cortex and to quantify their significance, sensitive parameters are warranted. In this context, multifocal visual evoked potentials (mfVEPs) can make a valuable contribution as they are not associated with cancellation artifacts and include also the peripheral visual field.

Objective: To investigate if occipital repetitive transcranial magnetic stimulation (rTMS) can induce mfVEP changes.

Methods: 18 healthy participants were included in a single-blind crossover-study receiving sessions of excitatory, occipital 10 Hz rTMS and sham stimulation. MfVEP was performed before and after each rTMS session and changes in amplitude and latency between both sessions were compared using generalized estimation equation models.

Results: There was no significant difference in amplitude or latency between verum and sham group.

Conclusion: We conclude that occipital 10 Hz rTMS has no effect on mfVEP measures, which is in line with previous studies using full field VEP.
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http://dx.doi.org/10.1186/s12868-020-00600-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7685624PMC
November 2020

Clinicogenomic factors of biotherapy immunogenicity in autoimmune disease: A prospective multicohort study of the ABIRISK consortium.

PLoS Med 2020 10 30;17(10):e1003348. Epub 2020 Oct 30.

CESP, INSERM UMR 1018, Faculty of Medicine, Paris-Sud University, UVSQ, Paris-Saclay University, Villejuif, France.

Background: Biopharmaceutical products (BPs) are widely used to treat autoimmune diseases, but immunogenicity limits their efficacy for an important proportion of patients. Our knowledge of patient-related factors influencing the occurrence of antidrug antibodies (ADAs) is still limited.

Methods And Findings: The European consortium ABIRISK (Anti-Biopharmaceutical Immunization: prediction and analysis of clinical relevance to minimize the RISK) conducted a clinical and genomic multicohort prospective study of 560 patients with multiple sclerosis (MS, n = 147), rheumatoid arthritis (RA, n = 229), Crohn's disease (n = 148), or ulcerative colitis (n = 36) treated with 8 different biopharmaceuticals (etanercept, n = 84; infliximab, n = 101; adalimumab, n = 153; interferon [IFN]-beta-1a intramuscularly [IM], n = 38; IFN-beta-1a subcutaneously [SC], n = 68; IFN-beta-1b SC, n = 41; rituximab, n = 31; tocilizumab, n = 44) and followed during the first 12 months of therapy for time to ADA development. From the bioclinical data collected, we explored the relationships between patient-related factors and the occurrence of ADAs. Both baseline and time-dependent factors such as concomitant medications were analyzed using Cox proportional hazard regression models. Mean age and disease duration were 35.1 and 0.85 years, respectively, for MS; 54.2 and 3.17 years for RA; and 36.9 and 3.69 years for inflammatory bowel diseases (IBDs). In a multivariate Cox regression model including each of the clinical and genetic factors mentioned hereafter, among the clinical factors, immunosuppressants (adjusted hazard ratio [aHR] = 0.408 [95% confidence interval (CI) 0.253-0.657], p < 0.001) and antibiotics (aHR = 0.121 [0.0437-0.333], p < 0.0001) were independently negatively associated with time to ADA development, whereas infections during the study (aHR = 2.757 [1.616-4.704], p < 0.001) and tobacco smoking (aHR = 2.150 [1.319-3.503], p < 0.01) were positively associated. 351,824 Single-Nucleotide Polymorphisms (SNPs) and 38 imputed Human Leukocyte Antigen (HLA) alleles were analyzed through a genome-wide association study. We found that the HLA-DQA1*05 allele significantly increased the rate of immunogenicity (aHR = 3.9 [1.923-5.976], p < 0.0001 for the homozygotes). Among the 6 genetic variants selected at a 20% false discovery rate (FDR) threshold, the minor allele of rs10508884, which is situated in an intron of the CXCL12 gene, increased the rate of immunogenicity (aHR = 3.804 [2.139-6.764], p < 1 × 10-5 for patients homozygous for the minor allele) and was chosen for validation through a CXCL12 protein enzyme-linked immunosorbent assay (ELISA) on patient serum at baseline before therapy start. CXCL12 protein levels were higher for patients homozygous for the minor allele carrying higher ADA risk (mean: 2,693 pg/ml) than for the other genotypes (mean: 2,317 pg/ml; p = 0.014), and patients with CXCL12 levels above the median in serum were more prone to develop ADAs (aHR = 2.329 [1.106-4.90], p = 0.026). A limitation of the study is the lack of replication; therefore, other studies are required to confirm our findings.

Conclusion: In our study, we found that immunosuppressants and antibiotics were associated with decreased risk of ADA development, whereas tobacco smoking and infections during the study were associated with increased risk. We found that the HLA-DQA1*05 allele was associated with an increased rate of immunogenicity. Moreover, our results suggest a relationship between CXCL12 production and ADA development independent of the disease, which is consistent with its known function in affinity maturation of antibodies and plasma cell survival. Our findings may help physicians in the management of patients receiving biotherapies.
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http://dx.doi.org/10.1371/journal.pmed.1003348DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7598520PMC
October 2020

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

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

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

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

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

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

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

Case Report: A Case of Severe Clinical Deterioration in a Patient With Multiple Sclerosis.

Front Neurol 2020 18;11:782. Epub 2020 Aug 18.

Department of Neurology, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.

Tumefactive multiple sclerosis (MS) is a rare variant of MS that may lead to a rapidly progressive clinical deterioration requiring a multidisciplinary diagnostic workup. Our report describes the diagnostic and therapeutic approach of a rare and extremely severe course of MS. A 51-year-old man with an 8-year history of relapsing-remitting MS (RRMS) was admitted with a subacute progressive left lower limb weakness and deterioration of walking ability. After extensive investigations including repeated MRI, microbiological, serological, cerebrospinal fluid (CSF) studies, and finally brain biopsy, the diagnosis of a tumefactive MS lesion was confirmed. Despite repeated intravenous (IV) steroids as well as plasma exchanges and IV foscarnet and ganciclovir owing to low copy numbers of human herpesvirus 6 (HHV-6) DNA in polymerase chain reaction (PCR) analysis, the patient did not recover. The clinical presentation of tumefactive MS is rare and variable. Brain biopsy for histopathological workup should be considered in immunocompromised patients with rapidly progressive clinical deterioration with brain lesions of uncertain cause.
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http://dx.doi.org/10.3389/fneur.2020.00782DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7461937PMC
August 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

Ocrelizumab Treatment in Patients with Primary Progressive Multiple Sclerosis: Short-term Safety Results from a Compassionate Use Programme in Germany.

Clin Neurol Neurosurg 2020 Oct 12;197:106142. Epub 2020 Aug 12.

Klinik für Neurologie, Medizinische Fakultät, Universitätsklinikum Düsseldorf, Düsseldorf, Germany. Electronic address:

Objectives: In January 2018, the European Union (EU) approved ocrelizumab in relapsing multiple sclerosis (RMS) and as the first disease-modifying therapy (DMT) for patients with primary progressive multiple sclerosis (PPMS) with efficacy proven in a phase 3 randomised controlled trial. Eleven months prior to the European regulatory approval, a compassionate use programme (CUP) made ocrelizumab available to 489 patients with PPMS in Germany, thereby for the first time providing a therapeutic option to patients with PPMS who could not participate in ocrelizumab studies. Here, we report real-world patient characteristics and short-term safety data of patients with PPMS treated with ocrelizumab in this CUP.

Patients And Methods: This CUP was initiated in February 2017 - shortly before US Food and Drug administration approval in March 2017 - and ended in January 2018, following ocrelizumab approval in the EU. Adult patients (age ≥18 years) with PPMS who had a positive benefit/risk ratio according to the treating physician were eligible for inclusion at German treatment centres. The main exclusion criteria were current/recent treatment with other immune therapies and unresolved/chronic/active infections. Patients received methylprednisolone and an antihistamine before treatment with intravenous ocrelizumab in 6-month cycles. The first ocrelizumab dose was a 300 mg infusion followed by a second 300 mg infusion 2 weeks later; subsequent doses were delivered as a single 600 mg infusion. Adverse events were reported immediately.

Results: Of 580 requests received from 104 centres, 525 patients met the eligibility criteria. Thirty-five patients did not participate due to withdrawal by the treating physician, and one due to death prior to treatment. A total of 489 patients received at least one 600 mg dose of ocrelizumab (administered as two 300 mg infusions) and 51 received a second dose. Due to termination of the CUP upon marketing authorisation, the maximum follow-up period was 12 months. Median patient age was 52 years (range: 24-73), and 49% were female. Previous immunomodulatory or immunosuppressive therapies had been received by 41% of patients, with the most commonly used being glucocorticoids, mitoxantrone, interferon-β and glatiramer acetate. Patients with a previous malignancy, serious disease or infection (42 patients, 9%) had recovered from this prior to the CUP. Nine serious adverse events and 70 non-serious adverse events were reported in 40 patients. Adverse event categories were generally consistent with the known safety profile of ocrelizumab; one patient had carry-over progressive multifocal leukoencephalopathy (PML) due to previous natalizumab treatment.

Conclusion: This CUP provides first real-world observations of ocrelizumab for the treatment of PPMS in a large patient cohort in Germany, supporting that ocrelizumab is generally well-tolerated in clinical practice. Physicians should be vigilant for early symptoms of PML, as to date, 9 PML cases that were all confounded have been reported in patients treated with ocrelizumab worldwide, with 8 carry-over cases from a prior DMT.
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http://dx.doi.org/10.1016/j.clineuro.2020.106142DOI Listing
October 2020

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

J Neuroinflammation 2020 Sep 3;17(1):262. Epub 2020 Sep 3.

Department of Pediatric Neurology, Children's Hospital Datteln, University Witten/Herdecke, Datteln, Germany.

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

Objective: To describe systematically the CSF profile in 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.
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http://dx.doi.org/10.1186/s12974-020-01825-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7470445PMC
September 2020

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

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

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

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

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

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

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

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

Retinal layers and visual conductivity changes in a case series of microangiopathic ischemic stroke patients.

BMC Neurol 2020 Sep 3;20(1):333. Epub 2020 Sep 3.

Department of Neurology, Medical Faculty, Heinrich-Heine-University, Duesseldorf, Germany.

Background: It is unknown whether microangiopathic ischemic strokes outside the visual pathway go along with subclinical changes of the retinal structure or the visual system. The objectives of this prospective non-interventional case series were to investigate if spectral-domain optical coherence tomography (SD-OCT) or multifocal visual evoked potentials (mfVEPs) can detect structural retinal changes or functional impairment of the visual system in patients with microangiopathic ischemic stroke.

Methods: We used SD-OCT to cross-sectionally analyze the retinal morphology of 15 patients with microangiopathic ischemic stroke according to the Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification not affecting the visual pathway. We employed semi-automated segmentation of macular volume scans to analyze the thickness of the macular retinal layers and peripapillary ring scans to investigate the retinal morphology in comparison to a control group without stroke. Visual function was assessed by the mfVEP technique in 13 microangiopathic ischemic stroke patients.

Results: First peak latency of mfVEPs was significantly delayed in the microangiopathic ischemic stroke group compared to the control patients. Neither the retinal layers nor the mfVEPs' amplitude differed between the microangiopathic ischemic stroke patients and the control group.

Conclusions: In conclusion, microangiopathic ischemic stroke patients presented a delayed first peak latency in mfVEPs as a sign of subclinical functional impairment of the visual pathway. However, our case series suggests no influence on retinal structure resulting from microangiopathic ischemic stroke outside the visual system. Larger and longitudinal studies are needed to confirm these mfVEP findings.
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http://dx.doi.org/10.1186/s12883-020-01894-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7469096PMC
September 2020

[Erratum to: Ocrelizumab for treatment of multiple sclerosis].

Nervenarzt 2020 Aug;91(8):735-736

Klinik für Neurologie, Universitätsklinikum Düsseldorf, Medizinische Fakultät der Heinrich-Heine-Universität, Moorenstraße 5, 40225, Düsseldorf, Deutschland.

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http://dx.doi.org/10.1007/s00115-020-00956-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7608094PMC
August 2020

Retinal Changes After Posterior Cerebral Artery Infarctions Display Different Patterns of the Nasal und Temporal Sector in a Case Series.

Front Neurol 2020 5;11:508. Epub 2020 Jun 5.

Department of Neurology, Medical Faculty, Heinrich-Heine-University, Duesseldorf, Germany.

Visual field defects are a common and disabling consequence of stroke and a negative prognostic factor of patient's quality of life. They result from lesions in different parts of the visual system, most commonly the visual cortex and optic radiation. An important pathophysiological mechanism is transsynaptic retrograde degeneration (TRD). In a case series 21 patients with posterior cerebral artery (PCA) territory infarctions were analyzed by spectral-domain optical coherence tomography (SD-OCT) and multifocal visual evoked potentials (mfVEPs) cross-sectionally and longitudinally for up to 6 months. In OCT, symptomatic affected nasal and temporal sectors and corresponding visual fields in mfVEPs were compared to the contralateral side. SD-OCT revealed a significant reduction (-2.92 ±2.53 μm, mean ± SD) of the symptomatic nasal macular retinal nerve fiber layer (RNFL) thickness and of the symptomatic temporal peripapillary RNFL after 6 months compared to baseline whereas the symptomatic temporal macular quadrant already showed a significantly thinner RNFL at baseline. The mfVEP first peak latency at baseline was significantly different (nasal visual field +11.69 ±11.17 ms, mean ± SD; temporal visual field +16.63 ±7.97 ms, mean ± SD) on the symptomatic compared to the asymptomatic field. The nasal visual fields partly recovered in amplitude and first peak latency of mfVEPs over the following 6 months compared to baseline. The dynamics of OCT and mfVEP outcomes for degeneration and recovery after PCA infarction differ between the nasal and temporal retinal sector. We postulate that retinal sectors may differ in their temporal pattern of TRD over time after retrogeniculate cerebral infarction.
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http://dx.doi.org/10.3389/fneur.2020.00508DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7290045PMC
June 2020

Altered fovea in AQP4-IgG-seropositive neuromyelitis optica spectrum disorders.

Neurol Neuroimmunol Neuroinflamm 2020 09 23;7(5). Epub 2020 Jun 23.

From the Experimental and Clinical Research Center (S.M., F.C.O., J.B.-S., H.G.Z., F.P., A.U.B.), Max-Delbrück Center for Molecular Medicine and Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health; NeuroCure Clinical Research Center (S.M., F.C.O., S.K.Y., E.M.K., J.B.-S., H.G.Z., F.P., A.U.B.), Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Germany; Division of Neuroinflammation and Glial Biology (F.C.O.), University of California, San Francisco; Nocturne GmbH (S.K.Y., E.M.K.), Berlin; Department of Neurology (M.W., M.R., O.A., P.A.), Medical Faculty, Heinrich Heine University, Düsseldorf; Institute of Clinical Neuroimmunology (J.H.), LMU Hospital, Ludwig-Maximilians University, Munich; Department of Neurology (M.R.), Center for Neurology and Neuropsychiatry, LVR-Klinikum Düsseldorf; Department of Neurology (K.R., F.P.), Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Germany; and Department of Neurology (A.U.B.), University of California, Irvine.

Objective: To investigate disease-specific foveal shape changes in patients with neuromyelitis optica spectrum disorders (NMOSDs) using foveal morphometry.

Methods: This cross-sectional study included macular spectral domain optical coherence tomography scans of 52 eyes from 28 patients with aquaporin-4 immunoglobulin G (AQP4-IgG)-seropositive NMOSD, 116 eyes from 60 patients with MS, and 123 eyes from 62 healthy controls (HCs), retrospectively, and an independent confirmatory cohort comprised 33/33 patients with NMOSD/MS. The fovea was characterized using 3D foveal morphometry. We included peripapillary retinal nerve fiber layer (pRNFL) thickness and combined macular ganglion cell and inner plexiform layer (GCIPL) volume to account for optic neuritis (ON)-related neuroaxonal damage.

Results: Group comparison showed significant differences compared with HC in the majority of foveal shape parameters in NMOSD, but not MS. Pit flat disk area, average pit flat disk diameter, inner rim volume, and major slope disk length, as selected parameters, showed differences between NMOSD and MS ( value = 0.017, 0.002, 0.005, and 0.033, respectively). This effect was independent of ON. Area under the curve was between 0.7 and 0.8 (receiver operating characteristic curve) for discriminating between NMOSD and MS. Pit flat disk area and average pit flat disk diameter changes independent of ON were confirmed in an independent cohort.

Conclusions: Foveal morphometry reveals a wider and flatter fovea in NMOSD in comparison to MS and HC. Comparison to MS and accounting for ON suggest this effect to be at least in part independent of ON. This supports a primary retinopathy in AQP4-IgG-seropositive NMOSD.
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http://dx.doi.org/10.1212/NXI.0000000000000805DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7413713PMC
September 2020

[Ocrelizumab for treatment of multiple sclerosis].

Nervenarzt 2020 Aug;91(8):722-734

Klinik für Neurologie, Universitätsklinikum Düsseldorf, Medizinische Fakultät, Heinrich-Heine-Universität, Moorenstraße 5, 40225, Düsseldorf, Deutschland.

Ocrelizumab is a monoclonal antibody directed against the differentiation antigen CD20, which leads to an effective long-term depletion of lymphocytes, in particular B cells. Recently published phase 3 studies confirmed that ocrelizumab is effective in the treatment of both relapsing multiple sclerosis (RMS) and primary progressive multiple sclerosis (PPMS). Based on these results, ocrelizumab was the first drug to be approved for primary chronic progressive MS. To place this therapeutic breakthrough in the context of the current MS therapeutic landscape, it is worthwhile taking a look back at the development of antibody-mediated CD20 depletion, the studies underlying the approval of ocrelizumab and their open extension phases. This review article discusses the available data on the efficacy and safety of long-term B‑cell depletion in MS patients and reviews current knowledge on the role of B‑lymphocytes in the immunopathogenesis of MS.
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http://dx.doi.org/10.1007/s00115-020-00937-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7286209PMC
August 2020

COVID-19 and management of neuroimmunological disorders.

Nat Rev Neurol 2020 07;16(7):347-348

Department of Neurology, Universitätsklinikum Düsseldorf, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany.

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http://dx.doi.org/10.1038/s41582-020-0368-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7242886PMC
July 2020

Cryptococcal meningoencephalitis in an IgG-deficient patient with multiple sclerosis on fingolimod therapy for more than five years - case report.

BMC Neurol 2020 Apr 27;20(1):158. Epub 2020 Apr 27.

Department of Neurology, Medical Faculty, Heinrich-Heine University Düsseldorf, 40225, Düsseldorf, Germany.

Background: Fingolimod (Gilenya®), a first-in-class sphingosine-1-phosphate receptor modulator is approved for the treatment of relapsing-remitting multiple sclerosis. Fingolimod-induced selective immunosuppression leads to an increased risk of opportunistic infections such as cryptococcosis. So far, a total of 8 cases of fingolimod-related cryptococcal meningoencephalitis have been published.

Case Presentation: A 49-year-old female with relapsing-remitting multiple sclerosis presented with cephalgia, fever, confusion and generalized weakness. She had been on fingolimod therapy for the past 5.5 years. Clinical examination suggested meningoencephalitis and laboratory findings showed an IgG deficiency. Initially no pathogen could be detected, but after 4 days Cryptococcus neoformans was found in the patient's blood cultures leading to the diagnosis of cryptococcal meningoencephalitis. After antimycotic therapy, her symptoms improved and the patient was discharged.

Conclusion: MS patients on immunomodulatory  therapy are at constant risk for opportunistic infections. Cephalgia, fever and generalized weakness in combination with fingolimod-induced lymphopenia should be considered a red flag for cryptococcosis.
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http://dx.doi.org/10.1186/s12883-020-01741-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7187502PMC
April 2020

Protective effects of 4-aminopyridine in experimental optic neuritis and multiple sclerosis.

Brain 2020 04;143(4):1127-1142

Department of Neurology, Medical Faculty, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany.

Chronic disability in multiple sclerosis is linked to neuroaxonal degeneration. 4-aminopyridine (4-AP) is used and licensed as a symptomatic treatment to ameliorate ambulatory disability in multiple sclerosis. The presumed mode of action is via blockade of axonal voltage gated potassium channels, thereby enhancing conduction in demyelinated axons. In this study, we provide evidence that in addition to those symptomatic effects, 4-AP can prevent neuroaxonal loss in the CNS. Using in vivo optical coherence tomography imaging, visual function testing and histologic assessment, we observed a reduction in retinal neurodegeneration with 4-AP in models of experimental optic neuritis and optic nerve crush. These effects were not related to an anti-inflammatory mode of action or a direct impact on retinal ganglion cells. Rather, histology and in vitro experiments indicated 4-AP stabilization of myelin and oligodendrocyte precursor cells associated with increased nuclear translocation of the nuclear factor of activated T cells. In experimental optic neuritis, 4-AP potentiated the effects of immunomodulatory treatment with fingolimod. As extended release 4-AP is already licensed for symptomatic multiple sclerosis treatment, we performed a retrospective, multicentre optical coherence tomography study to longitudinally compare retinal neurodegeneration between 52 patients on continuous 4-AP therapy and 51 matched controls. In line with the experimental data, during concurrent 4-AP therapy, degeneration of the macular retinal nerve fibre layer was reduced over 2 years. These results indicate disease-modifying effects of 4-AP beyond symptomatic therapy and provide support for the design of a prospective clinical study using visual function and retinal structure as outcome parameters.
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http://dx.doi.org/10.1093/brain/awaa062DOI Listing
April 2020

Old and new breakthroughs in neuromyelitis optica.

Lancet Neurol 2020 04 18;19(4):280-281. Epub 2020 Mar 18.

Department of Neurology, Medical Faculty, and Center of Neurology and Neuropsychiatry, LVR Klinikum, Heinrich-Heine-Universität, Düsseldorf D-40225, Germany.

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http://dx.doi.org/10.1016/S1474-4422(20)30062-4DOI Listing
April 2020

Capillary microscopy in Europeans with idiopathic Moyamoya angiopathy.

Microcirculation 2020 07 16;27(5):e12616. Epub 2020 Mar 16.

Department of Neurology, Alfried Krupp Hospital, Essen, Germany.

Objective: In Europe, MMA is a very rare non-inflammatory vasculopathy. MMA is an important differential diagnosis of cerebral vasculitis. Systemic manifestations, such as livedo racemosa or renal artery stenosis, associated with Moyamoya variants suggest the involvement also of non-cerebral vessels. Hypothetically, capillary microscopy could be a promising non-invasive screening method to visualize microcirculation, for example prior to cerebral angiography.

Methods: Standardized capillary microscopic images were taken in European patients with MMA and subsequently evaluated in a blinded analysis, using data obtained from a large NP cohort and a large SLE cohort by the same blinded Investigator as controls.

Results: Twenty-four European MMD patients and 14 healthy accompanying controls were included in this study. The results were compared to 116 SLE patients and 754 NP subjects. In MMD patients, no capillary morphological differences were found in comparison with NP, in particular no density reduction or increased neoangiogenesis. The pattern observed in the SLE cohort was clearly distinct from NP and MMD with regard to vascular density, vascular damage, and neoangiogenesis.

Conclusions: MMD is not associated with microvascular changes of the nailfold capillaries. In this respect, it is clearly distinct from SLE.
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http://dx.doi.org/10.1111/micc.12616DOI Listing
July 2020

The Rare Signal Peptide Coding Variant rs28385692 Decreases Secretion of IL-22BP Isoform-1, -2 and -3 and Is Associated with Risk for Multiple Sclerosis.

Cells 2020 01 10;9(1). Epub 2020 Jan 10.

Neurogenomiks Laboratory, University of the Basque Country (UPV/EHU), 48940 Leioa, Spain.

The locus is associated with risk for multiple sclerosis (MS) but causative variants are yet to be determined. In a single nucleotide polymorphism (SNP) screen of this locus in a Basque population, rs28385692, a rare coding variant substituting Leu for Pro at position 16 emerged significantly ( = 0.02). This variant is located in the signal peptide (SP) shared by the three secreted protein isoforms produced by (IL-22 binding protein-1(IL-22BPi1), IL-22BPi2 and IL-22BPi3). Genotyping was extended to a Europe-wide case-control dataset and yielded high significance in the full dataset ( = 3.17 × 10). Importantly, logistic regression analyses conditioning on the main known MS-associated SNP at this locus, rs17066096, revealed that this association was independent from the primary association signal in the full case-control dataset. In silico analysis predicted both disruption of the alpha helix of the H-region of the SP and decreased hydrophobicity of this region, ultimately affecting the SP cleavage site. We tested the effect of the p.Leu16Pro variant on the secretion of IL-22BPi1, IL-22BPi2 and IL-22BPi3 and observed that the Pro16 risk allele significantly lowers secretion levels of each of the isoforms to around 50%-60% in comparison to the Leu16 reference allele. Thus, our study suggests that genetically coded decreased levels of IL-22BP isoforms are associated with augmented risk for MS.
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http://dx.doi.org/10.3390/cells9010175DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7017210PMC
January 2020

Longitudinal optic neuritis-unrelated visual evoked potential changes in NMO spectrum disorders.

Neurology 2020 01 3;94(4):e407-e418. Epub 2019 Dec 3.

From the Department of Neurology, Medical Faculty (M.R., J. Harmel, J.G., H.-P.H., O.A., P.A.), and Department of Neurology, Center for Neurology and Neuropsychiatry, LVR-Klinikum (M.R.), Heinrich Heine University Düsseldorf; NeuroCure Clinical Research Center and Experimental and Clinical Research Center (H.Z., A.U.B., F.P.), Charité Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, and Max Delbrueck Center for Molecular Medicine, Germany; Department of Neurology (A.U.B.), University of California Irvine; Department of Neurology (A.H., M.B.), University of Würzburg; Department of Neurology (M.B.), Caritas Hospital, Bad Mergentheim; Clinical Neuroimmunology and Neurochemistry (M.W.H.), Department of Neurology (C.T.), Hannover Medical School; Department of Neurology (C.S., I.A., I.K., K.H.), St. Josef Hospital, Ruhr University Bochum, Germany; Department of Neurology (I.A.), Sechenov First Moscow State Medical University, Moscow, Russia; Marianne-Strauß-Klinik (I.K.), Behandlungszentrum Kempfenhausen für Multiple Sklerose Kranke, Berg; Institute of Clinical Neuroimmunology (J. Halva, T.K., H.P.), University Hospital, Ludwig-Maximilians University, Munich; Molecular Neuroimmunology Group, Department of Neurology (S.J., B.W.), University of Heidelberg, Germany; Department of Neurology (P.R.), Medical University of Vienna, Austria; Institute of Neuropathology (M.S.W.) and Department of Neurology (M.S.W., H.P., P.K.), University Medical Center Göttingen; Department of Neurology (L.R., C.G.), Jena University Hospital; Neuroimmunological Section, Department of Neurology (N.R., U.Z.), University of Rostock; Department of Neurology (M.D., L.K.), University of Münster; Department of Neurology and Institute of Neuroimmunology and MS (K.Y., J.-P.S.), University Medical Center Hamburg-Eppendorf; Department of Neurology (M.K., P.K.), Nordwest-Hospital Sanderbusch, Sande; Department of Neurology (W.M.), Helios Hanseklinikum Stralsund; Department of Neurology (F.L., H.T.), University of Ulm, Germany; and Faculty of Medicine and Health Sciences (A.K.), Macquarie University, Sydney, New South Wales, Australia.

Objective: To investigate if patients with neuromyelitis optica spectrum disorder (NMOSD) develop subclinical visual pathway impairment independent of acute attacks.

Methods: A total of 548 longitudinally assessed full-field visual evoked potentials (VEP) of 167 patients with NMOSD from 16 centers were retrospectively evaluated for changes of P100 latencies and P100-N140 amplitudes. Rates of change in latencies (RCL) and amplitudes (RCA) over time were analyzed for each individual eye using linear regression and compared using generalized estimating equation models.

Results: The rates of change in the absence of optic neuritis (ON) for minimal VEP intervals of ≥3 months between baseline and last follow-up were +1.951 ms/y (n = 101 eyes; SD = 6.274; = 0.012) for the P100 latencies and -2.149 µV/y (n = 64 eyes; SD = 5.013; = 0.005) for the P100-N140 amplitudes. For minimal VEP intervals of ≥12 months, the RCL was +1.768 ms/y (n = 59 eyes; SD = 4.558; = 0.024) and the RCA was -0.527 µV/y (n = 44 eyes; SD = 2.123; = 0.111). The history of a previous ON >6 months before baseline VEP had no influence on RCL and RCA. ONs during the observational period led to mean RCL and RCA of +11.689 ms/y (n = 16 eyes; SD = 17.593; = 0.003) and -1.238 µV/y (n = 11 eyes; SD = 3.708; = 0.308), respectively.

Conclusion: This first longitudinal VEP study of patients with NMOSD provides evidence of progressive VEP latency delay occurring independently of acute ON. Prospective longitudinal studies are needed to corroborate these findings and help to interpret the clinical relevance.
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http://dx.doi.org/10.1212/WNL.0000000000008684DOI Listing
January 2020

Meningitis gone viral: description of the echovirus wave 2013 in Germany.

BMC Infect Dis 2019 Nov 29;19(1):1010. Epub 2019 Nov 29.

Department of Neurology, University Hospital, Medical Faculty Heinrich-Heine University, Moorenstraße 5, 40225, Düsseldorf, Germany.

Background: Aseptic meningitis epidemics may pose various health care challenges.

Methods: We describe the German enterovirus meningitis epidemics in the university hospital centers of Düsseldorf, Cologne and Berlin between January 1st and December 31st, 2013 in order to scrutinize clinical differences from other aseptic meningitis cases.

Results: A total of 72 enterovirus (EV-positive) meningitis cases were detected in our multicenter cohort, corresponding to 5.8% of all EV-positive cases which were voluntarily reported within the National Enterovirus surveillance (EVSurv, based on investigation of patients with suspected aseptic meningitis/encephalitis and/or acute flaccid paralysis) by physicians within this period of time. Among these 72 patients, 38 (52.8%) were enterovirus positive and typed as echovirus (18 pediatric and 20 adult cases, median age 18.5 years; echovirus 18 (1), echovirus 2 (1), echovirus 30 (31), echovirus 33 (1), echovirus 9 (4)). At the same time, 45 aseptic meningitis cases in our cohort were excluded to be due to enteroviral infection (EV-negative). Three EV-negative patients were tested positive for varicella zoster virus (VZV) and 1 EV-negative patient for herpes simplex virus 2. Hospitalization was significantly longer in EV-negative cases. Cerebrospinal fluid analysis did not reveal significant differences between the two groups. After discharge, EV-meningitis resulted in significant burden of sick leave in our pediatric cohort as parents had to care for the children at home.

Conclusions: Voluntary syndromic surveillance, such as provided by the EVSurv in our study may be a valuable tool for epidemiological research. Our analyses suggest that EV-positive meningitis predominantly affects younger patients and may be associated with a rather benign clinical course, compared to EV-negative cases.
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http://dx.doi.org/10.1186/s12879-019-4635-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6883514PMC
November 2019

Monitoring retinal changes with optical coherence tomography predicts neuronal loss in experimental autoimmune encephalomyelitis.

J Neuroinflammation 2019 Nov 4;16(1):203. Epub 2019 Nov 4.

Division of Neuroimmunology and Glial Biology, Department of Neurology, University of California, San Francisco, San Francisco, USA.

Background: Retinal optical coherence tomography (OCT) is a clinical and research tool in multiple sclerosis, where it has shown significant retinal nerve fiber (RNFL) and ganglion cell (RGC) layer thinning, while postmortem studies have reported RGC loss. Although retinal pathology in experimental autoimmune encephalomyelitis (EAE) has been described, comparative OCT studies among EAE models are scarce. Furthermore, the best practices for the implementation of OCT in the EAE lab, especially with afoveate animals like rodents, remain undefined. We aimed to describe the dynamics of retinal injury in different mouse EAE models and outline the optimal experimental conditions, scan protocols, and analysis methods, comparing these to histology to confirm the pathological underpinnings.

Methods: Using spectral-domain OCT, we analyzed the test-retest and the inter-rater reliability of volume, peripapillary, and combined horizontal and vertical line scans. We then monitored the thickness of the retinal layers in different EAE models: in wild-type (WT) C57Bl/6J mice immunized with myelin oligodendrocyte glycoprotein peptide (MOG) or with bovine myelin basic protein (MBP), in TCR mice immunized with MOG, and in SJL/J mice immunized with myelin proteolipid lipoprotein (PLP). Strain-matched control mice were sham-immunized. RGC density was counted on retinal flatmounts at the end of each experiment.

Results: Volume scans centered on the optic disc showed the best reliability. Retinal changes during EAE were localized in the inner retinal layers (IRLs, the combination of the RNFL and the ganglion cell plus the inner plexiform layers). In WT, MOG EAE, progressive thinning of IRL started rapidly after EAE onset, with 1/3 of total loss occurring during the initial 2 months. IRL thinning was associated with the degree of RGC loss and the severity of EAE. Sham-immunized SJL/J mice showed progressive IRL atrophy, which was accentuated in PLP-immunized mice. MOG-immunized TCR mice showed severe EAE and retinal thinning. MBP immunization led to very mild disease without significant retinopathy.

Conclusions: Retinal neuroaxonal damage develops quickly during EAE. Changes in retinal thickness mirror neuronal loss and clinical severity. Monitoring of the IRL thickness after immunization against MOG in C57Bl/6J mice seems the most convenient model to study retinal neurodegeneration in EAE.
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http://dx.doi.org/10.1186/s12974-019-1583-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6827223PMC
November 2019