Publications by authors named "Marius Ringelstein"

59 Publications

The APOSTEL 2.0 Recommendations for Reporting Quantitative Optical Coherence Tomography Studies.

Neurology 2021 Apr 28. Epub 2021 Apr 28.

Department of Neurology with Institute of Translational Neurology, University of Münster, Münster, Germany.

Objective: To update the consensus recommendations for reporting of quantitative optical coherence tomography (OCT) study results, thus revising the previously published Advised Protocol for OCT Study Terminology and Elements (APOSTEL) recommendations.

Methods: To identify studies reporting quantitative OCT results, we performed a PubMed search for the terms "quantitative" and "optical coherence tomography" from 2015 to 2017. Corresponding authors of the identified publications were invited to provide feedback on the initial APOSTEL recommendations via online surveys following the principle of a modified Delphi method. The results were evaluated and discussed by a panel of experts, and changes to the initial recommendations were proposed. A final survey was recirculated among the corresponding authors to obtain a majority vote on the proposed changes.

Results: One hundred sixteen authors participated in the surveys, resulting in 15 suggestions, of which 12 were finally accepted and incorporated into an updated 9-point-checklist. We harmonized the nomenclature of the outer retinal layers, added the exact area of measurement to the description of volume scans; we suggested reporting device-specific features. We advised to address potential bias in manual segmentation or manual correction of segmentation errors. References to specific reporting guidelines and room light conditions were removed. The participants' consensus with the recommendations increased from 80% for the previous APOSTEL version to greater than 90%.

Conclusions: The modified Delphi method resulted in an expert-led guideline (evidence class III, GRADE criteria) concerning study protocol, acquisition device, acquisition settings, scanning protocol, fundoscopic imaging, post-acquisition data selection, post-acquisition analysis, nomenclature and abbreviations, and statistical approach. It will still be essential to update these recommendations to new research and practices regularly.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/WNL.0000000000012125DOI Listing
April 2021

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

Eur J Neurol 2021 May 11;28(5):1645-1658. Epub 2021 Feb 11.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/ene.14729DOI Listing
May 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/NXI.0000000000000913DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7757754PMC
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12868-020-00600-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7685624PMC
November 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.

Neurological Department and Institute of Experimental Neurology (INSPE) Scientific Institute, Hospital San Raffaele; and University Vita-Salute San Raffaele, Milan, Italy.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/bmjopen-2019-035397DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7597491PMC
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 Neurology, Medical Faculty, Heinrich Heine University Dusseldorf, Düsseldorf, 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12974-020-01824-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7470615PMC
September 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/NXI.0000000000000805DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7413713PMC
September 2020

Monoclonal antibody treatment during pregnancy and/or lactation in women with MS or neuromyelitis optica spectrum disorder.

Neurol Neuroimmunol Neuroinflamm 2020 07 23;7(4). Epub 2020 Apr 23.

From the Department of Neurology (A.I.C., S.T., R.G., K.H.), St. Josef Hospital, Ruhr University Bochum; Institute of Clinical Pharmacy and Pharmacotherapy (A.I.C.), Heinrich Heine University, Dusseldorf, Germany; Southern California Permanente Medical Group/Kaiser Permanente (A.L.-G.), Los Angeles Medical Center, Neurology Department, Los Angeles, CA; Sanquin Diagnostic Services (A.V., T.S.), Sanquin, Amsterdam, the Netherlands; Department of Neurology (M.R.), Medical Faculty, Heinrich Heine University; and Department of Neurology (M.R.), Center for Neurology and Neuropsychiatry, LVR-Klinikum, Heinrich Heine University Düsseldorf, Germany.

Objective: To assess possible adverse effects on breastfed infants of mothers receiving monoclonal antibodies (MAbs) during pregnancy and/or lactation.

Methods: We identified 23 patients from the German Multiple Sclerosis and Pregnancy Registry (DMSKW) who received MAbs (17 natalizumab and 6 anti-CD20) during lactation. Thirteen were already exposed to natalizumab during the third trimester of pregnancy, and 1 received ocrelizumab during pregnancy. Data were obtained from standardized, telephone-administered questionnaires completed by the mother during pregnancy and at 1, 3, 6, and 12 months postpartum. Natalizumab concentration in mother's milk was analyzed in 3 patients and natalizumab serum concentration in 2 of these patients and their breastfed infants.

Results: We did not observe a negative impact on infant health and development attributable to breast milk exposure after a median follow-up of 1 year. Infants exposed to natalizumab during the third trimester had a lower birth weight and more hospitalizations in the first year of life. The concentration of natalizumab in breast milk and serum of infants was low; B cells normal in infants breastfed under anti-CD20.

Conclusion: More data on the effect of Mab exposure during pregnancy are needed. Otherwise, our data suggest that treatment with natalizumab, ocrelizumab, or rituximab during lactation might be safe for breastfed infants.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/NXI.0000000000000723DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7188475PMC
July 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/micc.12616DOI Listing
July 2020

CD8 T cell-mediated endotheliopathy is a targetable mechanism of neuro-inflammation in Susac syndrome.

Nat Commun 2019 12 18;10(1):5779. Epub 2019 Dec 18.

Institute of Clinical Neuroimmunology, Biomedical Center and Hospital of the Ludwig-Maximilians-University Munich, Großhaderner Straße 9, Martinsried, 82152, Munich, Germany.

Neuroinflammation is often associated with blood-brain-barrier dysfunction, which contributes to neurological tissue damage. Here, we reveal the pathophysiology of Susac syndrome (SuS), an enigmatic neuroinflammatory disease with central nervous system (CNS) endotheliopathy. By investigating immune cells from the blood, cerebrospinal fluid, and CNS of SuS patients, we demonstrate oligoclonal expansion of terminally differentiated activated cytotoxic CD8 T cells (CTLs). Neuropathological data derived from both SuS patients and a newly-developed transgenic mouse model recapitulating the disease indicate that CTLs adhere to CNS microvessels in distinct areas and polarize granzyme B, which most likely results in the observed endothelial cell injury and microhemorrhages. Blocking T-cell adhesion by anti-α4 integrin-intervention ameliorates the disease in the preclinical model. Similarly, disease severity decreases in four SuS patients treated with natalizumab along with other therapy. Our study identifies CD8 T-cell-mediated endotheliopathy as a key disease mechanism in SuS and highlights therapeutic opportunities.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-019-13593-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6920411PMC
December 2019

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/WNL.0000000000008684DOI Listing
January 2020

Factors associated with headache in intravenous immunoglobulin treatment for neurological diseases.

Acta Neurol Scand 2019 Oct 23;140(4):290-295. Epub 2019 Jul 23.

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

Objectives: To identify possible risk factors influencing the incidence of intravenous immunoglobulin (IVIg) treatment-related cephalalgia in neurological diseases.

Materials & Methods: Retrospective chart review of neurological patients receiving IVIg treatment between July 13, 2017, and August 14, 2017. Patients with MS receiving natalizumab in the same setting were observed as a reference group.

Results: Patients with headache after IVIg infusion (n = 22 infusions) showed a reduced heart rate (by 6.0 ± 8.5 beats per minute [bpm]), but no significant difference in blood pressure. Patients without headache after IVIg infusion (n = 69 infusions) showed a higher systolic blood pressure increase and a stronger reduction in the heart rate (by 5.7 ± 8.6 bpm), compared to patients with headache after IVIg infusion. The infusion rate was significantly slower and age significantly lower in patients developing headache after IVIg infusion. Body temperature was unchanged in both groups. Binary logistic regression analysis revealed that blood pressure at baseline and age significantly influence the occurrence of cephalalgia. In reference, patients receiving natalizumab (ie, shorter infusions/smaller infusion volume), systolic blood pressure, and heart rate decreased, while body temperature increased. Here, one patient developed headache.

Conclusions: Intravenous immunoglobulin-associated headache is not associated with an increased blood pressure after infusion but with a reduced heart rate, a slower infusion rate, female sex and seems to be influenced by baseline systolic blood pressure and age. A reaction to immunoglobulin aggregates, stabilizers, or vasoactive mediators are possible explanations. The absence of an association with body temperature does not suggest a systemic immune response as a cause for headache.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/ane.13144DOI Listing
October 2019

Management and prognostic markers in patients with autoimmune encephalitis requiring ICU treatment.

Neurol Neuroimmunol Neuroinflamm 2019 01 30;6(1):e514. Epub 2018 Oct 30.

Hans-Berger-Department of Neurology (J.S., D.B., C.G., O.W.W., A.G.), Jena University Hospital; Department of Neurology (H.B.H., S.T.G.), University Hospital Erlangen; Department of Neurology and Neurophysiology (H.F), University Hospital Freiburg; Department of Neurology (N.M., A.D.), University Hospital Münster; Department of Neurology (H.P., L.-T.L), Charité University Medicine Berlin; Department of Neurology (K.F.), Bezirksklinikum Regensburg; Neuroimmunology Section (F.L., G.N.), Institute of Clinical Chemistry and Department of Neurology, University Hospital Schleswig-Holstein, Kiel; Department of Neurology (I.S.), University Hospital Giessen; Center for Neurology and Psychiatrics (C.D.), University Hospital Köln; Department of Neurology (J.B.), University Hospital Heidelberg; Department of Neurology (J.B.), Klinikum Kassel; Department of Neurology (J.L.), University Hospital Ulm; Institute of Clinical Neuroimmunology (F.T.), Ludwig-Maximillians-University München; Department of Neurology (A.K.), Martha Maria Hospital Halle; Department of Neurology (A.J.), Dortmund Hospital; Department of Neurology (M.R.), Medical Faculty, Heinrich Heine University Düsseldorf; Department of Neurology (K.-W.S.), University Hospital Hannover; Department of Neurology (C.U.), Hospital Ludwigshafen; Institute of Medical Statistics, Computer and Data Sciences (A.S), Jena University Hospital; and Center for Sepsis Control and Care (A.S., C.G.), Jena University Hospital, Germany.

Objective: To assess intensive care unit (ICU) complications, their management, and prognostic factors associated with outcomes in a cohort of patients with autoimmune encephalitis (AE).

Methods: This study was an observational multicenter registry of consecutively included patients diagnosed with AE requiring Neuro-ICU treatment between 2004 and 2016 from 18 tertiary hospitals. Logistic regression models explored the influence of complications, their management, and diagnostic findings on the dichotomized (0-3 vs 4-6) modified Rankin Scale score at hospital discharge.

Results: Of 120 patients with AE (median age 43 years [interquartile range 24-62]; 70 females), 101 developed disorders of consciousness, 54 autonomic disturbances, 42 status epilepticus, and 39 severe sepsis. Sixty-eight patients were mechanically ventilated, 85 patients had detectable neuronal autoantibodies, and 35 patients were seronegative. Worse neurologic outcome at hospital discharge was associated with necessity of mechanical ventilation (sex- and age-adjusted OR 6.28; 95% CI, 2.71-15.61) tracheostomy (adjusted OR 6.26; 95% CI, 2.68-15.73), tumor (adjusted OR 3.73; 95% CI, 1.35-11.57), sepsis (adjusted OR 4.54; 95% CI, 1.99-10.43), or autonomic dysfunction (adjusted OR 2.91; 95% CI, 1.24-7.3). No significant association was observed with autoantibody type, inflammatory changes in CSF, or pathologic MRI.

Conclusion: In patients with AE, mechanical ventilation, sepsis, and autonomic dysregulation appear to indicate longer or incomplete convalescence. Classic ICU complications better serve as prognostic markers than the individual subtype of AE. Increased awareness and effective management of these AE-related complications are warranted, and further prospective studies are needed to confirm our findings and to develop specific strategies for outcome improvement.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/NXI.0000000000000514DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6278855PMC
January 2019

High prevalence of neutralizing antibodies after long-term botulinum neurotoxin therapy.

Neurology 2019 01 21;92(1):e48-e54. Epub 2018 Nov 21.

From the Department of Neurology (P.A., A.J., J.-I.L., M.M., M.R., O.A., H.-P.H., H.H.), Medical Faculty, Heinrich Heine University Düsseldorf; and Toxogen GmbH (D.R., H.B.), Hannover, Germany.

Objective: To investigate the prevalence of neutralizing antibodies (NAbs) against botulinum neurotoxin type A (BoNT/A) during long-term BoNT/A treatment in different neurologic indications.

Methods: In this monocentric, observational cross-sectional study, 596 outpatients treated with BoNT/A for different indications were tested for BoNT/A binding antibodies by ELISA. Positive samples were investigated for NAbs with the mouse hemidiaphragm test. The prevalence of NAbs was analyzed for different indications: facial hemispasm, blepharospasm, cervical dystonia, other dystonia, and spasticity. Besides the rate of NAb-positive patients overall and per patient subgroup, a Kaplan-Meier analysis of the probability of remaining NAb negative with duration of treatment is provided, and a stepwise binary logistic regression analysis is performed to identify factors significantly contributing to the induction of NAbs.

Results: Overall, 83 of 596 patients (13.9%) had measurable NAbs. The probability of developing NAbs increased with the single and cumulative dose of treatment and was influenced by the BoNT/A formulation, while all other factors analyzed, including disease entity and treatment duration, had no additional influence.

Conclusions: We present the largest study to date of the prevalence of BoNT/A NAbs in a large unbiased cohort of patients including the relevant neurologic indications. Repeated injections of BoNT/A inevitably bear the risk of developing NAbs. However, in addition to avoiding booster injections and providing short intervals between injections, reducing the individual injected doses may diminish the risk of NAb induction independently of the indication for which BoNT/A is used.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/WNL.0000000000006688DOI Listing
January 2019

Racial differences in neuromyelitis optica spectrum disorder.

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

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

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

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

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

Conclusion: A review of a large international cohort revealed that race affected the clinical phenotype, age at onset, and severity of attacks, but the overall outcome was most dependent on early and effective immunosuppressive treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/WNL.0000000000006574DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6282238PMC
November 2018

Apheresis therapies for NMOSD attacks: A retrospective study of 207 therapeutic interventions.

Neurol Neuroimmunol Neuroinflamm 2018 Nov 26;5(6):e504. Epub 2018 Sep 26.

Department of Neurology (I.K., A.G., K.H.), St. Josef Hospital, Ruhr University Bochum; Marianne-Strauß-Klinik (I.K.), Behandlungszentrum Kempfenhausen für Multiple Sklerose Kranke, Berg; NeuroCure Clinical Research Center and Experimental and Clinical Research Center (N.B., F. Pache), Charité Universitätsmedizin Berlin, and Max Delbrueck Center for Molecular Medicine, Berlin; Department of Neurology (K.F., J.F.), Asklepios Fachklinikum Teupitz; CRO Sostana GmbH and Charité Universitätsmedizin Berlin (K.-D.W.); Department of Neurology and Clinical and Experimental Multiple Sclerosis Research Center (F.Pache, K.R.), Charité Universitätsmedizin Berlin; Institute of Clinical Neuroimmunology (J.H., T.K.), Ludwig Maximilians University, Munich; Department of Neurology (O.A., H.-P.H., M.R.), Medical Faculty, Heinrich Heine University Düsseldorf; Department of Neurology (C.G., M. Schwab), Jena University Hospital; Department of Neurology (C.K.), University Hospital Essen; Department of Neurology (A.B.), Klinikum rechts der Isar, Technische Universität München, Munich; Department of Neurology (B.H.), Klinikum rechts der Isar, Technische Universität München and Munich Cluster for Systems Neurology (SyNergy); Department of Neurology (K.A.), University Hospital Regensburg; Institute of Neuroimmunology and MS (INIMS) and Department of Neurology (J.-P.S.), University Medical Centre Hamburg-Eppendorf, HamburgKlinik und Poliklinik für Neurologie (S.S.), Universitätsklinikum Hamburg-Eppendorf; Clinical Neuroimmunology and Neurochemistry (M. Stangel), Department of Neurology, Hannover Medical School; Department of Neurology (F.L., H.T.), University of Ulm; Fachklinik für Neurologie Dietenbronn (H.T.), Akademisches Krankenhaus der Universität Ulm, Schwendi; Department of Neurology (C.M.), Goethe University Frankfurt; Department of Neurology & Stroke (M.K., L.Z., U. Ziemann), and Hertie-Institute for Clinical Brain Research, University of Tübingen; Department of Neurology (R.L.), Friedrich-Alexander University Erlangen-Nuremberg; Department of Neurology and Neurological Intensive Care (M.M.), Isar-Amper-Clinic, Munich-East, Haar; Department of Neurology (F.T.B.), University of Leipzig; Department of Neurology (U. Hofstadt-van Oy), Klinikum Westfalen, Dortmund; Department of Neurology (O.N.), SRH Krankenhaus Sigmaringen; Neuroimmunological Section (U. Zettl), Department of Neurology, University of Rostock; Molecular Neuroimmunology Group (B.W., S.J.), Department of Neurology, University of Heidelberg; NeuroCure Clinical Research Center (F. Paul), Charité Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, and Experimental and Clinical Research Center, Max Delbrück Center for Molecular Medicine and Charité-Universitätsmedizin Berlin; and Department of Neurology (C.T.), Hannover Medical School, Germany.

Objective: To analyze whether 1 of the 2 apheresis techniques, therapeutic plasma exchange (PE) or immunoadsorption (IA), is superior in treating neuromyelitis optica spectrum disorder (NMOSD) attacks and to identify predictive factors for complete remission (CR).

Methods: This retrospective cohort study was based on the registry of the German Neuromyelitis Optica Study Group, a nationwide network established in 2008. It recruited patients with neuromyelitis optica diagnosed according to the 2006 Wingerchuk criteria or with aquaporin-4 (AQP4-ab)-antibody-seropositive NMOSD treated at 6 regional hospitals and 16 tertiary referral centers until March 2013. Besides descriptive data analysis of patient and attack characteristics, generalized estimation equation (GEE) analyses were applied to compare the effectiveness of the 2 apheresis techniques. A GEE model was generated to assess predictors of outcome.

Results: Two hundred and seven attacks in 105 patients (87% AQP4-ab-antibody seropositive) were treated with at least 1 apheresis therapy. Neither PE nor IA was proven superior in the therapy of NMOSD attacks. CR was only achieved with early apheresis therapy. Strong predictors for CR were the use of apheresis therapy as first-line therapy (OR 12.27, 95% CI: 1.04-144.91, = 0.047), time from onset of attack to start of therapy in days (OR 0.94, 95% CI: 0.89-0.99, = 0.014), the presence of AQP4-ab-antibodies (OR 33.34, 95% CI: 1.76-631.17, = 0.019), and monofocal attack manifestation (OR 4.71, 95% CI: 1.03-21.62, = 0.046).

Conclusions: Our findings suggest early use of an apheresis therapy in NMOSD attacks, particularly in AQP4-ab-seropositive patients. No superiority was shown for one of the 2 apheresis techniques.

Classification Of Evidence: This study provides Class IV evidence that for patients with NMOSD, neither PE nor IA is superior in the treatment of attacks.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/NXI.0000000000000504DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6192689PMC
November 2018

Acute sarcoidosis in a multiple sclerosis patient after alemtuzumab treatment.

Mult Scler 2018 11 11;24(13):1776-1778. Epub 2018 Oct 11.

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

Background: Understanding the long-term effect of alemtuzumab on the immune system of multiple sclerosis (MS) patients is crucial.

Objective: To report a case of acute sarcoidosis (Löfgren's syndrome) in a relapsing-remitting MS patient, 1.5 years after the second course of alemtuzumab treatment.

Case Report: Sarcoidosis was confirmed dermatohistologically, radiologically, and serologically. Analysis of the lymphocyte subpopulations showed a persistent effect of alemtuzumab treatment (CD4/CD8 ratio increased, absolute lymphocyte count of CD19-positive cells increased while CD3/4/8-positive cells were decreased).

Conclusion: Our case highlights the profound effect of alemtuzumab on the immune system and its possible risk for autoimmune complications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/1352458518771276DOI Listing
November 2018

Multifocal visual evoked potentials in chronic inflammatory demyelinating polyneuropathy.

Ann Clin Transl Neurol 2018 Aug 7;5(8):952-961. Epub 2018 Jul 7.

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

Objective: Studies using conventional full-field visual evoked potentials (ffVEP) have reported subtle abnormalities in patients with chronic inflammatory demyelinating polyneuropathy (CIDP). We hypothesize that these abnormalities can be detected in the majority of CIDP patients using enhanced methods.

Methods: We performed a cross-sectional noninterventional study comparing 18 CIDP patients and 18 matched healthy controls using multifocal VEP (mfVEP) as a technique with enhanced sensitivity to detect conduction abnormalities across the spectrum of optic nerve fibers. Patients with confounding diseases (ophthalmologic, diabetes mellitus) were excluded.

Results: The mean amplitude and latency, as well as the low-contrast visual acuity, did not differ between CIDP patients and controls. Subanalyses revealed latency differences concerning the superior sector of the visual field. Severity markers of CIDP (ODSS, motor nerve conduction velocity) were associated with mfVEP latency delay.

Interpretation: We could not adduce evidence for clinically or diagnostically relevant visual pathway involvement in CIDP. The latency differences identified were very subtle and restricted to the superior visual field which cannot be readily explained biologically, anatomically, or pathologically. In summary, we conclude that our study revealed no relevant differences in mfVEP parameters between CIDP patients and controls.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/acn3.593DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6093840PMC
August 2018

Genetic predisposition in anti-LGI1 and anti-NMDA receptor encephalitis.

Ann Neurol 2018 04;83(4):863-869

Department of Neurology, Christian-Albrechts-University Kiel, Germany.

We performed a genome-wide association study in 1,194 controls and 150 patients with anti-N-methyl-D-aspartate receptor (anti-NMDAR, n = 96) or anti-leucine-rich glioma-inactivated1 (anti-LGI1, n = 54) autoimmune encephalitis. Anti-LGI1 encephalitis was highly associated with 27 single-nucleotide polymorphisms (SNPs) in the HLA-II region (leading SNP rs2858870 p = 1.22 × 10 , OR = 13.66 [7.50-24.87]). Potential associations, below genome-wide significance, were found with rs72961463 close to the doublecortin-like kinase 2 gene (DCLK2) and rs62110161 in a cluster of zinc-finger genes. HLA allele imputation identified association of anti-LGI1 encephalitis with HLA-II haplotypes encompassing DRB1*07:01, DQA1*02:01 and DQB1*02:02 (p < 2.2 × 10 ) and anti-NMDAR encephalitis with HLA-I allele B*07:02 (p = 0.039). No shared genetic risk factors between encephalitides were identified. Ann Neurol 2018;83:863-869.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ana.25216DOI Listing
April 2018

Infectious risk stratification in multiple sclerosis patients receiving immunotherapy.

Ann Clin Transl Neurol 2017 12 24;4(12):909-914. Epub 2017 Nov 24.

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

The increasing number of potent treatments for multiple sclerosis warrants screening for infections. To investigate the prevalence of infections in two independent German patient cohorts with multiple sclerosis/neuromyelitis optica spectrum disorders (NMOSD), we performed a retrospective chart review study of multiple sclerosis/NMOSD patients who underwent testing for infections between 2014 and 2016. We show that 6 out of 80 tested patients (Düsseldorf cohort) and 2 out of 97 tested patients (Münster cohort) had a latent tuberculosis infection; total 3.95%, 95% CI: 2-8%. Our findings suggest that latent tuberculosis infection is frequent (>1%). Screening should be performed before embarking on immunomodulatory therapies to allow treatment and mitigation of the risk of a reactivation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/acn3.491DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5740259PMC
December 2017

Fulminant intramedullary spinal cord sarcoidosis.

Mult Scler Relat Disord 2017 Nov 13;18:47-48. Epub 2017 Sep 13.

Department of Neurology, University Hospital, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany. Electronic address:

Neurosarcoidosis is a rare disease with various clinical phenotypes. Thus, case reports and series broaden the understanding of this entity (Ibitoye et al., 2017). We present a case of isolated intramedullary spinal cord sarcoidosis, an exceedingly rare phenotype, which needs to be distinguished especially from neuromyelitis optica spectrum disorders (NMOSD). This report exemplifies the need for a systematic approach to diagnosis and management of spinal cord sarcoidosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.msard.2017.09.010DOI Listing
November 2017

Aquaporin-4 antibodies in patients treated with natalizumab for suspected MS.

Neurol Neuroimmunol Neuroinflamm 2017 Jul 16;4(4):e363. Epub 2017 Jun 16.

Department of Neurology (A.G., A.-K.T., S.H., R.G., I.K.), St. Josef-Hospital, Ruhr-University Bochum; Department of Neurology (M.R., O.A.), Medical Faculty, Heinrich-Heine-University Düsseldorf; Department of Neurology (A.B.), Klinikum Rechts der Isar, Technische Universität München; and Molecular Neuroimmunology Group (B.W., S.J.), Department of Neurology, University of Heidelberg, Germany.

Objective: To evaluate (1) the frequency of aquaporin-4 antibody (AQP4-ab)-seropositive cases among patients treated with natalizumab (NAT) and previously diagnosed with MS (MS) in a nationwide cohort, (2) the clinical course of NAT-treated AQP4-ab-seropositive neuromyelitis optica spectrum disorder (NMOSD) patients (NMO), (3) AQP4-ab titers in NMO and AQP4-ab-seropositive NMOSD treated with other immunotherapies (NMO), and (4) immune mechanisms influencing disease activity in NMO.

Methods: MS serum samples were retrospectively screened with a cell-based assay for AQP4-IgG and titers determined by ELISA. The annualized relapse rate (ARR) and disability progression were assessed. Serum levels of proinflammatory cytokines (interleukin [IL]-1β, IL-4, IL-6, IL-8, IL-10, IL-17, IL-21, and interferon [IFN]-γ) and the chemokine CXCL-10 of NMO patients identified in this (n = 4) and a previous study (n = 5) were measured by cytometric bead array and ELISA.

Results: Of the 1,183 MS patients (851 female, median 9 NAT infusions), only 4 (0.33%; 3 female, 1 male) had AQP4-IgG. Of these, 2 fulfilled the 2006 NMO criteria and all met the 2015 NMOSD criteria. The ARR was higher in NMO vs MS ( = 0.0182). All 4 NMO patients had relapses and 2 had an increase of disability. AQP4-ab titers were higher in NMO (n = 9) vs NMO (n = 13; = 0.0059). IL-8, IL-1β, and IFN-γ serum levels were significantly higher, and CXCL-10 was significantly lower in NMO vs NMO.

Conclusions: Misdiagnosis of NMOSD with MS is rare. NAT was not able to control disease activity in NMO patients, who had higher serum levels of AQP4-IgG and proinflammatory cytokines than patients with NMOSD treated with other immunotherapies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/NXI.0000000000000363DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5473957PMC
July 2017

Optical coherence tomography for the diagnosis and monitoring of idiopathic intracranial hypertension.

J Neurol 2017 Jul 5;264(7):1370-1380. Epub 2017 Jun 5.

Focus Program Translational Neuroscience (FTN), Rhine Main Neuroscience Network (RMN(2)), Department of Neurology, Johannes Gutenberg University Medical Center, Mainz, Germany.

The objectives of the study were to investigate the value of optical coherence tomography in detecting papilledema in patients with idiopathic intracranial hypertension (IIH), a disease which is difficult to monitor and which can lead to permanent visual deficits; to analyze retinal changes over time. In this non-interventional case-control study, spectral-domain optical coherence tomography (SD-OCT) was used to analyze the retinal and optic nerve head (ONH) morphology of 21 patients with IIH and 27 age- and sex-matched healthy controls over time. We analyzed the ONH volume using a custom-made algorithm and employed semi-automated segmentation of macular volume scans to assess the macular retinal nerve fiber layer (RNFL) and ganglion cell layer and inner plexiform layer complex as well as the total macular volume. In IIH patients, the ONH volume was increased and correlated with cerebrospinal fluid (CSF) pressure. The ONH volume decreased after the initiation of treatment with acetazolamide. The macular RNFL volume decreased by 5% in 3.5 months, and a stepwise multivariate regression analysis identified CSF pressure as the main influence on macular RNFL volume at diagnosis. The only factor predicting macular RNFL volume loss over time was ONH volume. SD-OCT can non-invasively monitor changes in retinal and ONH morphology in patients with IIH. Increased ONH volume leads to retinal atrophy in the form of macular RNFL volume loss, presumably due to mechanic jamming of the optic nerve at the disc and subsequent axonal loss.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00415-017-8532-xDOI Listing
July 2017

Immunotherapies in neuromyelitis optica spectrum disorder: efficacy and predictors of response.

J Neurol Neurosurg Psychiatry 2017 08 1;88(8):639-647. Epub 2017 Jun 1.

Department of Neurology, University of Münster, Münster, Germany.

Objective: To analyse predictors for relapses and number of attacks under different immunotherapies in patients with neuromyelitis optica spectrum disorder (NMOSD).

Design: This is a retrospective cohort study conducted in neurology departments at 21 regional and university hospitals in Germany. Eligible participants were patients with aquaporin-4-antibody-positive or aquaporin-4-antibody-negative NMOSD. Main outcome measures were HRs from Cox proportional hazard regression models adjusted for centre effects, important prognostic factors and repeated treatment episodes.

Results: 265 treatment episodes with a mean duration of 442 days (total of 321 treatment years) in 144 patients (mean age at first attack: 40.9 years, 82.6% female, 86.1% aquaporin-4-antibody-positive) were analysed. 191 attacks occurred during any of the treatments (annual relapse rate=0.60). The most common treatments were rituximab (n=77, 111 patient-years), azathioprine (n=52, 68 patient-years), interferon-β (n=32, 61 patient-years), mitoxantrone (n=34, 32.1 patient-years) and glatiramer acetate (n=17, 10 patient-years). Azathioprine (HR=0.4, 95% CI 0.3 to 0.7, p=0.001) and rituximab (HR=0.6, 95% CI 0.4 to 1.0, p=0.034) reduced the attack risk compared with interferon-β, whereas mitoxantrone and glatiramer acetate did not. Patients who were aquaporin-4-antibody-positive had a higher risk of attacks (HR=2.5, 95% CI 1.3 to 5.1, p=0.009). Every decade of age was associated with a lower risk for attacks (HR=0.8, 95% CI 0.7 to 1.0, p=0.039). A previous attack under the same treatment tended to be predictive for further attacks (HR=1.5, 95% CI 1.0 to 2.4, p=0.065).

Conclusions: Age, antibody status and possibly previous attacks predict further attacks in patients treated for NMOSD. Azathioprine and rituximab are superior to interferon-β.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/jnnp-2017-315603DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5537514PMC
August 2017

Alterations of the outer retina in non-arteritic anterior ischaemic optic neuropathy detected using spectral-domain optical coherence tomography.

Clin Exp Ophthalmol 2017 Jul 9;45(5):496-508. Epub 2017 Mar 9.

Department of Ophthalmology, University of Düsseldorf, Düsseldorf, Germany.

Background: A characteristic disease pattern may be reflected by retinal layer thickness changes in non-arteritic anterior ischaemic optic neuropathy measured using spectraldomain optical coherence tomography. Retinal layer segmentation is enabled by advanced software. In this study, retinal layer thicknesses in acute and chronic non-arteritic anterior ischaemic optic neuropathy were compared.

Design: A single-centre cross-sectional analysis was used.

Participants: A total of 27 patients (20 age-matched healthy eyes) were included: 14 with acute (<7 days) and 13 patients with chronic non-arteritic anterior ischaemic optic neuropathy.

Methods: Macular volume and 12° peripapillary ring optical coherence tomography scans were used.

Main Outcome Measures: The peripapillary thicknesses of the following layers were determined by manual segmentation: retinal nerve fibres, ganglion cells + inner plexiform layer, inner nuclear layer + outer plexiform layer, outer nuclear layer + inner segments of the photoreceptors and outer segments of the photoreceptors to Bruch's membrane. Macular retinal layer thicknesses were automatically determined in volume cubes centred on the fovea.

Results: Peripapillary retinal swelling in acute nonarteritic anterior ischaemic optic neuropathy was attributable to retinal nerve fibre layer, ganglion cell layer/inner plexiform layer and outer nuclear layer/segments of the photoreceptors thickening. In chronic cases, peripapillary retinal nerve fibre layer, macular ganglion cell layer and inner plexiform layer thinning were observed.

Conclusions: In acute non-arteritic anterior ischaemic optic neuropathy, the inner and outer peripapillary retinal layers are affected by thickness changes. In chronic cases, atrophy of the ganglion cells and their axons and dendrites is evident by inner retinal layer thinning.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/ceo.12914DOI Listing
July 2017

Diagnostic criteria for Susac syndrome.

J Neurol Neurosurg Psychiatry 2016 Dec 25;87(12):1287-1295. Epub 2016 Oct 25.

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

Background: Susac syndrome is characterised by the triad of encephalopathy with or without focal neurological signs, branch retinal artery occlusions and hearing loss. Establishment of the diagnosis is often delayed because the triad is complete only in a minority of patients at disease onset. This leads to a critical delay in the initiation of appropriate treatment. Our objective was to establish criteria for diagnosis of either definite or probable Susac syndrome.

Method: The establishment of diagnostic criteria was based on the following three steps: (1) Definition of a reference group of 32 patients with an unambiguous diagnosis of Susac syndrome as assessed by all interdisciplinary experts of the European Susac Consortium (EuSaC) team (EuSaC cohort); (2) selection of diagnostic criteria, based on common clinical and paraclinical findings in the EuSaC cohort and on a review of the literature; and (3) validation of the proposed criteria in the previously published cohort of all Susac cases reported until 2012.

Results: Integrating the clinical presentation and paraclinical findings, we propose formal criteria and recommend a diagnostic workup to facilitate the diagnosis of Susac syndrome. More than 90% of the cases in the literature fulfilled the proposed criteria for probable or definite Susac syndrome. We surmise that more patients could have been diagnosed with the recommended diagnostic workup.

Conclusions: We propose diagnostic criteria for Susac syndrome that may help both experts and physicians not familiar with Susac syndrome to make a correct diagnosis and to prevent delayed treatment initiation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/jnnp-2016-314295DOI Listing
December 2016