Publications by authors named "Ilya Ayzenberg"

41 Publications

[Treatment of antibody-mediated encephalomyelitis : Strategies for the treatment of neuromyelitis optica spectrum disorder and myelin oligodendrocyte glycoprotein antibody-associated disease].

Nervenarzt 2021 Apr 30;92(4):334-348. Epub 2021 Mar 30.

Klinik für Neurologie, St. Josef Hospital Bochum, Ruhr-Universität Bochum, Bochum, Deutschland.

Background: Antibody-mediated encephalomyelitis, such as neuromyelitis optica spectrum disorder (NMOSD), myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), and glial fibrillary acidic protein (GFAP) antibody-associated astrocytopathy belong to a group of newly described autoimmune diseases.

Aim: Presentation of the treatment of antibody-mediated encephalomyelitis with a focus on NMOSD and MOGAD.

Methods: Selective literature search in PubMed taking the consultation version of the S2k guidelines of the German Society of Neurology (DGN) on the diagnosis and treatment of multiple sclerosis (MS), NMOSD and MOG IgG-associated diseases into account.

Results: Acute relapses are treated with high-dose steroid pulse therapy or apheresis therapy (plasma exchange or immunoadsorption). It is crucial to start treatment as quickly as possible and apheresis therapy can also be used as first-line treatment under certain conditions. For prophylactic immunotherapy, steroids, classical immunosuppressants and monoclonal antibodies with specific mechanisms of action are used. Eculizumab, inebilizumab and satralizumab are the first drugs approved for NMOSD. Symptomatic treatment and neurorehabilitation are important complementary measures.

Conclusion: Treatment of antibody-mediated encephalomyelitis differs from treatment of multiple sclerosis and requires specific measures.
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http://dx.doi.org/10.1007/s00115-021-01090-4DOI 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.
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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.
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http://dx.doi.org/10.1212/NXI.0000000000000913DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7757754PMC
January 2021

Gender issues of antibody-mediated diseases in neurology: (NMOSD/autoimmune encephalitis/MG).

Ther Adv Neurol Disord 2020 25;13:1756286420949808. Epub 2020 Aug 25.

Department of Neurology, St. Josef Hospital Bochum, Ruhr University of Bochum, Gudrunstrasse 56, Bochum, 44791, Germany.

Neuromyelitis optica spectrum disorder (NMOSD), autoimmune encephalitis (AE), myasthenia gravis (MG) and Lambert-Eaton myasthenic syndrome (LEMS) are antibody-mediated neurological diseases. They have mostly female predominance, affecting many women during childbearing age. Interactions between the underlying disease (or necessary treatment) and pregnancy can occur in every of these illnesses. Herein, we present the characteristics of NMOSD, AE, MG and LEMS in general, and review published data regarding the influence of the different diseases on fertility, pregnancy, puerperium, treatment strategy during pregnancy and post-partum period, and menopause but also male factors. We summarise key elements that should be borne in mind when confronted with such cases.
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http://dx.doi.org/10.1177/1756286420949808DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7450460PMC
August 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.
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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

The transitional phase of multiple sclerosis: Characterization and conceptual framework.

Mult Scler Relat Disord 2020 Sep 29;44:102242. Epub 2020 May 29.

Department of Neurology, University of Regensburg, Regensburg, Germany.

The conversion of relapsing-remitting multiple sclerosis (RRMS) to secondary progressive MS (SPMS) cannot be defined by a sharp threshold determined by event-based measures, but rather represents a gradual process. In consequence, there may exist a transitional phase between RRMS and clearly established SPMS. So far, transitional MS has been poorly characterized in terms of patient properties, course of disease and therapeutic interventions that may delay conversion to SPMS. Furthermore, the pathogenesis of transitional MS is incompletely understood, and no definitive imaging or laboratory test informs when exactly a patient has entered the transitional MS phase. Here we review the current knowledge and evidence characterizing the transitional phase of MS and propose potential designs and criteria for a prospective clinical study in patients with transitional MS.
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http://dx.doi.org/10.1016/j.msard.2020.102242DOI Listing
September 2020

Reader Response: Comparison of the Response to Rituximab between Myelin Oligodendrocyte Glycoprotein and Aquaporin-4 Antibody Diseases.

Ann Neurol 2020 08 23;88(2):430. Epub 2020 Jun 23.

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

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http://dx.doi.org/10.1002/ana.25805DOI Listing
August 2020

Early immunotherapy is highly effective in IgG1/IgG4 positive IgLON5 disease.

J Neurol 2020 Jul 22;267(7):2151-2153. Epub 2020 May 22.

Department of Neurology, St. Josef Hospital, Ruhr University Bochum, Gudrunstr. 56, 44791, Bochum, Germany.

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http://dx.doi.org/10.1007/s00415-020-09924-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7320942PMC
July 2020

Novel variants in a patient with late-onset hyperprolinemia type II: diagnostic key for status epilepticus and lactic acidosis.

BMC Neurol 2019 Dec 29;19(1):345. Epub 2019 Dec 29.

Department of Neurology, St. Josef-Hospital, Ruhr-University Bochum, Gudrunstrasse 56, 44791, Bochum, Germany.

Background: Hyperprolinemia type 2 (HPII) is a rare autosomal recessive disorder of the proline metabolism, that affects the ALDH4A1 gene. So far only four different pathogenic mutations are known. The manifestation is mostly in neonatal age, in early infancy or early childhood.

Case Presentation: The 64-years female patient had a long history of abdominal pain, and episode of an acute neuritis. Ten years later she was admitted into the neurological intensive-care-unit with acute abdominal pain, multiple generalized epileptic seizures, a vertical gaze palsy accompanied by extensive lactic acidosis in serum 26.0 mmol/l (reference: 0.55-2.2 mmol/l) and CSF 12.01 mmol/l (reference: 1.12-2.47 mmol/l). Due to repeated epileptic seizures and secondary complications a long-term sedation with a ventilation therapy over 20 days was administered. A diagnostic work-up revealed up to 400-times increased prolin-level in urine CSF and blood. Furthermore, a low vitamin-B serum value was found, consistent with a HPII causing secondary pyridoxine deficiency and seizures. The ALDH4A1 gene sequencing confirmed two previously unknown compound heterozygous variants (ALDH4A1 gene (NM_003748.3) Intron 1: c.62 + 1G > A - heterozygous and ALDH4A1 gene (NM_003748.3) Exon 5 c.349G > C, p.(Asp117His) - heterozygous). Under high-dose vitamin-B therapy no further seizures occurred.

Conclusion: We describe two novel ALDH4A1-variants in an adult patient with hyperprolinemia type II causing secondary pyridoxine deficiency and seizures. Severe and potentially life-threatening course of this treatable disease emphasizes the importance of diagnostic vigilance and thorough laboratory work-up including gene analysis even in cases with atypical late manifestation.
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http://dx.doi.org/10.1186/s12883-019-1583-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6935479PMC
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.
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http://dx.doi.org/10.1212/WNL.0000000000008684DOI Listing
January 2020

Effects of IVIg treatment on autoantibody testing in neurological patients: marked reduction in sensitivity but reliable specificity.

J Neurol 2020 Mar 14;267(3):715-720. Epub 2019 Nov 14.

Department of Neurology, St. Josef Hospital, Ruhr-University Bochum, Gudrunstr. 56, 44791, Bochum, Germany.

Background: Therapy of autoimmune diseases of the central and peripheral nervous system with intravenous IgG immunoglobulin (IVIg) is well established. Since IVIg is produced from pooled human plasma, autoantibodies can be found in IVIg products and, accordingly, in patient sera after transfusion. The de novo evidence or disappearance of anti-neural autoantibodies after IVIg treatment has so far not been systematically examined.

Methods: We screened 50 neurological patients before and after IVIg treatment for classical onconeural and the most common neurological surface autoantibodies as well as for ganglioside autoantibodies and 23 different antinuclear autoantibodies using immunoblot or cell-based indirect immunofluorescence assays. Furthermore, we screened 31 neurological patients with previously known seropositivity for disappearance of the corresponding antibody after treatment.

Results: After IVIg treatment, 90% of all sera were de novo positive for antinuclear antibodies, especially for Ro-52. In contrast, 94% of all sera did not show any de novo-positive anti-neural antibodies. In the remaining three cases, titers were very low. Importantly, 12.9% of all tested sera of patients with known antibody positivity turned false negative after IVIg treatment and titers were falsely low in 37% of the remaining sera.

Conclusions: Here, we present for the first time results of a broad screening for clinically relevant autoantibodies before and after IVIg treatment in neurological patients. We identified a high specificity but reduced sensitivity for anti-neural antibody testing after IVIg transfusion. In contrast, antinuclear antibody testing is not reliable after IVIg treatment. These results are of high practical importance for diagnostic of neuroimmunological diseases.
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http://dx.doi.org/10.1007/s00415-019-09614-4DOI Listing
March 2020

General principles and escalation options of immunotherapy in autoantibody-associated disorders of the CNS.

Neurol Res Pract 2019 1;1:32. Epub 2019 Oct 1.

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

Autoimmune diseases associated with antineuronal and antiglial autoantibodies (Abs) is one of the most rapidly expanding research fields in clinical neuroimmunology, with more than 30 autoantibodies described so far. Being associated with a wide range of clinical presentations these syndromes can be diagnostically challenging. Surface or intracellular antigen localizations are crucial for the treatment response and outcome. In the latter Abs are mostly of paraneoplastic cause and tumor management should be performed as soon as possible in order to stop peripheral antigen stimulation. Immunotherapy should be started early in both groups, before irreversible neuronal loss occurs. Despite serious prognosis, aggressive therapeutic approaches can be effective in many cases. In this article we review main pathogenic mechanisms leading to Abs-related syndromes and describe standard as well as emerging strategies of immunotherapy, including tocilizumab and bortezomib. Several special therapeutic approaches will be illustrated by clinical cases recently treated in our department.
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http://dx.doi.org/10.1186/s42466-019-0037-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7650108PMC
October 2019

Brainstem Encephalitis With Low-Titer Acetylcholine Receptor Antibodies Mimicking Myasthenia Gravis.

Front Neurol 2019 2;10:829. Epub 2019 Aug 2.

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

To report a rare case of brainstem encephalitis with low-titer acetylcholine receptor antibodies mimicking myasthenia gravis. The patient was investigated with repeated brain MRI, CSF examination, repetitive nerve stimulation, thoracic CT, and serologic screening. Our patient passed away and finally autopsy revealed a definitive diagnosis. Written informed consent was obtained from the relatives of the patient for access to clinical files for research purposes and publication. We present a young woman with a subacute bulbar syndrome, who was initially diagnosed with myasthenia gravis based on clinical finding and elevated acetylcholine receptor antibodies. Episodes of numbness in the pharynx and tongue and moderate saccadic horizontal and vertical pursuits were atypical. Despite initial stabilization with intravenous immunoglobulins she developed acute asphyxia after regurgitation of food and had to be resuscitated with ultimately lethal outcome. Autopsy revealed an autoimmune T-cell mediated brainstem encephalitis. Serological screening revealed positive GAD and Ma2 autoantibodies, indicating its probable paraneoplastic nature. Brainstem encephalitis is an important differential diagnosis even in seropositive bulbar myasthenia gravis, as several autoimmune processes often co-occur. Sudden unexpected death must be taken into account in brainstem encephalitis, requiring prolonged monitoring of the patients.
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http://dx.doi.org/10.3389/fneur.2019.00829DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6687845PMC
August 2019

Fingolimod for Irradiation-Induced Neurodegeneration.

Front Neurosci 2019 9;13:699. Epub 2019 Jul 9.

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

Background: Cranial irradiation is a common therapy for the treatment of brain tumors, but unfortunately patients suffer from side effects, particularly cognitive impairment, caused by neurodegenerative and neuroinflammatory mechanisms. Finding a therapeutic agent protecting hippocampal neurons would be beneficial. Fingolimod (FTY720), a sphingosine-1-phosphate receptor modulator approved for multiple sclerosis, is an immunosuppressant and known to enhance proliferation and differentiation of neuronal precursor cells (NPCs).

Objectives: To investigate whether pre-treatment with FTY720 protects NPCs and from irradiation-induced damage.

Methods: Neuronal precursor cells were isolated from E13 C57BL/6 wildtype mice, treated at day 0 of differentiation with FTY720 and irradiated on day 6 with 1 Gy. NPCs were analyzed for markers of cell death (PI, caspase-3), proliferation (Ki67), and differentiation (DCX, βIII-tubulin). Adult C57BL/6 wildtype mice were treated with FTY720 (1 mg/kg) and received a single dose of 6 Gy cranial irradiation at day 7. Using immunohistochemistry, we analyzed DCX and BrdU as markers of neurogenesis and Iba1, GFAP, and CD3 to visualize inflammation in the dentate gyrus (DG) and the subventricular zone (SVZ). B6(Cg)-Tyrc-2J/J DCX-luc reporter mice were used for bioluminescence imaging to evaluate the effect of FTY720 on neurogenesis in the DG and the spinal cord of naïve mice.

Results: FTY720 protected NPCs against irradiation induced cell death . Treatment with FTY720 dose-dependently reduced the number of PI cells 24 and 96 h after irradiation without effecting proliferation or neuronal differentiation. treatment resulted in a significant survival of DCX neurons in the DG and the SVZ 4 weeks after irradiation as well as a slight increase of proliferating cells. FTY720 inhibited microglia activation 24 h after X-ray exposure in the DG, while astrocyte activation was unaffected and no lymphocyte infiltrations were found. In naïve mice, FTY720 treatment for 4 weeks had no effect on neurogenesis.

Conclusion: FTY720 treatment of NPCs prior to X-ray exposure and of mice prior to cranial irradiation is neuroprotective. No effects on neurogenesis were found.
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http://dx.doi.org/10.3389/fnins.2019.00699DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6633210PMC
July 2019

Three cases of non-carryover fingolimod-PML: Is the risk in Japan increased?

Neurol Neuroimmunol Neuroinflamm 2019 05 10;6(3):e559. Epub 2019 Apr 10.

Department of Neurology (J.N., K. Kufukihara), Keio University School of Medicine, Tokyo; Department of Neurology (L.T., R.S., R.G., I.A.), St. Josef Hospital, Ruhr University Bochum, Bochum, Germany; Department of Gastroenterology and Neurology (K. Kume, T.T., M.K., K.D.), Kagawa University Faculty of Medicine, Japan; and Department of Neurology (I.A.), Sechenov First Moscow State Medical University, Moscow, Russia.

Objective: To report the course of 3 recent Japanese and European cases of fingolimod-associated progressive multifocal leukoencephalopathy (PML) and to analyze its risk factors and increased incidence in Japan.

Methods: Case series and literature review.

Results: Fingolimod-associated PML may cause both supratentorial and infratentorial lesions and a pronounced disability. Diagnosis can be challenging because PML lesions (especially infratentorial) can be initially misdiagnosed as extensive MS lesions. Immune reconstitution inflammatory syndrome (IRIS) develops a few weeks after fingolimod discontinuation and is usually mild. Age factor and therapy duration seem to be relevant because most reported patients were older than 45 years and were treated with fingolimod for more than 3 years. Combined IgG/IgM deficiency has been identified as a possible further predisposing condition in 1 case. Another patient developed an endogenous fungal skin infection, as a sign of generally compromised cellular immune response, shortly before PML. None of the reported patients had lymphocyte counts below 200/μl. Two of the 3 reported and 4 of the 21 (19%) registered fingolimod-PML cases occurred in Japan (estimated risk of 0.652 per 1,000 compared with 0.083 per 1.000 worldwide).

Conclusions: The risk of PML under fingolimod is low, but there are no reliable predictors. Despite a mild IRIS phase, it causes profound disability. Patients older than 45 years, especially with known comorbid immunodeficiencies or manifestation of other opportunistic infections, should be monitored more closely. Increased surveillance and identification of further risk factors are urgently needed in Japan.
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http://dx.doi.org/10.1212/NXI.0000000000000559DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6467684PMC
May 2019

Flaccid paralysis in neuromyelitis optica: An atypical presentation with possible involvement of the peripheral nervous system.

Mult Scler Relat Disord 2018 Oct 20;25:83-86. Epub 2018 Jul 20.

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

Background: Neuromyelitis optica spectrum disorders (NMOSD) typically lead to spastic paraparesis and spare the peripheral nervous system (PNS).

Case Report: Here, we describe an anti-aquaporin-4-seropositive NMOSD patient suffering from acute transverse myelitis with painful, flaccid paralysis and incontinence of urine and feces. Due to the involvement of the PNS as indicated by electrodiagnostic examination, we verified the expression of aquaporin-4-channels on the proximal dorsal spinal radix of rats by staining rat tissue with human NMOSD serum.

Conclusion: This case suggests a manifestation of the proximal PNS in NMOSD. Thus, NMOSD should be considered as a differential diagnosis for patients presenting with signs of spinal cord disease and additional radicular involvement.
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http://dx.doi.org/10.1016/j.msard.2018.07.032DOI Listing
October 2018

Laquinimod protects the optic nerve and retina in an experimental autoimmune encephalomyelitis model.

J Neuroinflammation 2018 Jun 14;15(1):183. Epub 2018 Jun 14.

Experimental Eye Research Institute, University Eye Hospital, Ruhr-University Bochum, In der Schornau 23-25, 44892, Bochum, Germany.

Background: The oral immunomodulatory agent laquinimod is currently evaluated for multiple sclerosis (MS) treatment. Phase II and III studies demonstrated a reduction of degenerative processes. In addition to anti-inflammatory effects, laquinimod might have neuroprotective properties, but its impact on the visual system, which is often affected by MS, is unknown. The aim of our study was to investigate potential protective effects of laquinimod on the optic nerve and retina in an experimental autoimmune encephalomyelitis (EAE) model.

Methods: We induced EAE in C57/BL6 mice via MOG immunization. Animals were divided into an untreated EAE group, three EAE groups receiving laquinimod (1, 5, or 25 mg/kg daily), starting the day post-immunization, and a non-immunized control group. Thirty days post-immunization, scotopic electroretinograms were carried out, and mice were sacrificed for histopathology (HE, LFB), immunohistochemistry (MBP, Iba1, Tmem119, F4/80, GFAP, vimentin, Brn-3a, cleaved caspase 3) of the optic nerve and retina, and retinal qRT-PCR analyses (Brn-3a, Iba1, Tmem119, AMWAP, CD68, GFAP). To evaluate the effect of a therapeutic approach, EAE animals were treated with 25 mg/kg laquinimod from day 16 when 60% of the animals had developed clinical signs of EAE.

Results: Laquinimod reduced neurological EAE symptoms and improved the neuronal electrical output of the inner nuclear layer compared to untreated EAE mice. Furthermore, cellular infiltration, especially recruited phagocytes, and demyelination in the optic nerve were reduced. Microglia were diminished in optic nerve and retina. Retinal macroglial signal was reduced under treatment, whereas in the optic nerve macroglia were not affected. Additionally, laquinimod preserved retinal ganglion cells and reduced apoptosis. A later treatment with laquinimod in a therapeutic approach led to a reduction of clinical signs and to an improved b-wave amplitude. However, no changes in cellular infiltration and demyelination of the optic nerves were observed. Also, the number of retinal ganglion cells remained unaltered.

Conclusion: From our study, we deduce neuroprotective and anti-inflammatory effects of laquinimod on the optic nerve and retina in EAE mice, when animals were treated before any clinical signs were noted. Given the fact that the visual system is frequently affected by MS, the agent might be an interesting subject of further neuro-ophthalmic investigations.
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http://dx.doi.org/10.1186/s12974-018-1208-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6002998PMC
June 2018

Tryptophan immunoadsorption during pregnancy and breastfeeding in patients with acute relapse of multiple sclerosis and neuromyelitis optica.

Ther Adv Neurol Disord 2018 28;11:1756286418774973. Epub 2018 May 28.

Department of Neurology, General Hospital Lüdenscheid, Märkische Kliniken GmbH, Germany.

Background: Up to every fourth woman with multiple sclerosis (MS) or neuromyelitis optica spectrum disorder (NMOSD) suffers a clinically relevant relapse during pregnancy. High doses of steroids bear some serious risks, especially within the first trimester of pregnancy. Immunoadsorption (IA) is an effective and more selective treatment option in disabling MS relapse than plasma exchange. Data on the use of IA during pregnancy and breastfeeding are scarce.

Methods: In this retrospective multicenter study, we analyzed the safety and efficacy of IA treatment in acute relapses during pregnancy or breastfeeding. The primary outcome parameter - change of acute relapse-related disability after IA - was assessed using Expanded Disability Status Scale (EDSS) and visual acuity (VA) measurements for patients with optic neuritis (ON).

Results: A total of 24 patients were analyzed, 23 with relapsing-remitting MS, and 1 with NMOSD. Twenty patients were treated with IA during pregnancy. Four patients received IA postnatally during the breastfeeding period. Treatment was started at a mean 22.5 [standard deviation (SD) 13.9] days after onset of relapse. Patients were treated with a series of 5.8 (mean, SD 0.7) IA treatments within 7-10 days. Sixteen patients received IA because of steroid-refractory relapse, eight were treated without preceding steroid pulse therapy. EDSS improved clinically relevant from 3.5 [median, interquartile range (IQR) 2] before IA to 2.5 (median, IQR 1.1) after IA, < 0.001. In patients with ON, VA improved in four out of five patients. Altogether, in 83% of patients, a rapid and marked improvement of relapse-related symptoms was observed after IA with either a decrease of ⩾1 EDSS grade or improvement in VA ⩾20%. No clinically relevant side effect was reported in 138 IA treatments.

Conclusions: Tryptophan-IA was found to be effective and well tolerated in MS/NMOSD relapses, both as an escalation option after insufficient response to steroid pulse therapy and as first-line relapse treatment during pregnancy and breastfeeding.
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http://dx.doi.org/10.1177/1756286418774973DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5974561PMC
May 2018

Twig-like Middle Cerebral Artery: a Seldom Vessel Anomaly of Important Relevance.

Clin Neuroradiol 2018 09 14;28(3):441-443. Epub 2017 Aug 14.

Department of Diagnostic and Interventional Radiology, St. Josef Hospital, Ruhr University Bochum, Gudrunstrasse 56, 44791, Bochum, Germany.

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http://dx.doi.org/10.1007/s00062-017-0613-9DOI Listing
September 2018

Rho-associated protein kinase 2 (ROCK2): a new target of autoimmunity in paraneoplastic encephalitis.

Acta Neuropathol Commun 2017 05 29;5(1):40. Epub 2017 May 29.

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

Onconeural antibodies are associated with cancer and paraneoplastic encephalitis. While their pathogenic role is still largely unknown, their high diagnostic value is undisputed. In this study we describe the discovery of a novel target of autoimmunity in an index case of paraneoplastic encephalitis associated with urogenital cancer.A 75-year-old man with a history of invasive bladder carcinoma 6 years ago with multiple recurrences and a newly discovered renal cell carcinoma presented with seizures and progressive cognitive decline followed by super-refractory status epilepticus. Clinical and ancillary findings including brain biopsy suggested paraneoplastic encephalitis. Immunohistochemistry of the brain biopsy was used to characterize the inflammatory response. Indirect immunofluorescence assay (IFA) was used for autoantibody screening. The autoantigen was identified by histo-immunoprecipitation and mass spectrometry and was validated by expressing the recombinant antigen in HEK293 cells and neutralization tests. Sera from 125 control patients were screened using IFA to test for the novel autoantibodies.IFA analysis of serum revealed a novel autoantibody against brain tissue. An intracellular enzyme, Rho-associated protein kinase 2 (ROCK2), was identified as target-antigen. ROCK2 was expressed in affected brain tissue and archival bladder tumor samples of this patient. Brain histopathology revealed appositions of cytotoxic CD8 T cells on ROCK2-positive neurons. ROCK2 antibodies were not found in the sera of 20 patients with bladder cancer and 17 with renal cancer, both without neurological symptoms, 49 healthy controls, and 39 patients with other antineuronal autoantibodies. In conclusion, novel onconeural antibodies targeting ROCK2 are associated with paraneoplastic encephalitis and should be screened for when paraneoplastic neurological syndromes, especially in patients with urogenital cancers, occur.
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http://dx.doi.org/10.1186/s40478-017-0447-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5448146PMC
May 2017

Two years' long-term follow up in chronic inflammatory demyelinating polyradiculoneuropathy: efficacy of intravenous immunoglobulin treatment.

Ther Adv Neurol Disord 2017 Feb 9;10(2):91-101. Epub 2016 Dec 9.

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

Background: Administration of intravenous immunoglobulins (IVIgs) is established for long-term treatment of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Prevention of secondary axonal loss going along with permanent clinical disability and muscular atrophy is a major aim in CIDP therapy. To assess long-term clinical efficacy of IVIg treatment despite heterogenous disease course and variable complaints reported by the patients, long-term electrophysiological monitoring was performed for systematic evaluation of therapeutic efficacy of IVIg.

Methods: A total of 21 patients with CIDP treated with IVIg 1 g/kg bodyweight every 3-6 weeks were examined electrophysiologically every 12 months over a period of 2 years.

Results: Assessment of clinical symptoms, using the Inflammatory Neuropathy Cause and Treatment (INCAT) and Hughes functional grading score (F-score) revealed improvement of motor and sensory symptoms over a period of 2 years. As electrophysiological results remained stable, IVIg treatment seems to be suitable to prevent axonal loss in CIDP.

Conclusions: This study confirms efficacy of IVIg as firstline therapy in CIDP. Doses and frequency of IVIg application should be adapted based on clinical evaluation and analysis of long-term electrophysiological findings.
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http://dx.doi.org/10.1177/1756285616679369DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5367649PMC
February 2017

Trigemino-autonomic headache and Horner syndrome as a first sign of granulomatous hypophysitis.

Neurol Neuroimmunol Neuroinflamm 2017 May 14;4(3):e332. Epub 2017 Feb 14.

Department of Neurology (J.M., A.L.F., C.B., C.S., K.P., R.G., I.A.), Department of Radiology (C.L.), and Institute of Pathology (J.v.d.N.), Ruhr University Bochum; Department of Neurosurgery (I.K.-A., O.M.), and Institute of Neuropathology (J.v.d.N.), University of Duisburg-Essen; and Department of Neuropathology (R.B.), Friedrich-Alexander University Erlangen-Nürnberg (FAU), Germany.

Objective: To report a rare case of incipient granulomatous hypophysitis presenting by atypical trigemino-autonomic cephalalgia (TAC) and Horner syndrome.

Methods: The patient was investigated with repeated brain MRI, CSF examination, thoracic CT, Doppler and duplex ultrasound of the cerebral arteries, and extensive serologic screening for endocrine and autoimmune markers. Written informed consent was obtained from the patient for access to clinical files for research purposes and for publication.

Results: We present a middle-aged woman with a history of an autoimmune pancreatitis type 2 who had therapy-refractory TAC with Horner syndrome. Initial cerebral MRI showed only indistinct and unspecific signs of a pathologic process. A biopsy revealed a granulomatous hypophysitis. The symptoms disappeared after transsphenoidal subtotal resection of the pituitary mass and anti-inflammatory therapy.

Conclusions: This case elucidates that inflammatory pituitary diseases must be taken into account in case of atypical and refractory TAC, especially in patients with a history of autoimmune diseases. To our knowledge, the association between TAC accompanied by Horner syndrome and hypophysitis has not yet been described before.
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http://dx.doi.org/10.1212/NXI.0000000000000332DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5310204PMC
May 2017

Charles Bonnet syndrome successfully treated with levetiracetam.

J Neurol 2016 Sep 2;263(9):1872-5. Epub 2016 Aug 2.

Department of Neurology, St. Josef Hospital, Ruhr University Bochum, Gudrunstr. 56, 44791, Bochum, Germany.

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http://dx.doi.org/10.1007/s00415-016-8240-yDOI Listing
September 2016

Headache in Caucasian patients with Moyamoya angiopathy - a systematic cohort study.

Cephalalgia 2017 Apr 25;37(5):496-500. Epub 2016 Apr 25.

3 Department of Neurology and Headache Center, University Hospital Essen, University of Duisburg-Essen, Germany.

Background Headache is common in patients with Moyanoya angiopathy (MMA), but usually underestimated in its management and not well characterized. Methods A validated self-administered headache screening questionnaire and a telephone interview were used in order to investigate headache characteristics, frequency and pain intensity in a large cohort of 55 German patients with MMA. Results Thirty-seven patients (67.3%) had suffered from headache in the past year. Headache intensity was rated 3.2 ± 1.3 on a verbal rating scale from 0 to 10. Seventeen patients (47.9%) reported migraine-like headache, 10 patients (27.0%) reported tension type-like headache and 10 patients (27.0%) had a combination of both. The majority of patients with migraine-like headache ( n = 10, 58.8%) described migrainous aura. Headache frequency and intensity improved significantly after revascularization surgery; however, nine patients developed new-onset headache postoperatively. Conclusion Headache is very common in MMA, often with a migraine-like phenotype. Tension type-like headache was also found in 27% of patients, which is a new finding that has not been reported before.
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http://dx.doi.org/10.1177/0333102416643516DOI Listing
April 2017

Tocilizumab, MS, and NMOSD.

Mult Scler 2016 12 11;22(14):1891-1892. Epub 2016 Apr 11.

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

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http://dx.doi.org/10.1177/1352458516643395DOI Listing
December 2016

Transorbital sonography in CIDP patients: No evidence for optic nerve hypertrophy.

J Neurol Sci 2016 Mar 22;362:206-8. Epub 2016 Jan 22.

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

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an acquired, chronic progressive or relapsing immune mediated disorder of the peripheral nervous system. Thickening of cranial nerves as a sign of central nerve involvement is increasingly reported in the last years. Our aim was to assess systematically for the first time the frequency of optic nerve hypertrophy in patients with CIDP by means of transorbital sonography (TOS). Thirty-four optic nerves of 17 patients with CIDP (age=60.8±13.3y, range=39-82y; 7 female) were examined by TOS. The diameter of Optic nerve (OND) as well as the intern and extern diameters of the sheath (ONDSi, ONSDe) was measured 3mm behind the optic disc. Findings were compared to the data of 15 healthy controls. CIDP-patients showed a mean OND of 2.8±0.4mm, an ONSDi of 4.7±0.7mm, and an ONSDe of 6.3±0.9mm. No papilledema was detectable. There was no significant difference to the healthy control group. Our study revealed no evidence for a frequent optic nerve involvement in CIDP. Reported cases seem to represent exceptions. Transorbital sonography could be a useful tool in these rare cases with optic nerve hypertrophy.
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http://dx.doi.org/10.1016/j.jns.2016.01.049DOI Listing
March 2016

Fingolimod for multiple sclerosis and emerging indications: appropriate patient selection, safety precautions, and special considerations.

Ther Clin Risk Manag 2016 19;12:261-72. Epub 2016 Feb 19.

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

Fingolimod (FTY720), an immunotherapeutic drug targeting the sphingosine-1-phosphate receptor, is a widely used medication for relapsing-remitting multiple sclerosis (MS). Apart from the pivotal Phase III trials demonstrating efficacy against placebo and interferon-β-1a once weekly, sufficient clinical data are now available to assess its real-world efficacy and safety profile. Approved indications of fingolimod differ between countries. This discrepancy, to some extent, reflects the intermediate position of fingolimod in the expanding lineup of MS medications. With individualization of therapy, appropriate patient selection gets more important. We discuss various scenarios for fingolimod use in relapsing-remitting MS and their pitfalls: as first-line therapy, as escalation therapy after failure of previous immunotherapies, and as de-escalation therapy following highly potent immunotherapies. Potential side effects such as bradycardia, infections, macular edema, teratogenicity, and progressive multifocal leukoencephalopathy as well as appropriate safety precautions are outlined. Disease reactivation has been described upon fingolimod cessation; therefore, patients should be closely monitored for MS activity for several months after stopping fingolimod. Finally, we discuss preclinical and clinical data indicating neuroprotective effects of fingolimod, which might open the way to future indications such as stroke, Alzheimer's disease, and other neurodegenerative disorders.
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http://dx.doi.org/10.2147/TCRM.S65558DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4767105PMC
March 2016

Efficacy of glatiramer acetate in neuromyelitis optica spectrum disorder: a multicenter retrospective study.

J Neurol 2016 Mar 25;263(3):575-82. Epub 2016 Jan 25.

Department of Neurology, St. Josef Hospital, Ruhr University Bochum, Gudrunstr. 56, 44791, Bochum, Germany.

Glatiramer acetate (GA) is an approved therapy for relapsing-remitting multiple sclerosis, but its efficacy for the prevention of attacks in neuromyelitis optica spectrum disorder (NMOSD) remains unknown. We did a multicenter retrospective analysis of GA-treated patients with NMOSD, identified through a national registry. Annualized relapse rate and expanded disability status scale (EDSS) were the main outcome measures. We identified 23 GA-treated patients (21 female, 16 aquaporin-4 antibody-positive). GA was given for <6 months in seven patients; reasons for stopping were relapses (n = 3), confirmation of NMOSD (n = 2) and side effects (n = 2). Of 16 patients treated ≥ 6 months with GA (15 female, 11 aquaporin-4 antibody-positive), 14 experienced at least one relapse. There was no reduction in the mean annualized relapse rate in the total group (1.9 ± 1.1 before vs. 1.8 ± 1.4 during GA therapy), as well as in those patients who were aquaporin-4 antibody-positive, or had a history of prior immunotherapy or not. The median EDSS increased (2.5 start vs. 3.5 finish of GA, P < 0.05). GA therapy was discontinued in 15/16 patients; reasons were therapeutic inefficacy in 13 and post-injection skin reactions in two patients. We conclude that GA is not beneficial for preventing attacks in most patients with NMOSD, particularly in aquaporin-4 antibody-positive cases.
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http://dx.doi.org/10.1007/s00415-015-7991-1DOI Listing
March 2016