Publications by authors named "Markus Krumbholz"

49 Publications

Treatment of progressive multiple sclerosis with high-dose all-trans retinoic acid - no clear evidence of positive disease modifying effects.

Neurol Res Pract 2021 May 10;3(1):25. Epub 2021 May 10.

Hertie Institute for Clinical Brain Research, Eberhard-Karls University, Tübingen, Germany.

Background: All-trans retinoic acid (ATRA) is an acid derivative of vitamin A which is discussed as a promising candidate to ameliorate the disease course of multiple sclerosis (MS) by immunomodulation or even by promoting regeneration in progressive MS. Here we report a patient who significantly improved for MS related disability following administration of chemotherapy including ATRA for mitoxantrone-related acute promyelocytic leukemia and assess the effect of high-dose ATRA in three additional patients with progressive MS.

Methods: Patients with progressive MS who had failed previous therapies were treated with high-dose ATRA. Patients underwent clinical and routine laboratory monitoring. Additionally, PBMCs were analyzed by flow cytometry for lymphocyte subsets.

Results: ATRA was well tolerated and no pathological laboratory abnormalities were observed. After initial mild (not statistically significant) improvement of EDSS and mean MSFC z-score, ongoing disease progression was observed. One patient subacutely experienced severe cognitive and motor worsening. Cerebral MRI revealed persistent gadolinium-enhancing lesions. Flow cytometric alterations of peripheral blood naïve, central memory and effector memory CD4 and CD8 T cells, B lymphocytes, plasma cells, memory B cells, plasmablasts and natural killer (NK) cells did not reach statistical significance.

Conclusions: Stand-alone therapy with ATRA did not ameliorate progressive MS in our limited cohort and we did not observe consistent alterations of T and B cell subsets. Intriguingly, application of ATRA may have caused marked disease exacerbation in one patient.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s42466-021-00121-4DOI Listing
May 2021

Closure or medical therapy of patent foramen ovale in cryptogenic stroke: prospective case series.

Neurol Res Pract 2021 Apr 1;3(1):16. Epub 2021 Apr 1.

Department of Neurology & Stroke, Eberhard-Karls University, Hoppe-Seyler-Str. 3, 72076, Tübingen, Germany.

Background: Results of randomized controlled trials (RCT) do not provide definite guidance for secondary prevention after ischemic stroke (IS)/transient ischemic attack (TIA) attributed to patent foramen ovale (PFO). No recommendations can be made for patients > 60 years. We aimed to compare interventional and medical PFO-management in cryptogenic IS/TIA patients, including patients > 60 years.

Methods: Prospective case series including consecutive cryptogenic IS/TIA patients with PFO at Tuebingen university stroke unit, Germany. 'PFO-closure' was recommended in patients ≤70 years when featuring high-risk PFO (i.e., with atrial septal aneurysm, spontaneous, or high-grade right-to-left shunt during Valsalva). Primary (recurrent IS/intracranial hemorrhage) and secondary endpoints (e.g., disability) were assessed during ≥1-year follow-up; planned subgroup analyses of patients ≤60/> 60 years.

Results: Among 236 patients with median age of 58 (range 18-88) years, 38.6% were females and median presenting National Institutes of Health Stroke Scale score was 1 (IQR 0-4). Mean follow-up was 2.8 ± 1.3 years. No intracranial hemorrhage was observed. Recurrent IS rate after 'PFO-closure' was 2.9% (95%CI 0-6.8%) and 7% (4-16.4) in high-risk PFO patients ≤60 (n = 103) and > 60 years (n = 43), respectively, versus 4% (0-11.5) during 'medical therapy alone' MTA (n = 28). 42 low-risk PFO patients treated with MTA experienced no recurrent IS/TIA.

Conclusions: In our real-world study, IS recurrence rate in 'PFO-closure' high-risk PFO patients ≤60 years was comparable to that observed in recent RCT. High-risk PFO patients > 60 years who underwent PFO-closure had similar IS recurrence rates than those who received MTA. MTA seems the appropriate treatment for low-risk PFO.

Trial Registration: ClinicalTrials.gov, registration number: NCT04352790 , registered on: April 20, 2020 - retrospectively registered.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s42466-021-00114-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8015114PMC
April 2021

TSPO PET imaging of natalizumab-associated progressive multifocal leukoencephalopathy.

Brain 2021 Mar 23. Epub 2021 Mar 23.

Institute of Clinical Neuroimmunology, University Hospital, Ludwig-Maximilians-Universität Munich, Munich, Germany.

Progressive multifocal leukoencephalopathy (PML) is a severe infection of the central nervous system caused by the polyomavirus JC (JCV) that can occur in multiple sclerosis (MS) patients treated with natalizumab. Clinical management of patients with natalizumab-associated PML is challenging not the least because current imaging tools for the early detection, longitudinal monitoring and differential diagnosis of PML lesions are limited. Here we evaluate whether TSPO positron emission tomography (PET) imaging can be applied to monitor the inflammatory activity of PML lesions over time and differentiate them from MS lesions. For this monocenter pilot study we followed 8 patients with natalizumab-associated PML with PET imaging using the TSPO radioligand [18F]GE-180 combined with frequent 3 T MRI imaging. In addition we compared TSPO PET signals in PML lesions with the signal pattern of MS lesions from 17 independent MS patients. We evaluated the standardized uptake value ratio (SUVR) as well as the morphometry of the TSPO uptake for putative PML and MS lesions areas compared to a radiologically unaffected pseudo-reference region in the cerebrum. Furthermore TSPO expression in situ was immunohistochemically verified by determining the density and cellular identity of TSPO-expressing cells in brain sections from four patients with early natalizumab-associated PML as well as five patients with other forms of PML and six patients with inflammatory demyelinating CNS lesions (clinically isolated syndrome/MS). Histological analysis revealed a reticular accumulation of TSPO expressing phagocytes in PML lesions, while such phagocytes showed a more homogenous distribution in putative MS lesions. TSPO PET imaging showed an enhanced tracer uptake in natalizumab-associated PML lesions that was present from the early to the chronic stages (up to 52 months after PML diagnosis). While gadolinium enhancement on MRI rapidly declined to baseline levels, TSPO tracer uptake followed a slow one phase decay curve. A TSPO-based 3-dimensional diagnostic matrix taking into account the uptake levels as well as the shape and texture of the TSPO signal differentiated more than 96% of PML and MS lesions. Indeed, treatment with rituximab after natalizumab-associated PML in three patients did not affect tracer uptake in the assigned PML lesions but reverted tracer uptake to baseline in the assigned active MS lesions. Taken together our study suggests that TSPO PET imaging can reveal CNS inflammation in natalizumab-associated PML. TSPO PET may facilitate longitudinal monitoring of disease activity and help to distinguish recurrent MS activity from PML progression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/brain/awab127DOI Listing
March 2021

Vagus nerve pressure palsy in hereditary neuropathy with liability to pressure palsies confirmed by neurosonography.

Clin Neurophysiol 2021 Apr 13;132(4):975-976. Epub 2021 Feb 13.

Department of Neurology & Stroke, University Hospital of Tübingen, Tübingen, Germany; Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany. Electronic address:

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.clinph.2021.02.002DOI Listing
April 2021

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

Clin Neurol Neurosurg 2020 10 12;197:106142. Epub 2020 Aug 12.

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

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

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

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

Conclusion: This CUP provides first real-world observations of ocrelizumab for the treatment of PPMS in a large patient cohort in Germany, supporting that ocrelizumab is generally well-tolerated in clinical practice. Physicians should be vigilant for early symptoms of PML, as to date, 9 PML cases that were all confounded have been reported in patients treated with ocrelizumab worldwide, with 8 carry-over cases from a prior DMT.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.clineuro.2020.106142DOI Listing
October 2020

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

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

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

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

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

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

Conclusions: This longitudinal multicentre study will reveal to what extent the prediction of disease progression in patients with PMS will be improved by the analysis of serum biomarkers in conjunction with routine clinical data and neuroimaging measures.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.conctc.2020.100574DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7251538PMC
June 2020

Cytokine and immune cell profiling in the cerebrospinal fluid of patients with neuro-inflammatory diseases.

J Neuroinflammation 2019 Nov 14;16(1):219. Epub 2019 Nov 14.

Department of Neurology and Hertie Institute for Clinical Brain Research, Eberhard Karl University, Tübingen, Germany.

Background: Cytokines play multiple roles during neuro-inflammatory processes and several cytokines have been studied in the context of specific diseases. This study provides a comprehensive picture of cerebrospinal fluid (CSF) changes during neuro-inflammation by analyzing multiple cytokines in combination with immune cell subsets and standard CSF parameters.

Methods: Using multiplex assays, we simultaneously measured 36 cytokines (CCL1-3, CCL7, CCL8, CCL11, CCL13, CCL19, CCL20, CCL22-27, CXCL1, CXCL2, CXCL5, CXCL6, CXCL8, CXCL9, CXCL11-13, CXCL16, CX3CL1, IL2, IL4, IL6, IL10, IL16, GM-CSF, IFNγ, MIF, TNFα, and MIB1β) in the CSF and serum of 75 subjects. Diagnoses included clinically isolated syndrome and relapsing-remitting multiple sclerosis (MS, n = 18), secondary progressive MS (n = 8), neuro-syphilis (n = 6), Lyme neuro-borreliosis (n = 13), bacterial and viral meningitis (n = 20), and patients with non-inflammatory neurological diseases (NIND, n = 10). Cytokine concentrations were correlated with CSF standard parameters and CSF immune cell subsets (CD4 and CD8 T cells, B cells, plasmablasts, monocytes, and NK cells) quantified by flow cytometry.

Results: We observed increased levels of multiple cytokines (26/36) in patients with neuro-inflammatory diseases when compared to NIND that consistently correlated with CSF cell count and Q. Most CSF cytokine concentrations correlated with each other, but correlations between CSF and serum values were scarce (3/36). Within the CSF compartment, CXCL13 showed a strong association with B cells when analyzing all patients, as well as patients with an intact blood-brain barrier (BBB). NK cells positively correlated with CSF concentrations of multiple cytokines (22/36) when analyzing all patients. These correlations were maintained when looking at patients with a disrupted BBB but not detectable in patients with an intact BBB.

Conclusions: Under conditions of neuro-inflammation, multiple CSF cytokines are regulated in parallel and most likely produced locally. A combined increase of CSF CXCL13 levels and B cells occurs under conditions of an intact BBB. Under conditions of a disrupted BBB, CSF NK cells show significantly increased values and seem to have a major contribution to overall inflammatory processes, reflected by a strong correlation with multiple cytokines. Future studies are necessary to address the exact kinetics of these cytokines during neuro-inflammation and their relation to specific diseases phenotypes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12974-019-1601-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6857241PMC
November 2019

Human immunodeficiency virus and multiple sclerosis: a review of the literature.

Neurol Res Pract 2019 20;1:24. Epub 2019 Aug 20.

Department of Neurology & Stroke, and Hertie Institute for Clinical Brain Research, Eberhard-Karls University of Tübingen, Hoppe-Seyler-Str. 3, 72076 Tübingen, Germany.

Multiple sclerosis (MS) and human immunodeficiency virus (HIV) infection are frequent and well-studied nosological entities. Yet, comorbidity of MS and HIV has only been rarely reported in the medical literature. We conducted a literature search using the databases PubMed, Ovid and Google Scholar, with the aim of identifying published studies and reports concerning HIV and MS. Recent epidemiological studies indicated a negative association between MS and HIV in terms of a reduced risk of developing MS in HIV positive patients. Accumulating clinical evidence additionally suggests a possibly reduced relapse rate of MS in HIV patients. Nevertheless, it remains currently unclear whether this observed inverse correlation could be due to the HIV infection itself, HIV treatment or the combination of both. Among the limited cases of MS in HIV infected patients, MS occurrence was mainly reported during acute HIV infection or during HIV seroconversion. This finding is in line with reports of HIV-related autoimmune disorders, which also occur in early phases of HIV disease. Beneficial effects of antiretroviral therapy on MS activity were reported in few clinical cases. Yet, the single phase II clinical trial (INSPIRE), which investigated the effects of antiretroviral medication (using the integrase inhibitor raltegravir) in patients with relapsing-remitting MS, failed to corroborate any beneficial effects at group level. Nevertheless, recently published experimental evidence suggests that HIV treatments may hold therapeutic potential for MS treatment. Thus, further studies are warranted to firstly, delineate the immunological mechanisms underlying possible efficacy of HIV treatments in MS, and to secondly, assess whether repurposing of HIV drugs for MS could be a worthwhile future research objective.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s42466-019-0030-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7650072PMC
August 2019

The Glycosylation Site of Myelin Oligodendrocyte Glycoprotein Affects Autoantibody Recognition in a Large Proportion of Patients.

Front Immunol 2019 11;10:1189. Epub 2019 Jun 11.

Biomedical Center and University Hospitals, Institute of Clinical Neuroimmunology, Ludwig-Maximilians-Universität München, Munich, Germany.

Autoantibodies to myelin oligodendrocytes glycoprotein (MOG) are found in a fraction of patients with inflammatory demyelination and are detected with MOG-transfected cells. While the prototype anti-MOG mAb 8-18C5 and polyclonal anti-MOG responses from different mouse strains largely recognize the FG loop of MOG, the human anti-MOG response is more heterogeneous and human MOG-Abs recognizing different epitopes were found to be pathogenic. The aim of this study was to get further insight into details of antigen-recognition by human MOG-Abs focusing on the impact of glycosylation. MOG has one known N-glycosylation site at N31 located in the BC loop linking two beta-sheets. We compared the reactivity to wild type MOG with that toward two different mutants in which the neutral asparagine of N31 was mutated to negatively charged aspartate or to the neutral alanine. We found that around 60% of all patients (16/27) showed an altered reactivity to one or both of the mutations. We noted seven different patterns of recognition of the two glycosylation-deficient mutants by different patients. The introduced negative charge at N31 enhanced recognition in some, but reduced recognition in other patients. In 7/27 patients the neutral glycosylation-deficient mutant was recognized stronger. The folding of the extracellular domain of MOG with the formation of beta-sheets did not depend on its glycosylation as seen by circular dichroism. We determined the glycan structure of MOG produced in HEK cells by mass spectrometry. The most abundant glycoforms of MOG expressed in HEK cells are diantennary, contain a core fucose, an antennary fucose, and are decorated with α2,6 linked Neu5Ac, while details of the glycoforms of MOG in myelin remain to be identified. Together, we (1) increase the knowledge about heterogeneity of human autoantibodies to MOG, (2) show that the BC loop affects recognition in about 60% of the patients, (3) report that all patients recognized the unglycosylated protein backbone, while (4) in about 20% of the patients the attached sugar reduces autoantibody binding presumably via steric hindrance. Thus, a neutral glycosylation-deficient mutant of MOG might enhance the sensitivity to identify MOG-Abs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2019.01189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6579858PMC
October 2020

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

Pathogenicity of human antibodies against myelin oligodendrocyte glycoprotein.

Ann Neurol 2018 08 9;84(2):315-328. Epub 2018 Sep 9.

Institute of Clinical Neuroimmunology, Biomedical Center and University Hospitals, Ludwig-Maximilians-Universität München, Munich, Germany.

Objective: Autoantibodies against myelin oligodendrocyte glycoprotein (MOG) occur in a proportion of patients with inflammatory demyelinating diseases of the central nervous system (CNS). We analyzed their pathogenic activity by affinity-purifying these antibodies (Abs) from patients and transferring them to experimental animals.

Methods: Patients with Abs to MOG were identified by cell-based assay. We determined the cross-reactivity to rodent MOG and the recognized MOG epitopes. We produced the correctly folded extracellular domain of MOG and affinity-purified MOG-specific Abs from the blood of patients. These purified Abs were used to stain CNS tissue and transferred in 2 models of experimental autoimmune encephalomyelitis. Animals were analyzed histopathologically.

Results: We identified 17 patients with MOG Abs from our outpatient clinic and selected 2 with a cross-reactivity to rodent MOG; both had recurrent optic neuritis. Affinity-purified Abs recognized MOG on transfected cells and stained myelin in tissue sections. The Abs from the 2 patients recognized different epitopes on MOG, the CC' and the FG loop. In both patients, these Abs persisted during our observation period of 2 to 3 years. The anti-MOG Abs from both patients were pathogenic upon intrathecal injection in 2 different rat models. Together with cognate MOG-specific T cells, these Abs enhanced T-cell infiltration; together with myelin basic protein-specific T cells, they induced demyelination associated with deposition of C9neo, resembling a multiple sclerosis type II pathology.

Interpretation: MOG-specific Abs affinity purified from patients with inflammatory demyelinating disease induce pathological changes in vivo upon cotransfer with myelin-reactive T cells, suggesting that these Abs are similarly pathogenic in patients. Ann Neurol 2018;84:315-328.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ana.25291DOI Listing
August 2018

Nerve Ultrasound Predicts Treatment Response in Chronic Inflammatory Demyelinating Polyradiculoneuropathy-a Prospective Follow-Up.

Neurotherapeutics 2018 04;15(2):439-451

Department of Neurology, Tübingen University Hospital, University of Tübingen, Hoppe-Seyler-Str. 3, 72076, Tubingen, Germany.

As reliable biomarkers of disease activity are lacking, monitoring of therapeutic response in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) remains a challenge. We sought to determine whether nerve ultrasound and electrophysiology scoring could close this gap. In CIDP patients (fulfilling EFNS/PNS criteria), we performed high-resolution nerve ultrasound to determine ultrasound pattern sum scores (UPSS) and predominant echotexture nerve conduction study scores (NCSS) as well as Medical Research Council sum scores (MRCSS) and inflammatory neuropathy cause and treatment disability scores (INCAT) at baseline and after 12 months of standard treatment. We retrospectively correlated ultrasound morphology with nerve histology when available. 72/80 CIDP patients featured multifocal nerve enlargement, and 35/80 were therapy-naïve. At baseline, clinical scores correlated with NCSS (r = 0.397 and r = 0.443, p < 0.01), but not or hardly with UPSS (Medical Research Council sum scores MRCSS r = 0.013, p = 0.332; inflammatory neuropathy cause and treatment disability scores INCAT r = 0.053, p = 0.048). Longitudinal changes in clinical scores, however, correlated significantly with changes in both UPSS and NCSS (r = 0.272-0.414, p < 0.0001). Combining nerve/fascicle size with echointensity and histology at baseline, we noted 3 distinct classes: 1) hypoechoic enlargement, reflecting active inflammation and onion bulbs; 2) nerve enlargement with additional hyperechogenic fascicles/perifascicular tissue in > 50% of measured segments, possibly reflecting axonal degeneration; and 3) almost no enlargement, reflecting "burned-out" or "cured" disease without active inflammation. Clinical improvement after 12 months was best in patients with pattern 1 (up to 75% vs up to 43% in pattern 2/3, Fisher's exact test p < 0.05). Nerve ultrasound has additional value not only for diagnosis, but also for classification of disease state and may predict treatment response.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s13311-018-0609-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5935640PMC
April 2018

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

Influence of female sex and fertile age on neuromyelitis optica spectrum disorders.

Mult Scler 2017 Jul 6;23(8):1092-1103. Epub 2016 Oct 6.

Department of Neurology, Leipzig University, Leipzig, Germany.

Background: Gender and age at onset are important epidemiological factors influencing prevalence, clinical presentation, and treatment response in autoimmune diseases.

Objective: To evaluate the impact of female sex and fertile age on aquaporin-4-antibody (AQP4-ab) status, attack localization, and response to attack treatment in patients with neuromyelitis optica (NMO) and its spectrum disorders (neuromyelitis optica spectrum disorder (NMOSD)).

Methods: Female-to-male ratios, diagnosis at last visit (NMO vs NMOSD), attack localization, attack treatment, and outcome were compared according to sex and age at disease or attack onset.

Results: A total of 186 NMO/SD patients (82% female) were included. In AQP4-ab-positive patients, female predominance was most pronounced during fertile age (female-to-male ratio 23:1). Female patients were more likely to be positive for AQP4-abs (92% vs 55%; p < 0.001). Interval between onset and diagnosis of NMO/SD was longer in women than in men (mean 54 vs 27 months; p = 0.023). In women, attacks occurring ⩽40 years of age were more likely to show complete remission ( p = 0.003) and better response to high-dose intravenous steroids ( p = 0.005) compared to woman at >40 years.

Conclusion: Our data suggest an influence of sex and age on susceptibility to AQP4-ab-positive NMO/SD. Genetic and hormonal factors might contribute to pathophysiology of NMO/SD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/1352458516671203DOI Listing
July 2017

Autoantibodies to MOG in a distinct subgroup of adult multiple sclerosis.

Neurol Neuroimmunol Neuroinflamm 2016 Oct 30;3(5):e257. Epub 2016 Jun 30.

Institute of Clinical Neuroimmunology (M.S., L.A.G., M.K., F.S.T., E.S., R.H., E.M., T.K.), Department of Radiology (B.E.-W.), and Laboratory for Immunogenetics (A.D.), Medical Campus Großhadern, Ludwig-Maximilians-Universität München; Department of Neurology (M.K.), Hertie Institut für klinische Hirnforschung, Universitätsklinikum Tübingen; Department of Neuropathology (I.M., W.B.), University Medical Center, Georg August University, Göttingen; Department of Paediatric Neurology and Developmental Medicine (A.B.), Dr. von Hauner Children's Hospital, Ludwig-Maximilians-Universität München; and Munich Cluster for Systems Neurology (SyNergy) (R.H.), Munich, Germany.

Objectives: To evaluate the presence of antibodies to conformation-intact myelin oligodendrocyte glycoprotein (MOG) in a subgroup of adult patients with clinically definite multiple sclerosis (MS) preselected for a specific clinical phenotype including severe spinal cord, optic nerve, and brainstem involvement.

Methods: Antibodies to MOG were investigated using a cell-based assay in 3 groups of patients: 104 preselected patients with MS (group 1), 55 age- and sex-matched, otherwise unselected patients with MS (group 2), and in 22 brain-biopsied patients with demyelinating diseases of the CNS (n = 19 with MS), 4 of whom classified as MS type II (group 3). Recognized epitopes were identified with mutated variants of MOG.

Results: Antibodies to MOG were found in about 5% (5/104) of preselected adult patients with MS. In contrast, in groups 2 and 3, none of the patients tested positive for MOG antibodies. Patients with MS with antibodies to MOG predominantly manifested with concomitant severe brainstem and spinal cord involvement and had a severe disease course with high relapse rates and failure to several disease-modifying therapies. Three of them had been treated with plasma exchange with a favorable response. All anti-MOG-positive patients with MS showed typical MS lesions on brain MRI. Longitudinal analysis up to 9 years revealed fluctuations and reappearance of anti-MOG reactivity. Epitope mapping indicated interindividual heterogeneity, yet intraindividual stability of the antibody response.

Conclusions: Antibodies to MOG can be found in a distinct subgroup of adult MS with a specific clinical phenotype and may indicate disease heterogeneity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/NXI.0000000000000257DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4949775PMC
October 2016

Features of Human CD3+CD20+ T Cells.

J Immunol 2016 08 13;197(4):1111-7. Epub 2016 Jul 13.

Institute of Clinical Neuroimmunology, Biomedical Center and University Hospital, Ludwig Maximilian University, 82152 Martinsried, Germany;

Monoclonal Abs against CD20 reduce the number of relapses in multiple sclerosis (MS); commonly this effect is solely attributed to depletion of B cells. Recently, however, a subset of CD3(+)CD20(+) T cells has been described that is also targeted by the anti-CD20 mAb rituximab. Because the existence of cells coexpressing CD3 and CD20 is controversial and features of this subpopulation are poorly understood, we studied this issue in detail. In this study, we confirm that 3-5% of circulating human T cells display CD20 on their surface and transcribe both CD3 and CD20. We report that these CD3(+)CD20(+) T cells pervade thymus, bone marrow, and secondary lymphatic organs. They are found in the cerebrospinal fluid even in the absence of inflammation; in the cerebrospinal fluid of MS patients they occur at a frequency similar to B cells. Phenotypically, these T cells are enriched in CD8(+) and CD45RO(+) memory cells and in CCR7(-) cells. Functionally, they show a higher frequency of IL-4-, IL-17-, IFN-γ-, and TNF-α-producing cells compared with T cells lacking CD20. CD20-expressing T cells respond variably to immunomodulatory treatments given to MS patients: they are reduced by fingolimod, alemtuzumab, and dimethyl fumarate, whereas natalizumab disproportionally increases them in the blood. After depletion by rituximab, they show earlier and higher repopulation than CD20(+) B cells. Taken together, human CD3(+)CD20(+) T cells pervade lymphatic organs and the cerebrospinal fluid, have a strong ability to produce different cytokines, and respond to MS disease modifying drugs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4049/jimmunol.1600089DOI Listing
August 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00415-015-7991-1DOI Listing
March 2016

Pro-inflammatory pattern of IgG1 Fc glycosylation in multiple sclerosis cerebrospinal fluid.

J Neuroinflammation 2015 Dec 18;12:235. Epub 2015 Dec 18.

Institute of Clinical Neuroimmunology, Biomedical Center (BMC) and University Hospital, Campus Martinsried-Grosshadern, LMU Munich, Munich, Germany.

Background: Immunoglobulin G (IgG) effector functions are regulated by the composition of glycans attached to a conserved N-glycosylation site in the Fc part. Intrathecal production of IgG, especially IgG1, is a hallmark of multiple sclerosis (MS), but nothing is known about IgG Fc glycosylation in MS and in cerebrospinal fluid (CSF) in general.

Methods: We applied mass spectrometry of tryptic Fc glycopeptides to analyze IgG Fc glycosylation (sialylation, galactosylation, fucosylation, and bisecting N-acetylglucosamine (GlcNAc)) in 48 paired CSF and serum samples from adult patients with MS or a first demyelinating event highly suggestive of MS (designated as MS cases), and from healthy volunteers and patients with other non-inflammatory diseases (control group). p values were adjusted for multiple testing.

Results: Our experiments revealed four main results. First, IgG1 glycosylation patterns were different in CSF vs. serum, in the MS group and even in control donors without intrathecal IgG synthesis. Second, in MS patients vs. controls, IgG1 glycosylation patterns were altered in CSF, but not in serum. Specifically, in CSF from the MS group, bisecting GlcNAc were elevated, and afucosylation and galactosylation were reduced. Elevated bisecting GlcNAc and reduced galactosylation are known to enhance IgG effector functions. Third, hypothesis-free regression analysis revealed that alterations of afucosylation and bisecting GlcNAc in CSF from MS cases peaked 2-3 months after the last relapse. Fourth, CSF IgG1 glycosylation correlated with the degree of intrathecal IgG synthesis and CSF cell count.

Conclusions: The CNS compartment as well as the inflammatory milieu in MS affect IgG1 Fc glycosylation. In MS, the CSF IgG1 glycosylation has features that enhance Fc effector functions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12974-015-0450-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4683913PMC
December 2015

Neuromyelitis optica: Evaluation of 871 attacks and 1,153 treatment courses.

Ann Neurol 2016 Feb 26;79(2):206-16. Epub 2015 Nov 26.

Hans Berger Department of Neurology, Jena University Hospital, Jena.

Objective: Neuromyelitis optica (NMO) attacks often are severe, are difficult to treat, and leave residual deficits. Here, we analyzed the frequency, sequence, and efficacy of therapies used for NMO attacks.

Methods: A retrospective review was made of patient records to assess demographic/diagnostic data, attack characteristics, therapies, and the short-term remission status (complete remission [CR], partial remission [PR], no remission [NR]). Inclusion criteria were NMO according to Wingerchuk's 2006 criteria or aquaporin-4 antibody-positive NMO spectrum disorder (NMOSD). Remission status was analyzed with generalized estimating equations (GEEs), a patient-based statistical approach.

Results: A total of 871 attacks in 185 patients (142 NMO/43 NMOSD, 82% female) were analyzed. The 1,153 treatment courses comprised high-dose intravenous steroids (HD-S; n = 810), plasma exchange (PE; n = 192), immunoadsorption (IA; n = 38), other (n = 80), and unknown (n = 33) therapies. The first treatment course led to CR in 19.1%, PR in 64.5%, and NR in 16.4% of attacks. Second, third, fourth, and fifth treatment courses were given in 28.2%, 7.1%, 1.4%, and 0.5% of attacks, respectively. This escalation of attack therapy significantly improved outcome (p < 0.001, Bowker test). Remission rates were higher for isolated optic neuritis versus isolated myelitis (p < 0.001), and for unilateral versus bilateral optic neuritis (p = 0.020). Isolated myelitis responded better to PE/IA than to HD-S as first treatment course (p = 0.037). Predictors of CR in multivariate GEE analysis were age (odds ratio [OR] = 0.97, p = 0.011), presence of myelitis (OR = 0.38, p = 0.002), CR from previous attack (OR = 6.85, p < 0.001), and first-line PE/IA versus HD-S (OR = 4.38, p = 0.006).

Interpretation: Particularly myelitis and bilateral optic neuritis have poor remission rates. Escalation of attack therapy improves outcome. PE/IA may increase recovery in isolated myelitis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ana.24554DOI Listing
February 2016

Fingolimod induces neuroprotective factors in human astrocytes.

J Neuroinflammation 2015 Sep 30;12:184. Epub 2015 Sep 30.

Institute of Clinical Neuroimmunology, Ludwig Maximilian University, 81377, Munich, Germany.

Background: Fingolimod (FTY720) is the first sphingosine-1-phosphate (S1P) receptor modulator approved for the treatment of multiple sclerosis. The phosphorylated active metabolite FTY720-phosphate (FTY-P) interferes with lymphocyte trafficking. In addition, it accumulates in the CNS and reduces brain atrophy in multiple sclerosis (MS), and neuroprotective effects are hypothesized.

Methods: Human primary astrocytes as well as human astrocytoma cells were stimulated with FTY-P or S1P. We analyzed gene expression by a genome-wide microarray and validated induced candidate genes by quantitative PCR (qPCR) and ELISA. To identify the S1P-receptor subtypes involved, we applied a membrane-impermeable S1P analog (dihydro-S1P), receptor subtype specific agonists and antagonists, as well as RNAi silencing.

Results: FTY-P induced leukemia inhibitory factor (LIF), interleukin 11 (IL11), and heparin-binding EGF-like growth factor (HBEGF) mRNA, as well as secretion of LIF and IL11 protein. In order to mimic an inflammatory milieu as observed in active MS lesions, we combined FTY-P application with tumor necrosis factor (TNF). In the presence of this key inflammatory cytokine, FTY-P synergistically induced LIF, HBEGF, and IL11 mRNA, as well as secretion of LIF and IL11 protein. TNF itself induced inflammatory, B-cell promoting, and antiviral factors (CXCL10, BAFF, MX1, and OAS2). Their induction was blocked by FTY-P. After continuous exposure of cells to FTY-P or S1P for up to 7 days, the extent of induction of neurotrophic factors and the suppression of TNF-induced inflammatory genes declined but was still detectable. The induction of neurotrophic factors was mediated via surface S1P receptors 1 (S1PR1) and 3 (S1PR3).

Conclusions: We identified effects of FTY-P on astrocytes, namely induction of neurotrophic mediators (LIF, HBEGF, and IL11) and inhibition of TNF-induced inflammatory genes (CXCL10, BAFF, MX1, and OAS2). This supports the view that a part of the effects of fingolimod may be mediated via astrocytes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12974-015-0393-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4589103PMC
September 2015

γ-Secretase directly sheds the survival receptor BCMA from plasma cells.

Nat Commun 2015 Jun 11;6:7333. Epub 2015 Jun 11.

Institute of Clinical Neuroimmunology, Ludwig Maximilian University Munich, 81377 Munich, Germany.

Survival of plasma cells is regulated by B-cell maturation antigen (BCMA), a membrane-bound receptor activated by its agonist ligands BAFF and APRIL. Here we report that γ-secretase directly cleaves BCMA, without prior truncation by another protease. This direct shedding is facilitated by the short length of BCMA's extracellular domain. In vitro, γ-secretase reduces BCMA-mediated NF-κB activation. In addition, γ-secretase releases soluble BCMA (sBCMA) that acts as a decoy neutralizing APRIL. In vivo, inhibition of γ-secretase enhances BCMA surface expression in plasma cells and increases their number in the bone marrow. Furthermore, in multiple sclerosis, sBCMA levels in spinal fluid are elevated and associated with intracerebral IgG production; in systemic lupus erythematosus, sBCMA levels in serum are elevated and correlate with disease activity. Together, shedding of BCMA by γ-secretase controls plasma cells in the bone marrow and yields a potential biomarker for B-cell involvement in human autoimmune diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ncomms8333DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4490565PMC
June 2015

Expanding spectrum of neurologic manifestations in patients with NLRP3 low-penetrance mutations.

Neurol Neuroimmunol Neuroinflamm 2015 Aug 14;2(4):e109. Epub 2015 May 14.

Institute of Clinical Neuroimmunology (E.S., M.K., L.-A.G., R.H., T.K.), Institute of Clinical Radiology (B.E.-W.), and Department of Rheumatology (M.W.), Ludwig-Maximillians University, Munich, Germany; Department of Neuroimmunology (E.S.), Center of Brain Research, Vienna, Austria; Institute of Laboratory Medicine and Human Genetics (P.L.), Singen, Germany; Comprehensive Pneumology Center (M.F.) (Ludwig-Maximilians University Munich, Asklepios Kliniken Gauting, Helmholtz Zentrum München, Germany); and Munich Cluster for Systems Neurology (SyNergy) (R.H.), Munich, Germany.

Objective: To evaluate the frequency of the cryoporin/NLRP3 low-penetrance mutations V198M and Q703K in patients who reported at least 2 symptoms compatible with cryopyrin-associated periodic syndromes (CAPS) and to characterize the phenotype in mutation-positive patients.

Methods: The frequency of the V198M and Q703K mutations was investigated in a selected cohort of 108 patients from our neuroimmunology department. We describe the clinical, neurologic, immunologic, and neuroradiologic features of the mutation carriers.

Results: Seventeen patients (16%) tested positive for either of the 2 mutations (V198M: n = 2; Q703K: n = 15). Eleven patients (65%) had severe headache syndromes. Six of these 11 patients were diagnosed with migraine. Nine patients (53%) had a concomitant diagnosis of multiple sclerosis (MS). In 3 patients, we identified additional family members with the respective mutation as well as the diagnosis of MS. Severe recurrent cranial nerve (CN) affection was the hallmark feature in 7 of the 8 (88%) non-MS mutation carriers. Brain MRI showed abnormalities in all but 2 patients (88%) and detected CN inflammation in 4 patients. Interleukin-6 was elevated in the CSF of 2 patients in the non-MS cohort during acute CAPS episodes with severe CNS inflammation. 5 of 9 treated patients (56%) responded to anti-interleukin-1 therapy.

Conclusion: CAPS constitute rare but treatable and commonly misdiagnosed autoinflammatory syndromes. Our data expand the spectrum of CAPS-associated neurologic manifestations. They also broaden our concept of autoimmunity and autoinflammation by linking CAPS and MS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/NXI.0000000000000109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4436598PMC
August 2015

Very late-onset neuromyelitis optica spectrum disorder beyond the age of 75.

J Neurol 2015 May 10;262(5):1379-84. Epub 2015 May 10.

Institute of Clinical Neuroimmunology, Ludwig Maximilian University, Max-Lebsche-Platz 31, 81377, Munich, Germany,

Aquaporin-4 antibody (AQP4-Ab)-positive neuromyelitis optica spectrum disorder (NMOSD) is a rare but often severe autoimmune disease with median onset around 40 years of age. We report characteristics of three very-late-onset NMOSD (including complete NMO) patients >75 years of age, in whom this diagnosis initially seemed unlikely because of their age and age-associated concomitant diseases, and briefly review the literature. All three patients, aged 79, 82 and 88 years, presented with a spinal cord syndrome as the first clinical manifestation of AQP4-Ab-positive NMOSD. They all had severe relapses unless immunosuppressive therapy was initiated, and one untreated patient died of a fatal NMOSD course. Two patients developed side effects of immunosuppression. We conclude that a first manifestation of NMOSD should be considered even in patients beyond the age of 75 years with a compatible syndrome, especially longitudinally extensive myelitis. Early diagnosis and treatment are feasible and highly relevant. Special attention is warranted in the elderly to recognize adverse effects of immunosuppressive therapies as early as possible.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00415-015-7766-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4441737PMC
May 2015

Histopathology and clinical course of MOG-antibody-associated encephalomyelitis.

Ann Clin Transl Neurol 2015 Mar 14;2(3):295-301. Epub 2015 Jan 14.

Institute of Clinical Neuroimmunology, Medical Campus Grosshadern, Ludwig Maximilian University Munich, Germany.

We present histological, MRI, and clinical features of an adult patient with relapsing encephalomyelitis and antibodies against myelin oligodendrocyte glycoprotein (MOG). Furthermore, we report molecular details of the recognized epitope that is specific for human MOG. A brain biopsy revealed multiple sclerosis (MS)-type II pathology. Some features overlapped with both MS and neuromyelitis optica spectrum disorders (NMOSD), whereas others were distinct from both MS and NMOSD. Immunoadsorption and rituximab induced clinical stabilization. This case contributes a new, so far missing link in the emerging spectrum of MOG-antibody-associated encephalomyelitis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/acn3.164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4369279PMC
March 2015

Transcript profiling of different types of multiple sclerosis lesions yields FGF1 as a promoter of remyelination.

Acta Neuropathol Commun 2014 Dec 11;2:168. Epub 2014 Dec 11.

Institute of Clinical Neuroimmunology, Ludwig Maximilian University Munich, Marchioninistraße 15, D-81377, Munich, Germany.

Chronic demyelination is a pathological hallmark of multiple sclerosis (MS). Only a minority of MS lesions remyelinates completely. Enhancing remyelination is, therefore, a major aim of future MS therapies. Here we took a novel approach to identify factors that may inhibit or support endogenous remyelination in MS. We dissected remyelinated, demyelinated active, and demyelinated inactive white matter MS lesions, and compared transcript levels of myelination and inflammation-related genes using quantitative PCR on customized TaqMan Low Density Arrays. In remyelinated lesions, fibroblast growth factor (FGF) 1 was the most abundant of all analyzed myelination-regulating factors, showed a trend towards higher expression as compared to demyelinated lesions and was significantly higher than in control white matter. Two MS tissue blocks comprised lesions with adjacent de- and remyelinated areas and FGF1 expression was higher in the remyelinated rim compared to the demyelinated lesion core. In functional experiments, FGF1 accelerated developmental myelination in dissociated mixed cultures and promoted remyelination in slice cultures, whereas it decelerated differentiation of purified primary oligodendrocytes, suggesting that promotion of remyelination by FGF1 is based on an indirect mechanism. The analysis of human astrocyte responses to FGF1 by genome wide expression profiling showed that FGF1 induced the expression of the chemokine CXCL8 and leukemia inhibitory factor, two factors implicated in recruitment of oligodendrocytes and promotion of remyelination. Together, this study presents a transcript profiling of remyelinated MS lesions and identified FGF1 as a promoter of remyelination. Modulation of FGF family members might improve myelin repair in MS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s40478-014-0168-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4359505PMC
December 2014

Interferon beta and vitamin D synergize to induce immunoregulatory receptors on peripheral blood monocytes of multiple sclerosis patients.

PLoS One 2014 31;9(12):e115488. Epub 2014 Dec 31.

Dept. of Neurology and Biomedicine, University Hospital Basel, Basel, Switzerland.

Immunoglobulin-like transcript (ILT) 3 and 4 are inhibitory receptors that modulate immune responses. Their expression has been reported to be affected by interferon, offering a possible mechanism by which this cytokine exerts its therapeutic effect in multiple sclerosis, a condition thought to involve excessive immune activity. To investigate this possibility, we measured expression of ILT3 and ILT4 on immune cells from multiple sclerosis patients, and in post-mortem brain tissue. We also studied the ability of interferon beta, alone or in combination with vitamin D, to induce upregulation of these receptors in vitro, and compared expression levels between interferon-treated and untreated multiple sclerosis patients. In vitro interferon beta treatment led to a robust upregulation of ILT3 and ILT4 on monocytes, and dihydroxyvitamin D3 increased expression of ILT3 but not ILT4. ILT3 was abundant in demyelinating lesions in postmortem brain, and expression on monocytes in the cerebrospinal fluid was higher than in peripheral blood, suggesting that the central nervous system milieu induces ILT3, or that ILT3 positive monocytes preferentially enter the brain. Our data are consistent with involvement of ILT3 and ILT4 in the modulation of immune responsiveness in multiple sclerosis by both interferon and vitamin D.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0115488PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4281069PMC
September 2015

The immunoregulator soluble TACI is released by ADAM10 and reflects B cell activation in autoimmunity.

J Immunol 2015 Jan 10;194(2):542-52. Epub 2014 Dec 10.

Institute of Clinical Neuroimmunology, Ludwig Maximilian University, Munich D-81377, Germany;

BAFF and a proliferation-inducing ligand (APRIL), which control B cell homeostasis, are therapeutic targets in autoimmune diseases. TACI-Fc (atacicept), a soluble fusion protein containing the extracellular domain of the BAFF-APRIL receptor TACI, was applied in clinical trials. However, disease activity in multiple sclerosis unexpectedly increased, whereas in systemic lupus erythematosus, atacicept was beneficial. In this study, we show that an endogenous soluble TACI (sTACI) exists in vivo. TACI proteolysis involved shedding by a disintegrin and metalloproteinase 10 releasing sTACI from activated B cells. The membrane-bound stub was subsequently cleaved by γ-secretase reducing ligand-independent signaling of the remaining C-terminal fragment. The shed ectodomain assembled ligand independently in a homotypic way. It functioned as a decoy receptor inhibiting BAFF- and APRIL-mediated B cell survival and NF-κB activation. We determined sTACI levels in autoimmune diseases with established hyperactivation of the BAFF-APRIL system. sTACI levels were elevated both in the cerebrospinal fluid of the brain-restricted autoimmune disease multiple sclerosis correlating with intrathecal IgG production, as well as in the serum of the systemic autoimmune disease systemic lupus erythematosus correlating with disease activity. Together, we show that TACI is sequentially processed by a disintegrin and metalloproteinase 10 and γ-secretase. The released sTACI is an immunoregulator that shares decoy functions with atacicept. It reflects systemic and compartmentalized B cell accumulation and activation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4049/jimmunol.1402070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4282951PMC
January 2015

B cells in MS and NMO: pathogenesis and therapy.

Semin Immunopathol 2014 May 16;36(3):339-50. Epub 2014 May 16.

Institute of Clinical Neuroimmunology, Ludwig Maximilian University of Munich, Max-Lebsche-Platz 31, 81377, Munich, Germany,

B linage cells are versatile players in multiple sclerosis (MS) and neuromyelitis optica/neuromyelitis optica spectrum disorder (NMO). New potential targets of autoantibodies have been described recently. Pathogenic mechanisms extend further to antigen presentation and cytokine production, which are increasingly recognized as therapeutic targets. In addition to pro-inflammatory effects of B cells, they may act also as anti-inflammatory via production of interleukin (IL)-10, IL-35, and other mechanisms. Definition of regulatory B cell subsets is an ongoing issue. Recent studies have provided evidence for a loss of B cell self-tolerance in MS. An immunogenetic approach demonstrated exchange of B cell clones between CSF and blood. The central nervous system (CNS) of MS patients fosters B cell survival, at least partly via BAFF and APRIL. The unexpected increase of relapses in a trial with a soluble BAFF/APRIL receptor (atacicept) suggests that this system is involved in MS, but with features that are not yet understood. In this review, we further discuss evidence for B cell and Ig contribution to human MS and NMO pathogenesis, pro-inflammatory and regulatory B cell effector functions, impaired B cell immune tolerance, the B cell-fostering microenvironment in the CNS, and B cell-targeted therapeutic interventions for MS and NMO, including CD20 depletion (rituximab, ocrelizumab, and ofatumumab), anti-IL6-R (tocilizumab), complement-blocking (eculizumab), inhibitors of AQP4-Ig binding (aquaporumab, small molecular compounds), and BAFF/BAFF-R-targeting agents.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00281-014-0424-xDOI Listing
May 2014

Disease-specific molecular events in cortical multiple sclerosis lesions.

Brain 2013 Jun 17;136(Pt 6):1799-815. Epub 2013 May 17.

Department of Neuroimmunology, Centre for Brain Research, Medical University of Vienna, Austria.

Cortical lesions constitute an important part of multiple sclerosis pathology. Although inflammation appears to play a role in their formation, the mechanisms leading to demyelination and neurodegeneration are poorly understood. We aimed to identify some of these mechanisms by combining gene expression studies with neuropathological analysis. In our study, we showed that the combination of inflammation, plaque-like primary demyelination and neurodegeneration in the cortex is specific for multiple sclerosis and is not seen in other chronic inflammatory diseases mediated by CD8-positive T cells (Rasmussen's encephalitis), B cells (B cell lymphoma) or complex chronic inflammation (tuberculous meningitis, luetic meningitis or chronic purulent meningitis). In addition, we performed genome-wide microarray analysis comparing micro-dissected active cortical multiple sclerosis lesions with those of tuberculous meningitis (inflammatory control), Alzheimer's disease (neurodegenerative control) and with cortices of age-matched controls. More than 80% of the identified multiple sclerosis-specific genes were related to T cell-mediated inflammation, microglia activation, oxidative injury, DNA damage and repair, remyelination and regenerative processes. Finally, we confirmed by immunohistochemistry that oxidative damage in cortical multiple sclerosis lesions is associated with oligodendrocyte and neuronal injury, the latter also affecting axons and dendrites. Our study provides new insights into the complex mechanisms of neurodegeneration and regeneration in the cortex of patients with multiple sclerosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/brain/awt110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3673462PMC
June 2013

Fingolimod reduces recurrence of disease activity after natalizumab withdrawal in multiple sclerosis.

J Neurol 2013 May 25;260(5):1382-7. Epub 2012 Dec 25.

Institute of Clinical Neuroimmunology, Medical Campus Grosshadern, Ludwig-Maximilians-University, Marchioninistr. 15, 81377 Munich, Germany.

After discontinuation of natalizumab (NAT), multiple sclerosis (MS) disease activity often recurs. We assessed the recurrence of clinical disease activity during the first year after switching from NAT to fingolimod (FTY) in patients with relapsing-remitting MS. The number of relapses and the annualized relapse rate (ARR) before, during and after NAT discontinuation were determined and compared between 26 MS patients who switched to FTY within 24 weeks, and 10 MS patients who remained without disease modifying therapy (therapy free group = TFG). Median follow-up post-NAT discontinuation was 55.1 weeks. In a subgroup (n = 20), the occurrence of contrast-enhancing-lesions (Gd+) on magnetic resonance imaging (MRI) was determined. Eleven patients (42 %) in the FTY group and seven patients (70 %) in the TFG had one or more relapses after cessation of NAT during follow-up (p < 0.05). One of the 11 (9 %) patients in the FTY group and 6/9 (67 %) patients in the TFG showed Gd+ lesions during follow-up (p < 0.05). Patients who switched to FTY ≤ 12 weeks after NAT discontinuation (n = 9) showed a trend for a lower post-NAT ARR compared to patients who started FTY therapy >12 weeks after NAT was stopped (n = 17). Most relapses in the FTY group occurred just before or within 8 weeks after starting FTY. Our observation suggests that initiation of FTY treatment after NAT discontinuation reduces the recurrence of disease activity compared to withdrawal without further immunomodulatory treatment. In the FTY group the ARR tended to depend on the time interval between discontinuation of NAT and initiation of FTY.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00415-012-6808-8DOI Listing
May 2013